X0306 4 2013-04-19 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, CEO and President Common Stock 2013-04-19 2013-04-19 4 M 0 30000 7.26 A 31661 D Common Stock 2013-04-19 2013-04-19 4 S 0 30000 20.006 D 1661 D Common Stock 2013-04-22 2013-04-22 4 M 0 20000 7.26 A 21661 D Common Stock 2013-04-22 2013-04-22 4 S 0 20000 20.99 D 1661 D Common Stock 2013-04-22 2013-04-22 4 S 0 10000 20.99 D 865391 I By Family Trust Common Stock 2013-04-23 2013-04-23 4 S 0 30000 22.0967 D 835391 I By Family Trust Common Stock 174 I By wife Employee Stock Option (right to buy) 7.26 2013-04-19 2013-04-19 4 M 0 30000 0 D 2010-09-21 2013-09-20 Common Stock 30000 20000 D Employee Stock Option (right to buy) 7.26 2013-04-22 2013-04-22 4 M 0 20000 0 D 2010-09-21 2013-09-20 Common Stock 20000 0 D Acquired as a result of exercising a stock option that was scheduled to expire on 9/20/2013. 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 6/27/2012. 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 6/27/2012. The price reported in Column 4 is a weighted average price. These shares were sold in multiple transactions at prices ranging from $22.005 to $22.16, inclusive. The reporting person undertakes to provide to Isis Pharmaceuticals, Inc., any security holder of Isis Pharmaceuticals, Inc. or the staff of the Securities and Exchange Commission, upon request, full information regarding the number of shares sold at each separate price within the ranges set forth in footnote (3) on this Form 4. /s/B. Lynne Parshall, attorney-in-fact 2013-04-23