0000874015-21-000056 | 10-K | XBRL Viewer | Ionis Pharmaceuticals INC

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Document and Entity Information - USD ($)	12 Months Ended
Document and Entity Information - USD ($)	Dec. 31, 2020	Feb. 18, 2021	Jun. 30, 2020
Cover [Abstract]
Entity Registrant Name	Ionis Pharmaceuticals, Inc
Entity Central Index Key	0000874015
Current Fiscal Year End Date	--12-31
Document Type	10-K
Amendment Flag	false
Document Annual Report	true
Document Period End Date	Dec. 31, 2020
Document Fiscal Year Focus	2020
Document Fiscal Period Focus	FY
Document Transition Report	false
Entity File Number	000-19125
Entity Incorporation, State or Country Code	DE
Entity Tax Identification Number	33-0336973
Entity Address, Address Line One	2855 Gazelle Court
Entity Address, City or Town	Carlsbad
Entity Address, State or Province	CA
Entity Address, Postal Zip Code	92010
City Area Code	760
Local Phone Number	931-9200
Title of 12(b) Security	Common Stock, $.001 Par Value
Trading Symbol	IONS
Security Exchange Name	NASDAQ
Entity Well-known Seasoned Issuer	Yes
Entity Voluntary Filers	No
Entity Current Reporting Status	Yes
Entity Interactive Data Current	Yes
Entity Filer Category	Large Accelerated Filer
Entity Small Business	false
Entity Emerging Growth Company	false
Entity Shell Company	false
Entity Public Float			$ 6,748,320,336
Entity Common Stock, Shares Outstanding		140,862,211

CONSOLIDATED BALANCE SHEETS - USD ($) $ in Thousands	Dec. 31, 2020	Dec. 31, 2019
Current assets:
Cash and cash equivalents	$ 397,664	$ 683,287
Short-term investments	1,494,711	1,816,257
Contracts receivable	76,204	63,034
Inventories	21,965	18,180
Other current assets	140,163	139,839
Total current assets	2,130,707	2,720,597
Property, plant and equipment, net	181,077	153,651
Patents, net	27,937	25,674
Long-term deferred tax assets	0	305,557
Deposits and other assets	50,034	27,633
Total assets	2,389,755	3,233,112
Current liabilities:
Accounts payable	17,199	16,067
Accrued compensation	65,728	37,357
Accrued liabilities	90,161	66,769
Income taxes payable	1,324	32,514
1 percent convertible senior notes	293,161	0
Current portion of long-term obligations	7,301	2,026
Current portion of deferred contract revenue	108,376	118,272
Total current liabilities	583,250	273,005
Long-term deferred contract revenue	424,046	490,060
Long-term obligations, less current portion	23,409	15,543
Long-term mortgage debt	59,984	59,913
Total liabilities	1,546,408	1,548,565
Stockholders' equity:
Common stock, $0.001 par value; 300,000,000 shares authorized, 140,365,594 and 140,339,615 shares issued and outstanding at December 31, 2020 and December 31, 2019, respectively	140	140
Additional paid-in capital	2,113,646	2,203,778
Accumulated other comprehensive loss	(21,071)	(25,290)
Accumulated deficit	(1,249,368)	(707,534)
Total Ionis stockholders' equity	843,347	1,471,094
Noncontrolling interest in Akcea Therapeutics, Inc.	0	213,453
Total stockholders' equity	843,347	1,684,547
Total liabilities and stockholders' equity	2,389,755	3,233,112
0.125 Percent Convertible Senior Notes [Member]
Current liabilities:
Convertible senior notes	455,719	434,711
1 Percent Convertible Senior Notes [Member]
Current liabilities:
1 percent convertible senior notes	293,200
Convertible senior notes	$ 0	$ 275,333

CONSOLIDATED BALANCE SHEETS (Parenthetical) - $ / shares	Dec. 31, 2020	Dec. 31, 2019
Stockholders' equity:
Common stock, par value (in dollars per share)	$ 0.001	$ 0.001
Common stock, shares authorized (in shares)	300,000,000	300,000,000
Common stock, shares issued (in shares)	140,365,594	140,339,615
Common stock, shares outstanding (in shares)	140,365,594	140,339,615
0.125 Percent Convertible Senior Notes [Member]
LIABILITIES AND STOCKHOLDERS' EQUITY
Interest rate on convertible senior notes	0.125%	0.125%
1 Percent Convertible Senior Notes [Member]
LIABILITIES AND STOCKHOLDERS' EQUITY
Interest rate on convertible senior notes	1.00%	1.00%

CONSOLIDATED STATEMENTS OF OPERATIONS - USD ($) shares in Thousands, $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Revenue:
Revenue	$ 729,264	$ 1,122,599	$ 599,674
Expenses:
Cost of products sold	11,947	4,384	1,820
Research, development and patent	535,077	465,688	414,604
Selling, general and administrative	354,322	286,644	244,622
Total operating expenses	901,346	756,716	661,046
Income (loss) from operations	(172,082)	365,883	(61,372)
Other income (expense):
Investment income	30,562	52,013	30,397
Interest expense	(44,990)	(48,768)	(44,789)
Gain (loss) on investments	16,540	192	(210)
Loss on early retirement of debt	0	(21,865)	0
Other expenses	(62)	(686)	(182)
Income (loss) before income tax benefit (expense)	(170,032)	346,769	(76,156)
Income tax benefit (expense)	(316,734)	(43,507)	291,141
Net income (loss)	(486,766)	303,262	214,985
Net (income) loss attributable to noncontrolling interest in Akcea Therapeutics, Inc.	35,480	(9,116)	58,756
Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders	$ (451,286)	$ 294,146	$ 273,741
Basic net income (loss) per share (in dollars per share)	$ (3.23)	$ 2.12	$ 2.09
Shares used in computing basic net income (loss) per share (in shares)	139,612	139,998	132,320
Diluted net income (loss) per share (in dollars per share)	$ (3.23)	$ 2.08	$ 2.07
Shares used in computing diluted net income (loss) per share (in shares)	139,612	142,872	134,056
Commercial Revenue [Member]
Revenue:
Revenue	$ 364,699	$ 352,450	$ 254,922
SPINRAZA Royalties [Member]
Revenue:
Revenue	286,583	292,992	237,930
Product Sales, Net [Member]
Revenue:
Revenue	69,999	42,253	2,237
Licensing and Other Royalty Revenue [Member]
Revenue:
Revenue	8,117	17,205	14,755
Research and Development Revenue Under Collaborative Agreements [Member]
Revenue:
Revenue	$ 364,565	$ 770,149	$ 344,752

CONSOLIDATED STATEMENTS OF COMPREHENSIVE INCOME (LOSS) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
CONSOLIDATED STATEMENTS OF COMPREHENSIVE INCOME (LOSS) [Abstract]
Net income (loss)	$ (486,766)	$ 303,262	$ 214,985
Unrealized gains (losses) on investments, net of tax	3,729	6,633	(280)
Currency translation adjustment	617	93	23
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.	(127)	0	0
Comprehensive income (loss)	(482,547)	309,988	214,728
Comprehensive income (loss) attributable to noncontrolling interest in Akcea Therapeutics, Inc.	(35,480)	9,118	(58,781)
Comprehensive income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders	$ (447,067)	$ 300,870	$ 273,509

- Definition

Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income (loss) and other comprehensive income (loss), attributable to noncontrolling interests. Excludes changes in equity resulting from investments by owners and distributions to owners.

+ References + Details

- Definition

Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income and other comprehensive income. Excludes changes in equity resulting from investments by owners and distributions to owners.

+ References + Details

- Definition

The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.

+ References

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+ Details

CONSOLIDATED STATEMENTS OF STOCKHOLDERS' EQUITY - USD ($) shares in Thousands, $ in Thousands	Common Stock [Member]	Additional Paid In Capital [Member]	Accumulated Other Comprehensive Loss [Member]	Accumulated Deficit [Member]	Total Ionis Stockholders' Equity [Member]	Noncontrolling Interest in Akcea Therapeutics, Inc. [Member]	Total
Balance at Dec. 31, 2017	$ 125	$ 1,553,681	$ (31,759)	$ (1,241,034)	$ 281,013	$ 84,267	$ 365,280
Balance (in shares) at Dec. 31, 2017	124,976
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Net income (loss)	$ 0	0	0	273,741	273,741	0	273,741
Change in unrealized gains (losses), net of tax	0	0	(280)	0	(280)	0	(280)
Foreign currency translation	0	0	23	0	23	0	23
Biogen stock purchase	$ 11	447,954	0	0	447,965	0	447,965
Biogen Stock purchase (in shares)	11,502
Issuance of common stock in connection with employee stock plans	$ 2	27,898	0	0	27,900	0	27,900
Issuance of common stock in connection with employee stock plans (in shares)	1,451
Stock-based compensation expense	$ 0	131,312	0	0	131,312	0	131,312
Noncontrolling interest in Akcea Therapeutics, Inc.	0	(113,595)	0	0	(113,595)	54,814	(58,781)
Balance at Dec. 31, 2018	$ 138	2,047,250	(32,016)	(967,293)	1,048,079	139,081	1,187,160
Balance (in shares) at Dec. 31, 2018	137,929
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Net income (loss)	$ 0	0	0	294,146	294,146	0	294,146
Change in unrealized gains (losses), net of tax	0	0	6,633	0	6,633	0	6,633
Foreign currency translation	0	0	93	0	93	0	93
Issuance of common stock in connection with employee stock plans	$ 3	119,654	0	0	119,657	0	119,657
Issuance of common stock in connection with employee stock plans (in shares)	3,100
1 percent convertible senior notes retirement, equity portion, net of tax	$ 0	(77,331)	0	0	(77,331)	0	(77,331)
0.125 percent convertible senior notes, equity portion, net of issuance costs and tax	0	81,877	0	0	81,877	0	81,877
Issuance of warrants	0	56,110	0	0	56,110	0	56,110
Purchase of note hedges, net of tax	0	(85,860)	0	0	(85,860)	0	(85,860)
Repurchases and retirements of common stock	$ (1)	0	0	(34,387)	(34,388)	0	(34,388)
Repurchases and retirements of common stock (in shares)	(535)
Stock-based compensation expense	$ 0	146,574	0	0	146,574	0	146,574
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options	$ 0	(19,242)	0	0	(19,242)	0	(19,242)
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)	(154)
Noncontrolling interest in Akcea Therapeutics, Inc.	$ 0	(65,254)	0	0	(65,254)	74,372	9,118
Balance at Dec. 31, 2019	$ 140	2,203,778	(25,290)	(707,534)	1,471,094	213,453	1,684,547
Balance (in shares) at Dec. 31, 2019	140,340
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Net income (loss)	$ 0	0	0	(451,286)	(451,286)	0	(451,286)
Change in unrealized gains (losses), net of tax	0	0	3,729	0	3,729	0	3,729
Foreign currency translation	0	0	617	0	617	0	617
Issuance of common stock in connection with employee stock plans	$ 1	52,033	0	0	52,034	0	52,034
Issuance of common stock in connection with employee stock plans (in shares)	1,721
Purchase of noncontrolling interest of Akcea Therapeutics, Inc., including cash payments for cancellation of Akcea Therapeutics, Inc. equity awards	$ 0	(324,022)	301	0	(323,721)	(220,965)	(544,686)
Repurchases and retirements of common stock	$ (1)	0	0	(90,548)	(90,549)	0	(90,549)
Repurchases and retirements of common stock (in shares)	(1,478)
Stock-based compensation expense	$ 0	230,117	0	0	230,117	0	230,117
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options	$ 0	(13,410)	0	0	(13,410)	0	(13,410)
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)	(217)
Deferred tax liability adjustment due to purchase of noncontrolling interest of Akcea Therapeutics, Inc.	$ 0	7,714	0	0	7,714	0	7,714
Noncontrolling interest in Akcea Therapeutics, Inc.	0	(42,564)	(428)	0	(42,992)	7,512	(35,480)
Balance at Dec. 31, 2020	$ 140	$ 2,113,646	$ (21,071)	$ (1,249,368)	$ 843,347	$ 0	$ 843,347
Balance (in shares) at Dec. 31, 2020	140,366

CONSOLIDATED STATEMENTS OF STOCKHOLDERS' EQUITY (Parenthetical)	Dec. 31, 2020	Dec. 31, 2019
1 Percent Convertible Senior Notes [Member]
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Interest rate on convertible senior notes	1.00%	1.00%
0.125 Percent Convertible Senior Notes [Member]
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Interest rate on convertible senior notes	0.125%	0.125%

CONSOLIDATED STATEMENTS OF CASH FLOWS - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Operating activities:
Net income (loss)	$ (486,766)	$ 303,262	$ 214,985
Adjustments to reconcile net income (loss) to net cash provided by operating activities:
Depreciation	13,365	12,540	10,706
Amortization of right-of-use operating lease assets	1,731	1,542	0
Amortization of patents	2,064	1,912	1,822
Amortization of premium (discount) on investments, net	11,521	(7,485)	(1,013)
Amortization of debt issuance costs	2,578	1,942	1,810
Amortization of convertible senior notes discount	36,157	37,338	33,363
Stock-based compensation expense	230,117	146,574	131,312
Loss on early retirement of debt	0	21,865	0
(Gain) loss on investments	(16,540)	(192)	210
Deferred income taxes, including changes in valuation allowance	313,272	(7,096)	(290,516)
Non-cash losses related to patents	1,948	2,226	802
Changes in operating assets and liabilities:
Contracts receivable	(13,170)	(47,674)	47,595
Inventories	(1,261)	(5,411)	1,400
Other current and long-term assets	(9,975)	(44,659)	(29,348)
Long-term income tax receivable	0	8,418	(223)
Accounts payable	(2,755)	(16,343)	(655)
Income taxes	(31,279)	31,656	(710)
Accrued compensation	28,371	8,089	4,117
Accrued liabilities and deferred rent	32,424	16,406	(17,005)
Deferred contract revenue	(75,910)	(119,283)	494,254
Net cash provided by operating activities	35,892	345,627	602,906
Investing activities:
Purchases of short-term investments	(1,570,410)	(1,946,726)	(1,794,735)
Proceeds from the sale of short-term investments	1,885,935	1,951,734	882,824
Purchases of property, plant and equipment	(35,120)	(30,905)	(13,608)
Acquisition of licenses and other assets, net	(5,928)	(5,377)	(4,044)
Purchase of strategic investments	0	(10,000)	0
Net cash provided by (used in) investing activities	274,477	(41,274)	(929,563)
Financing activities:
Proceeds from equity, net	52,036	119,657	27,900
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options	(13,411)	(19,242)	0
Proceeds from the issuance of 0.125 percent convertible senior notes	0	109,500	0
0.125 percent convertible senior notes issuance costs	0	(10,428)	0
Proceeds from issuance of warrants	0	56,110	0
Purchase of note hedges	0	(108,684)	0
Repurchases and retirements of common stock	(90,548)	(34,392)	0
Purchase of noncontrolling interest of Akcea Therapeutics, Inc., including cash payments for cancellation of Akcea Therapeutics, Inc. equity awards	(544,686)	0	0
Principal payments on line of credit	0	(12,500)	0
Proceeds from the issuance of common stock to Biogen	0	0	447,965
Net cash (used in) provided by financing activities	(596,609)	100,021	475,865
Effects of exchange rates on cash	617	93	(18)
Net (decrease) increase in cash and cash equivalents	(285,623)	404,467	149,190
Cash and cash equivalents at beginning of year	683,287	278,820	129,630
Cash and cash equivalents at end of year	397,664	683,287	278,820
Supplemental disclosures of cash flow information:
Interest paid	6,247	9,870	9,592
Income taxes paid	25,855	9,041	0
Supplemental disclosures of non-cash investing and financing activities:
Right-of-use assets obtained in exchange for lease liabilities	2,149	14,178	0
Amounts accrued for capital and patent expenditures	4,059	3,126	4,428
Purchases of property, plant and equipment included in long-term obligations	0	0	3,350
0.125 percent convertible senior notes principal issued related to our December 2019 debt exchange/issuance	0	439,326	0
1 percent convertible senior notes principal extinguished related to our December 2019 debt exchange	$ 0	$ 375,590	$ 0

CONSOLIDATED STATEMENTS OF CASH FLOWS (Parenthetical)	Dec. 31, 2020	Dec. 31, 2019
0.125 Percent Convertible Senior Notes [Member]
Consolidated Statements of Cash Flows [Abstract]
Interest rate on convertible senior notes	0.125%	0.125%
1 Percent Convertible Senior Notes [Member]
Consolidated Statements of Cash Flows [Abstract]
Interest rate on convertible senior notes	1.00%	1.00%

Organization and Significant Accounting Policies

12 Months Ended

Dec. 31, 2020

Organization and Significant Accounting Policies [Abstract]

Organization and Significant Accounting Policies

1. Organization and Significant Accounting Policies

Basis of Presentation

In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated results of our subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (“we”, “us” or “our”). We formed Akcea in December 2014. In July 2017, Akcea completed an initial public offering, or IPO. Prior to Akcea’s IPO in July 2017, we owned 100 percent of Akcea. In October 2020, we acquired the shares of Akcea’s common stock we did not own. We will refer to this transaction as the Akcea Acquisition throughout the remainder of this document. See Note 7, Akcea Acquisition, in the Notes to the Consolidated Financial Statements for further details. We reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling interest in the period the change occurred.

Organization and Business Activity

We incorporated in California on January 10, 1989. In conjunction with our IPO, we reorganized as a Delaware corporation in April 1991. We were organized principally to develop human therapeutic medicines using antisense technology. In December 2015, we changed our name from Isis Pharmaceuticals, Inc. to Ionis Pharmaceuticals, Inc.

Basic and Diluted Net Income (Loss) per Share

Basic net income (loss) per share

We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period.

The calculation of total net income (loss) attributable to our common stockholders for each year considered our net income (loss) for Ionis on a stand-alone basis plus our share of Akcea’s net income (loss) for the period. To calculate the portion of Akcea’s net income (loss) attributable to our ownership for each year, we multiplied Akcea’s income (loss) per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations for each year.

Our basic net income (loss) per share was calculated as follows (in thousands, except per share amounts):

Year Ended December 31, 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-acquisition period attributable to our ownership		77,095	$	(1.45	)	$	(111,775	)
Akcea’s net loss in the post-acquisition period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(197,762	)
Ionis’ stand-alone net loss							(253,725	)
Net loss available to Ionis common stockholders						$	(451,487	)
Weighted average shares outstanding							139,612
Basic net loss per share						$	(3.23	)

Year Ended December 31, 2019	Weighted Average Shares Owned in Akcea		Akcea’s Net Income Per Share		Basic Net Income Per Share Calculation
Common shares		70,100	$	0.49	$	34,073
Akcea’s net income attributable to our ownership					$	34,073
Ionis’ stand-alone net income						262,490
Net income available to Ionis common stockholders					$	296,563
Weighted average shares outstanding						139,998
Basic net income per share					$	2.12

Year Ended December 31, 2018	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Income Per Share Calculation
Common shares		59,812	$	(2.74	)	$	(163,938	)
Akcea’s net loss attributable to our ownership						$	(163,938	)
Ionis’ stand-alone net income							440,806
Net income available to Ionis common stockholders						$	276,868
Weighted average shares outstanding							132,320
Basic net income per share						$	2.09

Diluted net income per share

For the year ended December 31, 2020, we incurred a net loss; therefore, we did not include dilutive common equivalent shares in the computation of diluted net loss per share because the effect would have been anti-dilutive. Common stock from the following would have had an anti-dilutive effect on net loss per share:

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0.125 percent convertible senior notes;

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1 percent convertible senior notes;

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Dilutive stock options;

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Unvested restricted stock units, or RSUs; and

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Employee Stock Purchase Plan, or ESPP.

For the years ended December 31, 2019 and 2018, we had net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during each period. We calculated our diluted net income per share as follows (in thousands except per share amounts):

Year Ended December 31, 2019	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	296,563		139,998	$	2.12
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		2,090
Shares issuable upon restricted stock award issuance		—		766
Shares issuable related to our ESPP		—		18
	$	296,563		142,872	$	2.08

Year Ended December 31, 2018	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	276,868		132,320	$	2.09
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		1,216
Shares issuable upon restricted stock award issuance		—		514
Shares issuable related to our ESPP		—		6
	$	276,868		134,056	$	2.07

For each year presented, the calculation excluded our convertible senior notes because the effect on diluted earnings per share was anti-dilutive.

Revenue Recognition

Our Revenue Sources

We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue, we include the amounts in deferred revenue on our consolidated balance sheet.

Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue

We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as commercial revenue sales milestone payments and royalties we earn under our other partnerships.

Commercial Revenue: Product sales, net

We added product sales from TEGSEDI to our commercial revenue in the fourth quarter of 2018 and we added product sales from WAYLIVRA to our commercial revenue in the third quarter of 2019. In the U.S., we distribute TEGSEDI through an exclusive distribution agreement with a third-party logistics company, or 3PL, that takes title to TEGSEDI. The 3PL is our sole customer in the U.S. The 3PL then distributes TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distribute TEGSEDI to health care providers and patients.

In Europe, through 2020 we sold TEGSEDI and WAYLIVRA to hospitals and pharmacies using 3PLs as distributors. Beginning in 2021, we are commercializing TEGSEDI and WAYLIVRA in Europe through a distribution agreement with Swedish Orphan Biovitrum AB, or Sobi, an international biopharmaceutical company that focuses on rare diseases. Under the terms of this agreement, we retained the marketing authorization for both medicines in Europe.

In Latin America beginning in 2020, we sold TEGSEDI and WAYLIVRA to our partner, PTC Therapeutics. Under our collaboration agreement with PTC, PTC is commercializing TEGSEDI and WAYLIVRA in Latin America and Caribbean countries.

Research and development revenue under collaborative agreements

We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&D, services, and manufacturing services.

We provide details about our collaboration agreements in Note 6, Collaborative Arrangements and Licensing Agreements. Under each collaboration note we discuss our specific revenue recognition conclusions, including our significant performance obligations under each collaboration.

Steps to Recognize Revenue

We use a five-step process to determine the amount of revenue we should recognize and when we should recognize it. The five step process is as follows:

Identify the contract

Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the following criteria:

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We and our partner approved the contract and we are both committed to perform our obligations;

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We have identified our rights, our partner’s rights and the payment terms;

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We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the contract; and

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We believe collectability of the consideration is probable.

Identify the performance obligations

We next identify our performance obligations, which represent the distinct goods and services we are required to provide under the contract. We typically have only one performance obligation at the inception of a contract, which is to perform R&D services.

Often we enter into a collaboration agreement in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights because these items are contingent upon future events that may not occur and are not priced at a significant discount. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item.

In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do not have any additional material performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation.

Determine the transaction price

We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because the payments are not probable and are contingent on certain future events. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.

Milestone payments are our most common type of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and/ or are usually based on scientific progress which is inherently uncertain. For example, in the fourth quarter of 2020, we earned a $20 million milestone payment from AstraZeneca when AstraZeneca initiated a Phase 2b study for ION449, our medicine in development targeting PCSK9 to lower LDL-cholesterol. We did not consider the milestone payment probable until AstraZeneca achieved the milestone event because advancing ION449 was contingent on AstraZeneca initiating a Phase 2b study and was not within our control. We recognized the milestone payment in full in the period the milestone event was achieved because we did not have any remaining performance obligations related to the milestone payment.

Allocate the transaction price

Next, we allocate the transaction price to each of our performance obligations. When we have to allocate the transaction price to more than one performance obligation, we make estimates of the relative stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling price. We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.

We may engage a third party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement. We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected income to present value. The significant inputs we use to determine the projected income of a license could include:

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Estimated future product sales;

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Estimated royalties we may receive from future product sales;

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Estimated contractual milestone payments we may receive;

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Expenses we expect to incur;

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Estimated income taxes; and

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A discount rate.

We typically estimate the selling price of R&D services by using our internal estimates of the cost to perform the specific services. The significant inputs we use to determine the selling price of our R&D services include:

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The number of internal hours we estimate we will spend performing these services;

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The estimated cost of work we will perform;

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The estimated cost of work that we will contract with third parties to perform; and

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The estimated cost of API we will use.

For purposes of determining the stand-alone selling price of the R&D services we perform and the API we will deliver, accounting guidance requires us to include a markup for a reasonable profit margin.

Recognize revenue

We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&D services. We recognize revenue at a point in time when our partner receives full use of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.

For R&D services that we recognize over time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements change over the course of the collaboration, they may affect the timing and amount of revenue that we recognize in the current and future periods. Refer to Note 6, Collaborative Arrangements and Licensing Agreements, for further discussion of the cumulative catch up adjustment we made.

The following are examples of when we typically recognize revenue based on the types of payments we receive.

Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue

We recognize royalty revenue, including royalties from SPINRAZA sales, in the period in which the counterparty sells the related product and recognizes the related revenue, which in certain cases may require us to estimate our royalty revenue.

Commercial Revenue: Product sales, net

We recognize product sales in the period when our customer obtains control of our products, which occurs at a point in time upon transfer of title to the customer. We classify payments to customers or other parties in the distribution channel for services that are distinct and priced at fair value as selling, general and administrative, or SG&A, expenses in our consolidated statements of operations. Otherwise, payments to customers or other parties in the distribution channel that do not meet those criteria are classified as a reduction of revenue, as discussed further below. We exclude from revenues taxes collected from customers relating to product sales and remitted to governmental authorities.

Reserves for Product sales

We record product sales at our net sales price, or transaction price. We include in our transaction price estimated reserves for discounts, returns, chargebacks, rebates and other allowances that we offer within contracts between us and our customers, wholesalers, health care providers and other indirect customers. We estimate our reserves using the amounts we have earned or what we can claim on the associated sales. We classify our reserves as a reduction of accounts receivable when we are not required to make a payment or as a current liability when we are required to make a payment. In certain cases, our estimates include a range of possible outcomes that are probability weighted for relevant factors such as our historical experience, current contractual and statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflect our best estimates under the terms of our respective contracts. When calculating our reserves and related product sales, we only recognize amounts to the extent that we consider it probable that we would not have to reverse in a future period a significant amount of the cumulative sales we previously recognized. The actual amounts we receive may ultimately differ from our reserve estimates. If actual amounts in the future vary from our estimates, we will adjust these estimates, which would affect our net product sales in the respective period.

The following are the components of variable consideration related to product sales:

Chargebacks: In the U.S., we estimate obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer charges us for the difference between what it pays for the product and the selling price to the qualified healthcare providers. We also estimate the amount of chargebacks related to our estimated product remaining in the distribution channel at the end of the reporting period that we expect our customer to sell to healthcare providers in future periods. We record these reserves as a reduction to contracts receivable on our consolidated balance sheet.

Government rebates: We are subject to discount obligations under government programs, including Medicaid and Medicare programs in the U.S. and we record reserves for government rebates based on statutory discount rates and estimated utilization. We estimate Medicaid and Medicare rebates based on a range of possible outcomes that are probability weighted for the estimated payer mix. We record these reserves as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognize the related sale. For Medicare, we also estimate the number of patients in the prescription drug coverage gap for whom we will owe an additional liability under the Medicare Part D program. On a quarterly basis, we update our estimates and record any adjustments in the period that we identify the adjustments.

Managed care rebates: We are subject to rebates in connection with agreements with certain contracted commercial payers. We record these rebates as a liability on our consolidated balance sheet in the same period we recognize the related revenue. We estimate our managed care rebates based on our estimated payer mix and the applicable contractual rebate rate.

Trade discounts: We provide customary invoice discounts on product sales to our U.S. customer for prompt payment. We record this discount as a reduction of product sales in the period in which we recognize the related product revenue.

Distribution services: We receive and pay for various distribution services from our U.S. and European customers (prior to our agreement with Sobi) and wholesalers in the U.S. We classify the costs for services we receive that are either not distinct from the sale of the product or for which we cannot reasonably estimate the fair value as a reduction of product sales. To the extent that the services we receive are distinct from the sale of the product, we classify the costs for such services as SG&A expenses.

Product returns: Our U.S. customer has return rights and the wholesalers have limited return rights primarily related to the product’s expiration date. We estimate the amount of product sales that our customer may return. We record our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognize the related sale. Based on our distribution model for product sales, contractual inventory limits with our customer and wholesalers and the price of the product, we have had minimal returns to date and we believe we will continue to have minimal returns in the U.S. Our European customers generally only take title to the product after they receive an order and therefore they do not maintain excess inventory levels of our products. Accordingly, we have limited return risk in Europe and we do not estimate returns in Europe.

Research and development revenue under collaboration agreements:

Upfront payments

When we enter into a collaboration agreement with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&D services we will provide in the future. We amortize the upfront payment into revenue as we perform the R&D services. For example, under our collaboration agreement with Roche to develop IONIS-FB-L_Rx for the treatment of complement-mediated diseases, we received a $75 million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our single performance obligation, R&D services. We are amortizing the $75 million upfront payment using an input method over the estimated period of time we are providing R&D services.

Milestone payments

We are required to include additional consideration in the transaction price when it is probable. We typically include milestone payments for R&D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because typically there is considerable uncertainty in the research and development processes that trigger these payments. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales-based milestone payments in the period in which we achieve the milestone under the sales-based royalty exception allowed under accounting rules.

We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For example, in the fourth quarter of 2020, we achieved a $7.5 million milestone payment from Biogen when we advanced a target under our 2018 strategic collaboration. We added this payment to the transaction price and allocated it to our R&D services performance obligation. We are recognizing revenue related to this milestone payment over our estimated period of performance.

Conversely, we recognize in full those milestone payments that we earn based on our partners’ activities when our partner achieves the milestone event and we do not have a performance obligation. For example, in the third quarter of 2020, we recognized $18 million in milestone payments when Biogen initiated a Phase 1/2 trial for ION464, our medicine in development targeting alpha-synuclein to treat patients with multiple system atrophy. We concluded that the milestone payments were not related to our R&D services performance obligation. Therefore, we recognized the milestone payments in full in the third quarter of 2020.

License fees

We generally recognize as revenue the total amount we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery. For example, in the fourth quarter of 2020, we earned a $30 million license fee from AstraZeneca when AstraZeneca licensed ION455, an investigational medicine in development to treat nonalcoholic steatohepatitis, or NASH.

Sublicense fees

We recognize sublicense fee revenue in the period in which a party, who has already licensed our technology, further licenses the technology to another party because we do not have any performance obligations related to the sublicense. For example, in the fourth quarter of 2020, we earned a $41.2 million sublicense fee from Alnylam Pharmaceuticals for its sublicense of our technology to Sanofi Genzyme.

Amendments to Agreements

From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items to determine the accounting for the amendment:

If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and

If the goods and/or services are at a stand-alone selling price.

If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and are sold at a stand-alone selling price, we then assess whether the remaining goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our estimated revenue as a cumulative adjustment.

For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI_Rx for the prevention of thrombosis. As part of the agreement, Bayer paid us a $100 million upfront payment. At the onset of the agreement, we were responsible for completing a Phase 2 study of IONIS-FXI_Rx in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI_Rx and to initiate development of IONIS-FXI-L_Rx, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also eligible to receive milestone payments and tiered royalties on gross margins of IONIS-FXI_Rx and IONIS-FXI-L_Rx. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of IONIS-FXI-L_Rx, to provide R&D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. Refer to Note 6, Collaborative Arrangements and Licensing Agreements, in our audited financial statements included in our Annual Report on Form 10-K for the year ended December 31, 2019 for further discussion of the Bayer collaboration.

Multiple agreements

From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:

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Whether the agreements were negotiated together with a single objective;

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Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or

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Whether the goods and/or services promised under the agreements are a single performance obligation.

Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting guidance requires us to account for them as a combined arrangement.

For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: a new strategic neurology collaboration agreement and a stock purchase agreement, or SPA. We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis.

Contracts Receivable

Our contracts receivable balance represents the amounts we have billed our partners or customers and that are due to us unconditionally for goods we have delivered or services we have performed. When we bill our partners or customers with payment terms based on the passage of time, we consider the contracts receivable to be unconditional. We typically receive payment within one quarter of billing our partner or customer.

Unbilled SPINRAZA Royalties

Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet.

Deferred Revenue

We are often entitled to bill our customers and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet. During the years ended December 31, 2020 and 2019, we recognized $100.4 million and $159.5 million of revenue from amounts that were in our beginning deferred revenue balance for each respective period. For further discussion, refer to our revenue recognition policy above.

Cost of Products Sold

Our cost of products sold includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the manufacturing and distribution of our products. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of products sold. Prior to obtaining regulatory approval of TEGSEDI in July 2018 and WAYLIVRA in May 2019, we expensed as research and development expenses a significant portion of the costs we incurred to produce the initial commercial launch supply for each medicine.

Research, Development and Patent Expenses

Our research and development expenses include wages, benefits, facilities, supplies, external services, clinical trial and manufacturing costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development services prior to the services being rendered, we record those amounts as prepaid assets on our consolidated balance sheet and we expense them as the services are provided. For the years ended December 31, 2020, 2019 and 2018, research and development expenses were $531.0 million, $461.5 million and $411.9 million, respectively. A portion of the costs included in research and development expenses are costs associated with our partner agreements. For the years ended December 31, 2020, 2019 and 2018, research and development costs of approximately $49.8 million, $83.2 million and $58.7 million, respectively, were related to our partner agreements.

We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. The weighted average remaining amortizable life of our issued patents was 10.3 years at December 31, 2020.

The cost of our patents capitalized on our consolidated balance sheet at December 31, 2020 and 2019 was $37.0 million and $34.0 million, respectively. Accumulated amortization related to patents was $9.1 million and $8.3 million at December 31, 2020 and 2019, respectively.

Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:

Year Ending December 31,	Amortization (in millions)
2021	$	2.1
2022	$	2.0
2023	$	1.9
2024	$	1.7
2025	$	1.6

We review our capitalized patent costs regularly to ensure that they include costs for patents and patent applications that have future value. When we identify patents and patent applications that we are not actively pursuing, we write off any associated costs. In 2020, 2019 and 2018, patent expenses were $4.1 million, $4.2 million and $2.6 million, respectively, and included non-cash charges related to the write-down of our patent costs to their estimated net realizable values of $1.9 million, $2.2 million and $0.8 million, respectively.

Accrued Liabilities

Our accrued liabilities consisted of the following (in thousands):

	December 31,
	2020		2019
Clinical expenses	$	39,477	$	24,461
In-licensing expenses		8,264		10,289
Commercial expenses		11,559		6,020
Other miscellaneous expenses		30,861		25,999
Total accrued liabilities	$	90,161	$	66,769

Noncontrolling Interest in Akcea Therapeutics, Inc.

Since Akcea’s IPO in July 2017 and prior to the Akcea Acquisition in October 2020, the shares of Akcea’s common stock third parties owned represented an interest in Akcea’s equity that we did not control. During this period our ownership ranged from 68 percent to 77 percent. However, as we maintained overall control of Akcea through our voting interest, we reflected the assets, liabilities and results of operations of Akcea in our consolidated financial statements. Since Akcea’s IPO in July 2017 and through the closing of the Akcea Acquisition, we reflected the noncontrolling interest attributable to other owners of Akcea’s common stock on a separate line on our statement of operations and a separate line within stockholders’ equity in our consolidated balance sheet. In addition, through the closing of the Akcea Acquisition, we recorded a noncontrolling interest adjustment to account for the stock options Akcea granted, which if exercised, would have diluted our ownership in Akcea. This adjustment was a reclassification within stockholders’ equity from additional paid-in capital to noncontrolling interest in Akcea equal to the amount of stock-based compensation expense Akcea had recognized. Additionally, we reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling interest in the period the change occurred.

Concentration of Credit Risk

Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents, short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody’s, Standard & Poor’s, or S&P, or Fitch, respectively. We have established guidelines relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.

Cash, Cash Equivalents and Investments

We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents. Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as “available-for-sale” and carry them at fair market value based upon prices on the last day of the fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments in our consolidated statement of operations. We use the specific identification method to determine the cost of securities sold.

We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies that we received as part of a technology license or partner agreement. At December 31, 2020, we held equity investments in two publicly held companies, ProQR Therapeutics N.V., or ProQR, and Antisense Therapeutics Limited, or ATL. We also held equity investments in seven privately-held companies, Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico, Inc., Flamingo Therapeutics BV, Seventh Sense Biosystems and Suzhou-Ribo Life Science Co, Ltd.

We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our consolidated statement of operations. We account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer. For example, during the second and fourth quarters of 2020, we revalued our investments in three privately held companies, Dynacure, Suzhou-Ribo and Aro Biotherapeutics because the companies sold additional equity securities that were similar to the equity we own. These observable price changes resulted in us recognizing a $6.3 million gain on our investment in Dynacure, a $3.0 million gain on our investment in Suzhou-Ribo and a $5.5 million gain on our investment in Aro Biotherapeutics in our consolidated statement of operations during 2020 because the sales were at higher prices compared to our recorded value.

Inventory Valuation

We reflect our inventory on our consolidated balance sheet at the lower of cost or net realizable value under the first-in, first-out method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials, they have alternative future uses, which we refer to as clinical raw materials. We include in inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and, as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We expense these costs as R&D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency.

We obtained the first regulatory approval for TEGSEDI in July 2018 and for WAYLIVRA in May 2019. At December 31, 2020, our physical inventory for TEGSEDI and WAYLIVRA included API that we produced prior to when we obtained regulatory approval. As such, this API has no cost basis as we had previously expensed the costs as R&D expenses.

We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development and historical write-offs. We recorded an insignificant amount of inventory write-offs during the years ended December 31, 2020 and 2019. We did not record any inventory write-offs for the year ended December 31, 2018.

Our inventory consisted of the following (in thousands):

	December 31,
	2020		2019
Raw materials:
Raw materials- clinical	$	9,206	$	9,363
Raw materials- commercial		7,502		6,520
Total raw materials		16,708		15,883
Work in process		2,252		2,039
Finished goods		3,005		258
Total inventory	$	21,965	$	18,180

Property, Plant and Equipment

We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which consists of the following (in thousands):

	Estimated Useful Lives		December 31,
	(in years)		2020			2019
Computer software, laboratory, manufacturing and other equipment	3 to 10		$	68,990		$	60,965
Building, building improvements and building systems	15 to 40			137,879			119,830
Land improvements		20		8,391			2,853
Leasehold improvements	5 to 15			17,263			13,600
Furniture and fixtures	5 to 10			12,871			7,354
				245,394			204,602
Less accumulated depreciation				(87,379	)		(74,013	)
				158,015			130,589
Land				23,062			23,062
Total			$	181,077		$	153,651

We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.

Fair Value of Financial Instruments

We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable, accounts payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.

Leases

We determine if an arrangement contains a lease at inception. We currently only have operating leases. We recognize a right-of-use operating lease asset and associated short- and long-term operating lease liability on our consolidated balance sheet for operating leases greater than one year. Our right-of-use assets represent our right to use an underlying asset for the lease term and our lease liabilities represent our obligation to make lease payments arising from the lease arrangement. We recognize our right-of-use operating lease assets and lease liabilities based on the present value of the future minimum lease payments we will pay over the lease term. We determine the lease term at the inception of each lease, and in certain cases our lease term could include renewal options if we concluded we were reasonably certain that we will exercise the renewal option. When we exercise a lease option that was not previously included in the initial lease term, we reassess our right-of-use asset and lease liabilities for the new lease term.

As our current leases do not provide an interest rate implicit in the lease, we used our incremental borrowing rate, based on the information available on the date we adopted Topic 842 (January 2019), as of the lease inception date or at the lease option extension date in determining the present value of future payments. We recognize rent expense for our minimum lease payments on a straight-line basis over the expected term of our lease. We recognize period expenses, such as common area maintenance expenses, in the period we incur the expense.

Long-Lived Assets

We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets. We recorded charges of $1.9 million, $2.2 million and $0.8 million for the years ended December 31, 2020, 2019 and 2018, respectively, related to the write-down of patents.

Use of Estimates

The preparation of consolidated financial statements in conformity with accounting principles generally accepted in the U.S. requires management to make estimates and assumptions that affect the amounts reported in the consolidated financial statements and accompanying notes. Actual results could differ from those estimates.

Stock-Based Compensation Expense

We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, and stock purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the requisite service period in our consolidated statements of operations. We reduce stock-based compensation expense for estimated forfeitures at the time of grant and revise in subsequent periods if actual forfeitures differ from those estimates.

We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP. On the grant date, we use our stock price and assumptions regarding a number of variables to determine the estimated fair value of stock-based payment awards. These variables include, but are not limited to, our expected stock price volatility over the term of the awards, and actual and projected employee stock option exercise behaviors. The expected term of stock options granted represents the period of time that we expect them to be outstanding. We estimate the expected term of options granted based on historical exercise patterns.

We recognize compensation expense for option awards and RSUs using the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.

The fair value of RSUs is based on the market price of our common stock on the date of grant. The RSUs we have granted vest annually over a four-year period. RSUs granted after June 2020 to our board of directors vest annually.

See Note 4, Stockholders’ Equity, for additional information regarding our stock-based compensation plans.

Accumulated Other Comprehensive Loss

Accumulated other comprehensive loss is comprised of unrealized gains and losses on investments, net of taxes and currency translation adjustments. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2020, 2019 and 2018 (in thousands):

	Year Ended December 31,
	2020			2019			2018
Beginning balance accumulated other comprehensive loss	$	(25,290	)	$	(32,016	)	$	(31,759	)
Unrealized gains (losses) on securities, net of tax (1)		3,729			6,633			(280	)
Currency translation adjustment		617			93			23
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.		(127	)		—			—
Net other comprehensive loss for the period		4,219			6,726			(257	)
Ending balance accumulated other comprehensive loss	$	(21,071	)	$	(25,290	)	$	(32,016	)

________________

(1)	We did not have tax expense included in our other comprehensive loss for the year ended December 31, 2020. For the years ended December 31, 2019 and 2018, we had a tax benefit $1.4 million and $0.3 million included in other comprehensive loss respectively.

Convertible Debt

At issuance, we accounted for our convertible debt instruments, including our 0.125 percent senior convertible notes, or 0.125% Notes, and 1 percent senior convertible notes, or 1% Notes, that may be settled in cash upon conversion (including partial cash settlement) by separating the liability and equity components of the instruments in a manner that reflects our nonconvertible debt borrowing rate on the date the notes were issued. In reviewing debt issuances, we were not able to identify any comparable companies that issued non-convertible debt instruments at the time of the issuance of the convertible notes. Therefore, we estimated the fair value of the liability component of our notes by using assumptions that market participants would use in pricing a debt instrument, including market interest rates, credit standing, yield curves and volatilities.

We assigned a value to the debt component of our convertible notes equal to the estimated fair value of similar debt instruments without the conversion feature, which resulted in us recording our debt at a discount. We are amortizing our debt issuance costs and debt discount over the life of the convertible notes as additional non-cash interest expense utilizing the effective interest method. For additional information, see Note 3, Long-Term Obligations and Commitments.

The 1% Notes mature in November 2021. Therefore, as of December 31, 2020, we classified the liability component of the 1% Notes as a current liability on our consolidated balance sheet.

In August 2020, the FASB issued guidance simplifying the accounting for convertible debt instruments. See the section titled “Impact of Recently Issued Accounting Standards” below for details.

Call Spread

In conjunction with the issuance of our 0.125% Notes, we entered into a call spread transaction, which was comprised of purchasing note hedges and selling warrants. We account for the note hedges and warrants as separate freestanding financial instruments and treat each instrument as a separate unit of accounting. We determined that the note hedges and warrants do not meet the definition of a liability using the guidance contained in ASC Topic 480, therefore we account for the note hedges and warrants using the Derivatives and Hedging – Contracts in Entity’s Own Equity accounting guidance contained in ASC Topic 815. We determined that the note hedges and warrants meet the definition of a derivative, are indexed to our stock and meet the criteria to be classified in shareholders’ equity. We recorded the aggregate amount paid for the note hedges and the aggregate amount received for the warrants as additional paid-in capital in our consolidated balance sheet. We reassess our ability to continue to classify the note hedges and warrants in shareholders’ equity at each reporting period.

Segment Information

Through 2020, we had two operating segments, our Ionis Core segment and Akcea Therapeutics. Akcea was focused on developing and commercializing medicines to treat patients with serious and rare diseases. We have provided segment financial information and results for our Ionis Core segment and our Akcea Therapeutics segment based on the segregation of revenues and expenses that our chief decision maker reviewed to assess operating performance and to make operating decisions through 2020. We allocated a portion of Ionis’ development, R&D support and general and administrative expenses to Akcea for work Ionis performed on behalf of Akcea and we billed Akcea for these expenses.

Fair Value Measurements

We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity securities in publicly held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify most of our securities as Level 2. We obtain the fair value of our Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and comparing that fair value to the fair value based on observable market prices.

The following tables present the major security types we held at December 31, 2020 and 2019 that we regularly measure and carry at fair value. At December 31, 2019, our ProQR investment was subject to trading restrictions until the fourth quarter of 2020, as a result we included a lack of marketability discount in valuing this investment, which is a Level 3 input. As of December 31, 2020, our ProQR investment was no longer subject to trading restrictions. As of December 31, 2020, we did not have any investments which we valued using Level 3 inputs. The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities’ fair value (in thousands):

	At December 31, 2020		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	221,125	$	221,125	$	—
Corporate debt securities (2)		846,315		—		846,315
Debt securities issued by U.S. government agencies (4)		174,861		—		174,861
Debt securities issued by the U.S. Treasury (3)		358,497		358,497		—
Debt securities issued by states of the U.S. and political subdivisions of the states (4)		136,309		—		136,309
Other municipal debt securities (4)		6,225		—		6,225
Investment in ProQR Therapeutics N.V. (5)		2,031		2,031		—
Total	$	1,745,363	$	581,653	$	1,163,710

	At December 31, 2019		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)		Significant Unobservable Inputs (Level 3)
Cash equivalents (1)	$	418,406	$	418,406	$	—	$	—
Corporate debt securities (6)		1,102,568		—		1,102,568		—
Debt securities issued by U.S. government agencies (7)		329,404		—		329,404		—
Debt securities issued by the U.S. Treasury (4)		363,694		363,694		—		—
Debt securities issued by states of the U.S. and political subdivisions of the states (4)		40,407		—		40,407		—
Investment in ProQR Therapeutics N.V. (5)		4,506		—		—		4,506
Total	$	2,258,985	$	782,100	$	1,472,379	$	4,506

________________

(1)	Included in cash and cash equivalents on our consolidated balance sheet.

(2)	$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(3)	$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(4)	Included in short-term investments.

(5)	Included in other current assets on our consolidated balance sheet.

(6)	$19.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(7)	$0.8 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

Income Taxes

We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development credit carryforwards. We record a valuation allowance when necessary to reduce our net deferred tax assets to the amount expected to be realized.

We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.

We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes. Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust these reserves for changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for income taxes in the period in which such determination is made.

We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted. We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be realized.

We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries.

Impact of Recently Issued Accounting Standards

In June 2016, the FASB issued guidance that changes the measurement of credit losses for most financial assets and certain other instruments. If we have credit losses, this updated guidance requires us to record allowances for these instruments under a new expected credit loss model. This model requires us to estimate the expected credit loss of an instrument over its lifetime, which represents the portion of the amortized cost basis we do not expect to collect. The new guidance requires us to remeasure our allowance in each reporting period we have credit losses. We adopted this new guidance on January 1, 2020. This guidance did not have an impact on our consolidated financial statements.

In August 2018, the FASB issued clarifying guidance on how to account for implementation costs related to cloud-servicing arrangements. The guidance states that if these fees qualify to be capitalized and amortized over the service period, they need to be expensed in the same line item as the service expense and recognized in the same balance sheet category. The update can be applied either retrospectively or prospectively to all implementation costs incurred after the date of adoption. We adopted this guidance on January 1, 2020 on a prospective basis. This guidance did not have an impact on our consolidated financial statements.

In November 2018, the FASB issued clarifying guidance of the interaction between the collaboration accounting guidance and the new revenue recognition guidance we adopted on January 1, 2018 (Topic 606). Below is the clarifying guidance and how we implemented it (in italics):

When a participant is considered a customer in a collaborative arrangement, all of the associated accounting under Topic 606 should be applied.

●

We are applying all of the associated accounting under Topic 606 when we determine a participant in a collaborative arrangement is a customer.

Adds “unit of account” concept to collaboration accounting guidance to align with Topic 606. The “unit of account” concept is used to determine if revenue is recognized or if a contra expense is recognized from consideration received under a collaboration.

●

We use the “unit of account” concept when we receive consideration under a collaborative arrangement to determine when we recognize revenue or a contra expense.

The clarifying guidance precludes us from recognizing revenue under Topic 606 when we determine a transaction with a collaborative partner is not a customer and is not directly related to the sales to third parties.

●

When we conclude a collaboration partner is not a customer and is not directly related to the sales to third parties, we do not recognize revenue for the transaction.

We adopted this new guidance on January 1, 2020. This guidance did not have any impact on our consolidated financial statements.

In August 2020, the FASB issued guidance which simplifies the accounting for convertible instruments, amends the guidance on derivative scope exceptions for contracts in an entity’s own equity, and modifies the guidance on diluted earnings per share calculations as a result of these changes. Under our current outstanding convertible debt arrangements, we anticipate the following impacts:

We will no longer separate our existing convertible debt into liability and equity components. Therefore, we will no longer recognize a debt discount for the value of the conversion option, instead we will record the face value of the convertible debt as a liability on our consolidated balance sheet;

We will record cash interest expense plus amortization of debt issuance costs to interest expense. Since we will not recognize a debt discount, we will no longer record the amortization of a debt discount to interest expense; and

We do not expect our EPS calculation to not change under this update. We plan to continue to use the if-converted method to calculate diluted earnings per share.

We plan to adopt this guidance in the first quarter of 2021 under the full retrospective approach, meaning we will apply the guidance to all periods presented beginning in the first quarter of 2021.

Investments

12 Months Ended

Dec. 31, 2020

Investments [Abstract]

Investments

2. Investments

The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2020:

One year or less	73	%
After one year but within two years	18	%
After two years but within three and a half years	9	%
Total	100	%

As illustrated above, at December 31, 2020, 91 percent of our available-for-sale securities had a maturity of less than two years.

All of our available-for-sale securities are available to us for use in our current operations. As a result, we categorize all of these securities as current assets even though the stated maturity of some individual securities may be one year or more beyond the balance sheet date.

At December 31, 2020, we had an ownership interest of less than 20 percent in seven private companies and two public companies with which we conduct business. The privately-held companies are Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico, Inc., Flamingo Therapeutics BV, Seventh Sense Biosystems and Suzhou Ribo Life Science Co, Ltd. The publicly traded companies are ATL and ProQR.

The following is a summary of our investments (in thousands):

			Gross Unrealized					Estimated
December 31, 2020	Cost (1)		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (2)	$	514,182	$	2,194	$	(41	)	$	516,335
Debt securities issued by U.S. government agencies		94,234		354		(2	)		94,586
Debt securities issued by the U.S. Treasury (2)		307,576		233		(9	)		307,800
Debt securities issued by states of the U.S. and political subdivisions of the states		104,271		196		(12	)		104,455
Other municipal debt securities		5,191		—		(7	)		5,184
Total securities with a maturity of one year or less		1,025,454		2,977		(71	)		1,028,360
Corporate debt securities		325,079		4,941		(40	)		329,980
Debt securities issued by U.S. government agencies		80,099		185		(9	)		80,275
Debt securities issued by the U.S. Treasury		50,318		383		(4	)		50,697
Debt securities issued by states of the U.S. and political subdivisions of the states		31,779		91		(16	)		31,854
Other municipal debt securities		1,041		—		—			1,041
Total securities with a maturity of more than one year		488,316		5,600		(69	)		493,847
Total available-for-sale securities	$	1,513,770	$	8,577	$	(140	)	$	1,522,207
Equity securities:
Total equity securities included in other current assets (3)	$	4,712	$	—	$	(2,681	)	$	2,031
Total equity securities included in deposits and other assets (4)		15,062		15,938		—			31,000
Total equity securities	$	19,774	$	15,938	$	(2,681	)	$	33,031
Total available-for-sale and equity securities	$	1,533,544	$	24,515	$	(2,821	)	$	1,555,238

			Gross Unrealized					Estimated
December 31, 2019	Cost (1)		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (2)	$	669,665	$	1,451	$	(43	)	$	671,073
Debt securities issued by U.S. government agencies		188,216		303		(43	)		188,476
Debt securities issued by the U.S. Treasury (2)		327,670		232		(27	)		327,875
Debt securities issued by states of the U.S. and political subdivisions of the states		21,065		26		(5	)		21,086
Total securities with a maturity of one year or less		1,206,616		2,012		(118	)		1,208,510
Corporate debt securities		428,627		2,911		(43	)		431,495
Debt securities issued by U.S. government agencies		140,988		57		(117	)		140,928
Debt securities issued by the U.S. Treasury		35,822		9		(12	)		35,819
Debt securities issued by states of the U.S. and political subdivisions of the states		19,309		18		(6	)		19,321
Total securities with a maturity of more than one year		624,746		2,995		(178	)		627,563
Total available-for-sale securities	$	1,831,362	$	5,007	$	(296	)	$	1,836,073
Equity securities:
Total equity securities included in other current assets (3)	$	4,712	$	—	$	(870	)	$	3,842
Total equity securities included in deposits and other assets (4)		10,000		—		—			10,000
Total equity securities	$	14,712	$	—	$	(870	)	$	13,842
Total available-for-sale and equity securities	$	1,846,074	$	5,007	$	(1,166	)	$	1,849,915

________________

(1)	We hold our available-for-sale securities at amortized cost.

(2)	Includes investments classified as cash equivalents on our consolidated balance sheet.

(3)	Our equity securities included in other current assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.

(4)

Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer on our consolidated balance sheet.

The following is a summary of our investments we considered to be temporarily impaired at December 31, 2020 (in thousands). All of these investments have less than 12 months of temporary impairment. We believe that the decline in value of these securities is temporary and is primarily related to the change in market interest rates since purchase. We believe it is more likely than not that we will be able to hold our debt securities to maturity. Therefore, we anticipate full recovery of our debt securities’ amortized cost basis at maturity.

	Number of Investments		Estimated Fair Value		Unrealized Losses
Corporate debt securities		54	$	121,162	$	(81	)
Debt securities issued by U.S. government agencies		2		29,988		(11	)
Debt securities issued by the U.S. Treasury		8		76,941		(13	)
Debt securities issued by states of the U.S. and political subdivisions of the states		160		49,832		(28	)
Other municipal debt securities		2		6,225		(7	)
Total temporarily impaired securities		226	$	284,148	$	(140	)

Long-Term Obligations and Commitments

12 Months Ended

Dec. 31, 2020

Long-Term Obligations and Commitments [Abstract]

Long-Term Obligations and Commitments

3. Long-Term Obligations and Commitments

The carrying value of our long-term obligations was as follows (in thousands):

	December 31,
	2020			2019
0.125 percent convertible senior notes	$	455,719		$	434,711
1 percent convertible senior notes (1)		293,161			275,333
Long-term mortgage debt		59,984			59,913
Leases and other obligations		30,710			17,569
Total	$	839,574		$	787,526
Less: current portion (1)		(300,462	)		(2,026	)
Total Long-Term Obligations	$	539,112		$	785,500

________________

(1)	We classified the carrying value of our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matures in November 2021.

Convertible Notes and Call Spread

0.125 Percent Convertible Senior Notes

In December 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors and certain holders of our existing 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes, and to issue $109.5 million of our 0.125% Notes. We completed this exchange to reduce our cash interest payments, increase our conversion price and extend our maturity for a large portion of our debt. Additionally, in conjunction with the December 2019 exchange, we entered into a call spread transaction, which was comprised of purchasing note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our 0.125% Notes by increasing the effective conversion price even further.

Interest is payable semi-annually on June 15 and December 15 of each year for the 0.125% Notes. The 0.125% Notes are convertible at the option of the note holders prior to August 1, 2024 only under certain conditions. On or after August 1, 2024, the 0.125% Notes are initially convertible into approximately 6.6 million shares of common stock at a conversion price of approximately $83.28 per share. We will settle conversions of the notes, at our election, in cash, shares of our common stock or a combination of both. We may not redeem the 0.125% Notes prior to maturity, and no sinking fund is provided for them. If we undergo a fundamental change, holders may require us to purchase for cash all or any portion of their 0.125% Notes at a purchase price equal to 100 percent of the principal amount of the notes to be purchased, plus accrued and unpaid interest to, but excluding, the fundamental change purchase date.

At December 31, 2020, we had the following 0.125% Notes outstanding (amounts in millions except price per share data):

	0.125% Notes
Outstanding principal balance	$	548.8
Maturity date	December 15, 2024
Interest rate		0.125	%
Conversion price per share	$	83.28
Total shares of common stock subject to conversion		6.6

The following table summarizes information about the equity and liability components of our outstanding 0.125% Notes (in millions). We measured the fair values of the convertible notes outstanding based on quoted market prices, which is a Level 2 measurement at December 31, 2020 and 2019:

	December 31,
	2020		2019
Fair value of outstanding notes	$	564.9	$	558.7
Principal amount of convertible notes outstanding	$	548.8	$	548.8
Unamortized portion of debt discount	$	86.0	$	105.2
Long-term debt	$	455.7	$	434.7
Carrying value of equity component	$	105.8	$	105.8

Call Spread

Additionally, in conjunction with the December 2019 exchange, we entered into a call spread transaction, which was comprised of purchasing note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our 0.125% Notes by increasing the conversion price even further. The call spread cost us $52.6 million, of which $108.7 million was for the note hedge purchase, offset by $56.1 million we received for selling the warrants. We increased our effective conversion price to $123.38 with the same number of underlying shares as our 0.125% Notes. We accounted for our call spread transactions using the Derivatives and Hedging – Contracts in Entity’s Own Equity accounting guidance contained in Topic 815. We determined that the call spread transactions meet the definition of a derivative, are indexed to our stock and meet the criteria to be classified in shareholders’ equity.

Similar to our 0.125% Notes, our note hedges are subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the 0.125% Notes. The note hedges will expire upon maturity of 0.125% Notes, or December 2024. The note hedges and warrants are separate transactions and are not part of the terms of our 0.125% Notes. The holders of the 0.125% Notes do not have any rights with respect to the note hedges and warrants.

We recorded the aggregate amount paid for the note hedges and the aggregate amount received for the warrants in additional paid-in capital in our consolidated balance sheet. We reassess our ability to continue to classify the note hedges and warrants in shareholders’ equity at each reporting period. We excluded shares under the note hedges from our calculation of diluted earnings per share as they were antidilutive. We will include the shares issuable under the warrants in our calculation of diluted earnings per share when the average market price per share of our common stock for the reporting period exceeds the strike price of the warrants.

1 Percent Convertible Senior Notes

In November 2014, we completed a $500 million offering of convertible senior notes, which mature in 2021 and bear interest at 1 percent. We used a substantial portion of the net proceeds from the issuance of the 1% Notes to repurchase $140 million in principal of our 2¾ percent convertible senior notes, or 2¾%% Notes. In December 2016, we issued an additional $185.5 million of 1% Notes in exchange for the redemption of $61.1 million of our 2¾%% Notes. In December 2019, we exchanged a portion of our 1% Notes for 0.125% Notes. As a result, the principal balance of 1% Notes was $309.9 million. Additionally, we recorded a $21.9 million non-cash loss on early retirement of debt, reflecting the early retirement of a significant portion of our 1% Notes in December 2019.

At December 31, 2020, we had the following 1% Notes outstanding (amounts in millions except price per share data):

	1% Notes
Outstanding principal balance	$	309.9
Maturity date	November 30, 2021
Interest rate	1 percent
Conversion price per share	$	66.81
Total shares of common stock subject to conversion		4.6

Interest is payable semi-annually in arrears on May 15 and November 15 of each year for the 1% Notes. The 1% Notes are convertible at the option of the note holders prior to July 1, 2021 only under certain conditions. On or after July 1, 2021, the 1% Notes are initially convertible into approximately 4.6 million shares of common stock at a conversion price of approximately $66.81 per share. We will settle conversions of the notes, at our election, in cash, shares of our common stock or a combination of both. We may not redeem the 1% Notes prior to maturity, and no sinking fund is provided for them. If we undergo a fundamental change, holders may require us to purchase for cash all or any portion of their 1% Notes at a purchase price equal to 100 percent of the principal amount of the notes to be purchased, plus accrued and unpaid interest to, but excluding, the fundamental change purchase date.

The following table summarizes information about the equity and liability components of our outstanding 1% Notes (in millions). We measured the fair values of the convertible notes outstanding based on quoted market prices, which is a Level 2 measurement at December 31, 2020 and 2019:

	December 31,
	2020		2019
Fair value of outstanding notes	$	338.5	$	354.8
Principal amount of convertible notes outstanding	$	309.9	$	309.9
Unamortized portion of debt discount	$	15.8	$	32.8
Current/long-term debt	$	293.2	$	275.3
Carrying value of equity component	$	33.5	$	33.5

We account for our convertible notes using an accounting standard that requires us to assign a value to our convertible debt equal to the estimated fair value of similar debt instruments without the conversion feature and to record the remaining portion in equity. As a result, we recorded our convertible notes at a discount, which we are amortizing as additional non-cash interest expense over the expected life of the respective debt. We determined our nonconvertible debt borrowing rate using a combination of the present value of the debt’s cash flows and a Black-Scholes valuation model. The following table summarizes the nonconvertible borrowing rate, effective interest rate and amortization period of our debt discount for our convertible notes:

	1% Notes	0.125% Notes
Nonconvertible debt borrowing rate	7.4 percent	4.4 percent
Effective interest rate (1)	7.5 percent	4.9 percent
Amortization period of debt discount	7 years	5 years

________________

(1)	For our 1% Notes, our effective interest rate represents our effective interest rate after our December 2019 debt exchange.

Our total interest expense for our outstanding senior convertible notes for the years ended December 31, 2020, 2019 and 2018 included $38.7 million, $39.3 million and $35.2 million, respectively, of non-cash interest expense related to the amortization of the debt discount and debt issuance costs for our convertible notes.

Financing Arrangements

Line of Credit Arrangement

In June 2015, we entered into a five-year revolving line of credit agreement with Morgan Stanley Private Bank, National Association, or Morgan Stanley, which we amended in February 2016. Under the amended credit agreement, Morgan Stanley provided a maximum of $30 million of revolving credit for general working capital purposes. During the third quarter of 2019, we paid off our total outstanding borrowings of $12.5 million under the agreement and subsequently terminated the agreement.

Research and Development and Manufacturing Facilities

In July 2017, we purchased the building that houses our primary R&D facility for $79.4 million and our manufacturing facility for $14.0 million. We financed the purchase of these two facilities with mortgage debt of $60.4 million in total. Our primary R&D facility mortgage has an interest rate of 3.88 percent. Our manufacturing facility mortgage has an interest rate of 4.20 percent. During the first five years of both mortgages, we are only required to make interest payments. Both mortgages mature in August 2027.

Maturity Schedules

Annual debt and other obligation maturities, including fixed and determinable interest, at December 31, 2020 are as follows (in thousands):

2021	$	329,189
2022		3,495
2023		4,180
2024		553,006
2025		3,494
Thereafter		60,933
Subtotal	$	954,297
Less: current portion		(300,462	)
Less: fixed and determinable interest		(21,758	)
Less: unamortized portion of debt discount		(101,820	)
Less: debt issuance costs		(8,455	)
Plus: lease liabilities		17,310
Total long-term debt	$	539,112

Operating Leases

Carlsbad Leases

We lease a facility adjacent to our manufacturing facility that has laboratory and office space that we use to support our manufacturing facility. We lease this space under a non-cancelable operating lease. In May 2020, we exercised our option to extend our lease, extending our lease term from June 2021 to August 2026. We have one remaining option to extend the lease for an additional five-year period.

We also lease additional office spaces in Carlsbad. We lease these spaces under non-cancelable operating leases with initial terms ending in 2023 with options to extend each of the leases for one five-year period.

Boston Lease

We entered into an operating lease agreement for office space located in Boston, Massachusetts in the second quarter of 2018. The lease commencement date was in August 2018 and we took occupancy in September 2018. We are leasing this space under a non-cancelable operating lease with an initial term ending after 123 months and an option to extend the lease for an additional five-year term. Under the lease agreement, we received a three-month free rent period, which commenced on August 15, 2018, and a tenant improvement allowance up to $3.8 million. We provided the lessor with a letter of credit to secure its obligations under the lease in the initial amount of $2.4 million, to be reduced to $1.8 million on the third anniversary of the rent commencement date and to $1.2 million on the fifth anniversary of the rent commencement date if we meet certain conditions set forth in the lease at each such time.

When we determined our lease term for our operating lease right-of-use assets and lease liabilities for these leases, we did not include the extension options for these leases in the original lease term.

Amounts related to our operating leases were as follows (dollar amounts in millions):

	At December 31, 2020
Right-of-use operating lease assets (1)	$	13.1
Operating lease liabilities (2)	$	17.3
Weighted average remaining lease term	7.2 years
Weighted average discount rate		7.0	%

________________

(1)	Included in deposits and other assets on our consolidated balance sheet.

(2)	Current portion of $2.0 million was included in current portion of long-term obligations on our consolidated balance sheet, with the difference included in long-term obligations.

During the years ended December 31, 2020, 2019, and 2018 we paid $3.8 million, $3.9 million and $1.7 million of lease payments, which were included in operating activities in our consolidated statement of cash flows.

As of December 31, 2020, the future payments for our operating lease liabilities are as follows (in thousands):

	Operating Leases
Year ending December 31,	$
2021		3,193
2022		2,968
2023		2,707
2024		2,583
2025		2,442
Thereafter		7,038
Total minimum lease payments		20,931
Less:
Imputed interest		(3,621	)
Total operating lease liabilities	$	17,310

Rent expense was $3.7 million, $3.6 million and $2.6 million for the years ended December 31, 2020, 2019 and 2018, respectively.

Stockholders' Equity

12 Months Ended

Dec. 31, 2020

Stockholders' Equity [Abstract]

Stockholders' Equity

4. Stockholders’ Equity

Preferred Stock

We are authorized to issue up to 15 million shares of “blank check” Preferred Stock. As of December 31, 2020, there were no shares of Preferred Stock outstanding. We have designated Series C Junior Participating Preferred Stock but have no issued or outstanding shares as of December 31, 2020.

Common Stock

At December 31, 2020 and 2019, we had 300 million shares of common stock authorized, of which 140.4 million and 140.3 million were issued and outstanding, respectively. As of December 31, 2020, total common shares reserved for future issuance were 26.1 million.

During the years ended December 31, 2020, 2019 and 2018, we issued 1.7 million, 3.1 million and 1.5 million shares of common stock, respectively, for stock option exercises, vesting of restricted stock units, and ESPP purchases. We received net proceeds from these transactions of $52.0 million, $119.7 million and $27.9 million in 2020, 2019 and 2018, respectively.

Share Repurchase Program

In September 2019, our board of directors approved a share repurchase program of up to $125 million of our common stock. In 2019, we repurchased 535,000 shares for $34.4 million. In the first quarter of 2020, we repurchased an additional 1.5 million shares for $90.5 million.

Stock Plans

1989 Stock Option Plan

In June 1989, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that, as amended, provides for the issuance of non-qualified and incentive stock options for the purchase of up to 20.0 million shares of common stock to our employees, directors, and consultants. The plan expires in January 2024. The 1989 Plan does not allow us to grant stock bonuses or restricted stock awards and prohibits us from repricing any options outstanding under the plan unless our stockholders approve the repricing. Options vest over a four-year period, with 25percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. At December 31, 2020, a total of 30 thousand options were outstanding, of which options to purchase 30 thousand shares were exercisable, and 50 thousand shares were available for future grant under the 1989 Plan.

2011 Equity Incentive Plan

In March 2011, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that provides for the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to our employees, directors, and consultants. In June 2015, May 2017 and June 2019, after receiving approval from our stockholders, we amended our 2011 Equity Incentive Plan to increase the total number of shares reserved for issuance. We increased the shares available under our 2011 Equity Incentive Plan from 5.5 million to 11.0 million in June 2015, from 11.0 million to 16.0 million in May 2017 and from 16.0 million to 23.0 million in June 2019. The plan expires in June 2031. The 2011 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate awarding only options and restricted stock unit awards to our employees, directors and consultants. We have granted restricted stock unit awards to our employees under the 2011 Plan which vest annually over a four-year period. At December 31, 2020, a total of 11.4 million options were outstanding, of which 6.7 million were exercisable, 2.2 million restricted stock unit awards were outstanding, and 4.3 million shares were available for future grant under the 2011 Plan.

Under the 2011 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a change in control. In the absence of such provisions, no such acceleration will occur. The stock options and restricted stock unit awards we issued to Dr. Stanley T. Crooke in his former role as chief executive officer and certain stock options and restricted stock unit awards we issued to B. Lynne Parshall in her former role as chief operating officer will accelerate upon a change of control, as defined in the 2011 Plan. In addition, we implemented a change of control and severance benefit plan that provides for change of control and severance benefits to our executive officers, including our chief executive officer and chief financial officer. If we terminate one of our executive officers or if an executive officer resigns for good reason during the period that begins three months before and ends twelve months following a change in control of the company, the impacted executive officers’ stock options and RSUs vesting will accelerate for options and RSUs outstanding as of the termination date.

2020 Equity Incentive Plan

In connection with the Akcea Acquisition in October 2020, we assumed the unallocated portion of the available share reserve under the Akcea 2015 Equity Incentive Plan. In December 2020, we amended and restated the Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or 2020 Plan. The 2020 Plan provided for the issuance of up to 2.6 million shares of our Common Stock to our employees, directors and consultants who were employees of Akcea prior to the Akcea Acquisition.

The plan expires in December 2025. The 2020 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate awarding only options and restricted stock unit awards to our eligible employees, directors and consultants. We have granted stock options to our employees under the 2020 Plan which vest annually over a four-year period. At December 31, 2020, a total of 0.01 million options were outstanding, of which none were exercisable, and 2.6 million shares were available for future grant under the 2020 Plan.

Under the 2020 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a change in control. In the absence of such provisions, no such acceleration will occur.

Corporate Transactions and Change in Control under 2011 and 2020 Plans

In the event of certain significant corporate transactions, our Board of Directors has the discretion to take one or more of the following actions with respect to outstanding stock awards under the 2011 and 2020 Plans:

●

arrange for assumption, continuation, or substitution of a stock award by a surviving or acquiring entity (or its parent company);

●

arrange for the assignment of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award to the surviving or acquiring corporation (or its parent company);

●

accelerate the vesting and exercisability of a stock award followed by the termination of the stock award;

●

arrange for the lapse of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award;

●

cancel or arrange for the cancellation of a stock award, to the extent not vested or not exercised prior to the effective date of the corporate transaction, in exchange for cash consideration, if any, as the Board, in its sole discretion, may consider appropriate; and

●

arrange for the surrender of a stock award in exchange for a payment equal to the excess of (a) the value of the property the holder of the stock award would have received upon the exercise of the stock award, over (b) any exercise price payable by such holder in connection with such exercise.

2002 Non-Employee Directors’ Stock Option Plan

In September 2001, our Board of Directors adopted, and the stockholders subsequently approved, an amendment and restatement of the 1992 Non-Employee Directors’ Stock Option Plan, which provides for the issuance of non-qualified stock options and restricted stock units to our non-employee directors. The name of the resulting plan is the 2002 Non-Employee Directors’ Stock Option Plan, or the 2002 Plan. In June 2015, after receiving approval from our stockholders, we amended our 2002 Plan to increase the total number of shares reserved for issuance from 1.2 million to 2.0 million. In June 2020, after receiving approval from our stockholders, we further amended our 2002 Plan. The amendments included:

●

An increase to the total number of shares reserved for issuance under the plan from 2.0 million to 2.8 million shares;

●

A reduction to the amount of the automatic awards under the plan;

●

A revision to the vesting schedule of new awards granted; and

●

An extension of the term of the plan.

Options under this plan expire 10 years from the date of grant. At December 31, 2020, a total of 1.0 million options were outstanding, of which 0.6 million were exercisable, 0.1 million restricted stock unit awards were outstanding, and 0.8 million shares were available for future grant under the 2002 Plan.

Employee Stock Purchase Plan

In June 2009, our Board of Directors adopted, and the stockholders subsequently approved, the amendment and restatement of the ESPP and we reserved an additional 150,000 shares of common stock for issuance thereunder. In each of the subsequent years until 2019, we reserved an additional 150,000 shares of common stock for the ESPP resulting in a total of 3.2 million shares authorized under the plan as of December 31, 2020. The ESPP permits full-time employees to purchase common stock through payroll deductions (which cannot exceed 10percent of each employee’s compensation) at the lower of 85percent of fair market value at the beginning of the purchase period or the end of each purchase period. Under the amended and restated ESPP, employees must hold the stock they purchase for a minimum of six months from the date of purchase. During 2020, employees purchased and we issued to employees 0.06 million shares under the ESPP at a weighted average price of $43.65 per share. At December 31, 2020, there were 0.7 million shares available for purchase under the ESPP.

Stock Option Activity

The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2020 (in thousands, except per share and contractual life data):

	Number of Shares			Weighted Average Exercise Price Per Share		Average Remaining Contractual Term (Years)		Aggregate Intrinsic Value
Outstanding at December 31, 2019		11,001		$	51.48
Granted		2,764		$	59.89
Exercised		(1,069	)	$	40.88
Cancelled/forfeited/expired		(361	)	$	56.48
Outstanding at December 31, 2020		12,335		$	54.14		4.16	$	55,885
Exercisable at December 31, 2020		7,366		$	52.45		3.16	$	43,267

The weighted-average estimated fair values of options granted were $29.43, $28.76 and $25.49 for the years ended December 31, 2020, 2019 and 2018, respectively. The total intrinsic value of options exercised during the years ended December 31, 2020, 2019 and 2018 were $15.5 million, $83.8 million and $34.8 million, respectively, which we determined as of the date of exercise. The amount of cash received from the exercise of stock options was $43.7 million, $105.9 million and $18.9 million for the years ended December 31, 2020, 2019 and 2018, respectively. For the year ended December 31, 2020, the weighted-average fair value of options exercised was $55.33. As of December 31, 2020, total unrecognized compensation cost related to non-vested stock options was $54.1 million. We expect to recognize this cost over a weighted average period of 1.1 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.

Restricted Stock Unit Activity

The following table summarizes the RSU activity for the year ended December 31, 2020 (in thousands, except per share data):

	Number of Shares			Weighted Average Grant Date Fair Value Per Share
Non-vested at December 31, 2019		1,866		$	55.80
Granted		1,244		$	60.86
Vested		(602	)	$	53.68
Cancelled/forfeited		(134	)	$	58.96
Non-vested at December 31, 2020		2,374		$	58.81

For the years ended December 31, 2020, 2019 and 2018, the weighted-average grant date fair value of RSUs granted was $60.86, $60.23 and $51.06 per RSU, respectively. As of December 31, 2020, total unrecognized compensation cost related to RSUs was $55.3 million. We expect to recognize this cost over a weighted average period of 1.3 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.

Stock-based Compensation Expense and Valuation Information

The following table summarizes stock-based compensation expense for the years ended December 31, 2020, 2019 and 2018 (in thousands):

	Year Ended December 31,
	2020		2019		2018
Cost of products sold	$	1,991	$	438	$	160
Research, development and patent		115,584		95,348		76,557
Selling, general and administrative		112,542		50,788		54,595
Total	$	230,117	$	146,574	$	131,312

Our non-cash stock-based compensation expense included $94.8 million, $37.1 million and $44.3 million of stock-based compensation expense for Akcea employees for the years ended December 31, 2020, 2019 and 2018, respectively.

In October 2020, as part of the Akcea Acquisition, Akcea’s outstanding equity awards vested under Akcea’s Plan. As a result, in the fourth quarter of 2020, we recognized all unrecognized stock-based compensation ($59.3 million) under Akcea’s Plan. See Note 7, Akcea Acquisition, in the Notes to the Consolidated Financial Statements for further details.

In the third quarter of 2019, three Akcea executive officers terminated their employment and entered into separation agreements with Akcea. As a result, in the third quarter of 2019, Akcea reversed $19.1 million of stock-based compensation expense it had previously recognized related to the executive officers’ stock options and RSUs that were no longer going to vest.

Determining Fair Value

Valuation. We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, and stock purchase rights under the ESPP at the grant date, based on the estimated fair value of the award and we recognize the expense over the employee’s requisite service period. We value RSUs based on the market price of our common stock on the date of grant.

We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP. The expected term of stock options granted represents the period of time that we expect them to be outstanding. We estimate the expected term of options granted based on actual and projected exercise patterns. We recognize compensation expense for stock options granted, RSUs, and stock purchase rights under the ESPP using the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.

For the years ended December 31, 2020, 2019 and 2018, we used the following weighted-average assumptions in our Black-Scholes calculations:

Ionis Employee Stock Options:

	December 31,
	2020			2019			2018
Risk-free interest rate		1.5	%		2.3	%		2.4	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		58.6	%		60.3	%		63.0	%
Expected life	4.7 years			4.8 years			4.6 years

Ionis Board of Director Stock Options:

	December 31,
	2020			2019			2018
Risk-free interest rate		0.5	%		1.9	%		2.8	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		57.6	%		60.7	%		61.5	%
Expected life	6.7 years			6.6 years			6.6 years

Ionis ESPP:

	December 31,
	2020			2019			2018
Risk-free interest rate		0.8	%		2.4	%		1.8	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		47.9	%		45.6	%		47.3	%
Expected life	6 months			6 months			6 months

Risk-Free Interest Rate. We base the risk-free interest rate assumption on observed interest rates appropriate for the term of our stock option plans or ESPP.

Dividend Yield. We base the dividend yield assumption on our history and expectation of dividend payouts. We have not paid dividends in the past and do not expect to in the future.

Volatility. We use an average of the historical stock price volatility of our stock for the Black-Scholes model. We computed the historical stock volatility based on the expected term of the awards.

Expected Life. The expected term of stock options we have granted represents the period of time that we expect them to be outstanding. We estimated the expected term of options we have granted based on actual and projected exercise patterns.

Forfeitures. We reduce stock-based compensation expense for estimated forfeitures. We estimate forfeitures at the time of grant and revise, if necessary, in subsequent periods if actual forfeitures differ from those estimates. We estimate forfeitures based on historical experience.

In addition to our stock plans, Akcea had its own stock plan prior to the Akcea Acquisition, referred to as the Akcea 2015 Equity Incentive Plan, or Akcea Plan. Under the Akcea Plan, Akcea granted options and RSUs.

For the years ended December 31, 2020, 2019 and 2018, we used the following weighted-average assumptions in our Black-Scholes calculations for the Akcea Plan:

Akcea Employee Stock Options:

	December 31,
	2020			2019			2018
Risk-free interest rate		1.1	%		2.2	%		2.8	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		75.0	%		75.4	%		77.1	%
Expected life	6.08 years			6.09 years			6.08 years

Akcea Board of Director Stock Options:

	December 31,
	2020			2019			2018
Risk-free interest rate		0.8	%		1.8	%		2.9	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		75.3	%		73.8	%		78.2	%
Expected life	5.67 years			6.25 years			6.42 years

Akcea ESPP:

	December 31,
	2020			2019			2018
Risk-free interest rate		1.0	%		2.4	%		1.9	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		71.9	%		60.0	%		64.2	%
Expected life	6 months			6 months			6 months

The following summarizes the Black-Scholes input methodology for Akcea options that differs from the methodology we use for Ionis options:

Volatility. Since Akcea did not have sufficient history to estimate the volatility of its common stock, Akcea calculated its expected volatility based on a blend of its historical volatility and reported data from selected publicly traded peer companies for which historical information was available.

Expected Life. Since Akcea did not have sufficient historical information, it used the simplified method for estimating its expected term. Under the simplified method Akcea calculated its expected term as the average time-to-vesting and the contractual life of the options.

Akcea RSU’s

The fair value of RSUs was based on the market price of Akcea’s common stock on the date of grant. Akcea granted RSUs with various vesting terms between six months and four years. The weighted-average grant date fair value of RSUs granted to employees for years ended December 31, 2020 and 2019 was $15.57 and $21.95 per share, respectively.

Income Taxes

12 Months Ended

Dec. 31, 2020

Income Taxes [Abstract]

Income Taxes

5. Income Taxes

Income (loss) before income taxes is comprised of (in thousands):

	Year Ended December 31,
	2020			2019		2018
United States	$	(172,702	)	$	344,280	$	(69,576	)
Foreign		2,670			2,489		(6,580	)
Income (loss) before income taxes	$	(170,032	)	$	346,769	$	(76,156	)

Our income tax expense (benefit) was as follows (in thousands):

	Year Ended December 31,
	2020			2019			2018
Current:
Federal	$	(837	)	$	35,861		$	438
State		3,782			14,329			(1,442	)
Foreign		518			413			374
Total current income tax expense (benefit)		3,463			50,603			(630	)

Deferred:
Federal		313,271			(7,096	)		(290,511	)
State		—			—			—
Total deferred income tax benefit		313,271			(7,096	)		(290,511	)
Total income tax expense (benefit)	$	316,734		$	43,507		$	(291,141	)

Our expense (benefit) for income taxes differs from the amount computed by applying the U.S. federal statutory rate to income (loss) before taxes. The sources and tax effects of the differences are as follows (in thousands):

	Year Ended December 31,
	2020					2019					2018
Pre-tax income (loss)	$	(170,032	)			$	346,769				$	(76,156	)

Statutory rate		(35,707	)	21.0	%		72,822		21.0	%		(15,993	)	21.0	%
State income tax net of federal benefit		(39,230	)	23.1	%		49,119		14.2	%		(2,202	)	2.9	%
Foreign		49		0.0	%		340		0.1	%		1,735		(2.3	)%
Net change in valuation allowance		437,597		(257.4	)%		(37,765	)	(10.9	)%		(277,924	)	364.9	%
Net operating loss expiration		—		0.0	%		—		0.0	%		8,864		(11.6	)%
TEGSEDI licensing gain		—		0.0	%		—		0.0	%		59,583		(78.2	)%
Impact from outside basis differences		—		0.0	%		(16,344	)	(4.7	)%		—		0.0	%
Tax credits		(18,774	)	11.0	%		(22,296	)	(6.4	)%		(73,362	)	96.3	%
Deferred tax true-up		(206	)	0.1	%		646		0.2	%		9,947		(13.1	)%
Tax rate change		(29,131	)	17.1	%		1,811		0.5	%		(1,808	)	2.4	%
Non-deductible compensation		7,931		(4.7	)%		3,361		1.0	%		3,154		(4.1	)%
Other non-deductible items		193		(0.1	)%		329		0.1	%		(569	)	0.7	%
Stock-based compensation		17,435		(10.3	)%		(4,837	)	(1.4	)%		(4,199	)	5.5	%
Foreign-derived intangible income benefit		—		0.0	%		(2,071	)	(0.6	)%		—		0.0	%
Impacts from Akcea Acquisition		(22,032	)	13.0	%		—		—			—		—
Other		(1,391	)	0.8	%		(1,608	)	(0.5	)%		1,633		(2.1	)%
Effective rate	$	316,734		(186.4	)%	$	43,507		12.6	%	$	(291,141	)	382.3	%

Deferred income taxes reflect the net tax effects of temporary differences between the carrying amounts of assets and liabilities for financial reporting purposes and the amounts used for income tax purposes.

Significant components of our deferred tax assets and liabilities as of December 31, 2020 and 2019 are as follows (in thousands):

	Year Ended December 31,
	2020			2019
Deferred Tax Assets:
Net operating loss carryovers	$	83,681		$	20,191
Tax credits		245,746			210,455
Deferred revenue		124,452			127,763
Stock-based compensation		80,055			65,703
Intangible and capital assets		98,443			77,861
Other		13,402			12,510
Total deferred tax assets	$	645,779		$	514,483

Deferred Tax Liabilities:
Convertible debt	$	(2,920	)	$	(6,110	)
Fixed assets		(3,611	)		(1,958	)
Other		(5,808	)		(3,884	)
Net deferred tax asset	$	633,440		$	502,531
Valuation allowance		(633,440	)		(196,974	)
Total net deferred tax assets and liabilities	$	—		$	305,557

We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.

Ionis and Akcea have filed separate U.S. federal income tax returns since Akcea’s IPO in 2017. Accordingly, we were required to assess our Ionis stand-alone and Akcea’s valuation allowances separately even though we consolidate Akcea’s financial results in our consolidated financial statements. However, as a result of the Akcea acquisition, Ionis and Akcea will file a consolidated U.S. federal income tax return beginning in the fourth quarter of 2020, and we therefore assessed our U.S. federal valuation allowance requirements on a consolidated basis as of that period. We continue to assess the state portion of our valuation allowance on a consolidated basis.

We assessed our valuation allowance requirements and recorded a valuation allowance of $313 million against all of Ionis’ U.S. federal net deferred tax assets in the fourth quarter of 2020, due to uncertainties related to our ability to realize the tax benefits associated with these assets. This determination is based largely on Akcea rejoining the Ionis U.S. consolidated federal tax group in the fourth quarter of 2020. Due to Akcea’s historical and projected financial statement losses, and the negative impact this is expected to have on Ionis’ consolidated taxable income, there is uncertainty of generating sufficient consolidated pre-tax income in future periods to realize the Ionis deferred tax benefits. It is also expected that Ionis’ pre-tax income in future periods may be lower due to increased research and development expenses associated with our pipeline of wholly owned medicines. We now maintain a valuation allowance against all our consolidated U.S. federal and state net deferred tax assets.

Our valuation allowance increased by $436 million from December 31, 2019 to December 31, 2020. $313 million of the increase related to the valuation allowance established against our beginning of the year balance of Ionis’ U.S. federal net deferred tax assets as discussed above, which resulted in us recognizing income tax expense during 2020. The remaining increase in our valuation allowance related to current year changes in our net deferred tax assets.

At December 31, 2020, we had federal and state, primarily California, tax net operating loss carryforwards of $243.3 million and $346.3 million, respectively. Our federal tax loss carryforwards are available indefinitely. Our California tax loss carryforwards will begin to expire in 2031. At December 31, 2020, we also had federal and California research and development tax credit carryforwards of $210.5 million and $87.4 million, respectively. Our Federal research and development tax credit carryforwards will begin to expire in 2034. Our California research and development tax credit carryforwards are available indefinitely.

Utilization of the net operating loss and tax credit carryforwards may be subject to an annual limitation due to the ownership change limitations provided by the Internal Revenue Code of 1986, as amended, and similar state provisions. The annual limitation may result in the expiration of net operating losses and credits before utilization.

We analyze filing positions in all U.S. federal, state and foreign jurisdictions where we file income tax returns, and all open tax years in these jurisdictions to determine if we have any uncertain tax positions on any of our income tax returns. We recognize the impact of an uncertain tax position on an income tax return at the largest amount that the relevant taxing authority is more-likely-than not to sustain upon audit. We do not recognize uncertain income tax positions if they have less than 50 percent likelihood of the applicable tax authority sustaining our position.

The following table summarizes our gross unrecognized tax benefits (in thousands):

	Year Ended December 31,
	2020			2019			2018
Beginning balance of unrecognized tax benefits	$	69,784		$	68,301		$	78,014
Decrease for prior period tax positions		(24,154	)		(867	)		(12,814	)
Increase for prior period tax positions		7,023			736			—
Increase for current period tax positions		1,510			1,614			3,101
Ending balance of unrecognized tax benefits	$	54,163		$	69,784		$	68,301

Included in the balance of unrecognized tax benefits at December 31, 2020 and 2019 was $6.4 million and $0.4 million respectively, that if we recognized, could impact our effective tax rate, subject to our remaining valuation allowance. None of our unrecognized tax benefits recorded at December 31, 2018 would impact our effective tax rate, if we recognized them.

We do not foresee any material changes to our gross unrecognized tax benefits within the next twelve months.

We recognize interest and/or penalties related to income tax matters in income tax expense. During the year ended December 31, 2020, we recognized $0.3 million of accrued interest and penalties related to gross unrecognized tax benefits. We did not record any accrued interest and penalties for the years ended December 31, 2019 and 2018.

We are subject to taxation in the U.S. and various state and foreign jurisdictions. Our tax years for 1999 through 2019 are subject to examination by the U.S. federal, state and foreign tax authorities.

We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries as we consider those earnings to be permanently reinvested. It is not practicable for us to calculate the amount of unrecognized deferred tax liabilities associated with these earnings.

- Definition

The entire disclosure for income taxes. Disclosures may include net deferred tax liability or asset recognized in an enterprise's statement of financial position, net change during the year in the total valuation allowance, approximate tax effect of each type of temporary difference and carryforward that gives rise to a significant portion of deferred tax liabilities and deferred tax assets, utilization of a tax carryback, and tax uncertainties information.

+ References + Details

Collaborative Arrangements and Licensing Agreements

12 Months Ended

Dec. 31, 2020

Collaborative Arrangements and Licensing Agreements [Abstract]

Collaborative Arrangements and Licensing Agreements

6. Collaborative Arrangements and Licensing Agreements

Strategic Partnership

Biogen

We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen’s expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with spinal muscular atrophy, or SMA. We and Biogen are currently developing eight investigational medicines to treat neurodegenerative diseases under these collaborations, including medicines in development to treat people with ALS, Alzheimer’s diseaseand Parkinson’s disease. In addition to these medicines, our collaborations with Biogen include a substantial research pipeline that addresses a broad range of neurological diseases. From inception through December 2020, we have received more than $2.8 billion from our Biogen collaborations.

Spinal Muscular Atrophy Collaborations

SPINRAZA

In January 2012, we entered into a collaboration agreement with Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA. SPINRAZA is approved in over 50 countries around the world. From inception through December 2020, we earned more than $1.3 billion in total revenue under our SPINRAZA collaboration, including more than $930 million in revenue from SPINRAZA royalties and more than $435 million in R&D revenue. We are receiving tiered royalties ranging from 11 percent to 15 percent on net sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty on net sales of SPINRAZA. Biogen is responsible for all global development, regulatory and commercialization activities and costs for SPINRAZA. We completed our performance obligations under our collaboration in 2016.

New antisense medicines for the treatment of SMA

In December 2017, we entered into a collaboration agreement with Biogen to identify new antisense medicines for the treatment of SMA. Biogen has the option to license therapies arising out of this collaboration following the completion of preclinical studies. Upon licensing, Biogen will be responsible for global development, regulatory and commercialization activities and costs for such therapies. Under the collaboration agreement, we received a $25 million upfront payment in the fourth quarter of 2017. We will receive development and regulatory milestone payments from Biogen if new medicines advance towards marketing approval. In total over the term of our collaboration, we are eligible to receive up to $1.2 billion in license fees, milestone payments and other payments, including up to $80 million for the achievement of development milestones, up to $180 million for the achievement of commercialization milestones and up to $800 million for the achievement of sales milestones. In addition, we are eligible to receive tiered royalties from the mid-teens to mid-20 percent range on net sales. We will achieve the next payment of up to $60 millionfor the license of a medicine under this collaboration.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Biogen. We determined the transaction price to be the $25 million upfront payment we received when we entered into the collaboration. We allocated the transaction price to our single performance obligation. In the fourth quarter of 2019, we completed our R&D services performance obligation under this collaboration. We recognized revenue as we performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance obligation. We completed our performance obligation earlier than we previously estimated, as a result, we recognized $8.3 million of additional revenue in the fourth quarter of 2019. We do not have any remaining performance obligations under this collaboration. We will receive development and regulatory milestone payments from Biogen if Biogen advances the development candidate under this collaboration toward marketing approval.

Neurology Collaborations

2018 Strategic Neurology

In April 2018, we and Biogen entered into a strategic collaboration to develop novel antisense medicines for a broad range of neurological diseases and entered into a SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for these diseases for 10 years. We are responsible for the identification of antisense drug candidates based on selected medicines. Biogen is responsible for conducting IND-enabling toxicology studies for the selected medicine. Biogen will have the option to license the selected medicine after it completes the IND-enabling toxicology study. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.

In the second quarter of 2018, we received $1 billion from Biogen, comprised of $625 million to purchase our stock at an approximately 25 percent cash premium and $375 million in an upfront payment. We are eligible to receive up to $270 million in milestone payments for each medicine that achieves marketing approval. In addition, we are eligible to receive tiered royalties up to the 20 percent range on net sales. We are advancing eight programs under this collaboration and from inception through December 2020, we have received $1.05 billion in payments under this collaboration. We will achieve the next payment of $7.5 million if we advance a programunder this collaboration.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Biogen. We determined our transaction price to be $552 million, comprised of $375 million from the upfront payment and $177 million for the premium paid by Biogen for its purchase of our common stock. We determined the fair value of the premium we received by using the stated premium in the SPA and applying a lack of marketability discount. We included a lack of marketability discount in our valuation of the premium because Biogen received restricted shares of our common stock. We allocated the transaction price to our single performance obligation.

From inception through December 2020, we have included $608 million in payments in the transaction price for our R&D services performance obligation under this collaboration, including $11 million of milestone payments we achieved in 2020 and $30 million of milestone payments we achieved in 2019. These milestone payments did not create new performance obligations because they are part of our original R&D services performance obligation. Therefore, we included these amounts in our transaction price for our R&D services performance obligation in the period we achieved the milestone payment. We are recognizing revenue for our R&D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy our performance obligation at the end of the contractual term in June 2028.

2013 Strategic Neurology

In September 2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen will have the option to license antisense medicines after Phase 2 proof-of-concept. In October 2016, we expanded our collaboration to include additional research activities we will perform. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. We are currently advancing six investigational medicines in development under this collaboration, including a medicine for Parkinson’s disease (ION859), three medicines for ALS (tofersen, IONIS-C9_Rx and ION541), a medicine for multiple system atrophy (ION464) and a medicine for an undisclosed target. In the fourth quarter of 2018, Biogen exercised its option to license our most advanced ALS medicine, tofersen, our medicine in Phase 3 development for SOD1 ALS. As a result, Biogen is now responsible for global development, regulatory and commercialization activities and costs for tofersen.

Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone payments, license fees and royalty payments for all medicines developed under this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen. For each antisense molecule that is chosen for drug discovery and development under this collaboration, we are eligible to receive up to approximately $260 million in a license fee and milestone payments per program. The $260 million per program consists of approximately $60 million in development milestones, including amounts related to the cost of clinical trials, and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any antisense medicines developed under this collaboration. From inception through December 2020, we have received over $270 million in upfront fees, milestone payments and other payments under this collaboration. We will achieve the next payment of up to $10 million if we advance a program under this collaboration.

At the commencement of our 2013 strategic neurology collaboration, we identified one performance obligation, which was to perform R&D services for Biogen. At inception, we determined the transaction price to be the $100 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&D services, we include these amounts in our transaction price for our R&D services performance obligation. We recognized revenue for our R&D services performance obligation based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. In the third quarter of 2019, we updated our estimate of the total effort we expect to expend to satisfy our performance obligation. As a result, we recorded a cumulative catch up adjustment of $16.5 million to decrease revenue in the third quarter of 2019. During 2020, we completed our remaining research and development services and recognized the remaining revenue related to this performance obligation. From inception through the completion of our R&D services performance obligation in 2020, we included $145 million in total payments in the transaction price for our R&D services performance obligation.

Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because we did not have any performance obligations for the respective payment. The following are the payments we earned:

●

In the third quarter of 2018, we earned a $10 million milestone payment when Biogen initiated a Phase 1 study of IONIS-C9_Rx.

●

In the fourth quarter of 2018, we earned a $35 million license fee when Biogen licensed tofersen from us because Biogen had full use of the licenses without any continuing involvement from us.

●

In the fourth quarter of 2018, we earned a $5 million milestone when Biogen initiated a Proof-of-Concept study for tofersen.

●

In the third quarter of 2019, we earned an $8 million milestone payment when Biogen initiated a Phase 1/2 study of ION859 for the treatment of people with Parkinson’s disease under this collaboration.

●

In the fourth quarter of 2019, we earned a $10 million milestone payment when Biogen advanced IONIS-C9_Rx.

●

In the third quarter of 2020, we earned $18 million in milestone payments when Biogen initiated a Phase 1/2 trial for ION464, an investigational medicine in development targeting alpha-synuclein to treat patients with multiple system atrophy.

●

In the third quarter of 2020, we earned a $10 million milestone payment when Biogen initiated a Phase 1/2 trial for ION541, an investigational medicine in development targeting ataxin 2 to treat patients with ALS.

2012 Neurology

In December 2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense medicines to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the programs through the completion of the first Phase 2 study for each program. Under this collaboration, we are currently advancing IONIS-MAPT_Rx for Alzheimer’s disease and ION582 for Angelman syndrome. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. In the fourth quarter of 2019, Biogen exercised its option to license IONIS-MAPT_Rx. We are responsible for completing the Phase 1/2 in study patients with mild AD and a one-year long-term extension study. Biogen will have responsibility for global development, regulatory and commercialization activities and costs for IONIS-MAPT_Rx.

Under the terms of the agreement, we received an upfront payment of $30 million. Over the term of the collaboration, we are eligible to receive up to $210 million in a license fee and milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. The $210 million per program consists of up to $10 million in development milestone payments, plus a mark-up on the cost estimate of the Phase 1 and 2 studies and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales of any medicines resulting from each of the three programs. From inception through December 2020, we have received $154 million in payments under this collaboration, including $19.5 million we received from Biogen for achieving milestones for advancing IONIS-MAPT_Rxduring 2020. We will achieve the next payment of $25 million if we continue to advance IONIS-MAPT_Rx.

Under our collaboration, we determined we had a performance obligation to perform R&D services. We allocated $40 million in total payments to the transaction price for our R&D services performance obligation. In the third quarter of 2019, we completed our R&D services performance obligation when we designated a development candidate and Biogen accepted the development candidate. Biogen’s decision to accept the development candidate was not within our control. We were recognizing revenue as we performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance obligation. Because Biogen accepted the development candidate earlier than when we were previously estimating, we recognized $6.3 million of accelerated revenue in the third quarter of 2019.

When we commenced development for IONIS-MAPT_Rx we identified our development work as a separate performance obligation. We are recognizing our IONIS-MAPT_Rx development performance obligation based on the percentage of completion. From inception through December 2020, we have included $57 million in the transaction price for our IONIS-MAPT_Rx development performance obligation. We currently estimate we will satisfy our performance obligation in 2022. Our total transaction price for our IONIS-MAPT_Rxdevelopment performance obligation includes the following payments we achieved in 2019 and 2020 related to our development work:

●

In the second quarter of 2019, we achieved a $7.5 million milestone payment from Biogen when we advanced IONIS-MAPT_Rx.

●

In the fourth quarter of 2019, we achieved a $12 million milestone payment from Biogen when we entered into an agreement to conduct a long-term extension study for IONIS-MAPT_Rx.

●

In the first quarter of 2020, we achieved a $7.5 million milestone payment from Biogen when we advanced IONIS-MAPT_Rx.

●

In the third quarter of 2020, we achieved a $12 million milestone payment from Biogen when we advanced IONIS-MAPT_Rx in the long-term extension study for IONIS-MAPT_Rx.

In the fourth quarter of 2019, we identified another performance obligation upon Biogen’s license of IONIS-MAPT_Rx because the license we granted to Biogen is distinct from our other performance obligations. We recognized the $45 million license fee for IONIS-MAPT_Rx as revenue at that time because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen.

In the fourth quarter of 2019, we earned a $10 million milestone payment when Biogen advanced ION582. We recognized this milestone payment in full in the fourth quarter of 2019 because we did not have any performance obligations related to this milestone payment.

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
SPINRAZA royalties (commercial revenue)	$	286.6		$	293.0		$	237.9
R&D revenue		122.0			180.6			137.1
Total revenue from our relationship with Biogen	$	408.6		$	473.6		$	375.0
Percentage of total revenue		56	%		42	%		63	%

Our consolidated balance sheet at December 31, 2020 and 2019 included deferred revenue of $465.8 million and $525.8 million, respectively, related to our relationship with Biogen.

Research, Development and Commercialization Partners

AstraZeneca

We have two collaborations with AstraZeneca, one focused on the treatment of cardiovascular, renal and metabolic diseases and a second focused on the treatment of oncology diseases. We and AstraZeneca are currently developing several investigational medicines under these collaborations, including medicines in development to treat people with cardiovascular disease, a genetically associated form of kidney disease, nonalcoholic steatohepatitis, or NASH, and cancer. From inception through December 2020, we have received more than $380 million from our AstraZeneca collaborations.

Cardiovascular, Renal and Metabolic Diseases Collaboration

In July 2015, we and AstraZeneca formed a collaboration to discover and develop antisense therapies for treating cardiovascular, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed four medicines from us:

●

ION449 (formerly IONIS-AZ4-2.5-L_Rx), an investigational medicine we designed to reduce the liver production of PCSK9 and lower the plasma level of LDL-C and thus reduce the risk of cardiovascular disease;

●

ION532, an investigational medicine we designed to reduce the production of APOL1 for the treatment of APOL1-associated chronic kidney disease;

●

ION839, an investigational medicine we designed to inhibit the production of PNPLA3 protein, a major genetic determinant of NASH progression; and

●

ION455, an investigational medicine we designed as a potential treatment for NASH.

AstraZeneca is responsible for global development, regulatory and commercialization activities and costs for each of the medicines it has licensed and any medicines AstraZeneca licenses in the future.

Under the terms of the agreement, we received a $65 million upfront payment. We are eligible to receive license fees and milestone payments of up to more than $5.5 billion as medicines under this collaboration advance, including up to $1.1 billion for the achievement of development milestones, up to $2.9 billion for regulatory milestones and up to $1.5 billion for commercial milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. We will achieve the next payment of up to $30 million under this collaboration if AstraZeneca advances a medicine under this collaboration. From inception through December 2020, we have received over $235 million in upfront fees, license fees, milestone payments, and other payments under this collaboration, including $30 million we earned in 2020 when AstraZeneca licensed ION455 and $30 million in milestone payments we earned in 2020 when AstraZeneca advanced ION532 and ION449 in development.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for AstraZeneca. We determined the transaction price to be the $65 million upfront payment we received and we allocated it to our single performance obligation. We are recognizing revenue for our R&D services performance obligation as we perform services based on our effort to satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy this performance obligation in the third quarter of 2021. As we achieve milestone payments for our R&D services, we include these amounts in our transaction price for our R&D services performance obligation. From inception through December 2020, we have included $90 million in payments in the transaction price for our R&D services performance obligation.

Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. The following are the payments we have earned:

●

In the first quarter of 2018, we earned two $30 million license fees when AstraZeneca licensed ION532 and ION839 because AstraZeneca had full use of the licenses without any continuing involvement from us.

●

In the third quarter of 2018, we earned a $10 million milestone payment when AstraZeneca initiated a Phase 1 study of ION449.

●

In the fourth quarter of 2019, we earned a $10 million milestone payment when AstraZeneca initiated a Phase 1 study of ION839.

●

In the first quarter of 2020, we earned a $10 million milestone payment when AstraZeneca advanced ION532.

●

In the fourth quarter of 2020, we earned a $20 million milestone payment when AstraZeneca advanced ION449.

●

In the fourth quarter of 2020, we earned a $30 million license fee when AstraZeneca licensed ION455 because AstraZeneca had full use of the license without any continuing involvement from us.

Oncology Collaboration

In December 2012, we entered into a collaboration agreement with AstraZeneca to discover and develop antisense medicines to treat cancer. We and AstraZeneca also established an oncology research program. AstraZeneca has the option to license medicines resulting from the program, and if AstraZeneca exercises its option to license a medicine, it will be responsible for global development, regulatory and commercialization activities and costs for such medicine. In 2020, AstraZeneca licensed ION736, an investigational medicine in development targeting FOXP3 for the treatment of cancer.

Under the terms of this agreement, we received $31 million in upfront payments. We are eligible to receive milestone payments and license fees up to more than $265 million under this collaboration, including up to $107 million for the achievement of development milestones and up to $105 million for the achievement of regulatory milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. From inception through December 2020, we have received over $140 million in upfront fees, milestone payments, and other payments under this oncology collaboration, including $13 million we earned when AstraZeneca licensed ION736 in 2020. We will achieve the next payment of $12 million if AstraZeneca advances ION736 in development.

We completed all of the performance obligations we identified under this collaboration in the first quarter of 2018.

Under this collaboration, we have also generated additional payments that we concluded were not part of other performance obligations discussed above. We recognized each of these payments in full in the respective quarter we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. The following are the payments we have earned:

●

In the fourth quarter of 2018, we earned a $17.5 million milestone payment and a $10 million milestone payment when AstraZeneca advanced two programs under our collaboration.

●

In the second quarter of 2020, we earned a $13 million license fee when AstraZeneca licensed ION736 because AstraZeneca had full use of the license without any continuing involvement from us.

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	88.0		$	28.1		$	120.7
Percentage of total revenue		12	%		3	%		20	%

Our consolidated balance sheet at December 31, 2020 and 2019 included deferred revenue of $10.0 million and $25.0 million, respectively, related to our relationship with AstraZeneca.

Bayer

In May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI_Rx for the prevention of thrombosis. We were responsible for completing a Phase 2 study of IONIS-FXI_Rx in people with end-stage renal disease on hemodialysis. Under the terms of the agreement, we received a $100 million upfront payment in the second quarter of 2015. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI_Rx and to initiate development of IONIS-FXI-L_Rx, which Bayer licensed. In conjunction with the decision to advance these programs, we received a $75 million payment from Bayer. In October 2019, Bayer decided it would advance IONIS-FXI-L_Rx following positive clinical results. Bayer is now responsible for all global development, regulatory and commercialization activities and costs for the FXI program.

We are eligible to receive up to $385 million in license fees, milestone payments and other payments, including up to $125 million for the achievement of development milestones and up to $110 million for the achievement of commercialization milestones. In addition, we are eligible to receive tiered royalties in the low to high 20 percent range on gross margins of both medicines combined. From inception through December 2020, we have received over $185 million from this collaboration. We will achieve the next payment of $20 million if Bayer initiates a Phase 3 study for the FXI program.

At the commencement of this collaboration, we identified three performance obligations, the license of IONIS-FXI_Rx, R&D services and delivery of API, all of which we completed in 2016.

In February 2017, when we amended our collaboration with Bayer, we identified two new performance obligations, one for the license of IONIS-FXI-L_Rx and one for R&D services. We determined the transaction price to be the $75 million payment. We allocated $64.9 million to the license of IONIS-FXI-L_Rx based on its estimated relative stand-alone selling price and recognized the associated revenue upon our delivery of the license in the first quarter of 2017. We allocated $10.1 million to our R&D services performance obligation based on an estimated relative stand-alone selling price. We recognized revenue for our R&D services performance obligation as we performed services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We completed our obligation in the third quarter of 2019.

In the fourth quarter of 2019, we earned a $10 million milestone payment when Bayer decided it would advance IONIS-FXI-L_Rx. We recognized this milestone payment in full in the fourth quarter of 2019 because we did not have any performance obligations related to this milestone payment.

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	3.2		$	14.3		$	5.0
Percentage of total revenue		0	%		1	%		1	%

Our consolidated balance sheet at December 31, 2020 did not include any deferred revenue related to our relationship with Bayer. Our consolidated balance sheet at December 31, 2019 included deferred revenue of $2.4 million related to our relationship with Bayer.

GSK

In March 2010, we entered into an alliance with GSK using our antisense drug discovery platform to discover and develop new medicines against targets for serious and rare diseases, including infectious diseases and some conditions causing blindness. Under the terms of the agreement, we received upfront payments of $35 million. Our collaboration with GSK currently includes two medicines targeting hepatitis B virus, or HBV: IONIS-HBV_Rx and IONIS-HBV-L_Rx. We designed these medicines to reduce the production of viral proteins associated with HBV infection. In the third quarter of 2019, following positive Phase 2 results, GSK licensed our HBV program. GSK is responsible for all global development, regulatory and commercialization activities and costs for the HBV program.

Under our agreement, if GSK successfully develops these medicines and achieves pre-agreed sales targets, we could receive license fees and milestone payments of up to $262 million, including up to $47.5 million for the achievement of development milestones, up to $120 million for the achievement of regulatory milestones and up to $70 million for the achievement of commercialization milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product that GSK successfully commercializes under this alliance. From inception through December 2020, we have received more than $190 million in payments under this alliance with GSK. We will achieve the next payment of $15 million if GSK initiates a Phase 3 study of a medicine under this program.

We completed our R&D services performance obligations under our collaboration in the first quarter of 2015. We identified a new performance obligation when we granted GSK the license of the HBV program and assigned related intellectual property rights in the third quarter of 2019 because the license was distinct from our other performance obligations. We recognized the $25 million license fee for the HBV program as revenue at that time because GSK had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to GSK.

We do not have any remaining performance obligations under our collaboration with GSK; however, we can still earn additional payments and royalties as GSK advances the HBV program.

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	0.2		$	25.4		$	1.6
Percentage of total revenue		0	%		2	%		0	%

We did not have any deferred revenue from our relationship with GSK at December 31, 2020 and 2019.

Janssen Biotech, Inc.

In December 2014, we entered into a collaboration agreement with Janssen Biotech, Inc. to discover and develop antisense medicines that can be locally administered, including oral delivery, to treat autoimmune disorders of the GI tract. Under our collaboration, Janssen is currently advancing ION253 for the treatment of immune-mediated GI disease. Janssen licensed ION253 in the fourth quarter of 2017. Prior to Janssen’s license of ION253, we were responsible for the discovery activities to identify development candidates. Under the agreement, Janssen is responsible for global development, regulatory and commercialization activities and costs for ION253.

Under the terms of the agreement, we received $35 million in upfront payments. We are eligible to receive up to more than $285 million in license fees and milestone payments for these programs, including up to $65 million for the achievement of development milestones, up to $160 million for the achievement of regulatory milestones and up to $60 million for the achievement of commercialization milestones. From inception through December 2020, we have received over $80 million from this collaboration. In addition, we are eligible to receive tiered royalties up to the near teens on net sales from any medicines resulting from this collaboration. We will achieve the next payment of $5 million if Janssen continues to advance ION253 in development.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Janssen. We determined the transaction price to be the $35 million upfront payments we received. We allocated the $35 million to our single performance obligation. As we achieved milestone payments for our R&D services, we included these amounts in our transaction price for our R&D services performance obligation. We recognized revenue for our R&D services performance obligation over our period of performance, which ended in the fourth quarter of 2017.

Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services performance obligation. We recognized each of these payments in full in the respective quarter in which we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. In the third quarter of 2020, we earned a $5 million milestone payment when Janssen initiated a Phase 1 trial for ION253.

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with Janssen (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	5.0		$	0.1		$	6.6
Percentage of total revenue		1	%		0	%		1	%

We did not have any deferred revenue from our relationship with Janssen at December 31, 2020 and 2019.

Novartis

In January 2017, we initiated a collaboration with Novartis to develop and commercialize pelacarsen and IONIS-APOCIII-L_Rx.We received a $75 million upfront payment in the first quarter of 2017. In the first quarter of 2019, Novartis licensed pelacarsen and we earned a $150 million license fee. Novartis is responsible for conducting and funding future development and regulatory activities for pelacarsen, including a global Phase 3 cardiovascular outcomes study that Novartis initiated in the fourth quarter 2019. In connection with Novartis’ license of pelacarsen, we and Novartis established a more definitive framework under which the companies would negotiate the co-commercialization of pelacarsen in selected markets. Included in this framework is an option by which Novartis could solely commercialize pelacarsen in exchange for Novartis paying us increased sales milestone payments based on sales of pelacarsen. When Novartis decided to not exercise its option for IONIS-APOCIII-L_Rx, we retained rights to develop and commercialize IONIS-APOCIII-L_Rx.

Under the collaboration, we are eligible to receive up to $675 million in milestone payments, including $25 million for the achievement of a development milestone, up to $290 million for the achievement of regulatory milestones and up to $360 million for the achievement of commercialization milestones. From inception through December 2020, we have received $249 million in upfront payments, milestone payments, license fees and other payments from this collaboration. We are also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of pelacarsen. We will achieve the next payment of $25 million if Novartis advances pelacarsen.

In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6 million shares of our common stock for $100 million in the first quarter of 2017. As part of the SPA, Novartis was required to purchase $50 million of Akcea’s common stock at Akcea’s IPO price or our common stock at a premium if an IPO did not occur by April 2018. Under the SPA, in the second quarter of 2017, Novartis purchased $50 million of Akcea’s common stock in a separate private placement concurrent with the completion of Akcea’s IPO at a price per share equal to the IPO price.

At the commencement of this collaboration, we identified four separate performance obligations:

●

R&D services for pelacarsen;

●

R&D services for IONIS-APOCIII-L_Rx;

●

API for pelacarsen; and

●

API for IONIS-APOCIII-L_Rx.

We determined that the R&D services for each medicine and the API for each medicine were distinct performance obligations.

We determined our transaction price to be $108.4 million, comprised of the following:

●

$75 million from the upfront payment;

●

$28.4 million for the premium paid by Novartis for its purchase of our common stock at a premium in the first quarter of 2017; and

●

$5.0 million for the potential premium Novartis would have paid if they purchased our common stock in the future.

We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows:

●

$64.0 million for the R&D services for pelacarsen;

●

$40.1 million for the R&D services for IONIS-APOCIII-L_Rx;

●

$1.5 million for the delivery of pelacarsen API; and

●

$2.8 million for the delivery of IONIS-APOCIII-L_Rx API.

We recognized revenue related to each of the performance obligations as follows:

●

We completed our R&D services performance obligation for pelacarsenin second quarter of 2019. As such, we recognized all revenue we allocated to the pelacarsenR&D services as of the end of the second quarter of 2019;

●

We completed our R&D services performance obligation for IONIS-APOCIII-L_Rx in the fourth quarter of 2019 because Novartis elected to terminate the strategic collaboration for IONIS-APOCIII-L_Rx during the period. As a result, we were not required to provide any further R&D services, as such, we recognized all revenue allocated to the IONIS-APOCIII-L_Rx R&D services as of the end of the fourth quarter of 2019;

●

We recognized the amount attributed to pelacarsen API when we delivered it to Novartis in 2017; and

●

We recognized the amount attributed to IONIS-APOCIII-L_Rx API when we delivered it to Novartis in the second quarter of 2018.

We recognized revenue related to the R&D services for pelacarsen and IONIS-APOCIII-L_Rx performance obligations as we performed services based on our effort to satisfy our performance obligations relative to our total effort expected to satisfy our performance obligations.

During the years ended December 31, 2020 and 2019, we earned the following revenue from our relationship with Novartis (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	1.0		$	187.4		$	50.6
Percentage of total revenue		0	%		17	%		8	%

We did not have any deferred revenue from our relationship with Novartis at December 31, 2020 and 2019.

Pfizer

In October 2019, we entered into a license agreement with Pfizer for vupanorsen, an investigational medicine in development to treat people with certain cardiovascular diseases. We completed a Phase 2 study of vupanorsen in patients with elevated levels of triglycerides, or hypertriglyceridemia, type 2 diabetes and NAFLD. Pfizer is responsible for all global development, regulatory and commercialization activities and costs for vupanorsen, subject to our right to co-commercialize in the U.S. and certain additional markets.

Under the terms of the agreement, we received a $250 million upfront payment. We are also eligible to receive development, regulatory and sales milestone payments of up to $1.3 billion, including up to $205 million for the achievement of development milestones, up to $250 million for the achievement of regulatory milestones and up to $850 million for the achievement of commercialization milestones. From inception through December 2020, we have received over $330 million, including a $75 million milestone payment we earned in the fourth quarter of 2020 when Pfizer began the Phase 2b study of vupanorsen. We are also eligible to earn tiered royalties in the mid-teens to low 20 percent range on annual worldwide net sales. Prior to regulatory filing for marketing approval, we have the right, at our option to participate in certain commercialization activities with Pfizer in the U.S. and certain additional markets on pre-defined terms and based on meeting pre-defined criteria. We will achieve the next payment of $50 million if Pfizer advances vupanorsen.

At the commencement of the license agreement, we identified three separate performance obligations:

●

License of vupanorsen;

●

R&D services for vupanorsen; and

●

API for vupanorsen.

We determined the transaction price to be $250 million, the upfront payment we received. We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows:

●

$245.6 million for the license of vupanorsen;

●

$2.2 million for the R&D services for vupanorsen; and

●

$2.2 million for the delivery of vupanorsen API.

We are recognizing revenue related to each of our performance obligations as follows:

●

We recognized $245.6 million for the license of vupanorsen in the fourth quarter of 2019 because we determined the license we granted to Pfizer was distinct from our other performance obligations and Pfizer had full use of the license without any continuing involvement from us.

●

We recognized revenue related to the R&D services for vupanorsen as we performed services based on our effort to satisfy our performance obligation relative to our total effort to satisfy our performance obligation. We completed our R&D services in mid-2020.

●

We recognized the amount attributed to the API supply for vupanorsen when we delivered it to Pfizer in the fourth quarter of 2019.

In the fourth quarter of 2020, we earned a $75 million milestone payment when Pfizer began the Phase 2b study of vupanorsen. We recognized this milestone payment in full in the fourth quarter of 2020 because we did not have any performance obligations related to this milestone payment.

During the years ended December 31, 2020 and 2019, we earned the following revenue from our relationship with Pfizer (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019
R&D revenue	$	82.1		$	248.7
Percentage of total revenue		11	%		22	%

We did not have any deferred revenue from our relationship with Pfizer at December 31, 2020. Our consolidated balance sheet at December 31, 2019 included deferred revenue of $1.3 million related to our relationship with Pfizer.

PTC Therapeutics

In August 2018, we entered into an exclusive license agreement with PTC Therapeutics to commercialize TEGSEDI and WAYLIVRA in Latin America and certain Caribbean countries. Under the license agreement, we are eligible to receive up to $26 million in payments. From inception through December 2020, we have received $22 million from PTC. We are eligible to receive royalties from PTC in the mid-20 percent range on net sales in Latin America for each medicine. PTC’s obligation to pay us royalties begins on the earlier of 12 months after the first commercial sale of a product in Brazil or the date that PTC recognizes revenue of at least $10 million in Latin America.

In the third quarter of 2018 at the commencement of this collaboration, we identified two performance obligations, which were the licenses we granted to PTC to commercialize TEGSEDI and WAYLIVRA in Latin America and certain Caribbean countries. We recognized $12 million in license fee revenue at that time because PTC had full use of both licenses without any continuing involvement from us. We do not have any remaining performance obligations under our collaboration with PTC. We can still earn additional payments and royalties as PTC commercializes TEGSEDI and WAYLIVRA.

Under this collaboration, we have also generated milestone payments that we concluded were not part of the performance obligations discussed above. We recognized each of these milestone payments in full in the respective quarter in which we achieved the milestone payment because the payments were distinct and we did not have any performance obligations for the respective payment. The following are the payments we have earned:

●

In the second quarter of 2019, we earned a $6 million payment when WAYLIVRA was approved by the EMA.

●

In the fourth quarter of 2019, we earned $4 million when TEGSEDI was approved in Brazil.

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with PTC (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
Licensing and other royalty revenue (commercial revenue)	$	1.6		$	10.2		$	12.0
Percentage of total revenue		0	%		1	%		2	%

Our consolidated balance sheet at December 31, 2020 and 2019 did not include any deferred revenue related to our relationship with PTC.

Roche

Huntington’s Disease

In April 2013, we formed an alliance with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, to develop treatments for HD based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational medicine targeting HTT protein in Phase 3 development. We developed tominersen through completion of our Phase 1/2 clinical study in people with early stage HD. In the fourth quarter of 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersen. Roche is responsible for all global development, regulatory and commercialization activities and costs for tominersen.

Under the terms of the agreement, we received an upfront payment of $30 million in April 2013 and an additional $3 million payment in 2017. We are eligible to receive up to $365 million in a license fee and milestone payments including up to $70 million for the achievement of development milestones, up to $170 million for the achievement of regulatory milestones and up to $80 million for the achievement of commercialization milestones. In addition, we are eligible to receive up to $136.5 million in milestone payments for each additional medicine successfully developed. We are also eligible to receive tiered royalties up to the mid-teens on any net sales of any product resulting from this alliance. From inception through December 2020, we have received $150 million in upfront fees, milestone payments and license fees under this collaboration. We will achieve the next payment of $15 million if Roche advances tominersen.

Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services performance obligation. We recognized each of these payments in full in the respective quarter in which we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. The following are the payments we have earned:

●

In the fourth quarter of 2017, we earned a $45 million license fee when Roche licensed tominersen because Roche had full use of the license without any continuing involvement from us.

●

In the first quarter of 2019, we earned $35 million in milestone payments when Roche dosed the first patient in the Phase 3 study of tominersen in the first quarter of 2019.

We do not have any remaining performance obligations related to tominersen under this collaboration with Roche; however, we can still earn additional payments and royalties as Roche advances tominersen.

IONIS-FB-L_Rx for Complement-Mediated Diseases

In October 2018, we entered into a collaboration agreement with Roche to develop IONIS-FB-L_Rx for the treatment of complement-mediated diseases. We are currently conducting Phase 2 studies in two disease indications for IONIS-FB-L_Rx, one for the treatment of patients with GA, the advanced stage of dry AMD, and a second for the treatment of patients with IgA nephropathy. Roche has the option to license IONIS-FB-L_Rx at the completion of these studies. Upon licensing, Roche will be responsible for global development, regulatory and commercialization activities and costs.

Under the terms of this agreement, we received a $75 million upfront payment in the fourth quarter of 2018. We are eligible to receive up to $684 million in development, regulatory and sales milestone payments and license fees. In addition, we are also eligible to receive tiered royalties from the high teens to 20 percent on net sales. We will achieve the next payment of $20 million if we advance the Phase 2 study in patients with dry AMD.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Roche. We determined the transaction price to be the $75 million upfront payment we received and allocated it to our single performance obligation. We are recognizing revenue for our R&D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. During the fourth quarter of 2020, we updated our estimate of the total effort we expected to expend to satisfy our performance obligation under this collaboration. In the fourth quarter of 2020, we recorded a cumulative catch up adjustment of $9.2 million to decrease revenue because we updated our total cost estimate to complete the Phase 2 study of IONIS-FB-L_Rxfor the treatment of patients with GA. We currently estimate we will satisfy our performance obligation in the fourth quarter of 2023.

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	5.9		$	57.0		$	8.3
Percentage of total revenue		1	%		5	%		1	%

Our consolidated balance sheet at December 31, 2020 and 2019 included deferred revenue of $47.2 million and $52.3 million related to our relationship with Roche, respectively.

Other Agreement

Alnylam Pharmaceuticals, Inc.

Under the terms of our agreement with Alnylam, we exclusively licensed to Alnylam our patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics in exchange for a technology access fee, participation in fees from Alnylam’s partnering programs, as well as future milestone and royalty payments from Alnylam. We retained rights to a limited number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively licensed to us its patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry to research, develop and commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We also received a license to develop and commercialize double-stranded RNAi medicines targeting a limited number of therapeutic targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual property. Under this alliance, we and Alnylam each obtained exclusive license rights to four therapeutic programs. Alnylam granted us an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four targets, including FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four other targets. Alnylam also granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics.

In the fourth quarter 2020, we completed an arbitration process with Alnylam. The arbitration panel awarded us $41.2 million for payments owed to us by Alnylam related to Alnylam’s agreement with Sanofi Genzyme. We recognized the $41.2 million payment from Alnylam as revenue in the fourth quarter of 2020 because we did not have any performance obligations for the respective payment.

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	47.9		$	24.1		$	2.0
Percentage of total revenue		7	%		2	%		—

Our consolidated balance sheet at December 31, 2020 and 2019 did not include any deferred revenue related to our relationship with Alnylam.

Akcea Acquisition

12 Months Ended

Dec. 31, 2020

Akcea Acquisition [Abstract]

Akcea Acquisition

7. Akcea Acquisition

Purchase Price and Direct Transaction Costs Accounting for the Akcea Acquisition

In October 2020, we acquired the shares of Akcea’s common stock we did not own, increasing our ownership from 76 percent to 100 percent. Under the purchase agreement, we purchased 24.8 million shares at $18.15 per share, resulting in a total purchase price of $450.6 million.

To reflect our 100 percent ownership, we accounted for the increase in our ownership by eliminating the noncontrolling interest adjustment in stockholders’ equity in accordance with the Consolidation accounting guidance (ASC Topic 810). We recognized the difference between the purchase price and the adjustment to noncontrolling interest in stockholders’ equity as additional-paid-in capital. Refer to our Statement of Stockholders’ Equity for detailed amounts.

We accounted for the transaction costs related to the Akcea Acquisition as a direct charge to stockholders’ equity. We incurred $40.6 million of direct transaction costs from the Akcea Acquisition, primarily comprised of banking and legal fees.

Equity Award Payouts related to the Akcea Acquisition

In October 2020, as part of the Akcea Acquisition, Ionis cancelled all of Akcea’s equity awards. In exchange for the cancelled awards, if eligible under the terms of the Acquisition, we paid holder’s a cash payment. We paid $18.15 for each outstanding RSU. For each outstanding option with an exercise price less than $18.15, we paid $18.15 less the exercise price. As a result, we paid out $53.4 million in the fourth quarter of 2020 related to Akcea’s cancelled equity awards. We accounted for these payments as part of the transaction costs recorded to stockholders’ equity in the fourth quarter of 2020. Because we did not replace the Akcea awards, we recognized all unrecognized non-cash stock-based compensation ($59.3 million) under Akcea’s Plan in our statement of operations in the post-acquisition period in the fourth quarter of 2020.

Severance and Retention Costs related to the Akcea Acquisition

As a result of the Akcea Acquisition, we expect to incur severance expenses of up to $9.3 million and retention expenses of up to $19.2 million. During the fourth quarter of 2020, we recorded $15.3 million of severance and retention related costs in operating expenses. We will recognize the remaining severance and retention costs through October 2021.

The following table summarizes the costs by category related to the Akcea Acquisition (in millions):

	Three Months Ended December 31, 2020
R&D expenses	$	3.9
SG&A expenses		11.4
Total	$	15.3

The following table summarizes the severance and retention reserve included in accrued compensation for the period indicated related to Akcea Acquisition (in millions):

	Three Months Ended December 31, 2020
Severance & retention reserve beginning balance	$	—
Severance & retention expensed during period		15.3
Amounts paid during the period		(0.6	)
Severance & retention reserve ending balance	$	14.7

Severance and Retention Costs related to our Restructured European Operations

12 Months Ended

Dec. 31, 2020

Severance and Retention Costs related to our Restructured European Operations

Severance and Retention Costs related to our Restructured European Operations

8. Severance and Retention Costs related to our Restructured European Operations

In the fourth quarter of 2020, we entered into a distribution agreement with Sobi to commercialize TEGSEDI and WAYLIVRA in Europe. Under the distribution agreement, Sobi took over all material distribution operations at the end of January 2021. We remain the marketing authorization holder for TEGSEDI and WAYLIVRA in Europe. We will continue to maintain limited European operations including regulatory, manufacturing, and the management of relationships with key opinion leaders. We will also continue to lead the TEGSEDI and WAYLIVRA global commercial strategy.

As a result of this change, we expect to incur up to $14.8 million of severance and retention expenses. During the fourth quarter of 2020, we recorded $12.5 million of severance and retention related costs in operating expenses related to this agreement. We will recognize the remaining expenses through October 2021, of which we will recognize the majority of the remaining expenses in the first quarter of 2021.

The following table summarizes the costs by category related to our restructured European operations (in millions):

	Three Months Ended December 31, 2020
R&D expenses	$	4.2
SG&A expenses		8.3
Total	$	12.5

The following table summarizes the severance and retention reserve included in accrued compensation for the periods indicated related to our restructured European operations (in millions):

	Three Months Ended December 31, 2020
Severance & retention reserve beginning balance	$	—
Severance & retention expensed during period		12.5
Amounts paid during the period		(0.1	)
Severance & retention reserve ending balance	$	12.4

Segment Information and Concentration of Business Risk

12 Months Ended

Dec. 31, 2020

Segment Information and Concentration of Business Risk [Abstract]

Segment Information and Concentration of Business Risk

9. Segment Information and Concentration of Business Risk

Through 2020, we had two reportable segments, our Ionis Core segment and Akcea Therapeutics. We have provided segment financial information and results for our Ionis Core segment and our Akcea Therapeutics segment based on the segregation of revenues and expenses that our chief decision maker reviewed to assess operating performance and to make operating decisions through 2020. Segment income (loss) from operations includes revenue less operating expenses attributable to each segment.

In our Ionis Core segment, we are exploiting our antisense technology to generate a broad pipeline of first-in-class and/or best-in-class medicines for us and our partners. Our Ionis Core segment generates revenue from a multifaceted partnering strategy.

Akcea was focused on developing and commercializing medicines to treat patients with serious and rare diseases. Akcea generated revenue from TEGSEDI and WAYLIVRA product sales and from its collaborations.

The following tables show our segment revenue and income (loss) from operations for 2020, 2019 and 2018 (in thousands), respectively.

2020	Ionis Core		Akcea Therapeutics			Elimination of Intercompany Activity			Total
Revenue:
Commercial revenue:
SPINRAZA royalties	$	286,583	$	—		$	—		$	286,583
Product sales, net		—		69,999			—			69,999
Licensing and other royalty revenue		11,334		—			(3,217	)		8,117
Total commercial revenue		297,917		69,999			(3,217	)		364,699
R&D revenue under collaborative agreements		325,024		82,321			(42,780	)		364,565
Total segment revenue	$	622,941	$	152,320		$	(45,997	)	$	729,264
Total operating expenses	$	563,647	$	389,575		$	(51,876	)	$	901,346
Income (loss) from operations	$	59,294	$	(237,255	)	$	5,879		$	(172,082	)

2019	Ionis Core		Akcea Therapeutics		Elimination of Intercompany Activity			Total
Revenue:
Commercial revenue:
SPINRAZA royalties	$	292,992	$	—	$	—		$	292,992
Product sales, net		—		42,253		—			42,253
Licensing and other royalty revenue		12,616		10,172		(5,583	)		17,205
Total commercial revenue		305,608		52,425		(5,583	)		352,450
R&D revenue under collaborative agreements		553,038		436,118		(219,007	)		770,149
Total segment revenue	$	858,646	$	488,543	$	(224,590	)	$	1,122,599
Total operating expenses	$	523,207	$	450,469	$	(216,960	)	$	756,716
Income (loss) from operations	$	335,439	$	38,074	$	(7,630	)	$	365,883

2018	Ionis Core		Akcea Therapeutics			Elimination of Intercompany Activity			Total
Revenue:
Commercial revenue:
SPINRAZA royalties	$	237,930	$	—		$	—		$	237,930
Product sales, net		—		2,237			—			2,237
Licensing and other royalty revenue		2,755		12,000			—			14,755
Total commercial revenue		240,685		14,237			—			254,922
R&D revenue under collaborative agreements		401,259		50,630			(107,137	)		344,752
Total segment revenue	$	641,944	$	64,867		$	(107,137	)	$	599,674
Total operating expenses	$	380,212	$	295,683		$	(14,849	)	$	661,046
Income (loss) from operations	$	261,732	$	(230,816	)	$	(92,288	)	$	(61,372	)

The following table shows our total assets by segment at December 31, 2020 and 2019 (in thousands), respectively.

Total Assets	Ionis Core		Akcea Therapeutics		Elimination of Intercompany Activity			Total
December 31, 2020	$	2,792,222	$	435,824	$	(838,291	)	$	2,389,755
December 31, 2019	$	3,478,081	$	599,250	$	(844,219	)	$	3,233,112

Contracts receivables at December 31, 2020 was comprised of approximately 99.5percent from two significant partners. Contracts receivables at December 31, 2019 was comprised of approximately 75 percent from one significant partner.

- Definition

The entire disclosure for reporting segments including data and tables. Reportable segments include those that meet any of the following quantitative thresholds a) it's reported revenue, including sales to external customers and intersegment sales or transfers is 10 percent or more of the combined revenue, internal and external, of all operating segments b) the absolute amount of its reported profit or loss is 10 percent or more of the greater, in absolute amount of 1) the combined reported profit of all operating segments that did not report a loss or 2) the combined reported loss of all operating segments that did report a loss c) its assets are 10 percent or more of the combined assets of all operating segments.

+ References

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+ Details

Employment Benefits	12 Months Ended
Employment Benefits	Dec. 31, 2020
Employment Benefits [Abstract]
Employment Benefits	10. Employment Benefits We have employee 401(k) salary deferral plans covering all employees. Employees could make contributions by withholding a percentage of their salary up to the IRS annual limits of $19,500 and $26,000 in 2020 for employees under 50 years old and employees 50 years old or over, respectively. We made approximately $5.7 million, $6.4 million and $5.7 million in matching contributions for the years ended December 31, 2020, 2019 and 2018, respectively.

- Definition

The entire disclosure for retirement benefits.

+ References

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+ Details

Legal Proceedings	12 Months Ended
Legal Proceedings	Dec. 31, 2020
Legal Proceedings [Abstract]
Legal Proceedings	11. Legal Proceedings From time to time, we are involved in legal proceedings arising in the ordinary course of our business. Periodically, we evaluate the status of each legal matter and assess our potential financial exposure. If the potential loss from any legal proceeding is considered probable and the amount can be reasonably estimated, we accrue a liability for the estimated loss. Significant judgment is required to determine the probability of a loss and whether the amount of the loss is reasonably estimable. The outcome of any proceeding is not determinable in advance. As a result, the assessment of a potential liability and the amount of accruals recorded are based only on the information available to us at the time. As additional information becomes available, we reassess the potential liability related to the legal proceeding, and may revise our estimates. On July 16, 2020, a purported stockholder of Akcea filed an action in the Delaware Court of Chancery captioned John Makris, et al. v. Stanley T. Crooke, et al., C.A. No. 2020-0587, or the “Delaware Action.” The plaintiff in the Delaware Action asserts claims against (i) current and former members of Akcea’s board of directors; and (ii) Ionis, or collectively, the “Defendants”. The plaintiff asserts derivative claims on behalf of Akcea, which is a nominal defendant in the Delaware Action, as well as putatively direct claims on behalf of a purported class of Akcea’s stockholders. The plaintiff in the Delaware action asserts that the Defendants breached their fiduciary duties in connection with the licensing transaction that we and Akcea entered into regarding TEGSEDI and IONIS-TTR-L_Rx. The plaintiff also asserts an unjust enrichment claim against Ionis. The plaintiff’s claims are similar to those asserted in a prior action in the Delaware Court of Chancery captioned City of Cambridge Retirement System v. Crooke, et al., C.A. No. 2019-0905, which was dismissed with prejudice to the named plaintiff only on April 8, 2020. We believe that the claims asserted in the Delaware Action are without merit and anticipate filing a motion to dismiss the claims. In light of the August 31, 2020 public announcement of the Akcea Acquisition, the parties to the Delaware Action entered into a stipulation whereby the Defendants need to respond to the complaint filed on July 16, 2020, and the plaintiff will file an amended complaint. The amended complaint has not yet been filed.

Fourth Quarter Financial Data (Unaudited)

12 Months Ended

Dec. 31, 2020

Fourth Quarter Financial Data (Unaudited) [Abstract]

Fourth Quarter Financial Data (Unaudited)

12. Fourth Quarter Financial Data (Unaudited)

The following financial information reflects all normal recurring adjustments, which are, in the opinion of management, necessary for a fair statement of the results of the interim periods. Summarized fourth quarter data for 2020 and 2019 are as follows (in thousands, except per share data).

Three Months Ended December 31,	2020			2019
Revenue	$	290,281		$	493,680
Operating expenses	$	312,945		$	233,028
Income (loss) from operations	$	(22,664	)	$	260,652
Net income (loss)	$	(341,426	)	$	203,957
Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders	$	(340,271	)	$	184,415
Basic net income (loss) per share (1) (2)	$	(2.44	)	$	1.31
Diluted net income (loss) per share (1) (3)	$	(2.44	)	$	1.28

________________

(1)	We compute net income (loss) per share independently for each quarter during the year.

(2)

As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income (loss) per share calculation for each of the fourth quarters in 2020 and 2019 considered our net income (loss) for Ionis on a stand-alone basis plus our share of Akcea’s net loss for the period. To calculate the portion of Akcea’s net loss attributable to our ownership, we multiplied Akcea’s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.

Our basic net income (loss) per share the quarter referenced was calculated as follows (in thousands, except per share amounts):

Three Months Ended December 31 , 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-acquisition period attributable to our ownership		77,095	$	(0.05	)	$	(3,603	)
Akcea’s net loss in the post-acquisition period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(89,590	)
Ionis’ stand-alone net loss							(250,682	)
Net loss available to Ionis common stockholders						$	(340,272	)
Weighted average shares outstanding							139,956
Basic net loss per share						$	(2.44	)

Three Months Ended December 31 , 2019	Weighted Average Shares Owned in Akcea		Akcea’s Net Income Per Share		Basic Net Income Per Share Calculation
Common shares		71,342	$	0.87	$	62,243
Akcea’s net income attributable to our ownership					$	62,243
Ionis’ stand-alone net income						121,552
Net income available to Ionis common stockholders					$	183,795
Weighted average shares outstanding						140,583
Basic net income per share					$	1.31

(3)

We had net income available to Ionis common stockholders for the fourth quarter of 2019. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period as follows (in thousands except per share amounts):

Three Months Ended December 31, 2019	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	183,795		140,583	$	1.31
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		1,467
Shares issuable upon restricted stock award issuance		—		848
Shares issuable related to our ESPP		—		18
Shares issuable related to our 0.125 percent convertible notes		644		860
Shares issuable related to our 1 percent convertible notes		12,046		9,527
Income available to Ionis common stockholders, plus assumed conversions	$	196,485		153,303	$	1.28

Organization and Significant Accounting Policies (Policies)

12 Months Ended

Dec. 31, 2020

Organization and Significant Accounting Policies [Abstract]

Basis of Presentation

Basic and Diluted Net Income (Loss) per Share

Basic net income (loss) per share

Our basic net income (loss) per share was calculated as follows (in thousands, except per share amounts):

Year Ended December 31, 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-acquisition period attributable to our ownership		77,095	$	(1.45	)	$	(111,775	)
Akcea’s net loss in the post-acquisition period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(197,762	)
Ionis’ stand-alone net loss							(253,725	)
Net loss available to Ionis common stockholders						$	(451,487	)
Weighted average shares outstanding							139,612
Basic net loss per share						$	(3.23	)

Year Ended December 31, 2019	Weighted Average Shares Owned in Akcea		Akcea’s Net Income Per Share		Basic Net Income Per Share Calculation
Common shares		70,100	$	0.49	$	34,073
Akcea’s net income attributable to our ownership					$	34,073
Ionis’ stand-alone net income						262,490
Net income available to Ionis common stockholders					$	296,563
Weighted average shares outstanding						139,998
Basic net income per share					$	2.12

Year Ended December 31, 2018	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Income Per Share Calculation
Common shares		59,812	$	(2.74	)	$	(163,938	)
Akcea’s net loss attributable to our ownership						$	(163,938	)
Ionis’ stand-alone net income							440,806
Net income available to Ionis common stockholders						$	276,868
Weighted average shares outstanding							132,320
Basic net income per share						$	2.09

Diluted net income per share

●

0.125 percent convertible senior notes;

●

1 percent convertible senior notes;

●

Dilutive stock options;

●

Unvested restricted stock units, or RSUs; and

●

Employee Stock Purchase Plan, or ESPP.

Year Ended December 31, 2019	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	296,563		139,998	$	2.12
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		2,090
Shares issuable upon restricted stock award issuance		—		766
Shares issuable related to our ESPP		—		18
	$	296,563		142,872	$	2.08

Year Ended December 31, 2018	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	276,868		132,320	$	2.09
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		1,216
Shares issuable upon restricted stock award issuance		—		514
Shares issuable related to our ESPP		—		6
	$	276,868		134,056	$	2.07

For each year presented, the calculation excluded our convertible senior notes because the effect on diluted earnings per share was anti-dilutive.

Revenue Recognition

Our Revenue Sources

Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue

Commercial Revenue: Product sales, net

Research and development revenue under collaborative agreements

Steps to Recognize Revenue

We use a five-step process to determine the amount of revenue we should recognize and when we should recognize it. The five step process is as follows:

Identify the contract

Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the following criteria:

●

We and our partner approved the contract and we are both committed to perform our obligations;

●

We have identified our rights, our partner’s rights and the payment terms;

●

We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the contract; and

●

We believe collectability of the consideration is probable.

Identify the performance obligations

Determine the transaction price

Allocate the transaction price

●

Estimated future product sales;

●

Estimated royalties we may receive from future product sales;

●

Estimated contractual milestone payments we may receive;

●

Expenses we expect to incur;

●

Estimated income taxes; and

●

A discount rate.

●

The number of internal hours we estimate we will spend performing these services;

●

The estimated cost of work we will perform;

●

The estimated cost of work that we will contract with third parties to perform; and

●

The estimated cost of API we will use.

Recognize revenue

The following are examples of when we typically recognize revenue based on the types of payments we receive.

Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue

Commercial Revenue: Product sales, net

Reserves for Product sales

The following are the components of variable consideration related to product sales:

Research and development revenue under collaboration agreements:

Upfront payments

Milestone payments

License fees

Sublicense fees

Amendments to Agreements

From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items to determine the accounting for the amendment:

If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and

If the goods and/or services are at a stand-alone selling price.

Multiple agreements

●

Whether the agreements were negotiated together with a single objective;

●

Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or

●

Whether the goods and/or services promised under the agreements are a single performance obligation.

Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting guidance requires us to account for them as a combined arrangement.

Contracts Receivable

Unbilled SPINRAZA Royalties

Deferred Revenue

Cost of Products Sold

Research and Development Expenses

Patent Expenses

Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:

Year Ending December 31,	Amortization (in millions)
2021	$	2.1
2022	$	2.0
2023	$	1.9
2024	$	1.7
2025	$	1.6

Noncontrolling Interest in Akcea Therapeutics, Inc.

Concentration of Credit Risk

Cash, Cash Equivalents and Investments

Inventory Valuation

Our inventory consisted of the following (in thousands):

	December 31,
	2020		2019
Raw materials:
Raw materials- clinical	$	9,206	$	9,363
Raw materials- commercial		7,502		6,520
Total raw materials		16,708		15,883
Work in process		2,252		2,039
Finished goods		3,005		258
Total inventory	$	21,965	$	18,180

Property, Plant and Equipment

We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which consists of the following (in thousands):

	Estimated Useful Lives		December 31,
	(in years)		2020			2019
Computer software, laboratory, manufacturing and other equipment	3 to 10		$	68,990		$	60,965
Building, building improvements and building systems	15 to 40			137,879			119,830
Land improvements		20		8,391			2,853
Leasehold improvements	5 to 15			17,263			13,600
Furniture and fixtures	5 to 10			12,871			7,354
				245,394			204,602
Less accumulated depreciation				(87,379	)		(74,013	)
				158,015			130,589
Land				23,062			23,062
Total			$	181,077		$	153,651

We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.

Fair Value of Financial Instruments

Leases

Long-Lived Assets

Use of Estimates

Stock-Based Compensation Expense

See Note 4, Stockholders’ Equity, for additional information regarding our stock-based compensation plans.

Accumulated Other Comprehensive Loss

	Year Ended December 31,
	2020			2019			2018
Beginning balance accumulated other comprehensive loss	$	(25,290	)	$	(32,016	)	$	(31,759	)
Unrealized gains (losses) on securities, net of tax (1)		3,729			6,633			(280	)
Currency translation adjustment		617			93			23
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.		(127	)		—			—
Net other comprehensive loss for the period		4,219			6,726			(257	)
Ending balance accumulated other comprehensive loss	$	(21,071	)	$	(25,290	)	$	(32,016	)

________________

(1)	We did not have tax expense included in our other comprehensive loss for the year ended December 31, 2020. For the years ended December 31, 2019 and 2018, we had a tax benefit $1.4 million and $0.3 million included in other comprehensive loss respectively.

Convertible Debt

The 1% Notes mature in November 2021. Therefore, as of December 31, 2020, we classified the liability component of the 1% Notes as a current liability on our consolidated balance sheet.

In August 2020, the FASB issued guidance simplifying the accounting for convertible debt instruments. See the section titled “Impact of Recently Issued Accounting Standards” below for details.

Call Spread

Segment Information

Fair Value Measurements

	At December 31, 2020		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	221,125	$	221,125	$	—
Corporate debt securities (2)		846,315		—		846,315
Debt securities issued by U.S. government agencies (4)		174,861		—		174,861
Debt securities issued by the U.S. Treasury (3)		358,497		358,497		—
Debt securities issued by states of the U.S. and political subdivisions of the states (4)		136,309		—		136,309
Other municipal debt securities (4)		6,225		—		6,225
Investment in ProQR Therapeutics N.V. (5)		2,031		2,031		—
Total	$	1,745,363	$	581,653	$	1,163,710

	At December 31, 2019		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)		Significant Unobservable Inputs (Level 3)
Cash equivalents (1)	$	418,406	$	418,406	$	—	$	—
Corporate debt securities (6)		1,102,568		—		1,102,568		—
Debt securities issued by U.S. government agencies (7)		329,404		—		329,404		—
Debt securities issued by the U.S. Treasury (4)		363,694		363,694		—		—
Debt securities issued by states of the U.S. and political subdivisions of the states (4)		40,407		—		40,407		—
Investment in ProQR Therapeutics N.V. (5)		4,506		—		—		4,506
Total	$	2,258,985	$	782,100	$	1,472,379	$	4,506

________________

(1)	Included in cash and cash equivalents on our consolidated balance sheet.

(2)	$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(3)	$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(4)	Included in short-term investments.

(5)	Included in other current assets on our consolidated balance sheet.

(6)	$19.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(7)	$0.8 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

Income Taxes

We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries.

Impact of Recently Issued Accounting Standards

When a participant is considered a customer in a collaborative arrangement, all of the associated accounting under Topic 606 should be applied.

●

We are applying all of the associated accounting under Topic 606 when we determine a participant in a collaborative arrangement is a customer.

●

We use the “unit of account” concept when we receive consideration under a collaborative arrangement to determine when we recognize revenue or a contra expense.

●

When we conclude a collaboration partner is not a customer and is not directly related to the sales to third parties, we do not recognize revenue for the transaction.

We adopted this new guidance on January 1, 2020. This guidance did not have any impact on our consolidated financial statements.

We do not expect our EPS calculation to not change under this update. We plan to continue to use the if-converted method to calculate diluted earnings per share.

We plan to adopt this guidance in the first quarter of 2021 under the full retrospective approach, meaning we will apply the guidance to all periods presented beginning in the first quarter of 2021.

Organization and Significant Accounting Policies (Tables)

12 Months Ended

Dec. 31, 2020

Organization and Significant Accounting Policies [Abstract]

Basic Net Income (Loss) per Share

Our basic net income (loss) per share was calculated as follows (in thousands, except per share amounts):

Year Ended December 31, 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-acquisition period attributable to our ownership		77,095	$	(1.45	)	$	(111,775	)
Akcea’s net loss in the post-acquisition period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(197,762	)
Ionis’ stand-alone net loss							(253,725	)
Net loss available to Ionis common stockholders						$	(451,487	)
Weighted average shares outstanding							139,612
Basic net loss per share						$	(3.23	)

Year Ended December 31, 2019	Weighted Average Shares Owned in Akcea		Akcea’s Net Income Per Share		Basic Net Income Per Share Calculation
Common shares		70,100	$	0.49	$	34,073
Akcea’s net income attributable to our ownership					$	34,073
Ionis’ stand-alone net income						262,490
Net income available to Ionis common stockholders					$	296,563
Weighted average shares outstanding						139,998
Basic net income per share					$	2.12

Year Ended December 31, 2018	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Income Per Share Calculation
Common shares		59,812	$	(2.74	)	$	(163,938	)
Akcea’s net loss attributable to our ownership						$	(163,938	)
Ionis’ stand-alone net income							440,806
Net income available to Ionis common stockholders						$	276,868
Weighted average shares outstanding							132,320
Basic net income per share						$	2.09

Basic and Diluted Net Income Per Share

Year Ended December 31, 2019	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	296,563		139,998	$	2.12
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		2,090
Shares issuable upon restricted stock award issuance		—		766
Shares issuable related to our ESPP		—		18
	$	296,563		142,872	$	2.08

Year Ended December 31, 2018	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	276,868		132,320	$	2.09
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		1,216
Shares issuable upon restricted stock award issuance		—		514
Shares issuable related to our ESPP		—		6
	$	276,868		134,056	$	2.07

Amortization Expense for Patents

Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:

Year Ending December 31,	Amortization (in millions)
2021	$	2.1
2022	$	2.0
2023	$	1.9
2024	$	1.7
2025	$	1.6

Accrued Liabilities

Our accrued liabilities consisted of the following (in thousands):

	December 31,
	2020		2019
Clinical expenses	$	39,477	$	24,461
In-licensing expenses		8,264		10,289
Commercial expenses		11,559		6,020
Other miscellaneous expenses		30,861		25,999
Total accrued liabilities	$	90,161	$	66,769

Inventory

Our inventory consisted of the following (in thousands):

	December 31,
	2020		2019
Raw materials:
Raw materials- clinical	$	9,206	$	9,363
Raw materials- commercial		7,502		6,520
Total raw materials		16,708		15,883
Work in process		2,252		2,039
Finished goods		3,005		258
Total inventory	$	21,965	$	18,180

Property, Plant and Equipment

We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which consists of the following (in thousands):

	Estimated Useful Lives		December 31,
	(in years)		2020			2019
Computer software, laboratory, manufacturing and other equipment	3 to 10		$	68,990		$	60,965
Building, building improvements and building systems	15 to 40			137,879			119,830
Land improvements		20		8,391			2,853
Leasehold improvements	5 to 15			17,263			13,600
Furniture and fixtures	5 to 10			12,871			7,354
				245,394			204,602
Less accumulated depreciation				(87,379	)		(74,013	)
				158,015			130,589
Land				23,062			23,062
Total			$	181,077		$	153,651

Changes in Accumulated Other Comprehensive Loss

	Year Ended December 31,
	2020			2019			2018
Beginning balance accumulated other comprehensive loss	$	(25,290	)	$	(32,016	)	$	(31,759	)
Unrealized gains (losses) on securities, net of tax (1)		3,729			6,633			(280	)
Currency translation adjustment		617			93			23
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.		(127	)		—			—
Net other comprehensive loss for the period		4,219			6,726			(257	)
Ending balance accumulated other comprehensive loss	$	(21,071	)	$	(25,290	)	$	(32,016	)

________________

(1)	We did not have tax expense included in our other comprehensive loss for the year ended December 31, 2020. For the years ended December 31, 2019 and 2018, we had a tax benefit $1.4 million and $0.3 million included in other comprehensive loss respectively.

Assets Measured at Fair Value on a Recurring Basis

	At December 31, 2020		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	221,125	$	221,125	$	—
Corporate debt securities (2)		846,315		—		846,315
Debt securities issued by U.S. government agencies (4)		174,861		—		174,861
Debt securities issued by the U.S. Treasury (3)		358,497		358,497		—
Debt securities issued by states of the U.S. and political subdivisions of the states (4)		136,309		—		136,309
Other municipal debt securities (4)		6,225		—		6,225
Investment in ProQR Therapeutics N.V. (5)		2,031		2,031		—
Total	$	1,745,363	$	581,653	$	1,163,710

	At December 31, 2019		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)		Significant Unobservable Inputs (Level 3)
Cash equivalents (1)	$	418,406	$	418,406	$	—	$	—
Corporate debt securities (6)		1,102,568		—		1,102,568		—
Debt securities issued by U.S. government agencies (7)		329,404		—		329,404		—
Debt securities issued by the U.S. Treasury (4)		363,694		363,694		—		—
Debt securities issued by states of the U.S. and political subdivisions of the states (4)		40,407		—		40,407		—
Investment in ProQR Therapeutics N.V. (5)		4,506		—		—		4,506
Total	$	2,258,985	$	782,100	$	1,472,379	$	4,506

________________

(1)	Included in cash and cash equivalents on our consolidated balance sheet.

(2)	$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(3)	$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(4)	Included in short-term investments.

(5)	Included in other current assets on our consolidated balance sheet.

(6)	$19.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(7)	$0.8 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

Investments (Tables)

12 Months Ended

Dec. 31, 2020

Investments [Abstract]

Contract Maturity of Available-for-Sale Securities

The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2020:

One year or less	73	%
After one year but within two years	18	%
After two years but within three and a half years	9	%
Total	100	%

Summary of Investments

The following is a summary of our investments (in thousands):

			Gross Unrealized					Estimated
December 31, 2020	Cost (1)		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (2)	$	514,182	$	2,194	$	(41	)	$	516,335
Debt securities issued by U.S. government agencies		94,234		354		(2	)		94,586
Debt securities issued by the U.S. Treasury (2)		307,576		233		(9	)		307,800
Debt securities issued by states of the U.S. and political subdivisions of the states		104,271		196		(12	)		104,455
Other municipal debt securities		5,191		—		(7	)		5,184
Total securities with a maturity of one year or less		1,025,454		2,977		(71	)		1,028,360
Corporate debt securities		325,079		4,941		(40	)		329,980
Debt securities issued by U.S. government agencies		80,099		185		(9	)		80,275
Debt securities issued by the U.S. Treasury		50,318		383		(4	)		50,697
Debt securities issued by states of the U.S. and political subdivisions of the states		31,779		91		(16	)		31,854
Other municipal debt securities		1,041		—		—			1,041
Total securities with a maturity of more than one year		488,316		5,600		(69	)		493,847
Total available-for-sale securities	$	1,513,770	$	8,577	$	(140	)	$	1,522,207
Equity securities:
Total equity securities included in other current assets (3)	$	4,712	$	—	$	(2,681	)	$	2,031
Total equity securities included in deposits and other assets (4)		15,062		15,938		—			31,000
Total equity securities	$	19,774	$	15,938	$	(2,681	)	$	33,031
Total available-for-sale and equity securities	$	1,533,544	$	24,515	$	(2,821	)	$	1,555,238

			Gross Unrealized					Estimated
December 31, 2019	Cost (1)		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (2)	$	669,665	$	1,451	$	(43	)	$	671,073
Debt securities issued by U.S. government agencies		188,216		303		(43	)		188,476
Debt securities issued by the U.S. Treasury (2)		327,670		232		(27	)		327,875
Debt securities issued by states of the U.S. and political subdivisions of the states		21,065		26		(5	)		21,086
Total securities with a maturity of one year or less		1,206,616		2,012		(118	)		1,208,510
Corporate debt securities		428,627		2,911		(43	)		431,495
Debt securities issued by U.S. government agencies		140,988		57		(117	)		140,928
Debt securities issued by the U.S. Treasury		35,822		9		(12	)		35,819
Debt securities issued by states of the U.S. and political subdivisions of the states		19,309		18		(6	)		19,321
Total securities with a maturity of more than one year		624,746		2,995		(178	)		627,563
Total available-for-sale securities	$	1,831,362	$	5,007	$	(296	)	$	1,836,073
Equity securities:
Total equity securities included in other current assets (3)	$	4,712	$	—	$	(870	)	$	3,842
Total equity securities included in deposits and other assets (4)		10,000		—		—			10,000
Total equity securities	$	14,712	$	—	$	(870	)	$	13,842
Total available-for-sale and equity securities	$	1,846,074	$	5,007	$	(1,166	)	$	1,849,915

________________

(1)	We hold our available-for-sale securities at amortized cost.

(2)	Includes investments classified as cash equivalents on our consolidated balance sheet.

(3)	Our equity securities included in other current assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.

(4)

Temporarily Impaired Investments

	Number of Investments		Estimated Fair Value		Unrealized Losses
Corporate debt securities		54	$	121,162	$	(81	)
Debt securities issued by U.S. government agencies		2		29,988		(11	)
Debt securities issued by the U.S. Treasury		8		76,941		(13	)
Debt securities issued by states of the U.S. and political subdivisions of the states		160		49,832		(28	)
Other municipal debt securities		2		6,225		(7	)
Total temporarily impaired securities		226	$	284,148	$	(140	)

Long-Term Obligations and Commitments (Tables)

12 Months Ended

Dec. 31, 2020

Long-Term Obligations and Commitments [Abstract]

Long-Term Obligations

The carrying value of our long-term obligations was as follows (in thousands):

	December 31,
	2020			2019
0.125 percent convertible senior notes	$	455,719		$	434,711
1 percent convertible senior notes (1)		293,161			275,333
Long-term mortgage debt		59,984			59,913
Leases and other obligations		30,710			17,569
Total	$	839,574		$	787,526
Less: current portion (1)		(300,462	)		(2,026	)
Total Long-Term Obligations	$	539,112		$	785,500

________________

(1)	We classified the carrying value of our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matures in November 2021.

Convertible Notes

At December 31, 2020, we had the following 0.125% Notes outstanding (amounts in millions except price per share data):

	0.125% Notes
Outstanding principal balance	$	548.8
Maturity date	December 15, 2024
Interest rate		0.125	%
Conversion price per share	$	83.28
Total shares of common stock subject to conversion		6.6

	December 31,
	2020		2019
Fair value of outstanding notes	$	564.9	$	558.7
Principal amount of convertible notes outstanding	$	548.8	$	548.8
Unamortized portion of debt discount	$	86.0	$	105.2
Long-term debt	$	455.7	$	434.7
Carrying value of equity component	$	105.8	$	105.8

At December 31, 2020, we had the following 1% Notes outstanding (amounts in millions except price per share data):

	1% Notes
Outstanding principal balance	$	309.9
Maturity date	November 30, 2021
Interest rate	1 percent
Conversion price per share	$	66.81
Total shares of common stock subject to conversion		4.6

	December 31,
	2020		2019
Fair value of outstanding notes	$	338.5	$	354.8
Principal amount of convertible notes outstanding	$	309.9	$	309.9
Unamortized portion of debt discount	$	15.8	$	32.8
Current/long-term debt	$	293.2	$	275.3
Carrying value of equity component	$	33.5	$	33.5

	1% Notes	0.125% Notes
Nonconvertible debt borrowing rate	7.4 percent	4.4 percent
Effective interest rate (1)	7.5 percent	4.9 percent
Amortization period of debt discount	7 years	5 years

________________

(1)	For our 1% Notes, our effective interest rate represents our effective interest rate after our December 2019 debt exchange.

Maturity Schedules

Annual debt and other obligation maturities, including fixed and determinable interest, at December 31, 2020 are as follows (in thousands):

2021	$	329,189
2022		3,495
2023		4,180
2024		553,006
2025		3,494
Thereafter		60,933
Subtotal	$	954,297
Less: current portion		(300,462	)
Less: fixed and determinable interest		(21,758	)
Less: unamortized portion of debt discount		(101,820	)
Less: debt issuance costs		(8,455	)
Plus: lease liabilities		17,310
Total long-term debt	$	539,112

Amounts Related to Operating Leases

Amounts related to our operating leases were as follows (dollar amounts in millions):

	At December 31, 2020
Right-of-use operating lease assets (1)	$	13.1
Operating lease liabilities (2)	$	17.3
Weighted average remaining lease term	7.2 years
Weighted average discount rate		7.0	%

________________

(1)	Included in deposits and other assets on our consolidated balance sheet.

(2)	Current portion of $2.0 million was included in current portion of long-term obligations on our consolidated balance sheet, with the difference included in long-term obligations.

Future Payments for Operating Lease Liabilities

As of December 31, 2020, the future payments for our operating lease liabilities are as follows (in thousands):

	Operating Leases
Year ending December 31,	$
2021		3,193
2022		2,968
2023		2,707
2024		2,583
2025		2,442
Thereafter		7,038
Total minimum lease payments		20,931
Less:
Imputed interest		(3,621	)
Total operating lease liabilities	$	17,310

- Definition

Tabular disclosure of long-debt instruments or arrangements, including identification, terms, features, collateral requirements and other information necessary to a fair presentation. These are debt arrangements that originally required repayment more than twelve months after issuance or greater than the normal operating cycle of the entity, if longer.

+ References

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Reference 9: http://fasb.org/us-gaap/role/ref/legacyRef
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-Name Accounting Standards Codification
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Reference 10: http://fasb.org/us-gaap/role/ref/legacyRef
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+ Details

Stockholders' Equity (Tables)

12 Months Ended

Dec. 31, 2020

Stockholders' Equity [Abstract]

Stock Option Activity

The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2020 (in thousands, except per share and contractual life data):

	Number of Shares			Weighted Average Exercise Price Per Share		Average Remaining Contractual Term (Years)		Aggregate Intrinsic Value
Outstanding at December 31, 2019		11,001		$	51.48
Granted		2,764		$	59.89
Exercised		(1,069	)	$	40.88
Cancelled/forfeited/expired		(361	)	$	56.48
Outstanding at December 31, 2020		12,335		$	54.14		4.16	$	55,885
Exercisable at December 31, 2020		7,366		$	52.45		3.16	$	43,267

RSU Activity

The following table summarizes the RSU activity for the year ended December 31, 2020 (in thousands, except per share data):

	Number of Shares			Weighted Average Grant Date Fair Value Per Share
Non-vested at December 31, 2019		1,866		$	55.80
Granted		1,244		$	60.86
Vested		(602	)	$	53.68
Cancelled/forfeited		(134	)	$	58.96
Non-vested at December 31, 2020		2,374		$	58.81

Stock-Based Compensation Expense

The following table summarizes stock-based compensation expense for the years ended December 31, 2020, 2019 and 2018 (in thousands):

	Year Ended December 31,
	2020		2019		2018
Cost of products sold	$	1,991	$	438	$	160
Research, development and patent		115,584		95,348		76,557
Selling, general and administrative		112,542		50,788		54,595
Total	$	230,117	$	146,574	$	131,312

Stockholders' Equity [Abstract]

Weighted-Average Assumptions for Stock Options

Ionis Employee Stock Options:

	December 31,
	2020			2019			2018
Risk-free interest rate		1.5	%		2.3	%		2.4	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		58.6	%		60.3	%		63.0	%
Expected life	4.7 years			4.8 years			4.6 years

Ionis Board of Director Stock Options:

	December 31,
	2020			2019			2018
Risk-free interest rate		0.5	%		1.9	%		2.8	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		57.6	%		60.7	%		61.5	%
Expected life	6.7 years			6.6 years			6.6 years

Weighted-Average Assumptions for ESPP

Ionis ESPP:

	December 31,
	2020			2019			2018
Risk-free interest rate		0.8	%		2.4	%		1.8	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		47.9	%		45.6	%		47.3	%
Expected life	6 months			6 months			6 months

Akcea [Member]

Stockholders' Equity [Abstract]

Weighted-Average Assumptions for Stock Options

Akcea Employee Stock Options:

	December 31,
	2020			2019			2018
Risk-free interest rate		1.1	%		2.2	%		2.8	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		75.0	%		75.4	%		77.1	%
Expected life	6.08 years			6.09 years			6.08 years

Akcea Board of Director Stock Options:

	December 31,
	2020			2019			2018
Risk-free interest rate		0.8	%		1.8	%		2.9	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		75.3	%		73.8	%		78.2	%
Expected life	5.67 years			6.25 years			6.42 years

Weighted-Average Assumptions for ESPP

Akcea ESPP:

	December 31,
	2020			2019			2018
Risk-free interest rate		1.0	%		2.4	%		1.9	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		71.9	%		60.0	%		64.2	%
Expected life	6 months			6 months			6 months

Income Taxes (Tables)

12 Months Ended

Dec. 31, 2020

Income Taxes [Abstract]

Income (Loss) Before Income Taxes

Income (loss) before income taxes is comprised of (in thousands):

	Year Ended December 31,
	2020			2019		2018
United States	$	(172,702	)	$	344,280	$	(69,576	)
Foreign		2,670			2,489		(6,580	)
Income (loss) before income taxes	$	(170,032	)	$	346,769	$	(76,156	)

Income Tax Expense (Benefit)

Our income tax expense (benefit) was as follows (in thousands):

	Year Ended December 31,
	2020			2019			2018
Current:
Federal	$	(837	)	$	35,861		$	438
State		3,782			14,329			(1,442	)
Foreign		518			413			374
Total current income tax expense (benefit)		3,463			50,603			(630	)

Deferred:
Federal		313,271			(7,096	)		(290,511	)
State		—			—			—
Total deferred income tax benefit		313,271			(7,096	)		(290,511	)
Total income tax expense (benefit)	$	316,734		$	43,507		$	(291,141	)

Reconciliation of Statutory to Effective Tax Rate

	Year Ended December 31,
	2020					2019					2018
Pre-tax income (loss)	$	(170,032	)			$	346,769				$	(76,156	)

Statutory rate		(35,707	)	21.0	%		72,822		21.0	%		(15,993	)	21.0	%
State income tax net of federal benefit		(39,230	)	23.1	%		49,119		14.2	%		(2,202	)	2.9	%
Foreign		49		0.0	%		340		0.1	%		1,735		(2.3	)%
Net change in valuation allowance		437,597		(257.4	)%		(37,765	)	(10.9	)%		(277,924	)	364.9	%
Net operating loss expiration		—		0.0	%		—		0.0	%		8,864		(11.6	)%
TEGSEDI licensing gain		—		0.0	%		—		0.0	%		59,583		(78.2	)%
Impact from outside basis differences		—		0.0	%		(16,344	)	(4.7	)%		—		0.0	%
Tax credits		(18,774	)	11.0	%		(22,296	)	(6.4	)%		(73,362	)	96.3	%
Deferred tax true-up		(206	)	0.1	%		646		0.2	%		9,947		(13.1	)%
Tax rate change		(29,131	)	17.1	%		1,811		0.5	%		(1,808	)	2.4	%
Non-deductible compensation		7,931		(4.7	)%		3,361		1.0	%		3,154		(4.1	)%
Other non-deductible items		193		(0.1	)%		329		0.1	%		(569	)	0.7	%
Stock-based compensation		17,435		(10.3	)%		(4,837	)	(1.4	)%		(4,199	)	5.5	%
Foreign-derived intangible income benefit		—		0.0	%		(2,071	)	(0.6	)%		—		0.0	%
Impacts from Akcea Acquisition		(22,032	)	13.0	%		—		—			—		—
Other		(1,391	)	0.8	%		(1,608	)	(0.5	)%		1,633		(2.1	)%
Effective rate	$	316,734		(186.4	)%	$	43,507		12.6	%	$	(291,141	)	382.3	%

Deferred Tax Assets and Liabilities

Significant components of our deferred tax assets and liabilities as of December 31, 2020 and 2019 are as follows (in thousands):

	Year Ended December 31,
	2020			2019
Deferred Tax Assets:
Net operating loss carryovers	$	83,681		$	20,191
Tax credits		245,746			210,455
Deferred revenue		124,452			127,763
Stock-based compensation		80,055			65,703
Intangible and capital assets		98,443			77,861
Other		13,402			12,510
Total deferred tax assets	$	645,779		$	514,483

Deferred Tax Liabilities:
Convertible debt	$	(2,920	)	$	(6,110	)
Fixed assets		(3,611	)		(1,958	)
Other		(5,808	)		(3,884	)
Net deferred tax asset	$	633,440		$	502,531
Valuation allowance		(633,440	)		(196,974	)
Total net deferred tax assets and liabilities	$	—		$	305,557

Gross Unrecognized Tax Benefits

The following table summarizes our gross unrecognized tax benefits (in thousands):

	Year Ended December 31,
	2020			2019			2018
Beginning balance of unrecognized tax benefits	$	69,784		$	68,301		$	78,014
Decrease for prior period tax positions		(24,154	)		(867	)		(12,814	)
Increase for prior period tax positions		7,023			736			—
Increase for current period tax positions		1,510			1,614			3,101
Ending balance of unrecognized tax benefits	$	54,163		$	69,784		$	68,301

Collaborative Arrangements and Licensing Agreements (Tables)

12 Months Ended

Dec. 31, 2020

Biogen [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
SPINRAZA royalties (commercial revenue)	$	286.6		$	293.0		$	237.9
R&D revenue		122.0			180.6			137.1
Total revenue from our relationship with Biogen	$	408.6		$	473.6		$	375.0
Percentage of total revenue		56	%		42	%		63	%

AstraZeneca [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	88.0		$	28.1		$	120.7
Percentage of total revenue		12	%		3	%		20	%

Bayer [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	3.2		$	14.3		$	5.0
Percentage of total revenue		0	%		1	%		1	%

GSK [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	0.2		$	25.4		$	1.6
Percentage of total revenue		0	%		2	%		0	%

Janssen Biotech, Inc. [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with Janssen (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	5.0		$	0.1		$	6.6
Percentage of total revenue		1	%		0	%		1	%

Novartis [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2020 and 2019, we earned the following revenue from our relationship with Novartis (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	1.0		$	187.4		$	50.6
Percentage of total revenue		0	%		17	%		8	%

Pfizer [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2020 and 2019, we earned the following revenue from our relationship with Pfizer (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019
R&D revenue	$	82.1		$	248.7
Percentage of total revenue		11	%		22	%

PTC Therapeutics [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with PTC (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
Licensing and other royalty revenue (commercial revenue)	$	1.6		$	10.2		$	12.0
Percentage of total revenue		0	%		1	%		2	%

Roche [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2020, 2019 and 2018, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	5.9		$	57.0		$	8.3
Percentage of total revenue		1	%		5	%		1	%

Alnylam Pharmaceuticals, Inc. [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

	Year Ended December 31,
	2020			2019			2018
R&D revenue	$	47.9		$	24.1		$	2.0
Percentage of total revenue		7	%		2	%		—

Akcea Acquisition (Tables)

12 Months Ended

Dec. 31, 2020

Akcea Acquisition [Abstract]

Akcea Acquisition

The following table summarizes the costs by category related to the Akcea Acquisition (in millions):

	Three Months Ended December 31, 2020
R&D expenses	$	3.9
SG&A expenses		11.4
Total	$	15.3

The following table summarizes the severance and retention reserve included in accrued compensation for the period indicated related to Akcea Acquisition (in millions):

	Three Months Ended December 31, 2020
Severance & retention reserve beginning balance	$	—
Severance & retention expensed during period		15.3
Amounts paid during the period		(0.6	)
Severance & retention reserve ending balance	$	14.7

Severance and Retention Costs related to our Restructured European Operations (Tables)

12 Months Ended

Dec. 31, 2020

Severance and Retention Costs related to our Restructured European Operations

Severance and Retention Costs related to our Restructured European Operations

The following table summarizes the costs by category related to our restructured European operations (in millions):

	Three Months Ended December 31, 2020
R&D expenses	$	4.2
SG&A expenses		8.3
Total	$	12.5

The following table summarizes the severance and retention reserve included in accrued compensation for the periods indicated related to our restructured European operations (in millions):

	Three Months Ended December 31, 2020
Severance & retention reserve beginning balance	$	—
Severance & retention expensed during period		12.5
Amounts paid during the period		(0.1	)
Severance & retention reserve ending balance	$	12.4

Segment Information and Concentration of Business Risk (Tables)

12 Months Ended

Dec. 31, 2020

Segment Information and Concentration of Business Risk [Abstract]

Segment Information

The following tables show our segment revenue and income (loss) from operations for 2020, 2019 and 2018 (in thousands), respectively.

2020	Ionis Core		Akcea Therapeutics			Elimination of Intercompany Activity			Total
Revenue:
Commercial revenue:
SPINRAZA royalties	$	286,583	$	—		$	—		$	286,583
Product sales, net		—		69,999			—			69,999
Licensing and other royalty revenue		11,334		—			(3,217	)		8,117
Total commercial revenue		297,917		69,999			(3,217	)		364,699
R&D revenue under collaborative agreements		325,024		82,321			(42,780	)		364,565
Total segment revenue	$	622,941	$	152,320		$	(45,997	)	$	729,264
Total operating expenses	$	563,647	$	389,575		$	(51,876	)	$	901,346
Income (loss) from operations	$	59,294	$	(237,255	)	$	5,879		$	(172,082	)

2019	Ionis Core		Akcea Therapeutics		Elimination of Intercompany Activity			Total
Revenue:
Commercial revenue:
SPINRAZA royalties	$	292,992	$	—	$	—		$	292,992
Product sales, net		—		42,253		—			42,253
Licensing and other royalty revenue		12,616		10,172		(5,583	)		17,205
Total commercial revenue		305,608		52,425		(5,583	)		352,450
R&D revenue under collaborative agreements		553,038		436,118		(219,007	)		770,149
Total segment revenue	$	858,646	$	488,543	$	(224,590	)	$	1,122,599
Total operating expenses	$	523,207	$	450,469	$	(216,960	)	$	756,716
Income (loss) from operations	$	335,439	$	38,074	$	(7,630	)	$	365,883

2018	Ionis Core		Akcea Therapeutics			Elimination of Intercompany Activity			Total
Revenue:
Commercial revenue:
SPINRAZA royalties	$	237,930	$	—		$	—		$	237,930
Product sales, net		—		2,237			—			2,237
Licensing and other royalty revenue		2,755		12,000			—			14,755
Total commercial revenue		240,685		14,237			—			254,922
R&D revenue under collaborative agreements		401,259		50,630			(107,137	)		344,752
Total segment revenue	$	641,944	$	64,867		$	(107,137	)	$	599,674
Total operating expenses	$	380,212	$	295,683		$	(14,849	)	$	661,046
Income (loss) from operations	$	261,732	$	(230,816	)	$	(92,288	)	$	(61,372	)

The following table shows our total assets by segment at December 31, 2020 and 2019 (in thousands), respectively.

Total Assets	Ionis Core		Akcea Therapeutics		Elimination of Intercompany Activity			Total
December 31, 2020	$	2,792,222	$	435,824	$	(838,291	)	$	2,389,755
December 31, 2019	$	3,478,081	$	599,250	$	(844,219	)	$	3,233,112

Fourth Quarter Financial Data (Unaudited) (Tables)

12 Months Ended

Dec. 31, 2020

Fourth Quarter Financial Data (Unaudited) [Abstract]

Fourth Quarter Financial Data (Unaudited)

Three Months Ended December 31,	2020			2019
Revenue	$	290,281		$	493,680
Operating expenses	$	312,945		$	233,028
Income (loss) from operations	$	(22,664	)	$	260,652
Net income (loss)	$	(341,426	)	$	203,957
Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders	$	(340,271	)	$	184,415
Basic net income (loss) per share (1) (2)	$	(2.44	)	$	1.31
Diluted net income (loss) per share (1) (3)	$	(2.44	)	$	1.28

________________

(1)	We compute net income (loss) per share independently for each quarter during the year.

(2)

Our basic net income (loss) per share the quarter referenced was calculated as follows (in thousands, except per share amounts):

Three Months Ended December 31 , 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-acquisition period attributable to our ownership		77,095	$	(0.05	)	$	(3,603	)
Akcea’s net loss in the post-acquisition period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(89,590	)
Ionis’ stand-alone net loss							(250,682	)
Net loss available to Ionis common stockholders						$	(340,272	)
Weighted average shares outstanding							139,956
Basic net loss per share						$	(2.44	)

Three Months Ended December 31 , 2019	Weighted Average Shares Owned in Akcea		Akcea’s Net Income Per Share		Basic Net Income Per Share Calculation
Common shares		71,342	$	0.87	$	62,243
Akcea’s net income attributable to our ownership					$	62,243
Ionis’ stand-alone net income						121,552
Net income available to Ionis common stockholders					$	183,795
Weighted average shares outstanding						140,583
Basic net income per share					$	1.31

(3)

Three Months Ended December 31, 2019	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	183,795		140,583	$	1.31
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		1,467
Shares issuable upon restricted stock award issuance		—		848
Shares issuable related to our ESPP		—		18
Shares issuable related to our 0.125 percent convertible notes		644		860
Shares issuable related to our 1 percent convertible notes		12,046		9,527
Income available to Ionis common stockholders, plus assumed conversions	$	196,485		153,303	$	1.28

Organization and Significant Accounting Policies, Basis of Presentation (Details)	Oct. 31, 2020	Sep. 30, 2020	Jun. 30, 2017
Akcea [Member]
Basis of Presentation [Abstract]
Percentage ownership	100.00%	76.00%	100.00%

Organization and Significant Accounting Policies, Basic and Diluted Net Income (Loss) per Share (Details) - USD ($)
$ / shares in Units, shares in Thousands, $ in Thousands

2 Months Ended

3 Months Ended

10 Months Ended

12 Months Ended

Dec. 31, 2020

Dec. 31, 2019

Oct. 31, 2020

Dec. 31, 2020

Dec. 31, 2019

Dec. 31, 2018

Basic Net Income (Loss) per Share [Abstract]

Basic net income (loss) per share (in dollars per share)

$ (2.44)

^[1],[2]

$ 1.31

^[1],[2]

$ (3.23)

$ 2.12

$ 2.09

Net income (loss)

$ (340,271)

$ 184,415

$ (451,286)

$ 294,146

$ 273,741

Net income (loss) available to Ionis common stockholders

$ (340,272)

$ 183,795

$ (451,487)

$ 296,563

$ 276,868

Weighted average shares outstanding (in shares)

139,956

140,583

139,612

139,998

132,320

Net income available to Ionis common shareholders

$ 196,485

$ 296,563

$ 276,868

Shares issuable related to our ESPP (in shares)

Shares used in computing diluted net income per share (in shares)

153,303

139,612

142,872

134,056

Diluted net income per share (in dollars per share)

$ (2.44)

^[2],[3]

$ 1.28

^[2],[3]

$ (3.23)

$ 2.08

$ 2.07

0.125 Percent Convertible Senior Notes [Member]

Basic Net Income (Loss) per Share [Abstract]

Interest rate on convertible senior notes

0.125%

1 Percent Convertible Senior Notes [Member]

Basic Net Income (Loss) per Share [Abstract]

Interest rate on convertible senior notes

1.00%

Stock Options [Member]

Basic Net Income (Loss) per Share [Abstract]

Shares issuable related to stock-based compensation (in shares)

1,467

2,090

1,216

Restricted Stock Awards [Member]

Basic Net Income (Loss) per Share [Abstract]

Shares issuable related to stock-based compensation (in shares)

848

766

514

Ionis [Member]

Basic Net Income (Loss) per Share [Abstract]

Net income (loss)

$ (250,682)

$ 121,552

$ (253,725)

$ 262,490

$ 440,806

Akcea [Member]

Basic Net Income (Loss) per Share [Abstract]

Net income (loss)

$ (85,987)

$ (197,762)

$ 34,073

$ (163,938)

Akcea [Member] | Common Stock [Member]

Basic Net Income (Loss) per Share [Abstract]

Weighted average shares owned in Akcea (in shares)

77,095

70,100

59,812

Basic net income (loss) per share (in dollars per share)

$ (1.45)

$ 0.49

$ (2.74)

Net income (loss)

$ (111,775)

$ 34,073

$ (163,938)

[1]	As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income (loss) per share calculation for each of the fourth quarters in 2020 and 2019 considered our net income (loss) for Ionis on a stand-alone basis plus our share of Akcea’s net loss for the period. To calculate the portion of Akcea’s net loss attributable to our ownership, we multiplied Akcea’s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.
[2]	We compute net income (loss) per share independently for each quarter during the year.
[3]	We had net income available to Ionis common stockholders for the fourth quarter of 2019. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period

Organization and Significant Accounting Policies, Revenue Recognition (Details) $ in Thousands	1 Months Ended				3 Months Ended						12 Months Ended
	Feb. 28, 2017 USD ($) PerformanceObligation	Jul. 31, 2015 USD ($) PerformanceObligation	May 31, 2015 USD ($) PerformanceObligation	Sep. 30, 2013 USD ($) PerformanceObligation	Dec. 31, 2020 USD ($)	Sep. 30, 2020 USD ($)	Sep. 30, 2019 USD ($)	Dec. 31, 2018 USD ($)	Jun. 30, 2018 USD ($) Agreement	Jun. 30, 2015 USD ($)	Dec. 31, 2020 USD ($) PerformanceObligation	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)	Oct. 31, 2018 USD ($) PerformanceObligation	Apr. 30, 2018 USD ($) PerformanceObligation
Revenue Recognition [Abstract]
Number of performance obligations at inception of contract \| PerformanceObligation											1
Revenue											$ 729,264	$ 1,122,599	$ 599,674
Biogen [Member]
Revenue Recognition [Abstract]
Number of agreements \| Agreement									2
Licensing and Other Royalties [Member]
Revenue Recognition [Abstract]
Revenue											8,117	$ 17,205	$ 14,755
AstraZeneca [Member]
Revenue Recognition [Abstract]
Revenue					$ 20,000
Upfront payment received		$ 65,000
Number of separate performance obligations \| PerformanceObligation		1
Transaction price		$ 65,000
AstraZeneca [Member] \| ION455 [Member]
Revenue Recognition [Abstract]
Revenue					30,000						$ 30,000
Roche IONIS-FB-L for Complement-Mediated Diseases [Member]
Revenue Recognition [Abstract]
Revenue					(9,200)
Upfront payment received								$ 75,000
Number of separate performance obligations \| PerformanceObligation														1
Transaction price														$ 75,000
Biogen 2018 Strategic Neurology [Member]
Revenue Recognition [Abstract]
Milestone payment received and added to transaction price					7,500
Upfront payment received									$ 375,000
Number of separate performance obligations \| PerformanceObligation															1
Transaction price															$ 552,000
Biogen 2013 Strategic Neurology [Member]
Revenue Recognition [Abstract]
Revenue						$ 18,000	$ (16,500)
Upfront payment received				$ 100,000
Number of separate performance obligations \| PerformanceObligation				1
Transaction price				$ 100,000
Biogen 2013 Strategic Neurology [Member] \| Licensing and Other Royalties [Member]
Revenue Recognition [Abstract]
Revenue								$ 35,000
Alnylam [Member]
Revenue Recognition [Abstract]
Revenue					$ 41,200
Bayer [Member]
Revenue Recognition [Abstract]
Upfront payment received			$ 100,000							$ 100,000
Number of separate performance obligations \| PerformanceObligation			3
Bayer [Member]
Revenue Recognition [Abstract]
Upfront payment received	$ 75,000
Number of separate performance obligations \| PerformanceObligation	3
Transaction price	$ 75,000

Organization and Significant Accounting Policies, Contracts Receivable (Details)	12 Months Ended
	Dec. 31, 2020
Contracts Receivable [Abstract]
Period of time after billing when payment is received	3 months

Organization and Significant Accounting Policies, Deferred Revenue (Details) - USD ($) $ in Millions	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019
Deferred Revenue [Abstract]
Revenue recognized from amounts in beginning deferred revenue balance	$ 100.4	$ 159.5

Organization and Significant Accounting Policies, Research, Development and Patent Expenses (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Research, Development and Patent Expenses [Abstract]
Research and development expenses	$ 531,000	$ 461,500	$ 411,900
Estimated Amortization Expense [Abstract]
Non-cash charges related to write-down	1,948	2,226	802
Patents [Member]
Research, Development and Patent Expenses [Abstract]
Research and development expenses	$ 4,100	4,200	2,600
Estimated useful life	10 years 3 months 18 days
Cost	$ 37,000	34,000
Accumulated amortization	9,100	8,300
Estimated Amortization Expense [Abstract]
2021	2,100
2022	2,000
2023	1,900
2024	1,700
2025	1,600
Non-cash charges related to write-down	1,900	2,200	800
Collaborative Agreements [Member]
Research, Development and Patent Expenses [Abstract]
Research and development expenses	$ 49,800	$ 83,200	$ 58,700

Organization and Significant Accounting Policies, Accrued Liabilities (Details) - USD ($) $ in Thousands	Dec. 31, 2020	Dec. 31, 2019
Accrued Liabilities [Abstract]
Clincial expenses	$ 39,477	$ 24,461
In-licensing expenses	8,264	10,289
Commercial expenses	11,559	6,020
Other miscellaneous expenses	30,861	25,999
Total accrued liabilities	$ 90,161	$ 66,769

Organization and Significant Accounting Policies, Noncontrolling Interest in Akcea Therapeutics, Inc. (Details) - Akcea [Member]	Oct. 31, 2020	Sep. 30, 2020	Jun. 30, 2017
Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]
Percentage ownership	100.00%	76.00%	100.00%
Minimum [Member]
Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]
Percentage ownership	68.00%
Maximum [Member]
Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]
Percentage ownership	77.00%

Organization and Significant Accounting Policies, Cash, Cash Equivalents and Investments (Details) $ in Thousands	3 Months Ended		9 Months Ended	12 Months Ended
	Dec. 31, 2020 USD ($) Company	Jun. 30, 2020 USD ($)	Dec. 31, 2020 Company Investment	Dec. 31, 2020 USD ($) Company	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)
Cash, Cash Equivalents and Investments [Abstract]
Number of publicly held companies in which there is an equity ownership interest of less than 20% \| Company	2		2	2
Number of privately held companies in which there is an equity ownership interest of less than 20% \| Company	7		7	7
Number of investments in privately held companies that were revalued \| Investment			3
Gain on investment				$ 16,540	$ 192	$ (210)
Dynacure SAS [Member]
Cash, Cash Equivalents and Investments [Abstract]
Gain on investment		$ 6,300
Suzhou-Ribo [Member]
Cash, Cash Equivalents and Investments [Abstract]
Gain on investment	$ 3,000
Aro Biotherapeutics [Member]
Cash, Cash Equivalents and Investments [Abstract]
Gain on investment	$ 5,500

Organization and Significant Accounting Policies, Inventory Valuation (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Inventory Valuation [Abstract]
Inventory write-off			$ 0
Raw materials	16,708	15,883
Work in process	2,252	2,039
Finished goods	3,005	258
Total inventory	21,965	18,180
Clinical Member]
Inventory Valuation [Abstract]
Raw materials	9,206	9,363
Commercial [Member]
Inventory Valuation [Abstract]
Raw materials	$ 7,502	$ 6,520

Organization and Significant Accounting Policies, Property, Plant and Equipment (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019
Property, Plant and Equipment [Abstract]
Less accumulated depreciation	$ (87,379)	$ (74,013)
Property, plant and equipment, net	181,077	153,651
Property, Plant and Equipment, Excluding Land [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	245,394	204,602
Property, plant and equipment, net	158,015	130,589
Computer Software, Laboratory, Manufacturing and Other Equipment [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 68,990	60,965
Computer Software, Laboratory, Manufacturing and Other Equipment [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	3 years
Computer Software, Laboratory, Manufacturing and Other Equipment [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	10 years
Building, Building Improvements and Building Systems [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 137,879	119,830
Building, Building Improvements and Building Systems [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	15 years
Building, Building Improvements and Building Systems [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	40 years
Land Improvements [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 8,391	2,853
Estimated useful lives	20 years
Leasehold Improvements [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 17,263	13,600
Leasehold Improvements [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	5 years
Leasehold Improvements [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	15 years
Furniture and Fixtures [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 12,871	7,354
Furniture and Fixtures [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	5 years
Furniture and Fixtures [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	10 years
Land [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 23,062	$ 23,062

Organization and Significant Accounting Policies, Long-Lived Assets (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Long-Lived Assets [Abstract]
Charges related to write-down of patents	$ 1,948	$ 2,226	$ 802

Organization and Significant Accounting Policies, Stock-Based Compensation Expense (Details)	12 Months Ended
	Dec. 31, 2020
RSUs [Member]
Stock-Based Compensation Expense [Abstract]
Vesting period	4 years

Organization and Significant Accounting Policies, Accumulated Other Comprehensive Loss (Details) - USD ($)
$ in Thousands

12 Months Ended

Dec. 31, 2020

Dec. 31, 2019

Dec. 31, 2018

Accumulated Other Comprehensive Loss [Roll Forward]

Balance

$ 1,684,547

$ 1,187,160

$ 365,280

Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.

(127)

Net other comprehensive loss for the period

4,219

6,726

(257)

Balance

843,347

1,684,547

1,187,160

Income tax expense (benefit) included in other comprehensive loss

(1,400)

(300)

Accumulated Other Comprehensive Loss [Member]

Accumulated Other Comprehensive Loss [Roll Forward]

Balance

(25,290)

(32,016)

(31,759)

Balance

(21,071)

(25,290)

(32,016)

Unrealized Gains (Losses) on Securities [Member]

Accumulated Other Comprehensive Loss [Roll Forward]

Other comprehensive loss before reclassifications, net of tax

^[1]

3,729

6,633

(280)

Currency Translation Adjustment [Member]

Accumulated Other Comprehensive Loss [Roll Forward]

Other comprehensive loss before reclassifications, net of tax

$ 617

$ 93

$ 23

[1]	We did not have tax expense included in our other comprehensive loss for the year ended December 31, 2020. For the years ended December 31, 2019 and 2018, we had a tax benefit $1.4 million and $0.3 million included in other comprehensive loss respectively.

- Definition

Amount after tax and reclassification adjustments of other comprehensive income (loss).

+ References

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- Definition

Amount of tax expense (benefit) allocated to other comprehensive income (loss).

+ References

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Amount of stockholders' equity (deficit), net of receivables from officers, directors, owners, and affiliates of the entity, attributable to both the parent and noncontrolling interests. Amount excludes temporary equity. Alternate caption for the concept is permanent equity.

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+ Details

Organization and Significant Accounting Policies, Convertible Debt (Details)	Dec. 31, 2020	Dec. 31, 2019
0.125 Percent Convertible Senior Notes [Member]
Convertible Debt [Abstract]
Interest rate on convertible senior notes	0.125%	0.125%
1 Percent Convertible Senior Notes [Member]
Convertible Debt [Abstract]
Interest rate on convertible senior notes	1.00%	1.00%

Organization and Significant Accounting Policies, Call Spread (Details)	Dec. 31, 2020	Dec. 31, 2019
0.125 Percent Convertible Senior Notes [Member]
Call Spread [Abstract]
Interest rate on convertible senior notes	0.125%	0.125%

Organization and Significant Accounting Policies, Segment Information (Details)	12 Months Ended
	Dec. 31, 2020 Segment
Segment Information [Abstract]
Number of operating segments	2

Organization and Significant Accounting Policies, Fair Value Measurements (Details) - Recurring Basis [Member] - USD ($)
$ in Thousands

Dec. 31, 2020

Dec. 31, 2019

Fair Value Measurements [Abstract]

Cash equivalents

^[1]

$ 221,125

$ 418,406

Investment in ProQR NV

^[2]

2,031

4,506

Total

1,745,363

2,258,985

Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

846,315

^[3]

1,102,568

^[4]

Corporate Debt Securities [Member] | Cash and Cash Equivalents [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

10,000

19,000

Debt Securities issued by U.S. Government Agencies [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

174,861

^[5]

329,404

^[6]

Debt Securities issued by U.S. Government Agencies [Member] | Cash and Cash Equivalents [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

800

Debt Securities issued by the U.S. Treasury [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

358,497

^[7]

363,694

^[5]

Debt Securities issued by the U.S. Treasury [Member] | Cash and Cash Equivalents [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

17,500

Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

^[5]

136,309

40,407

Other Municipal Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

^[5]

6,225

Quoted Prices in Active Markets (Level 1) [Member]

Fair Value Measurements [Abstract]

Cash equivalents

221,125

418,406

Investment in ProQR NV

2,031

Total

581,653

782,100

Quoted Prices in Active Markets (Level 1) [Member] | Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities issued by U.S. Government Agencies [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities issued by the U.S. Treasury [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

358,497

363,694

Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Quoted Prices in Active Markets (Level 1) [Member] | Other Municipal Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Significant Other Observable Inputs (Level 2) [Member]

Fair Value Measurements [Abstract]

Cash equivalents

Investment in ProQR NV

Total

1,163,710

1,472,379

Significant Other Observable Inputs (Level 2) [Member] | Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

846,315

1,102,568

Significant Other Observable Inputs (Level 2) [Member] | Debt Securities issued by U.S. Government Agencies [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

174,861

329,404

Significant Other Observable Inputs (Level 2) [Member] | Debt Securities issued by the U.S. Treasury [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Significant Other Observable Inputs (Level 2) [Member] | Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

136,309

40,407

Significant Other Observable Inputs (Level 2) [Member] | Other Municipal Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

$ 6,225

Significant Unobservable Inputs (Level 3) [Member]

Fair Value Measurements [Abstract]

Cash equivalents

Investment in ProQR NV

4,506

Total

4,506

Significant Unobservable Inputs (Level 3) [Member] | Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Significant Unobservable Inputs (Level 3) [Member] | Debt Securities issued by U.S. Government Agencies [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Significant Unobservable Inputs (Level 3) [Member] | Debt Securities issued by the U.S. Treasury [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Significant Unobservable Inputs (Level 3) [Member] | Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

$ 0

[1]	Included in cash and cash equivalents on our consolidated balance sheet.
[2]	Included in other current assets on our consolidated balance sheet.
[3]	$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.
[4]	$19.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.
[5]	Included in short-term investments.
[6]	$0.8 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.
[7]	$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

Investments, Contract Maturity of Available-for-Sale Securities (Details)	12 Months Ended
	Dec. 31, 2020 Company
Contract Maturity of Available-for-Sale Securities [Abstract]
One year or less	73.00%
After one year but within two years	18.00%
After two years but within three and a half years	9.00%
Total	100.00%
Percentage of available-for-sale securities with a maturity of less than two years	91.00%
Maximum contract maturity period, range 1	1 year
Maximum contract maturity period, range 2	2 years
Maximum contract maturity period, range 3	3 years 6 months
Ownership Interests in Private and Public Companies [Abstract]
Number of privately held companies in which there is an equity ownership interest of less than 20%	7
Number of publicly held companies in which there is an equity ownership interest of less than 20%	2

Investments, Summary of Investments (Details) - USD ($)
$ in Thousands

12 Months Ended

Dec. 31, 2020

Dec. 31, 2019

Summary of Investments [Abstract]

Cost

$ 1,533,544

$ 1,846,074

Gross unrealized gains

24,515

5,007

Gross unrealized losses

(2,821)

(1,166)

Estimated fair value

1,555,238

1,849,915

Available-for-sale Securities [Member]

Summary of Investments [Abstract]

Cost

^[1]

1,513,770

1,831,362

Gross unrealized gains

8,577

5,007

Gross unrealized losses

(140)

(296)

Estimated fair value

1,522,207

1,836,073

Available-for-sale Securities [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Cost

^[1]

1,025,454

1,206,616

Gross unrealized gains

2,977

2,012

Gross unrealized losses

(71)

(118)

Estimated fair value

1,028,360

1,208,510

Available-for-sale Securities [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Cost

^[1]

488,316

624,746

Gross unrealized gains

5,600

2,995

Gross unrealized losses

(69)

(178)

Estimated fair value

493,847

627,563

Corporate Debt Securities [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Cost

^[1],[2]

514,182

669,665

Gross unrealized gains

2,194

1,451

Gross unrealized losses

(41)

(43)

Estimated fair value

516,335

671,073

Corporate Debt Securities [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Cost

^[1]

325,079

428,627

Gross unrealized gains

4,941

2,911

Gross unrealized losses

(40)

(43)

Estimated fair value

329,980

431,495

Debt Securities issued by U.S. Government Agencies [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Cost

^[1]

94,234

188,216

Gross unrealized gains

354

303

Gross unrealized losses

(2)

(43)

Estimated fair value

94,586

188,476

Debt Securities issued by U.S. Government Agencies [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Cost

^[1]

80,099

140,988

Gross unrealized gains

185

Gross unrealized losses

(9)

(117)

Estimated fair value

80,275

140,928

Debt Securities issued by the U.S. Treasury [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Cost

^[1],[2]

307,576

327,670

Gross unrealized gains

233

232

Gross unrealized losses

(9)

(27)

Estimated fair value

307,800

327,875

Debt Securities issued by the U.S. Treasury [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Cost

^[1]

50,318

35,822

Gross unrealized gains

383

Gross unrealized losses

(4)

(12)

Estimated fair value

50,697

35,819

Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Cost

^[1]

104,271

21,065

Gross unrealized gains

196

Gross unrealized losses

(12)

(5)

Estimated fair value

104,455

21,086

Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Cost

^[1]

31,779

19,309

Gross unrealized gains

Gross unrealized losses

(16)

(6)

Estimated fair value

31,854

19,321

Other Municipal Debt Securities [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Cost

^[1]

5,191

Gross unrealized gains

Gross unrealized losses

(7)

Estimated fair value

5,184

Other Municipal Debt Securities [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Cost

^[1]

1,041

Gross unrealized gains

Gross unrealized losses

Estimated fair value

1,041

Equity Securities [Member]

Summary of Investments [Abstract]

Cost

19,774

14,712

Gross unrealized gains

15,938

Gross unrealized losses

(2,681)

(870)

Estimated fair value

33,031

13,842

Equity Securities in Publicly Traded Company [Member]

Summary of Investments [Abstract]

Cost

^[3]

4,712

Gross unrealized gains

Gross unrealized losses

(2,681)

(870)

Estimated fair value

2,031

3,842

Equity Securities in Private Companies [Member]

Summary of Investments [Abstract]

Cost

^[4]

15,062

10,000

Gross unrealized gains

15,938

^[4]

Gross unrealized losses

^[4]

Estimated fair value

$ 31,000

$ 10,000

^[4]

[1]	We hold our available-for-sale securities at amortized cost.
[2]	Includes investments classified as cash equivalents on our consolidated balance sheet.
[3]	Our equity securities included in other current assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.
[4]	Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer on our consolidated balance sheet.

Investments, Investments Temporarily Impaired (Details) $ in Thousands	Dec. 31, 2020 USD ($) Investment
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	226
Estimated fair value, less than 12 months of temporary impairment	$ 284,148
Unrealized losses, less than 12 months of temporary impairment	$ (140)
Corporate Debt Securities [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	54
Estimated fair value, less than 12 months of temporary impairment	$ 121,162
Unrealized losses, less than 12 months of temporary impairment	$ (81)
Debt Securities issued by U.S. Government Agencies [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	2
Estimated fair value, less than 12 months of temporary impairment	$ 29,988
Unrealized losses, less than 12 months of temporary impairment	$ (11)
Debt Securities issued by the U.S. Treasury [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	8
Estimated fair value, less than 12 months of temporary impairment	$ 76,941
Unrealized losses, less than 12 months of temporary impairment	$ (13)
Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	160
Estimated fair value, less than 12 months of temporary impairment	$ 49,832
Unrealized losses, less than 12 months of temporary impairment	$ (28)
Other Municipal Debt Securities [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	2
Estimated fair value, less than 12 months of temporary impairment	$ 6,225
Unrealized losses, less than 12 months of temporary impairment	$ (7)

Long-Term Obligations and Commitments, Long-Term Obligations (Details) - USD ($)
$ in Thousands

Dec. 31, 2020

Dec. 31, 2019

Long-Term Obligations [Abstract]

Long-term mortgage debt

$ 59,984

$ 59,913

Leases and other obligations

30,710

17,569

Total

839,574

787,526

Less: current portion

(300,462)

(2,026)

Total Long-Term Obligations

539,112

785,500

0.125 Percent Convertible Senior Notes [Member]

Long-Term Obligations [Abstract]

Convertible senior notes

$ 455,719

$ 434,711

Interest rate on convertible senior notes

0.125%

1 Percent Convertible Senior Notes [Member]

Long-Term Obligations [Abstract]

Convertible senior notes

$ 293,161

^[1]

$ 275,333

Interest rate on convertible senior notes

1.00%

[1]	We classified the carrying value of our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matures in November 2021.

Long-Term Obligations and Commitments, Convertible Notes (Details)
$ / shares in Units, $ in Thousands, shares in Millions

1 Months Ended

12 Months Ended

Dec. 31, 2019

USD ($)

$ / shares

Dec. 31, 2020

USD ($)

$ / shares

Dec. 31, 2019

USD ($)

$ / shares

Dec. 31, 2018

USD ($)

Dec. 31, 2016

USD ($)

Nov. 30, 2014

USD ($)

Convertible Notes [Abstract]

Cost of call spread

$ 52,600

Purchase of note hedges

108,700

$ 0

$ 108,684

$ 0

Proceeds from issuance of warrants

$ 56,100

$ 56,110

Conversion price per share, including note hedges (in dollars per share) | $ / shares

$ 123.38

Current debt

$ 0

293,161

$ 0

Loss on early retirement of debt

(21,865)

Amortization of debt discount and debt issuance costs

$ 38,700

$ 39,300

$ 35,200

0.125% Convertible Senior Notes [Member]

Convertible Notes [Abstract]

Maturity date

Dec. 15, 2024

Interest rate

0.125%

Conversion price per share (in dollars per share) | $ / shares

$ 83.28

Total shares of common stock subject to conversion (in shares) | shares

6.6

Percentage of principal amount used as purchase price upon occurrence of fundamental change

100.00%

Principal amount of convertible notes outstanding

$ 548,800

Unamortized portion of debt discount

105,200

86,000

105,200

Long-term debt

434,711

455,719

434,711

Carrying value of equity component

105,800

$ 105,800

105,800

Effective interest rate

4.90%

Amortization period of debt discount

5 years

0.125% Convertible Senior Notes [Member] | Level 2 [Member]

Convertible Notes [Abstract]

Fair value of outstanding notes

558,700

$ 564,900

558,700

0.125% Convertible Senior Notes [Member] | Borrowing Rate [Member]

Convertible Notes [Abstract]

Nonconvertible debt measurement input rate

0.044

0.125 Percent Convertible Senior Notes Issued in Exchange for 1 Percent Notes [Member]

Convertible Notes [Abstract]

Face amount of offering

439,300

0.125 Percent Convertible Senior Notes Issued under Subscription Agreements [Member]

Convertible Notes [Abstract]

Face amount of offering

109,500

1% Convertible Senior Notes [Member]

Convertible Notes [Abstract]

Principal amount repurchased

$ 375,600

Face amount of offering

$ 185,500

$ 500,000

Maturity date

Nov. 30, 2021

Interest rate

1.00%

Conversion price per share (in dollars per share) | $ / shares

$ 66.81

Total shares of common stock subject to conversion (in shares) | shares

4.6

Percentage of principal amount used as purchase price upon occurrence of fundamental change

100.00%

Principal amount of convertible notes outstanding

$ 309,900

Unamortized portion of debt discount

32,800

15,800

32,800

Current debt

293,200

Long-term debt

275,333

Carrying value of equity component

33,500

$ 33,500

33,500

Loss on early retirement of debt

(21,900)

Effective interest rate

^[1]

7.50%

Amortization period of debt discount

7 years

1% Convertible Senior Notes [Member] | Level 2 [Member]

Convertible Notes [Abstract]

Fair value of outstanding notes

$ 354,800

$ 338,500

$ 354,800

1% Convertible Senior Notes [Member] | Borrowing Rate [Member]

Convertible Notes [Abstract]

Nonconvertible debt measurement input rate

0.074

2 3/4 Percent Convertible Senior Notes [Member]

Convertible Notes [Abstract]

Principal amount repurchased

$ 61,100

$ 140,000

Interest rate

2.75%

[1]	For our 1% Notes, our effective interest rate represents our effective interest rate after our December 2019 debt exchange.

Long-Term Obligations and Commitments, Line of Credit Arrangement (Details) - USD ($) $ in Thousands	3 Months Ended	12 Months Ended
	Sep. 30, 2019	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Line of Credit Arrangement [Abstract]
Payment of outstanding borrowings		$ 0	$ 12,500	$ 0
Fixed Rate Note with Morgan Stanley [Member]
Line of Credit Arrangement [Abstract]
Payment of outstanding borrowings	$ 12,500
Morgan Stanley [Member] \| Revolving Line of Credit [Member]
Line of Credit Arrangement [Abstract]
Term of agreement		5 years
Maximum borrowing capacity		$ 30,000

Long-Term Obligations and Commitments, Research and Development and Manufacturing Facilities (Details) $ in Millions	1 Months Ended		12 Months Ended
	Jul. 31, 2017 USD ($)	Jul. 31, 2015 Facility	Dec. 31, 2020
Research and Development and Manufacturing Facilities [Abstract]
Number of purchased facilities financed with mortgage debt \| Facility		2
Long-term Mortgage Debt [Member]
Research and Development and Manufacturing Facilities [Abstract]
Face amount	$ 60.4
Primary R&D Facility [Member]
Research and Development and Manufacturing Facilities [Abstract]
Payment to acquire building	$ 79.4
Interest rate	3.88%
Period to make interest only payments on mortgage loan			5 years
Manufacturing Facility [Member]
Research and Development and Manufacturing Facilities [Abstract]
Payment to acquire building	$ 14.0
Interest rate	4.20%
Period to make interest only payments on mortgage loan			5 years

Long-Term Obligations and Commitments, Maturity Schedules (Details) - USD ($) $ in Thousands	Dec. 31, 2020	Dec. 31, 2019
Annual Debt and Other Obligation Maturities [Abstract]
2021	$ 329,189
2022	3,495
2023	4,180
2024	553,006
2025	3,494
Thereafter	60,933
Subtotal	954,297
Less: current portion	(300,462)	$ (2,026)
Less: fixed and determinable interest	(21,758)
Less: unamortized portion of debt discount	(101,820)
Less: debt issuance costs	(8,455)
Plus: lease liabilities	17,310
Total long-term debt	$ 539,112	$ 785,500

Long-Term Obligations and Commitments, Operating Leases (Details)
$ in Thousands

12 Months Ended

Dec. 31, 2020

USD ($)

Option

Dec. 31, 2019

USD ($)

Dec. 31, 2018

USD ($)

Operating Leases [Abstract]

Right-of-use operating lease assets

^[1]

$ 13,100

Operating Lease, Right-of-Use Asset, Statement of Financial Position [Extensible List]

us-gaap:OtherAssetsNoncurrent

Operating lease liabilities

^[2]

$ 17,310

Weighted average remaining lease term

7 years 2 months 12 days

Weighted average discount rate

7.00%

Current portion of operating lease liabilities

$ 2,000

Operating Lease, Liability, Current, Statement of Financial Position [Extensible List]

us-gaap:LongTermDebtAndCapitalLeaseObligationsCurrent

Operating Lease, Liability, Noncurrent, Statement of Financial Position [Extensible List]

ions:LongTermObligationsNoncurrent

Operating lease cash payments

$ 3,800

$ 3,900

$ 1,700

Annual Future Payments for Operating Lease Liabilities [Abstract]

3,193

2,968

2,707

2,583

2,442

7,038

Total minimum lease payments

20,931

Imputed interest

(3,621)

Total operating lease liabilities

^[2]

17,310

Rent expense

$ 3,700

$ 3,600

$ 2,600

Carlsbad Facility [Member]

Operating Leases [Abstract]

Number of options to extend lease | Option

Term of lease extension

5 years

Carlsbad Office Spaces [Member]

Operating Leases [Abstract]

Number of options to extend lease | Option

Term of lease extension

5 years

Akcea [Member] | Boston Office Space [Member]

Operating Leases [Abstract]

Term of lease extension

5 years

Term of lease

123 months

Period of free rent under lease

3 months

Tenant improvement allowance

$ 3,800

Initial amount of letter of credit

2,400

Letter of credit on third anniversary of rent commencement date

1,800

Letter of credit on fifth anniversary of rent commencement date

$ 1,200

[1]	Included in deposits and other assets on our consolidated balance sheet.
[2]	Current portion of $2.0 million was included in current portion of long-term obligations on our consolidated balance sheet, with the difference included in long-term obligations.

Stockholders' Equity, Preferred and Common Stock (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Common Stock [Abstract]
Common stock, shares authorized to issue (in shares)	300,000,000	300,000,000
Common stock, shares issued (in shares)	140,365,594	140,339,615
Common stock, shares outstanding (in shares)	140,365,594	140,339,615
Net proceeds from stock option exercises, vesting of restricted stock units, and ESPP purchases	$ 52,036	$ 119,657	$ 27,900
Preferred Stock [Member]
Preferred Stock [Abstract]
Preferred stock, shares authorized (in shares)	15,000,000
Preferred stock, shares outstanding (in shares)	0
Series C Junior Participating Preferred Stock [Member]
Preferred Stock [Abstract]
Preferred stock, shares issued (in shares)	0
Preferred stock, shares outstanding (in shares)	0
Common Stock [Member]
Common Stock [Abstract]
Common stock, shares authorized to issue (in shares)	300,000,000	300,000,000
Common stock, shares issued (in shares)	140,400,000	140,300,000
Common stock, shares outstanding (in shares)	140,400,000	140,300,000
Common shares reserved for future issuance (in shares)	26,100,000
Number of shares issued for stock option exercises, vesting of restricted stock units, and ESPP purchases (in shares)	1,700,000	3,100,000	1,500,000
Net proceeds from stock option exercises, vesting of restricted stock units, and ESPP purchases	$ 52,000	$ 119,700	$ 27,900

Stockholders' Equity, Share Repurchase Program (Details) - USD ($) $ in Thousands	3 Months Ended	12 Months Ended
	Mar. 31, 2020	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018	Sep. 30, 2019
Share Repurchase Program [Abstract]
Authorized amount of share repurchase program					$ 125,000
Shares repurchased (in shares)	1,500,000		535,000
Shares repurchased	$ 90,500	$ 90,548	$ 34,392	$ 0

Stockholders' Equity, Stock Plans (Details)	1 Months Ended	12 Months Ended
Stockholders' Equity, Stock Plans (Details)	Jun. 30, 2009 shares	Dec. 31, 2020 Officer $ / shares shares	Jun. 30, 2020 shares	Dec. 31, 2019 shares	Jun. 30, 2019 shares	May 31, 2017 shares	Jun. 30, 2015 shares	May 31, 2015 shares
Stock Options [Member]
Stock Plans [Abstract]
Number of options outstanding (in shares)		12,335,000		11,001,000
Number of options exercisable (in shares)		7,366,000
Restricted Stock Units [Member]
Stock Plans [Abstract]
Vesting period		4 years
1989 Stock Option Plan [Member]
Stock Plans [Abstract]
Number of shares authorized (in shares)		20,000,000.0
Number of options outstanding (in shares)		30,000
Number of options exercisable (in shares)		30,000
Number of shares available for grant (in shares)		50,000
1989 Stock Option Plan [Member] \| Stock Options [Member]
Stock Plans [Abstract]
Vesting period		4 years
Award term		7 years
1989 Stock Option Plan [Member] \| Stock Options [Member] \| One Year from Date of Grant [Member]
Stock Plans [Abstract]
Vesting percentage		25.00%
Period before options are exercisable		1 year
2011 Equity Incentive Plan [Member]
Stock Plans [Abstract]
Number of shares authorized (in shares)					23,000,000.0	16,000,000.0	11,000,000.0	5,500,000
Number of options outstanding (in shares)		11,400,000
Number of options exercisable (in shares)		6,700,000
Number of shares available for grant (in shares)		4,300,000
Number of executive officers terminated before change in control when vesting will accelerate for executive officers \| Officer		1
Period before change in control when vesting will accelerate for executive officers		3 months
Period after change in control when vesting will accelerate for executive officers		12 months
2011 Equity Incentive Plan [Member] \| Restricted Stock Units [Member]
Stock Plans [Abstract]
Vesting period		4 years
Number of awards outstanding (in shares)		2,200,000
2020 Equity Incentive Plan [Member]
Stock Plans [Abstract]
Number of shares authorized (in shares)		2,600,000
Number of options outstanding (in shares)		10,000.00
Number of options exercisable (in shares)		0
Number of shares available for grant (in shares)		2,600,000
2020 Equity Incentive Plan [Member] \| Stock Options [Member]
Stock Plans [Abstract]
Vesting period		4 years
2002 Non-Employee Directors' Stock Option Plan [Member]
Stock Plans [Abstract]
Number of shares authorized (in shares)			2,800,000				2,000,000.0	1,200,000
Number of options outstanding (in shares)		1,000,000.0
Number of options exercisable (in shares)		600,000
Number of shares available for grant (in shares)		800,000
2002 Non-Employee Directors' Stock Option Plan [Member] \| Stock Options [Member]
Stock Plans [Abstract]
Award term		10 years
2002 Non-Employee Directors' Stock Option Plan [Member] \| Restricted Stock Units [Member]
Stock Plans [Abstract]
Number of awards outstanding (in shares)		100,000
Employee Stock Purchase Plan [Member]
Stock Plans [Abstract]
Number of shares authorized (in shares)		3,200,000
Number of additional shares reserved for issuance (in shares)	150,000	150,000
Maximum percentage of employee compensation used to purchase shares		10.00%
Percentage of fair market value used to determine purchase price of stock		85.00%
Holding period for purchased stock		6 months
Shares purchased and issued under ESPP (in shares)		60,000.00
Weighted average purchase price (in dollars per share) \| $ / shares		$ 43.65
Shares available for purchase under ESPP (in shares)		700,000

Stockholders' Equity, Stock Option Activity (Details) - Stock Options [Member] - USD ($) $ / shares in Units, shares in Thousands, $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Number of Shares [Abstract]
Outstanding at beginning of period (in shares)	11,001
Granted (in shares)	2,764
Exercised (in shares)	(1,069)
Cancelled/forfeited/expired (in shares)	(361)
Outstanding at end of period (in shares)	12,335	11,001
Exercisable at end of period (in shares)	7,366
Weighted Average Exercise Price Per Share [Abstract]
Outstanding at beginning of period (in dollars per share)	$ 51.48
Granted (in dollars per share)	59.89
Exercised (in dollars per share)	40.88
Cancelled/forfeited/expired (in dollars per share)	56.48
Outstanding at end of period (in dollars per share)	54.14	$ 51.48
Exercisable at end of period (in dollars per share)	$ 52.45
Average Remaining Contractual Term, Aggregate Intrinsic Value and Other [Abstract]
Average remaining contractual term, outstanding at end of period	4 years 1 month 28 days
Average remaining contractual term, exercisable at end of period	3 years 1 month 28 days
Aggregate intrinsic value, outstanding at end of period	$ 55,885
Aggregate intrinsic value, exercisable at end of period	$ 43,267
Weighted average fair value of options granted (in dollars per share)	$ 29.43	$ 28.76	$ 25.49
Intrinsic value of options exercised	$ 15,500	$ 83,800	$ 34,800
Cash received from exercise of stock options	$ 43,700	$ 105,900	$ 18,900
Weighted-average fair value of options exercised (in dollars per share)	$ 55.33
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation cost related to non-vested stock options	$ 54,100
Weighted average period for recognition	1 year 1 month 6 days

Stockholders' Equity, Restricted Stock Unit Activity (Details) - Restricted Stock Units [Member] - USD ($) $ / shares in Units, shares in Thousands, $ in Millions	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Number of Shares [Abstract]
Non-vested at beginning of period (in shares)	1,866
Granted (in shares)	1,244
Vested (in shares)	(602)
Cancelled/forfeited (in shares)	(134)
Non-vested at end of period (in shares)	2,374	1,866
Weighted Average Grant Date Fair Value per Share [Abstract]
Non-vested at beginning of period (in dollars per share)	$ 55.80
Granted (in dollars per share)	60.86	$ 60.23	$ 51.06
Vested (in dollars per share)	53.68
Cancelled/forfeited (in dollars per share)	58.96
Non-vested at end of period (in dollars per share)	$ 58.81	$ 55.80
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation cost related to non-vested RSUs	$ 55.3
Weighted average period for recognition	1 year 3 months 18 days

Stockholders' Equity, Stock-based Compensation Expense (Details) $ in Thousands	3 Months Ended	12 Months Ended
	Sep. 30, 2019 USD ($) Officer	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)	Oct. 31, 2020 USD ($)
Stock-Based Compensation [Abstract]
Stock-based compensation expense		$ 230,117	$ 146,574	$ 131,312
Cost of Products Sold [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense		1,991	438	160
Research, Development and Patent [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense		115,584	95,348	76,557
Selling, General and Administrative [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense		112,542	50,788	54,595
Akcea [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense	$ (19,100)	$ 94,800	$ 37,100	$ 44,300
Unrecognized compensation cost related to non-vested RSUs					$ 59,300
Number of executive officers terminating employment \| Officer	3

Stockholders' Equity, Stock-based Valuation Information (Details) - $ / shares	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Employee Stock Options [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	1.50%	2.30%	2.40%
Dividend yield	0.00%	0.00%	0.00%
Volatility	58.60%	60.30%	63.00%
Expected life	4 years 8 months 12 days	4 years 9 months 18 days	4 years 7 months 6 days
Board of Director Stock Options [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	0.50%	1.90%	2.80%
Dividend yield	0.00%	0.00%	0.00%
Volatility	57.60%	60.70%	61.50%
Expected life	6 years 8 months 12 days	6 years 7 months 6 days	6 years 7 months 6 days
ESPP [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	0.80%	2.40%	1.80%
Dividend yield	0.00%	0.00%	0.00%
Volatility	47.90%	45.60%	47.30%
Expected life	6 months	6 months	6 months
RSUs [Member]
Akcea RSU's [Abstract]
Weighted-average grant date fair value (in dollars per share)	$ 60.86	$ 60.23	$ 51.06
Akcea [Member] \| Employee Stock Options [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	1.10%	2.20%	2.80%
Dividend yield	0.00%	0.00%	0.00%
Volatility	75.00%	75.40%	77.10%
Expected life	6 years 29 days	6 years 1 month 2 days	6 years 29 days
Akcea [Member] \| Board of Director Stock Options [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	0.80%	1.80%	2.90%
Dividend yield	0.00%	0.00%	0.00%
Volatility	75.30%	73.80%	78.20%
Expected life	5 years 8 months 1 day	6 years 3 months	6 years 5 months 1 day
Akcea [Member] \| ESPP [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	1.00%	2.40%	1.90%
Dividend yield	0.00%	0.00%	0.00%
Volatility	71.90%	60.00%	64.20%
Expected life	6 months	6 months	6 months
Akcea [Member] \| RSUs [Member]
Akcea RSU's [Abstract]
Weighted-average grant date fair value (in dollars per share)	$ 15.57	$ 21.95
Akcea [Member] \| RSUs [Member] \| Minimum [Member]
Akcea RSU's [Abstract]
Award term	6 months
Akcea [Member] \| RSUs [Member] \| Maximum [Member]
Akcea RSU's [Abstract]
Award term	4 years

Income Taxes, Income (Loss) Before Income Taxes (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Income Taxes [Abstract]
United States	$ (172,702)	$ 344,280	$ (69,576)
Foreign	2,670	2,489	(6,580)
Income (loss) before income tax benefit (expense)	$ (170,032)	$ 346,769	$ (76,156)

Income Taxes, Income Tax Expense (Benefit) (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Current [Abstract]
Federal	$ (837)	$ 35,861	$ 438
State	3,782	14,329	(1,442)
Foreign	518	413	374
Total current income tax expense (benefit)	3,463	50,603	(630)
Deferred [Abstract]
Federal	313,271	(7,096)	(290,511)
State	0	0	0
Total deferred income tax benefit	313,271	(7,096)	(290,511)
Total income tax expense (benefit)	$ 316,734	$ 43,507	$ (291,141)

Income Taxes, Reconciliation of Statutory to Effective Tax Rate (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Reconciliation Between Effective and Statutory Tax Rate [Abstract]
Pre-tax income (loss)	$ (170,032)	$ 346,769	$ (76,156)
Statutory rate	(35,707)	72,822	(15,993)
State income tax net of federal benefit	(39,230)	49,119	(2,202)
Foreign	49	340	1,735
Net change in valuation allowance	437,597	(37,765)	(277,924)
Net operating loss expiration	0	0	8,864
TEGSEDI licensing gain	0	0	59,583
Impact from outside basis differences	0	(16,344)	0
Tax credits	(18,774)	(22,296)	(73,362)
Deferred tax true-up	(206)	646	9,947
Tax rate change	(29,131)	1,811	(1,808)
Non-deductible compensation	7,931	3,361	3,154
Other non-deductible items	193	329	(569)
Stock-based compensation	17,435	(4,837)	(4,199)
Foreign-derived intangible income benefit	0	(2,071)	0
Impacts from Akcea Acquisition	(22,032)	0	0
Other	(1,391)	(1,608)	1,633
Total income tax expense (benefit)	$ 316,734	$ 43,507	$ (291,141)
Reconciliation Between Effective and Statutory Tax Rate Percentage [Abstract]
Statutory rate	21.00%	21.00%	21.00%
State income tax net of federal benefit	23.10%	14.20%	2.90%
Foreign	0.00%	0.10%	(2.30%)
Net change in valuation allowance	(257.40%)	(10.90%)	364.90%
Net operating loss expiration	0.00%	0.00%	(11.60%)
TEGSEDI licensing gain	0.00%	0.00%	(78.20%)
Impact from outside basis differences	0.00%	(4.70%)	0.00%
Tax credits	11.00%	(6.40%)	96.30%
Deferred tax true-up	0.10%	0.20%	(13.10%)
Tax rate change	17.10%	0.50%	2.40%
Non-deductible compensation	(4.70%)	1.00%	(4.10%)
Other nondeductible items	(0.10%)	0.10%	0.70%
Stock-based compensation	(10.30%)	(1.40%)	5.50%
Foreign-derived intangible income benefit	0.00%	(0.60%)	0.00%
Impacts from Akcea Acquisition	13.00%	0.00%	0.00%
Other	0.80%	(0.50%)	(2.10%)
Effective rate	(186.40%)	12.60%	382.30%

Income Taxes, Deferred Tax Assets and Liabilities (Details) - USD ($) $ in Thousands	3 Months Ended	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2020	Dec. 31, 2019
Deferred Tax Assets [Abstract]
Net operating loss carryovers	$ 83,681	$ 83,681	$ 20,191
Tax credits	245,746	245,746	210,455
Deferred revenue	124,452	124,452	127,763
Stock-based compensation	80,055	80,055	65,703
Intangible and capital assets	98,443	98,443	77,861
Other	13,402	13,402	12,510
Total deferred tax assets	645,779	645,779	514,483
Deferred Tax Liabilities [Abstract]
Convertible debt	(2,920)	(2,920)	(6,110)
Fixed assets	(3,611)	(3,611)	(1,958)
Other	(5,808)	(5,808)	(3,884)
Net deferred tax asset	633,440	633,440	502,531
Valuation allowance	(633,440)	(633,440)	(196,974)
Total net deferred tax assets and liabilities	0	0	$ 305,557
Increase in valuation allowance	$ 313,000	$ 436,000

Income Taxes, Tax Credit Carryforwards (Details) $ in Millions	Dec. 31, 2020 USD ($)
Federal [Member]
Operating Loss Carryforwards [Abstract]
Net operating loss carryforwards	$ 243.3
Federal [Member] \| Research and Development [Member]
Tax Credit Carryforwards [Abstract]
Tax credit carryforwards	210.5
California [Member]
Operating Loss Carryforwards [Abstract]
Net operating loss carryforwards	346.3
California [Member] \| Research and Development [Member]
Tax Credit Carryforwards [Abstract]
Tax credit carryforwards	$ 87.4

Income Taxes, Gross Unrecognized Tax Benefits (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Gross Unrecognized Tax Benefits [Roll Forward]
Beginning balance of unrecognized tax benefits	$ 69,784	$ 68,301	$ 78,014
Decrease for prior period tax positions	(24,154)	(867)	(12,814)
Increase for prior period tax positions	7,023	736	0
Increase for current period tax positions	1,510	1,614	3,101
Ending balance of unrecognized tax benefits	54,163	69,784	68,301
Unrecognized tax benefits that could impact effective tax rate, if recognized	6,400	400	0
Interest and penalties on unrecognized tax benefits	$ 300	$ 0	$ 0

Collaborative Arrangements and Licensing Agreements, Biogen (Details) $ in Thousands	1 Months Ended		3 Months Ended									12 Months Ended
	Sep. 30, 2013 USD ($) PerformanceObligation	Dec. 31, 2012 USD ($) Program	Sep. 30, 2020 USD ($)	Mar. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Sep. 30, 2019 USD ($)	Jun. 30, 2019 USD ($)	Dec. 31, 2018 USD ($)	Sep. 30, 2018 USD ($)	Jun. 30, 2018 USD ($)	Dec. 31, 2017 USD ($) PerformanceObligation	Dec. 31, 2020 USD ($) Medicine Country Program	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)	Apr. 30, 2018 USD ($) PerformanceObligation
Collaborative Arrangement and Licensing Agreement [Abstract]
Proceeds from issuance of common stock												$ 0	$ 0	$ 447,965
Revenue												729,264	1,122,599	599,674
SPINRAZA Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue												286,583	292,992	237,930
Licensing and Other Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue												8,117	17,205	14,755
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue												$ 364,565	770,149	344,752
Biogen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being developed \| Medicine												8
Revenue												$ 408,600	473,600	$ 375,000
Deferred revenue					$ 525,800							$ 465,800	$ 525,800
Biogen [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage												56.00%	42.00%	63.00%
Biogen [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received												$ 2,800,000
Biogen [Member] \| SPINRAZA Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue												286,600	$ 293,000	$ 237,900
Biogen [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue												$ 122,000	180,600	$ 137,100
SPINRAZA [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of countries where SPINRAZA is approved for use \| Country												50
Cumulative revenue earned												$ 1,300,000
Royalty percentage received on net sales of drug												11.00%
SPINRAZA [Member] \| Maximum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Royalty percentage received on net sales of drug												15.00%
SPINRAZA [Member] \| SPINRAZA Royalties [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative revenue earned												$ 930,000
SPINRAZA [Member] \| R&D Revenue [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative revenue earned												$ 435,000
New Antisense Medicines for the Treatment of SMA [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Royalty percentage received on net sales of drug												20.00%
Upfront payment received											$ 25,000
Maximum amount of payments receivable for license fees and milestones												$ 1,200,000
Maximum amount of payments receivable for development milestones												80,000
Maximum amount of payments receivable for commercialization milestones												180,000
Maximum amount of payments receivable for sales milestones												800,000
Next prospective payment												60,000
Number of separate performance obligations \| PerformanceObligation											1
Transaction price											$ 25,000
Revenue					8,300
2018 Strategic Neurology [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received												$ 1,050,000
Royalty percentage received on net sales of drug												20.00%
Upfront payment received										$ 375,000
Next prospective payment												$ 7,500
Number of separate performance obligations \| PerformanceObligation															1
Transaction price															$ 552,000
Term of collaboration agreement												10 years
Upfront payment received, including purchase of stock										1,000,000
Proceeds from issuance of common stock										$ 625,000
Percentage cash premium paid on shares purchased										25.00%
Maximum amount of payments receivable per drug for substantive milestone payments												$ 270,000
Number of programs being advanced \| Program												8
Premium paid on shares purchased										$ 177,000
Cumulative payments included in transaction price for performance obligation												$ 608,000
Milestone payments achieved and included in transaction price for performance obligation												11,000	$ 30,000
2013 Strategic Neurology [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received	$ 100,000
Next prospective payment												$ 10,000
Number of separate performance obligations \| PerformanceObligation	1
Transaction price	$ 100,000
Number of medicines currently being advanced \| Medicine												6
Revenue			$ 18,000			$ (16,500)
2013 Strategic Neurology [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received												$ 270,000
2013 Strategic Neurology [Member] \| Licensing and Other Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue								$ 35,000
2013 Strategic Neurology [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation												$ 145,000
2013 Strategic Neurology [Member] \| Medicines for Parkinson's Disease [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine												1
2013 Strategic Neurology [Member] \| Medicines for ALS [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine												3
2013 Strategic Neurology [Member] \| Medicines for Multiple System Atrophy [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine												1
2013 Strategic Neurology [Member] \| Medicines for Undisclosed Targets [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine												1
2013 Strategic Neurology [Member] \| Antisense Molecule [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable per program for license fee and milestone payments												$ 260,000
Maximum amount of payments receivable per program for development milestones												60,000
Maximum amount of payments receivable per program for regulatory milestones												130,000
2013 Strategic Neurology [Member] \| IONIS-C9 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue					10,000				$ 10,000
2013 Strategic Neurology [Member] \| Tofersen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue								$ 5,000
2013 Strategic Neurology [Member] \| ION859 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue						8,000
2013 Strategic Neurology [Member] \| ION464 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			18,000
2013 Strategic Neurology [Member] \| ION541 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			10,000
2012 Neurology [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received												154,000
Upfront payment received		$ 30,000
Next prospective payment												25,000
Maximum amount of payments receivable per program for license fee and milestone payments												210,000
Maximum amount of payments receivable per program for development milestones												10,000
Maximum amount of payments receivable per program for regulatory milestones												130,000
Number of programs under which drugs are to be developed and commercialized \| Program		3
Revenue						$ 6,300
2012 Neurology [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation												40,000
2012 Neurology [Member] \| IONIS-MAPT [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation												57,000
Milestone payments achieved and included in transaction price for performance obligation			$ 12,000	$ 7,500	12,000		$ 7,500					$ 19,500
Term of extension study												1 year
Revenue					45,000
2012 Neurology [Member] \| ION582 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue					$ 10,000

Collaborative Arrangements and Licensing Agreements, AstraZeneca (Details) $ in Thousands	1 Months Ended		3 Months Ended							12 Months Ended
	Jul. 31, 2015 USD ($) PerformanceObligation	Dec. 31, 2012 USD ($)	Dec. 31, 2020 USD ($) Agreement Medicine	Jun. 30, 2020 USD ($)	Mar. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($) Program	Sep. 30, 2018 USD ($)	Mar. 31, 2018 USD ($) LicenseFee	Dec. 31, 2020 USD ($) Agreement Medicine	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue										$ 729,264	$ 1,122,599	$ 599,674
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue										$ 364,565	770,149	$ 344,752
AstraZeneca [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of collaboration agreements \| Agreement			2							2
Deferred revenue			$ 10,000			$ 25,000				$ 10,000	$ 25,000
AstraZeneca [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage										12.00%	3.00%	20.00%
AstraZeneca [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received			$ 380,000							$ 380,000
AstraZeneca [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue										$ 88,000	$ 28,100	$ 120,700
Cardiovascular, Renal and Metabolic Diseases [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of collaboration agreements \| Agreement			1							1
Number of licensed medicines \| Medicine			4							4
Upfront payment received	$ 65,000
Minimum amount of payments receivable for license fees and milestones			$ 5,500,000							$ 5,500,000
Maximum amount of payments receivable for development milestones			1,100,000							1,100,000
Maximum amount of payments receivable for regulatory milestones			2,900,000							2,900,000
Maximum amount of payments receivable for commercialization milestones			1,500,000							1,500,000
Next prospective payment			30,000							30,000
Number of separate performance obligations \| PerformanceObligation	1
Transaction price	$ 65,000
Number of license fees earned \| LicenseFee									2
Revenue			20,000
Cardiovascular, Renal and Metabolic Diseases [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received			235,000							235,000
Cardiovascular, Renal and Metabolic Diseases [Member] \| ION455 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			30,000							30,000
Cardiovascular, Renal and Metabolic Diseases [Member] \| ION532 and ION449 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue										30,000
Cardiovascular, Renal and Metabolic Diseases [Member] \| ION532 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue					$ 10,000				$ 30,000
Cardiovascular, Renal and Metabolic Diseases [Member] \| ION839 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue						$ 10,000			$ 30,000
Cardiovascular, Renal and Metabolic Diseases [Member] \| ION449[Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			20,000					$ 10,000
Cardiovascular, Renal and Metabolic Diseases [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation			$ 90,000							$ 90,000
Oncology [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of collaboration agreements \| Agreement			1							1
Upfront payment received		$ 31,000
Minimum amount of payments receivable for license fees and milestones			$ 265,000							$ 265,000
Maximum amount of payments receivable for development milestones			107,000							107,000
Maximum amount of payments receivable for regulatory milestones			105,000							105,000
Next prospective payment			12,000							12,000
Number of programs advanced \| Program							2
Oncology [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received			$ 140,000							140,000
Oncology [Member] \| Danvatirsen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue							$ 17,500
Oncology [Member] \| ION736 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 13,000			$ 10,000			$ 13,000

Collaborative Arrangements and Licensing Agreements, Bayer (Details) $ in Thousands	1 Months Ended		3 Months Ended		12 Months Ended
	Feb. 28, 2017 USD ($) PerformanceObligation	May 31, 2015 USD ($) PerformanceObligation	Dec. 31, 2019 USD ($)	Jun. 30, 2015 USD ($)	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue					$ 729,264	$ 1,122,599	$ 599,674
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue					364,565	770,149	$ 344,752
Bayer [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 10,000
Deferred revenue			$ 2,400		$ 0	$ 2,400
Bayer [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage					0.00%	1.00%	1.00%
Bayer [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue					$ 3,200	$ 14,300	$ 5,000
Bayer [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received		$ 100,000		$ 100,000
Maximum amount of payments receivable for license fees and milestones					385,000
Maximum amount of payments receivable for development milestones					125,000
Maximum amount of payments receivable for commercialization milestones					$ 110,000
Royalty percentage received on gross margins of both drugs combined					20.00%
Next prospective payment					$ 20,000
Number of separate performance obligations \| PerformanceObligation		3
Bayer [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received					$ 185,000
Bayer [Member] \| R&D Services for IONIS-FXI-L [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price	$ 10,100
Bayer [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received	75,000
Payment received for advancing programs	$ 75,000
Number of separate performance obligations \| PerformanceObligation	3
Number of new performance obligations \| PerformanceObligation	2
Transaction price	$ 75,000
Bayer [Member] \| IONIS-FXI-L [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of new performance obligations \| PerformanceObligation	1
Transaction price	$ 64,900
Bayer [Member] \| R&D Services for IONIS-FXI-L [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of new performance obligations \| PerformanceObligation	1

Collaborative Arrangements and Licensing Agreements, GSK (Details) $ in Thousands	1 Months Ended	3 Months Ended	12 Months Ended
	Mar. 31, 2010 USD ($)	Sep. 30, 2019 USD ($)	Dec. 31, 2020 USD ($) Medicine	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 729,264	$ 1,122,599	$ 599,674
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 364,565	770,149	$ 344,752
GSK [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received	$ 35,000
Number of medicines currently being developed \| Medicine			2
Maximum amount of payments receivable for license fees and milestones			$ 262,000
Maximum amount of payments receivable for development milestones			47,500
Maximum amount of payments receivable for regulatory milestones			120,000
Maximum amount of payments receivable for commercialization milestones			70,000
Next prospective payment			15,000
Revenue		$ 25,000
Deferred revenue			$ 0	$ 0
GSK [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage			0.00%	2.00%	0.00%
GSK [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received			$ 190,000
GSK [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 200	$ 25,400	$ 1,600

Collaborative Arrangements and Licensing Agreements, Janssen Biotech, Inc. (Details) $ in Thousands	1 Months Ended	3 Months Ended	12 Months Ended
	Dec. 31, 2014 USD ($) PerformanceObligation	Sep. 30, 2020 USD ($)	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 729,264	$ 1,122,599	$ 599,674
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			364,565	770,149	$ 344,752
Janssen Biotech, Inc. [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received	$ 35,000
Minimum amount of payments receivable for license fees and milestones			285,000
Maximum amount of payments receivable for development milestones			65,000
Maximum amount of payments receivable for regulatory milestones			160,000
Maximum amount of payments receivable for commercialization milestones			60,000
Next prospective payment			5,000
Number of separate performance obligations \| PerformanceObligation	1
Transaction price	$ 35,000
Revenue		$ 5,000
Deferred revenue			$ 0	$ 0
Janssen Biotech, Inc. [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage			1.00%	0.00%	1.00%
Janssen Biotech, Inc. [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received			$ 80,000
Janssen Biotech, Inc. [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 5,000	$ 100	$ 6,600

Collaborative Arrangements and Licensing Agreements, Novartis (Details) $ in Thousands, shares in Millions	3 Months Ended			12 Months Ended
	Mar. 31, 2019 USD ($)	Jun. 30, 2017 USD ($)	Mar. 31, 2017 USD ($) PerformanceObligation shares	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 729,264	$ 1,122,599	$ 599,674
Licensing and Other Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				8,117	17,205	14,755
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				364,565	770,149	$ 344,752
Novartis [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received			$ 75,000
Maximum amount of payments receivable for milestones				675,000
Maximum amount of payments receivable for development milestones				25,000
Maximum amount of payments receivable for regulatory milestones				290,000
Maximum amount of payments receivable for commercialization milestones				360,000
Cumulative payments received				$ 249,000
Royalty percentage received on sales of drug				20.00%
Next prospective payment				$ 25,000
Shares issued (in shares) \| shares			1.6
Proceeds from sale of common stock			$ 100,000
Additional amount of common stock required to be purchased			$ 50,000
Proceeds from sale of common stock to Novartis in a private placement		$ 50,000
Number of separate performance obligations \| PerformanceObligation			4
Transaction price			$ 108,400
Premium received on shares issued			28,400
Potential premium received if common stock is purchased in the future			5,000
Deferred revenue				$ 0	$ 0
Novartis [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage				0.00%	17.00%	8.00%
Novartis [Member] \| Licensing and Other Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue	$ 150,000
Novartis [Member] \| R&D Services for Pelacarsen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price			64,000
Novartis [Member] \| R&D Services for IONIS-APOCIII-L [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price			40,100
Novartis [Member] \| Pelacarsen API [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price			1,500
Novartis [Member] \| IONIS-APOCIII-L API [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price			$ 2,800
Novartis [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 1,000	$ 187,400	$ 50,600

Collaborative Arrangements and Licensing Agreements, Pfizer (Details) $ in Thousands	1 Months Ended	3 Months Ended		12 Months Ended
	Oct. 31, 2019 USD ($) PerformanceObligation	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 729,264	$ 1,122,599	$ 599,674
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				364,565	770,149	$ 344,752
Pfizer [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received	$ 250,000
Maximum amount of payments receivable for development, regulatory and sales milestones		$ 1,300,000		1,300,000
Maximum amount of payments receivable for development milestones		205,000		205,000
Maximum amount of payments receivable for regulatory milestones		250,000		250,000
Maximum amount of payments receivable for commercialization milestones		850,000		$ 850,000
Royalty percentage received on net sales of drug				20.00%
Next prospective payment		50,000		$ 50,000
Number of separate performance obligations \| PerformanceObligation	3
Transaction price	$ 250,000
Revenue		75,000
Deferred revenue		0	$ 1,300	$ 0	$ 1,300
Pfizer [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage				11.00%	22.00%
Pfizer [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received		$ 330,000		$ 330,000
Pfizer [Member] \| Vupanorsen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price	245,600
Revenue			$ 245,600
Pfizer [Member] \| R&D Services for Vupanorsen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price	2,200
Pfizer [Member] \| Vupanorsen API [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price	$ 2,200
Pfizer [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 82,100	$ 248,700

Collaborative Arrangements and Licensing Agreements, PTC Therapeutics (Details) $ in Thousands	3 Months Ended			12 Months Ended
	Dec. 31, 2019 USD ($)	Jun. 30, 2019 USD ($)	Sep. 30, 2018 USD ($)	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)	Aug. 31, 2018 PerformanceObligation
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 729,264	$ 1,122,599	$ 599,674
Licensing and Other Royalty Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				8,117	17,205	$ 14,755
PTC Therapeutics [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum payment receivable under license agreement				26,000
Cumulative payments received				$ 22,000
Royalty percentage received on net sales of each drug in Latin America from PTC				20.00%
Period before PTC pays royalties on net sales of product after first commercial sale in Brazil				12 months
Minimum revenue recognized in Latin America by PTC before paying royalties				$ 10,000
Number of separate performance obligations \| PerformanceObligation							2
Deferred revenue	$ 0			$ 0	$ 0
PTC Therapeutics [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage				0.00%	1.00%	2.00%
PTC Therapeutics [Member] \| Licensing and Other Royalty Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 12,000	$ 1,600	$ 10,200	$ 12,000
PTC Therapeutics [Member] \| WAYLIVRA [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		$ 6,000
PTC Therapeutics [Member] \| TEGSEDI [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue	$ 4,000

Collaborative Arrangements and Licensing Agreements, Roche (Details) $ in Thousands	1 Months Ended	3 Months Ended				12 Months Ended
	Apr. 30, 2013 USD ($) PerformanceObligation	Dec. 31, 2020 USD ($)	Mar. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)	Dec. 31, 2017 USD ($)	Dec. 31, 2020 USD ($) Indication	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)	Dec. 31, 2017 USD ($)	Oct. 31, 2018 USD ($) PerformanceObligation
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue						$ 729,264	$ 1,122,599	$ 599,674
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue						364,565	770,149	$ 344,752
Roche [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Deferred revenue		$ 47,200				$ 47,200	$ 52,300
Roche [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage						1.00%	5.00%	1.00%
Roche [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue						$ 5,900	$ 57,000	$ 8,300
Huntington's Disease [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received	$ 30,000
Milestone payment received									$ 3,000
Maximum amount of payments receivable for license fees and milestones		365,000				365,000
Maximum amount of payments receivable for development milestones		70,000				70,000
Maximum amount of payments receivable for regulatory milestones		170,000				170,000
Maximum amount of payments receivable for commercialization milestones		80,000				80,000
Maximum amount of payment receivable for each additional drug developed		136,500				136,500
Cumulative payments received		150,000				150,000
Next prospective payment		15,000				15,000
Number of separate performance obligations \| PerformanceObligation	1
Transaction price	$ 30,000
Revenue			$ 35,000		$ 45,000
IONIS-FB-L for Complement-Mediated Diseases [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received				$ 75,000
Maximum amount of payments receivable for license fees and milestones		684,000				684,000
Next prospective payment		20,000				$ 20,000
Number of separate performance obligations \| PerformanceObligation										1
Transaction price										$ 75,000
Number of disease indications \| Indication						2
Royalty percentage received on net sales of drug						20.00%
Revenue		$ (9,200)
IONIS-FB-L for Complement-Mediated Diseases [Member] \| GA [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of disease indications \| Indication						1
IONIS-FB-L for Complement-Mediated Diseases [Member] \| IgA Nephropathy [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of disease indications \| Indication						1

Collaborative Arrangements and Licensing Agreements, Alnylam Pharmaceuticals, Inc. (Details) - USD ($) $ in Thousands	3 Months Ended	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		$ 729,264	$ 1,122,599	$ 599,674
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		364,565	770,149	$ 344,752
Alnylam [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Award from arbitration panel	$ 41,200
Revenue	41,200
Deferred revenue	$ 0	$ 0	$ 0
Alnylam [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage		7.00%	2.00%	0.00%
Alnylam [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		$ 47,900	$ 24,100	$ 2,000

- Definition

Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.

+ References

Reference 1: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 30
-Subparagraph (a)
-URI http://asc.fasb.org/extlink&oid=120311839&loc=d3e8906-108599

Reference 2: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 40
-URI http://asc.fasb.org/extlink&oid=120311839&loc=d3e9031-108599

Reference 3: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 41
-Subparagraph (a)
-URI http://asc.fasb.org/extlink&oid=120311839&loc=d3e9038-108599

Reference 4: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 32
-Subparagraph (b)
-URI http://asc.fasb.org/extlink&oid=120311839&loc=d3e8933-108599

Reference 5: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 32
-Subparagraph (a)
-URI http://asc.fasb.org/extlink&oid=120311839&loc=d3e8933-108599

Reference 6: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 606
-SubTopic 10
-Section 50
-Paragraph 4
-Subparagraph (a)
-URI http://asc.fasb.org/extlink&oid=121604090&loc=SL49130543-203045

Reference 7: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 22
-Subparagraph (b)
-URI http://asc.fasb.org/extlink&oid=120311839&loc=d3e8736-108599

Reference 8: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 22
-Subparagraph (a)
-URI http://asc.fasb.org/extlink&oid=120311839&loc=d3e8736-108599

Reference 9: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 42
-URI http://asc.fasb.org/extlink&oid=120311839&loc=d3e9054-108599

Reference 10: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 606
-SubTopic 10
-Section 50
-Paragraph 5
-URI http://asc.fasb.org/extlink&oid=121604090&loc=SL49130545-203045

Reference 11: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 924
-SubTopic 10
-Section S99
-Paragraph 1
-Subparagraph (SAB Topic 11.L)
-URI http://asc.fasb.org/extlink&oid=6472922&loc=d3e499488-122856

+ Details

Akcea Acquisition (Details) - USD ($) $ / shares in Units, shares in Millions, $ in Millions	1 Months Ended	3 Months Ended
	Oct. 31, 2020	Dec. 31, 2020	Sep. 30, 2020	Jun. 30, 2017
Severance and Retention Related to Akcea Acquisition [Member]
Severance and Retention Costs [Abstract]
Beginning balance	$ 0.0	$ 0.0
Severance and retention expense		15.3
Amounts paid during the period		(0.6)
Severance and Retention Related to Akcea Acquisition [Member] \| Accrued Compensation [Member]
Severance and Retention Costs [Abstract]
Ending balance		14.7
Severance and Retention Related to Akcea Acquisition [Member] \| R&D Expenses [Member]
Severance and Retention Costs [Abstract]
Severance and retention expense		3.9
Severance and Retention Related to Akcea Acquisition [Member] \| SG&A Expenses [Member]
Severance and Retention Costs [Abstract]
Severance and retention expense		11.4
Severance Related to Akcea Acquisition [Member] \| Maximum [Member]
Severance and Retention Costs [Abstract]
Expected expenses		9.3
Retention Related to Akcea Acquisition [Member] \| Maximum [Member]
Severance and Retention Costs [Abstract]
Expected expenses		19.2
Akcea [Member]
Akcea Acquisition [Abstract]
Percentage ownership	100.00%		76.00%	100.00%
Shares purchased (in shares)	24.8
Purchase price per share (in dollars per share)	$ 18.15
Purchase price	$ 450.6
Direct transaction costs		$ 40.6
Cash purchase price of equity awards (in dollars per share)		$ 18.15
Payments for cancelled equity awards		$ 53.4
Unrecognized compensation cost related to non-vested RSUs	$ 59.3
Akcea [Member] \| Maximum [Member]
Akcea Acquisition [Abstract]
Percentage ownership	77.00%

Severance and Retention Costs related to our Restructured European Operations (Details) - Severance and Retention Related to Updated European Distribution Model [Member] $ in Millions	3 Months Ended
	Dec. 31, 2020 USD ($)
Severance and Retention Costs related to our Restructured European Operations [Abstract]
Beginning balance	$ 0.0
Severance and retention expense	12.5
Amounts paid during the period	(0.1)
Accrued Compensation [Member]
Severance and Retention Costs related to our Restructured European Operations [Abstract]
Ending balance	12.4
R&D Expenses [Member]
Severance and Retention Costs related to our Restructured European Operations [Abstract]
Severance and retention expense	4.2
SG&A Expenses [Member]
Severance and Retention Costs related to our Restructured European Operations [Abstract]
Severance and retention expense	8.3
Maximum [Member]
Severance and Retention Costs related to our Restructured European Operations [Abstract]
Expected expenses	$ 14.8

Segment Information and Concentration of Business Risk, Segment Information (Details) $ in Thousands	3 Months Ended		12 Months Ended
	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Dec. 31, 2020 USD ($) Segment	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)
Segment Information and Concentration of Business Risk [Abstract]
Number of reportable segments \| Segment			2
Segment Information [Abstract]
Revenue			$ 729,264	$ 1,122,599	$ 599,674
Total operating expenses	$ 312,945	$ 233,028	901,346	756,716	661,046
Income (loss) from operations	(22,664)	260,652	(172,082)	365,883	(61,372)
Total assets	2,389,755	3,233,112	2,389,755	3,233,112
Commercial Revenue [Member]
Segment Information [Abstract]
Revenue			364,699	352,450	254,922
SPINRAZA Royalties [Member]
Segment Information [Abstract]
Revenue			286,583	292,992	237,930
Product Sales, Net [Member]
Segment Information [Abstract]
Revenue			69,999	42,253	2,237
Licensing and Other Royalty Revenue [Member]
Segment Information [Abstract]
Revenue			8,117	17,205	14,755
R&D Revenue Under Collaborative Agreements [Member]
Segment Information [Abstract]
Revenue			364,565	770,149	344,752
Operating Segments [Member] \| Ionis Core [Member]
Segment Information [Abstract]
Revenue			622,941	858,646	641,944
Total operating expenses			563,647	523,207	380,212
Income (loss) from operations			59,294	335,439	261,732
Total assets	2,792,222	3,478,081	2,792,222	3,478,081
Operating Segments [Member] \| Ionis Core [Member] \| Commercial Revenue [Member]
Segment Information [Abstract]
Revenue			297,917	305,608	240,685
Operating Segments [Member] \| Ionis Core [Member] \| SPINRAZA Royalties [Member]
Segment Information [Abstract]
Revenue			286,583	292,992	237,930
Operating Segments [Member] \| Ionis Core [Member] \| Product Sales, Net [Member]
Segment Information [Abstract]
Revenue			0	0	0
Operating Segments [Member] \| Ionis Core [Member] \| Licensing and Other Royalty Revenue [Member]
Segment Information [Abstract]
Revenue			11,334	12,616	2,755
Operating Segments [Member] \| Ionis Core [Member] \| R&D Revenue Under Collaborative Agreements [Member]
Segment Information [Abstract]
Revenue			325,024	553,038	401,259
Operating Segments [Member] \| Akcea Therapeutics [Member]
Segment Information [Abstract]
Revenue			152,320	488,543	64,867
Total operating expenses			389,575	450,469	295,683
Income (loss) from operations			(237,255)	38,074	(230,816)
Total assets	435,824	599,250	435,824	599,250
Operating Segments [Member] \| Akcea Therapeutics [Member] \| Commercial Revenue [Member]
Segment Information [Abstract]
Revenue			69,999	52,425	14,237
Operating Segments [Member] \| Akcea Therapeutics [Member] \| SPINRAZA Royalties [Member]
Segment Information [Abstract]
Revenue			0	0	0
Operating Segments [Member] \| Akcea Therapeutics [Member] \| Product Sales, Net [Member]
Segment Information [Abstract]
Revenue			69,999	42,253	2,237
Operating Segments [Member] \| Akcea Therapeutics [Member] \| Licensing and Other Royalty Revenue [Member]
Segment Information [Abstract]
Revenue			0	10,172	12,000
Operating Segments [Member] \| Akcea Therapeutics [Member] \| R&D Revenue Under Collaborative Agreements [Member]
Segment Information [Abstract]
Revenue			82,321	436,118	50,630
Elimination of Intercompany Activity [Member]
Segment Information [Abstract]
Revenue			(45,997)	(224,590)	(107,137)
Total operating expenses			(51,876)	(216,960)	(14,849)
Income (loss) from operations			5,879	(7,630)	(92,288)
Total assets	$ (838,291)	$ (844,219)	(838,291)	(844,219)
Elimination of Intercompany Activity [Member] \| Commercial Revenue [Member]
Segment Information [Abstract]
Revenue			(3,217)	(5,583)	0
Elimination of Intercompany Activity [Member] \| SPINRAZA Royalties [Member]
Segment Information [Abstract]
Revenue			0	0	0
Elimination of Intercompany Activity [Member] \| Product Sales, Net [Member]
Segment Information [Abstract]
Revenue			0	0	0
Elimination of Intercompany Activity [Member] \| Licensing and Other Royalty Revenue [Member]
Segment Information [Abstract]
Revenue			(3,217)	(5,583)	0
Elimination of Intercompany Activity [Member] \| R&D Revenue Under Collaborative Agreements [Member]
Segment Information [Abstract]
Revenue			$ (42,780)	$ (219,007)	$ (107,137)

Segment Information and Concentration of Business Risk, Contracts Receivable from Significant Partners (Details) - Partner	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2019
Significant Partners [Abstract]
Number of significant partners	2	1
Contracts Receivables [Member] \| Credit Concentration [Member] \| Significant Partners [Member]
Significant Partners [Abstract]
Concentration percentage	99.50%	75.00%

Employment Benefits (Details) - USD ($)	12 Months Ended
Employment Benefits (Details) - USD ($)	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2018
Employee Benefits [Abstract]
Matching contributions	$ 5,700,000	$ 6,400,000	$ 5,700,000
Minimum [Member]
Employee Benefits [Abstract]
Employee contribution limit per calendar year	19,500
Maximum [Member]
Employee Benefits [Abstract]
Employee contribution limit per calendar year	$ 26,000

Fourth Quarter Financial Data (Unaudited) (Details) - USD ($)
$ / shares in Units, shares in Thousands, $ in Thousands

1 Months Ended

2 Months Ended

3 Months Ended

12 Months Ended

Oct. 31, 2020

Dec. 31, 2020

Dec. 31, 2019

Dec. 31, 2020

Dec. 31, 2019

Dec. 31, 2018

Fourth Quarter Financial Data (Unaudited) [Abstract]

Revenue

$ 290,281

$ 493,680

Operating expenses

312,945

233,028

$ 901,346

$ 756,716

$ 661,046

Income (loss) from operations

(22,664)

260,652

(172,082)

365,883

(61,372)

Net income (loss)

(341,426)

203,957

(486,766)

303,262

214,985

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

$ (340,271)

$ 184,415

$ (451,286)

$ 294,146

$ 273,741

Basic net income (loss) per share (in dollars per share)

$ (2.44)

^[1],[2]

$ 1.31

^[1],[2]

$ (3.23)

$ 2.12

$ 2.09

Diluted net income (loss) per share (in dollars per share)

$ (2.44)

^[2],[3]

$ 1.28

^[2],[3]

$ (3.23)

$ 2.08

$ 2.07

Income (Numerator) [Abstract]

Income (loss) available to Ionis common stockholders

$ (340,272)

$ 183,795

$ (451,487)

$ 296,563

$ 276,868

Net income available to Ionis common shareholders

$ 196,485

$ 296,563

$ 276,868

Shares (Denominator) [Abstract]

Shares used in computing basic net income (loss) per share (in shares)

139,956

140,583

139,612

139,998

132,320

Effect of Diluted Securities [Abstract]

Shares issuable related to our ESPP (in shares)

Shares used in computing diluted net income per share (in shares)

153,303

139,612

142,872

134,056

0.125 Percent Convertible Senior Notes [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Interest rate on convertible senior notes

0.125%

Income (Numerator) [Abstract]

Shares issuable related to our convertible notes

$ 644

Effect of Diluted Securities [Abstract]

Shares issuable related to our convertible notes

860

1 Percent Convertible Senior Notes [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Interest rate on convertible senior notes

1.00%

Income (Numerator) [Abstract]

Shares issuable related to our convertible notes

$ 12,046

Effect of Diluted Securities [Abstract]

Shares issuable related to our convertible notes

9,527

Stock Options [Member]

Effect of Diluted Securities [Abstract]

Shares issuable related to stock-based compensation (in shares)

1,467

2,090

1,216

Restricted Stock Awards [Member]

Effect of Diluted Securities [Abstract]

Shares issuable related to stock-based compensation (in shares)

848

766

514

Ionis [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

$ (250,682)

$ 121,552

$ (253,725)

$ 262,490

$ 440,806

Akcea [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

$ (3,603)

$ (85,987)

$ (89,590)

$ 62,243

Basic net income (loss) per share (in dollars per share)

$ (0.05)

$ 0.87

Weighted average shares owned in Akcea (in shares)

77,095

71,342

[1]	As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income (loss) per share calculation for each of the fourth quarters in 2020 and 2019 considered our net income (loss) for Ionis on a stand-alone basis plus our share of Akcea’s net loss for the period. To calculate the portion of Akcea’s net loss attributable to our ownership, we multiplied Akcea’s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.
[2]	We compute net income (loss) per share independently for each quarter during the year.
[3]	We had net income available to Ionis common stockholders for the fourth quarter of 2019. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period