X0306 4 2015-10-21 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 2015-10-21 2015-10-21 4 M 0 15000 11.27 A 29642 D Common Stock 2015-10-21 2015-10-21 4 S 0 15000 43.00 D 14642 D Common Stock 2015-10-21 2015-10-21 4 M 0 1000 11.27 A 2297 I By wife Common Stock 2015-10-21 2015-10-21 4 S 0 1000 43.00 D 1297 I By wife Common Stock 2015-10-21 2015-10-21 4 M 0 500 9.22 A 1797 I By wife Common Stock 2015-10-21 2015-10-21 4 S 0 500 43.00 D 1297 I By wife Common Stock 2015-10-23 2015-10-23 4 M 0 4163 11.27 A 18805 D Common Stock 2015-10-23 2015-10-23 4 S 0 4163 43.90 D 14642 D Common Stock 2015-10-23 2015-10-23 4 M 0 15837 10.29 A 30479 D Common Stock 2015-10-23 2015-10-23 4 S 0 15837 44.175 D 14642 D Common Stock 2015-10-23 2015-10-23 4 M 0 5000 10.29 A 19642 D Common Stock 2015-10-23 2015-10-23 4 S 0 5000 45.30 D 14642 D Common Stock 2015-10-23 2015-10-23 4 M 0 2000 9.22 A 3297 I By wife Common Stock 2015-10-23 2015-10-23 4 S 0 2000 44.175 D 1297 I By wife Common Stock 2015-10-23 2015-10-23 4 M 0 500 9.22 A 1797 I By wife Common Stock 2015-10-23 2015-10-23 4 S 0 500 45.30 D 1297 I By wife Common Stock 725391 I By Trust Employee Stock Option (right to buy) 11.27 2015-10-21 2015-10-21 4 M 0 15000 0 D 2014-01-04 2017-01-03 Common Stock 15000 4163 D Employee Stock Option (right to buy) 11.27 2015-10-21 2015-10-21 4 M 0 1000 0 D 2014-01-04 2017-01-03 Common Stock 1000 0 I By wife Employee Stock Option (right to buy) 9.22 2015-10-21 2015-10-21 4 M 0 500 0 D 2014-07-19 2017-07-18 Common Stock 500 4500 I By wife Employee Stock Option (right to buy) 11.27 2015-10-23 2015-10-23 4 M 0 4163 0 D 2014-01-04 2017-01-03 Common Stock 4163 0 D Employee Stock Option (right to buy) 10.29 2015-10-23 2015-10-23 4 M 0 20837 0 D 2015-01-03 2018-01-02 Common Stock 20837 101259 D Employee Stock Option (right to buy) 9.22 2015-10-23 2015-10-23 4 M 0 2500 0 D 2014-07-19 2017-07-18 Common Stock 2500 2000 I By wife Acquired as a result of exercising a stock option pursuant to Rule 10b5-1 Trading Plan. The purchase and sale reported on this Form 4 was effective pursuant to Rule 10b5-1 Trading Plan adopted by the reporting person on 9/21/2015. The price reported in Column 4 is a weighted average price. These shares were sold in multiple transactions at prices ranging from $42.60 to $43.40, 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 (2) on this Form 4. Acquired as a result of exercising a stock option pursuant to Rule 10b5-1 Trading Plan. The purchase and sale reported on this Form 4 was effective pursuant to Rule 10b5-1 Trading Plan adopted by the reporting person's wife on 9/21/2015. The price reported in Column 4 is a weighted average price. These shares were sold in multiple transactions at prices ranging from $43.90 to $44.70, 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 (4) on this Form 4. /s/B. Lynne Parshall, attorney-in-fact 2015-10-23