<SUBMISSION>
<ACCESSION-NUMBER>0001104659-05-061018
<TYPE>8-K
<PUBLIC-DOCUMENT-COUNT>2
<PERIOD>20051213
<ITEMS>5.02
<ITEMS>9.01
<FILING-DATE>20051215
<DATE-OF-FILING-DATE-CHANGE>20051215
<FILER>
<COMPANY-DATA>
<CONFORMED-NAME>ISIS PHARMACEUTICALS INC
<CIK>0000874015
<ASSIGNED-SIC>2834
<IRS-NUMBER>330336973
<STATE-OF-INCORPORATION>DE
<FISCAL-YEAR-END>1231
</COMPANY-DATA>
<FILING-VALUES>
<FORM-TYPE>8-K
<ACT>34
<FILE-NUMBER>000-19125
<FILM-NUMBER>051266409
</FILING-VALUES>
<BUSINESS-ADDRESS>
<STREET1>1896 RUTHERFORD ROAD
<CITY>CARLSBAD
<STATE>CA
<ZIP>92008
<PHONE>7609319200
</BUSINESS-ADDRESS>
<MAIL-ADDRESS>
<STREET1>1896 RUTHERFORD ROAD
<CITY>CARLSBAD
<STATE>CA
<ZIP>92008
</MAIL-ADDRESS>
</FILER>
<DOCUMENT>
<TYPE>8-K
<SEQUENCE>1
<FILENAME>a05-21748_18k.htm
<DESCRIPTION>CURRENT REPORT OF MATERIAL EVENTS OR CORPORATE CHANGES
<TEXT>
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<p align="center" style="border:none;margin:0in 0in .0001pt;padding:0in;text-align:center;text-indent:0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

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<p align="center" style="margin:0in 0in .0001pt;text-align:center;text-indent:0in;"><b><font size="5" face="Times New Roman" style="font-size:18.0pt;font-weight:bold;">SECURITIES AND EXCHANGE COMMISSION</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Washington, D.C.&#160;
20549</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;text-indent:0in;"><b><font size="5" face="Times New Roman" style="font-size:18.0pt;font-weight:bold;">FORM&nbsp;8-K</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;text-indent:0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;text-indent:0in;"><b><font size="3" face="Times New Roman" style="font-size:12.0pt;font-weight:bold;">CURRENT REPORT<br>
PURSUANT TO SECTION&nbsp;13 OR 15(d)&nbsp;OF THE<br>
SECURITIES EXCHANGE ACT OF 1934</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;text-indent:0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Date of report (Date of earliest event reported):&#160; <b><font style="font-weight:bold;">December&nbsp;13, 2005</font></b></font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;text-indent:0in;"><b><font size="5" face="Times New Roman" style="font-size:18.0pt;font-weight:bold;">ISIS PHARMACEUTICALS, INC.</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(Exact Name of Registrant as Specified in Charter)</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Delaware</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(State or Other Jurisdiction of Incorporation)</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<table border="0" cellspacing="0" cellpadding="0" width="100%" style="border-collapse:collapse;width:100.0%;">
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  <td width="49%" valign="top" style="padding:0in 0in 0in 0in;width:49.0%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">000-19125</font></b></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in 0in 0in 0in;width:2.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><b><font size="2" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></p>
  </td>
  <td width="49%" valign="top" style="padding:0in 0in 0in 0in;width:49.0%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">33-0336973</font></b></p>
  </td>
 </tr>
 <tr>
  <td width="49%" valign="top" style="padding:0in 0in 0in 0in;width:49.0%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(Commission File No.)</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in 0in 0in 0in;width:2.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="49%" valign="top" style="padding:0in 0in 0in 0in;width:49.0%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(IRS Employer Identification No.)</font></p>
  </td>
 </tr>
</table>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">1896 Rutherford Road</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Carlsbad, CA 92008</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(Address of Principal Executive Offices and Zip Code)</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Registrant&#146;s
telephone number, including area code: <b><font style="font-weight:bold;">(760) 931-9200</font></b></font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Check the appropriate box below if the Form&nbsp;8-K
filing is intended to simultaneously satisfy the filing obligation of the
registrant under any of the following provisions:</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman">&nbsp;</font></p>

<table border="0" cellspacing="0" cellpadding="0" width="100%" style="border-collapse:collapse;width:100.0%;">
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  <td width="4%" valign="top" style="padding:0in 0in 0in 0in;width:4.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Wingdings" style="font-size:10.0pt;">o</font></p>
  </td>
  <td width="96%" valign="top" style="padding:0in 0in 0in 0in;width:96.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Written communications pursuant to Rule&nbsp;425
  under the Securities Act (17 CFR 230.425)</font></p>
  </td>
 </tr>
 <tr>
  <td width="4%" valign="top" style="padding:0in 0in 0in 0in;width:4.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="96%" valign="top" style="padding:0in 0in 0in 0in;width:96.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
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 <tr>
  <td width="4%" valign="top" style="padding:0in 0in 0in 0in;width:4.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Wingdings" style="font-size:10.0pt;">o</font></p>
  </td>
  <td width="96%" valign="top" style="padding:0in 0in 0in 0in;width:96.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Soliciting material pursuant to Rule&nbsp;14a-12
  under the Exchange Act (17 CFR 240.14a-12)</font></p>
  </td>
 </tr>
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  <td width="4%" valign="top" style="padding:0in 0in 0in 0in;width:4.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="96%" valign="top" style="padding:0in 0in 0in 0in;width:96.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="4%" valign="top" style="padding:0in 0in 0in 0in;width:4.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Wingdings" style="font-size:10.0pt;">o</font></p>
  </td>
  <td width="96%" valign="top" style="padding:0in 0in 0in 0in;width:96.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Pre-commencement communications pursuant to Rule&nbsp;14d-2(b)&nbsp;under
  the Exchange Act (17 CFR 240.14d-2(b))</font></p>
  </td>
 </tr>
 <tr>
  <td width="4%" valign="top" style="padding:0in 0in 0in 0in;width:4.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="96%" valign="top" style="padding:0in 0in 0in 0in;width:96.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
 </tr>
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  <td width="4%" valign="top" style="padding:0in 0in 0in 0in;width:4.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Wingdings" style="font-size:10.0pt;">o</font></p>
  </td>
  <td width="96%" valign="top" style="padding:0in 0in 0in 0in;width:96.0%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Pre-commencement communications pursuant to Rule&nbsp;13e-4(c)&nbsp;under
  the Exchange Act (17 CFR 240.13e-4(c))</font></p>
  </td>
 </tr>
</table>

<div style="border:none;border-bottom:double windowtext 9.0pt;padding:0in 0in 0in 0in;">

<p align="left" style="border:none;margin:0in 0in .0001pt;padding:0in;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

</div>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<div align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">

<hr size="2" width="100%" noshade color="gray" align="left">

</font></div>

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<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="left" style="font-size:10.0pt;margin:0in 0in .0001pt;text-align:left;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Item 5.02.</font></b><b><font size="1" style="font-size:3.0pt;font-weight:bold;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; </font>Election
of Director.</b></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">On December&nbsp;13, 2005, the Board of Directors of
Isis Pharmaceuticals,&nbsp;Inc. (the &#147;Company&#148;) elected Joseph &#147;Skip&#148; Klein,&nbsp;III
as a member of the Company&#146;s Board of Directors.</font></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">A copy of the press release announcing his election is
included with this report as exhibit 99.1</font></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="left" style="font-size:10.0pt;margin:0in 0in .0001pt;text-align:left;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Item 9.01.</font></b><b><font size="1" style="font-size:3.0pt;font-weight:bold;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; </font>Financial
Statements and Exhibits.</b></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(c)&nbsp; Exhibits.</font></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="left" style="font-size:10.0pt;margin:0in 0in .0001pt;text-align:left;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">99.1</font><font size="1" style="font-size:3.0pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; </font>Press
Release dated December&nbsp;15, 2005.</p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">2</font></p>

<div align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">

<hr size="2" width="100%" noshade color="gray" align="left">

</font></div>

</div>
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<div>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="font-weight:bold;margin:0in 0in .0001pt;page-break-after:auto;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-variant:normal !important;">SIGNATURE</font></b></p>

<p style="font-weight:bold;margin:0in 0in .0001pt;page-break-after:auto;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-variant:normal !important;font-weight:normal;">&nbsp;</font></b></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Pursuant to the
requirements of the Securities Exchange Act of 1934, as amended, the registrant
has duly caused this report to be signed on its behalf by the undersigned,
thereunto duly authorized.</font></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<table border="0" cellspacing="0" cellpadding="0" width="100%" style="border-collapse:collapse;width:100.0%;">
 <tr>
  <td width="52%" valign="top" style="padding:0in 0in 0in 0in;width:52.76%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></p>
  </td>
  <td width="47%" colspan="4" valign="top" style="padding:0in 0in 0in 0in;width:47.24%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">ISIS PHARMACEUTICALS, INC.</font></b></p>
  </td>
 </tr>
 <tr>
  <td width="52%" valign="top" style="padding:0in 0in 0in 0in;width:52.76%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="47%" colspan="4" valign="top" style="padding:0in 0in 0in 0in;width:47.24%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="52%" valign="top" style="padding:0in 0in 0in 0in;width:52.76%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="47%" colspan="4" valign="top" style="padding:0in 0in 0in 0in;width:47.24%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="52%" valign="top" style="padding:0in 0in 0in 0in;width:52.76%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Dated: December&nbsp;13, 2005</font></p>
  </td>
  <td width="3%" valign="top" style="padding:0in 0in 0in 0in;width:3.5%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">By:</font></p>
  </td>
  <td width="0%" valign="top" style="padding:0in 0in 0in 0in;width:.4%;">
  <p align="left" style="margin:0in 0in .0001pt 2.15pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="31%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in 0in 0in 0in;width:31.84%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">/s/ B. Lynne Parshall</font></p>
  </td>
  <td width="11%" valign="top" style="padding:0in 0in 0in 0in;width:11.5%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="52%" valign="top" style="padding:0in 0in 0in 0in;width:52.76%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><b><font size="2" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></p>
  </td>
  <td width="3%" valign="top" style="padding:0in 0in 0in 0in;width:3.5%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><b><font size="2" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></p>
  </td>
  <td width="43%" colspan="3" valign="top" style="padding:0in 0in 0in 0in;width:43.74%;">
  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">B. LYNNE PARSHALL</font></b></p>
  </td>
 </tr>
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  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Executive Vice President,</font></p>
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  <p align="left" style="margin:0in 0in .0001pt;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Chief Financial Officer and Director</font></p>
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<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">3</font></p>

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<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;text-indent:0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">INDEX TO EXHIBITS</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;text-indent:0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="left" style="font-size:10.0pt;margin:0in 0in .0001pt 1.25in;text-align:left;text-indent:-.75in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">99.1</font><font size="1" style="font-size:3.0pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; </font>Press
Release dated December&nbsp;15, 2005.</p>

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<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4</font></p>

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<p align="right" style="margin:0in 0in .0001pt;text-align:right;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Exhibit&nbsp;99.1</font></b></p>

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  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Navjot Rai</font></p>
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  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Investor Relations&nbsp;&amp; Corporate Communications</font></p>
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  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">760-603-2331</font></p>
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<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">ISIS PHARMACEUTICALS ADDS SKIP KLEIN TO BOARD OF
DIRECTORS</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="font-size:10.0pt;margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Carlsbad,
CA &#150;December&nbsp;15, 2005 -</font></b> Isis Pharmaceuticals,&nbsp;Inc. (Nasdaq: ISIS) announced today that Joseph
&#147;Skip&#148; Klein,&nbsp;III has joined the Company&#146;s Board of Directors. Mr.&nbsp;Klein
is currently Managing Director of Gauss Capital Advisors, LLC, a financial
consulting and investment advisory firm focused on biopharmaceuticals, which he
founded in March&nbsp;1998. In addition to his investment advisory and
financial consulting activities, Mr.&nbsp;Klein currently serves as a Venture
Partner of Red Abbey Venture Partners, LP, a life sciences private equity fund.
As an active life sciences investor and industry analyst, Mr.&nbsp;Klein has
over 15 years of experience finding and analyzing life sciences opportunities
for mutual funds, investment banks and biopharmaceutical companies.</p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#147;We
are very pleased to have Skip join our Board.&#160;
In addition to his in-depth knowledge and understanding of the life
sciences sector, Skip&#146;s financial and investing expertise in the
biopharmaceutical industry should provide valuable insight as a member of our
Board as we continue to implement our business strategy of balancing equity and
corporate partnering to move our drugs and products forward,&#148; said Stanley T.
Crooke, M.D., Ph.D., Chairman and CEO of Isis Pharmaceuticals.</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Mr.&nbsp;Klein&#146;s
extensive experience in the life sciences industry includes positions at
venture capital firms, the private sector, and investment firms.&#160; Mr.&nbsp;Klein was a venture partner at MPM
Capital Management, LLC, one of the largest venture capital and public equity
investors devoted exclusively to health care (September&nbsp;2001 to September&nbsp;2002).
Mr.&nbsp;Klein also served as the Health Care Investment Analyst at Edgemont
Asset Management,&nbsp;Inc. for The Kaufmann Fund, an aggressive growth company
mutual fund. Responsible for investments across all sectors of the health care
industry, Mr.&nbsp;Klein repositioned the portfolio away from health care
services toward biotechnology, medical devices and health care information
technology (June&nbsp;1998 to June&nbsp;1999).</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">For
over nine years, Mr.&nbsp;Klein served as Vice President and Health Care
Investment Analyst for T. Rowe Price Associates,&nbsp;Inc., an investment
management firm, where he created, launched, and managed growth of the T. Rowe
Price Health Sciences Fund from $2 million in assets in December&nbsp;1995 to
$290 million in assets upon departure in March&nbsp;1998. Under his management,
the Health Sciences Fund was the top performing health care fund in 1996, and
third best performing of 18 funds monitored by Lipper Analytical from inception
to December&nbsp;31, 1997 (December&nbsp;1988-March&nbsp;1998).</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Mr.&nbsp;Klein
currently serves on the board of directors of BioMarin Pharmaceuticals,&nbsp;Inc.,
Clinical Data,&nbsp;Inc., and NPS Pharmaceuticals,&nbsp;Inc. as well as two
private health care companies. Mr.&nbsp;Klein received a B.A. summa cum laude
in economics from Yale University, where he was elected to Phi Beta Kappa, and
an M.B.A. from the Stanford Graduate School of Business. Mr.&nbsp;<strong><b><font face="Times New Roman" style="font-weight:normal;">Klein</font></b></strong>
is a Chartered Financial Analyst and Chartered Financial Consultant.</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">-more-</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

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<p style="margin:0in 0in .0001pt;text-autospace:none;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">ABOUT ISIS
PHARMACEUTICALS, INC.</font></b></p>

<p style="margin:0in 0in .0001pt;text-autospace:none;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt;text-autospace:none;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Isis is exploiting its
expertise in RNA to discover and develop novel drugs for its product pipeline
and for its partners.&#160; The Company has
successfully commercialized the world&#146;s first antisense drug and has 12
antisense drugs in development
to treat metabolic, cardiovascular, ocular and inflammatory diseases, and
cancer.&#160; In its Ibis division, Isis is developing and commercializing the
TIGER biosensor system, a revolutionary system to identify infectious
organisms.&#160; As an innovator in RNA-based
drug discovery and development, Isis is the owner or exclusive licensee of
approximately 1,500 issued patents worldwide.&#160;
Additional information about Isis is available at www.isispharm.com.</font></p>

<p style="margin:0in 0in .0001pt;text-autospace:none;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">This
press release includes forward-looking statements regarding Isis
Pharmaceuticals and the Company&#146;s business. Any statement describing Isis&#146; goals, expectations, intentions or beliefs
is a forward-looking statement and should be considered an at-risk statement,
including those statements that are described as Isis&#146; goals.&#160; Such statements are subject to certain risks
and uncertainties, particularly those inherent in the process of discovering,
developing, and commercializing drugs that are safe and effective for use as
human therapeutics, in developing and commercializing systems to identify
infectious organisms that are effective and commercially attractive, and in the
endeavor of building a business around such products.&#160; Isis&#146; forward-looking statements also involve
assumptions that, if they never materialize or prove correct, could cause its
results to differ materially from those expressed or implied by such forward-looking
statements.&#160; Although Isis&#146;
forward-looking statements reflect the good faith judgment of its management,
these statements are based only on facts and factors currently known by
Isis.&#160; As a result, you are cautioned not
to rely on these forward-looking statements.&#160;
These and other risks concerning Isis&#146; programs are described in
additional detail in Isis&#146; annual report on Form&nbsp;10-K for the year ended December&nbsp;31,
2004, and its quarterly report on Form&nbsp;10-Q for the quarter ended September&nbsp;30,
2005, which are on file with the SEC.&#160;
Copies of these and other documents are available from the Company.</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">###</font></p>

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