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CONSOLIDATED STATEMENTS OF CASH FLOWS - USD ($) $ in Thousands | 12 Months Ended
--- | ---
Dec. 31, 2021 | Dec. 31, 2020 | Dec. 31, 2019
Operating activities: |  |  |
Net income (loss) | $ (28,597) | $ (479,743) | $ 287,259
Adjustments to reconcile net income (loss) to net cash used in operating activities: |  |  |
Depreciation | 15,487 | 13,365 | 12,540
Amortization of right-of-use operating lease assets | 1,721 | 1,731 | 1,542
Amortization of patents | 2,352 | 2,064 | 1,912
Amortization of premium (discount) on investments, net | 17,776 | 11,521 | (7,485)
Amortization of debt issuance costs | 4,958 | 3,255 | 2,945
Stock-based compensation expense | 120,678 | 230,117 | 146,574
Loss on early retirement of debt | 8,627 | 0 | 66,196
Gain on investments | (1,092) | (16,540) | (192)
Deferred income taxes, including changes in valuation allowance | 0 | 341,729 | 911
Non-cash losses related to patents | 2,707 | 1,948 | 2,226
Changes in operating assets and liabilities: |  |  |
Contracts receivable | 14,308 | (13,170) | (47,674)
Inventories | (2,841) | (1,261) | (5,411)
Other current and long-term assets | (877) | (9,975) | (44,659)
Long-term income taxes receivable (payable) | 1,008 | (89) | 8,418
Accounts payable | (6,000) | (2,755) | (16,343)
Income taxes | (1,288) | (31,190) | 31,656
Accrued compensation | (26,918) | 28,371 | 8,089
Accrued liabilities and other current liabilities | (8,381) | 32,424 | 16,406
Deferred contract revenue | (82,829) | (75,910) | (119,283)
Net cash used in operating activities | 30,799 | 35,892 | 345,627
Investing activities: |  |  |
Purchases of short-term investments | (1,124,193) | (1,570,410) | (1,946,726)
Proceeds from sale of short-term investments | 1,344,185 | 1,885,935 | 1,951,734
Purchases of property, plant and equipment | (11,955) | (35,120) | (30,905)
Acquisition of licenses and other assets, net | (5,946) | (5,928) | (5,377)
Purchases of strategic investments | (7,185) | 0 | (10,000)
Net cash provided by (used in) investing activities | 194,906 | 274,477 | (41,274)
Financing activities: |  |  |
Proceeds from equity, net | 11,565 | 52,036 | 119,657
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options | (16,725) | (13,411) | (19,242)
Repurchase of $247.9 million principal amount of 1 percent convertible senior notes | (256,963) | 0 | 0
Repayment of remaining principal amount of 1 percent convertible senior notes at maturity | (61,967) | 0 | 0
Proceeds from issuance of warrants | 89,752 | 0 | 56,110
Purchase of note hedges | (136,620) | 0 | (108,684)
Repurchases and retirements of common stock | 0 | (90,548) | (34,392)
Purchase of noncontrolling interest of Akcea Therapeutics, Inc., including cash payments for cancellation of Akcea Therapeutics, Inc. equity awards | 0 | (544,686) | 0
Principal payments on line of credit | 0 | 0 | (12,500)
Net cash provided by (used in) financing activities | 245,933 | (596,609) | 100,021
Effects of exchange rates on cash | (111) | 617 | 93
Net increase (decrease) in cash and cash equivalents | 471,527 | (285,623) | 404,467
Cash and cash equivalents at beginning of year | 397,664 | 683,287 | 278,820
Cash and cash equivalents at end of year | 869,191 | 397,664 | 683,287
Supplemental disclosures of cash flow information: |  |  |
Interest paid | 4,778 | 6,247 | 9,870
Income taxes paid | 38 | 25,855 | 9,041
Supplemental disclosures of non-cash investing and financing activities: |  |  |
Right-of-use assets obtained in exchange for lease liabilities | 6,641 | 2,149 | 14,178
Amounts accrued for capital and patent expenditures | 705 | 4,059 | 3,126
0.125 percent convertible senior notes principal issued related to our December 2019 debt exchange/issuance | 0 | 0 | 439,326
1 percent convertible senior notes principal extinguished related to our December 2019 debt exchange | 0 | 0 | 375,590
0 Percent Convertible Senior Notes [Member] |  |  |
Financing activities: |  |  |
Proceeds from the issuance of convertible senior notes | 632,500 | 0 | 0
Convertible senior notes issuance costs | (15,609) | 0 | 0
0.125 Percent Convertible Senior Notes [Member] |  |  |
Financing activities: |  |  |
Proceeds from the issuance of convertible senior notes | 0 | 0 | 109,500
Convertible senior notes issuance costs | $ 0 | $ 0 | $ (10,428)

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- Definition Amount of noncash expense for share-based payment arrangement. + References Reference 1: http://fasb.org/us-gaap/role/ref/legacyRef -Publisher FASB -Name Accounting Standards Codification -Topic 230 -SubTopic 10 -Section 45 -Paragraph 28 -Subparagraph (a) -URI http://asc.fasb.org/extlink&oid=123570139&loc=d3e3602-108585 + Details
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