X0306 4 2013-06-27 0000874015 ISIS PHARMACEUTICALS INC ISIS 0000897667 CROOKE STANLEY T C/O ISIS PHARMACEUTICALS, INC. 2855 GAZELLE COURT CARLSBAD CA 92010 1 1 0 0 Chairman and CEO Common Stock 2013-06-27 2013-06-27 4 M 0 10000 6.81 A 11661 D Common Stock 2013-06-27 2013-06-27 4 S 0 10000 28.30 D 1661 D Common Stock 2013-06-27 2013-06-27 4 M 0 10000 6.81 A 11661 D Common Stock 2013-06-27 2013-06-27 4 S 0 10000 27.40 D 1661 D Common Stock 2013-06-28 2013-06-28 4 M 0 10000 6.81 A 11661 D Common Stock 2013-06-28 2013-06-28 4 S 0 10000 27.07 D 1661 D Common Stock 2013-06-28 2013-06-28 4 M 0 4725 6.81 A 4899 I By Wife Common Stock 2013-06-28 2013-06-28 4 S 0 4725 27.31 D 174 I By Wife Common Stock 2013-06-28 2013-06-28 4 M 0 5958 11.12 A 6132 I By Wife Common Stock 2013-06-28 2013-06-28 4 S 0 5958 27.31 D 174 I By Wife Common Stock 2013-07-01 2013-07-01 4 S 0 10000 28.17 D 775391 I By Trust Employee Stock Option (right to buy) 6.81 2013-06-27 2013-06-27 4 M 0 20000 0 D 2008-01-02 2014-01-01 Common Stock 20000 10000 D Employee Stock Option (right to buy) 6.81 2013-06-28 2013-06-28 4 M 0 10000 0 D 2008-01-02 2014-01-01 Common Stock 10000 0 D Employee Stock Option (right to buy) 6.81 2013-06-28 2013-06-28 4 M 0 4725 0 D 2008-01-02 2014-01-14 Common Stock 4725 0 I By wife Employee Stock Option (right to buy) 11.12 2013-06-28 2013-06-28 4 M 0 5958 0 D 2008-01-02 2014-01-01 Common Stock 5958 0 I By wife Acquired as a result of exercising a stock option that was scheduled to expire on 1/1/14. The purchase and sale reported on this Form 4 was effective pursuant to a Rule 10b5-1 Trading Plan adopted by the reporting person on 6/27/12. Acquired as a result of exercising a stock option that was scheduled to expire on 1/1/14. The purchase and sale reported on this Form 4 was effective pursuant to a Rule 10b5-1 Trading Plan adopted by the reporting person's wife on 6/27/12. The sale was a result of shares owned. The sale reported on this Form 4 was effective pursuant to a Rule 10b5-1 Trading Plan adopted by the reporting person on 2/4/2013. /s/B. Lynne Parshall, attorney-in-fact 2013-07-01