X0306 4 2015-01-01 0000874015 ISIS PHARMACEUTICALS INC ISIS 0001537529 Monia Brett P C/O ISIS PHARMACEUTICALS, INC. 2855 GAZELLE COURT CARLSBAD CA 92010 0 1 0 0 SVP, Antisense Drug Discovery Common Stock 2015-01-01 2015-01-01 5 J 0 198 30.0475 A 2011 D Common Stock 2015-01-02 2015-01-02 4 S 0 76 62.75 D 1935 D Employee Stock Option (right to buy) 61.57 2015-01-02 2015-01-02 4 A 0 36423 0 A 2016-01-02 2022-01-01 Common Stock 36423 36423 D Reporting 198 shares acquired under the Isis Pharmaceuticals, Inc. Amended and Restated 2000 Employee Stock Purchase Plan on January 1, 2015. These 198 share may not be sold until July 2, 2015. The sale reported in this Form 4 was effected pursuant to a Rule 10b5-1 trading plan adopted by the reporting person on 7/1/2014. Grant of 1/2/2015 to reporting person of stock options under the Isis Pharmacueticals, Inc. 2011 Equity Incentive Plan. 25% of the shares subject to the option vest and become exercisable on 1/2/2016. Thereafter, the remaining shares subject to the option vest and become exercisable in 36 equal monthly installments, at the rate of 9,106 shares per year. The option was exercisable as to 0 on 1/2/2015. /s/Brett Monia 2015-01-05