The 2015 Stock Incentive Plan, as amended (“2015 Plan”), was approved at the Company’s annual meeting of stockholders in June 2015. Under the 2015 Plan, equity awards may be granted to officers, directors, employees, and consultants of and advisors to the Company and any present or future subsidiary.

The 2015 Plan authorizes the issuance of up to 12.4 million shares of common stock under equity awards granted under the 2015 Plan, which includes an increase of 1.5 million shares approved for issuance under the 2015 Plan at the Company’s 2021 annual meeting of stockholders. All such shares authorized for issuance under the 2015 Plan have been reserved. The 2015 Plan will expire on March 4, 2025.

The Amended and Restated 2005 Stock Incentive Plan (“2005 Plan”) expired in February 2015 and no new awards may be made under such plan, although awards will continue to be outstanding in accordance with their terms.

The 2015 Plan permits and the 2005 Plan permitted the grant of stock options (including incentive stock options), restricted stock, stock appreciation rights, and restricted stock units. In addition, under the 2015 Plan, unrestricted stock, stock units, and performance awards may be granted. Stock options and stock appreciation rights generally have a maximum term of 10 years and may be or were granted with an exercise price that is no less than 100% of the fair market value of the Company’s common stock at the time of grant. Grants of stock options are generally subject to vesting over periods ranging from one to four years.


	Year Ended December 31,
	2021		2020		2019
Research and development	$	86,928	$	55,955	$	8,436
General and administrative	96,698		72,080		8,612
Total stock-based compensation expense	$	183,626	$	128,035	$	17,048

As of December 31, 2021, there was approximately $190 million of total unrecognized compensation expense related to unvested stock options, stock appreciation rights, restricted stock units and the Employee Stock Purchase Plan, as amended (the “ESPP”). This unrecognized non-cash compensation expense is expected to be recognized over a weighted-average period of 1.2 years and will be allocated between research and development and general and administrative expenses accordingly. This estimate does not include the impact of other possible stock-based awards that may be made during future periods and awards that require approval by the stockholders.

The aggregate intrinsic value represents the total intrinsic value (the difference between the Company’s closing stock price on the last trading day of the period and the exercise price, multiplied by the number of in-the-money stock options and stock appreciation rights) that would have been received by the holders had all stock option and stock appreciation rights holders exercised their stock options and stock appreciation rights on December 31, 2021. This amount is subject to change based on changes to the closing price of the Company’s common stock. The aggregate intrinsic value of stock options and stock appreciation rights exercises and vesting of restricted stock units for 2021, 2020, and 2019 was $453.8 million, $187.3 million, and $0.5 million, respectively.

The following is a summary of stock options and stock appreciation rights activity under the 2015 Plan and the 2005 Plan for the year ended December 31, 2021:


	2015 Plan			2005 Plan
	Stock Options	Weighted- Average Exercise Price		Stock Options	Weighted- Average Exercise Price
Outstanding at January 1, 2021	5,420,463	$	38.05	214,186	$	88.11
Granted	81,959	$	177.84	—	$	—
Exercised	(1,778,688)	$	31.11	(145,961)	$	78.11
Canceled	(87,897)	$	120.62	—	$	—
Outstanding at December 31, 2021	3,635,837	$	42.60	68,225	$	109.52
Shares exercisable at December 31, 2021	1,170,259	$	57.01	68,225	$	109.52
Shares available for grant at December 31, 2021	3,716,636

The fair value of stock options granted under the 2015 Plan was estimated at the date of grant or the date upon which the 2015 Plan was approved by the Company’s stockholders for certain stock options granted in 2020 and 2019 using the Black-Scholes option-pricing model with the following assumptions:


	Year Ended December 31,
	2021	2020	2019
Weighted average Black-Scholes fair value of stock options and SARs granted	$158.02	$80.48	$4.98
Risk-free interest rate	0.5%-1.3%	0.2%-1.5%	1.5%-2.6%
Dividend yield	—%	—%	—%
Volatility	124.7%-142.0%	116.0%-152.2%	105.4%-134.1%
Expected term (in years)	4.1-6.1	3.9-7.6	3.9-7.5

The total aggregate intrinsic value and weighted-average remaining contractual term of stock options and stock appreciation rights outstanding under the 2015 Plan and 2005 Plan as of December 31, 2021 was approximately $376 million and 7.7 years, respectively. The total aggregate intrinsic value and weighted-average remaining contractual term of stock options and stock appreciation rights exercisable under the 2015 Plan and 2005 Plan as of December 31, 2020 was approximately $108 million and 6.8 years, respectively.


	Number of Shares	Per Share Weighted- Average Fair Value
Outstanding and unvested at January 1, 2021	1,044,980	$	72.59
Restricted stock units granted	316,571	$	191.82
Restricted stock units vested	(488,370)	$	69.02
Restricted stock units forfeited	(53,353)	$	141.01
Outstanding and unvested at December 31, 2021	819,828	$	116.70

The ESPP was approved at the Company’s annual meeting of stockholders in June 2013. The ESPP currently authorizes an aggregate of 600,000 shares of common stock to be purchased. The ESPP allows employees to purchase shares of common stock of the Company at each purchase date through payroll deductions of up to a maximum of 15% of their

compensation, at 85% of the lesser of the market price of the shares at the time of purchase or the market price on the beginning date of an option period (or, if later, the date during the option period when the employee was first eligible to participate). At December 31, 2021, there were 164,495 shares available for issuance under the ESPP.

The ESPP is considered compensatory for financial reporting purposes. As such, the fair value of ESPP shares was estimated at the date of grant using the Black-Scholes option-pricing model with the following assumptions:


	Year Ended December 31,
	2021	2020	2019
Range of Black-Scholes fair values of ESPP shares granted	$83.47-$238.85	$2.57-$92.67	$2.57-$35.00
Risk-free interest rate	0.1%-0.2%	0.2%-2.6%	1.2%-2.6%
Dividend yield	—%	—%	—%
Volatility	114.9%-159.4%	66.6%-189.7%	52.2%-171.6%
Expected term (in years)	0.5-2.0	0.5-2.0	0.5-2.0