<SUBMISSION>
<ACCESSION-NUMBER>0001104659-05-062396
<TYPE>S-3
<PUBLIC-DOCUMENT-COUNT>3
<FILING-DATE>20051222
<DATE-OF-FILING-DATE-CHANGE>20051222
<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>S-3
<ACT>33
<FILE-NUMBER>333-130639
<FILM-NUMBER>051282793
</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>S-3
<SEQUENCE>1
<FILENAME>a05-22096_1s3.htm
<DESCRIPTION>REGISTRATION STATEMENT FOR FACE-AMOUNT CERTIFICATE COMPANIES
<TEXT>
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<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;">As
filed with the Securities and Exchange Commission on December 22, 2005</font></b></p>

<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;">Registration No. 333-&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</font></b></p>

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

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

</div>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><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 6.0pt;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Washington, D.C. 20549</font></b></p>

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<hr size="1" width="25%" noshade color="black" align="center">

</font></div>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="5" face="Times New Roman" style="font-size:18.0pt;font-weight:bold;">FORM S-3</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="3" face="Times New Roman" style="font-size:12.0pt;font-weight:bold;">REGISTRATION
STATEMENT</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="3" face="Times New Roman" style="font-size:12.0pt;font-weight:bold;">Under</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="3" face="Times New Roman" style="font-size:12.0pt;font-weight:bold;">THE
SECURITIES ACT OF 1933</font></b></p>

<div align="center" style="margin:0in 0in 4.0pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">

<hr size="1" width="25%" noshade color="black" align="center">

</font></div>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><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 its charter)</font></p>

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<hr size="1" width="25%" noshade color="black" align="center">

</font></div>

<div align="center">

<table border="0" cellspacing="0" cellpadding="0" width="100%" style="border-collapse:collapse;width:100.0%;">
 <tr>
  <td width="45%" valign="top" style="padding:0in .7pt 0in .7pt;width:45.0%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Delaware</font></p>
  </td>
  <td width="10%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:10.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="45%" valign="top" style="padding:0in .7pt 0in .7pt;width:45.0%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">33-0336973</font></p>
  </td>
 </tr>
 <tr>
  <td width="45%" valign="top" style="padding:0in .7pt 0in .7pt;width:45.0%;">
  <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</font></p>
  </td>
  <td width="10%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:10.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="45%" valign="top" style="padding:0in .7pt 0in .7pt;width:45.0%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(I.R.S.
  Employer</font></p>
  </td>
 </tr>
 <tr>
  <td width="45%" valign="top" style="padding:0in .7pt 0in .7pt;width:45.0%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">of
  incorporation or organization)</font></p>
  </td>
  <td width="10%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:10.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="45%" valign="top" style="padding:0in .7pt 0in .7pt;width:45.0%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Identification
  Number)</font></p>
  </td>
 </tr>
</table>

</div>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">1896 Rutherford Road</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;">Carlsbad, California 92008</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;">(760) 931-9200</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;">(Address, including zip code, and telephone number, including area
code, of Registrant&#146;s principal executive offices)</font></p>

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

<hr size="1" width="25%" noshade color="black" align="center">

</font></div>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">B. Lynne Parshall, Esq.</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;">Executive Vice President</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, 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;">1896 Rutherford Road</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;">Carlsbad, California 92008</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;">(760) 931-9200</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;">(Name, address, including zip code, and telephone number, including
area code, of agent for service)</font></p>

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

<hr size="1" width="25%" noshade color="black" align="center">

</font></div>

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

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Julie M. Robinson, Esq.</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;">Cooley Godward LLP</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;">4401 Eastgate Mall</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;">San Diego, CA&#160; 92121</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;">(858) 550-6000</font></p>

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

<hr size="1" width="25%" noshade color="black" align="center">

</font></div>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Approximate
date of commencement of proposed sale to the public:</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;">From
time to time after the effective date of this Registration Statement.</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 style="margin:0in 0in 2.0pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If
the only securities being registered on this Form are being offered pursuant to
dividend or interest reinvestment plans, please check the following box. </font><font size="2" face="Wingdings" style="font-size:10.0pt;">o</font></p>

<p style="margin:0in 0in 2.0pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If
any of the securities being registered on this Form are to be offered on a
delayed or continuous basis pursuant to Rule 415 under the Securities Act of
1933, other than securities offered only in connection with dividend or
interest reinvestment plans, check the following box. </font><font size="2" face="Wingdings" style="font-size:10.0pt;">&#253;</font></p>

<p style="margin:0in 0in 2.0pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If
this Form is filed to register additional securities for an offering pursuant
to Rule 462(b) under the Securities Act, please check the following box and
list the Securities Act registration statement number of the earlier effective
registration statement for the same offering. </font><font size="2" face="Wingdings" style="font-size:10.0pt;">o</font></p>

<p style="margin:0in 0in 2.0pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If
this Form is a post-effective amendment filed pursuant to Rule 462(c) under the
Securities Act, check the following box and list the Securities Act
registration statement number of the earlier effective registration statement
for the same offering. </font><font size="2" face="Wingdings" style="font-size:10.0pt;">o</font></p>

<p style="margin:0in 0in 2.0pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If
this Form is a registration statement pursuant to General Instruction I.D. or a
post-effective amendment thereto that shall become effective upon filing with
the Commission pursuant to Rule 462(e) under the Securities Act, check the
following box. </font><font size="2" face="Wingdings" style="font-size:10.0pt;">o</font></p>

<p style="margin:0in 0in 2.0pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If
this is a post-effective amendment to a registration statement filed pursuant
to General Instruction I.D. filed to register additional securities or
additional classes of securities pursuant to Rule 413(b) under the Securities
Act, check the following box. </font><font size="2" face="Wingdings" style="font-size:10.0pt;">o</font></p>

<p align="center" style="margin:0in 0in 3.0pt;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">CALCULATION OF REGISTRATION FEE</font></b></p>

<table border="0" cellspacing="0" cellpadding="0" width="100%" style="border-collapse:collapse;width:100.0%;">
 <tr>
  <td width="41%" valign="bottom" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:41.9%;">
  <p align="center" style="margin:0in 0in .0001pt 10.0pt;text-align:center;text-indent:-10.0pt;"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">Title of each class of
  securities to<br>
  be registered</font></b></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.04%;">
  <p style="margin:0in 0in .0001pt;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></p>
  </td>
  <td width="25%" valign="bottom" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:25.76%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">Proposed maximum aggregate<br>
  offering price</font></b></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.02%;">
  <p style="margin:0in 0in .0001pt;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></p>
  </td>
  <td width="27%" valign="bottom" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:27.78%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">Amount of<br>
  registration fee(3)</font></b></p>
  </td>
  <td width="0%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:.52%;">
  <p style="margin:0in 0in .0001pt;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></p>
  </td>
 </tr>
 <tr>
  <td width="41%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:41.9%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Common Stock, $0.001 per
  share (1)</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.04%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="25%" valign="bottom" style="border:none;padding:0in .7pt 0in .7pt;width:25.76%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">$200,000,000(2)</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.02%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="27%" valign="bottom" style="border:none;padding:0in .7pt 0in .7pt;width:27.78%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">$21,400</font></p>
  </td>
  <td width="0%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:.52%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
</table>

<div style="margin:3.0pt 0in .0001pt .5in;text-indent:-.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">

<hr size="1" width="25%" noshade color="black" align="left">

</font></div>

<p style="margin:3.0pt 0in .0001pt .5in;text-indent:-.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(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; </font><font size="2" style="font-size:10.0pt;">An
indeterminate number of shares of common stock of the registrant may be sold
from time to time by the registrant.&#160; The
common stock includes associated Series C Junior Participating Preferred Stock
Rights pursuant to Rights Agreement dated as of December 8, 2000 between the
Registrant and American Stock Transfer &amp; Trust Company.</font></p>

<p style="margin:3.0pt 0in .0001pt .5in;text-indent:-.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(2)</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; </font><font size="2" style="font-size:10.0pt;">In no event
will the aggregate offering price of all securities issued from time to time
pursuant to this registration statement exceed $200,000,000.00.</font></p>

<p style="margin:3.0pt 0in .0001pt .5in;text-indent:-.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(3)</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; </font><font size="2" style="font-size:10.0pt;">Calculated
pursuant to Rule 457(o) of the Securities Act of 1933.</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:3.0pt 0in .0001pt;text-indent:.5in;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">The Registrant hereby amends this Registration Statement on such date
or dates as may be necessary to delay its effective date until the Registrant
shall file a further amendment that specifically states that this Registration
Statement shall thereafter become effective in accordance with Section 8(a) of
the Securities Act of 1933 or until the Registration Statement shall become
effective on such date as the Commission, acting pursuant to said Section 8
(a), may determine.</font></b></p>

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

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

</div>

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

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

</font></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>

</div>
<!-- SEQ.=1,FOLIO='',FILE='C:\JMS\schella\05-22096-1\task720615\22096-1-ba.htm',USER='schellamuthu',CD='Dec 22 20:06 2005' -->



<br clear="all" style="page-break-before:always;">

<div style="font-family:Times New Roman;">

<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;">SUBJECT
TO COMPLETION, DATED DECEMBER 22, 2005</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="margin:0in 0in .0001pt;"><b><font size="2" color="red" face="Times New Roman" style="color:red;font-size:10.0pt;font-weight:bold;">The information
in this prospectus is not complete and may be changed.&#160; We may not sell these securities until the
registration statement filed with the Securities and Exchange Commission is
effective.&#160; This prospectus is not an
offer to sell these securities and we are not soliciting offers to buy these
securities in any state where the offer or sale is not permitted.</font></b></p>

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

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

<p style="margin:0in 0in .0001pt;"><font size="3" face="Times New Roman" style="font-size:12.0pt;">&nbsp;</font></p>

<p style="font-weight:bold;margin:0in 0in .0001pt;page-break-after:auto;text-align:center;text-transform:uppercase;"><b><font size="4" face="Times New Roman" style="font-size:14.0pt;text-transform:none;">$200,000,000</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;"><br>
</font></b><b><font size="5" 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;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="4" face="Times New Roman" style="font-size:14.0pt;font-weight:bold;">Common Stock</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>

<div align="center" style="margin:0in 0in 12.0pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">

<hr size="1" width="25%" noshade color="black" align="center">

</font></div>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We may from time to time sell common stock in
one or more offerings for an aggregate initial offering price of $200,000,000.
This prospectus describes the general manner in which our common stock may be
offered using this prospectus. We will specify in the accompanying prospectus
supplement the terms of the securities to be offered and sold. We may sell
these securities to or through underwriters or dealers and also to other
purchasers or through agents. We will set forth the names of any underwriters,
dealers or agents in the accompanying prospectus supplement.</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;">Our common stock is currently traded on the
Nasdaq National Market under the symbol &#147;ISIS.&#148;&#160;
On December 21, 2005, the last reported sales price for our common stock
was $5.25 per share.</font></p>

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

<div align="center" style="margin:0in 0in 12.0pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">

<hr size="1" width="25%" noshade color="black" align="center">

</font></div>

<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;">Investing
in our common stock involves risks.</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;">See &#147;Risk
Factors&#148; beginning on page 3.</font></b></p>

<div align="center" style="margin:0in 0in 12.0pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">

<hr size="1" width="25%" noshade color="black" align="center">

</font></div>

<p style="margin:0in 0in 12.0pt;text-indent:.5in;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Neither the securities and exchange commission nor any state securities
commission has approved or disapproved of these securities or passed upon the
adequacy or accuracy of this prospectus. Any representation to the contrary is
a criminal offense.</font></b></p>

<div align="center" style="margin:0in 0in 12.0pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">

<hr size="1" width="25%" noshade color="black" align="center">

</font></div>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">This prospectus may not be used to consummate
sales of securities unless it is accompanied by a prospectus supplement.</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;">The
date of this Prospectus is December 22, 2005</font></p>

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

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

</font></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>

</div>
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<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;">TABLE
OF CONTENTS</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;">&nbsp;</font></b></p>

<table border="0" cellspacing="0" cellpadding="0" width="100%" style="border-collapse:collapse;width:100.0%;">
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:0in .25in .0001pt 0in;"><font size="1" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="8%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">Page</font></b></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#AboutThisProspectus_101402" title="Click to goto ">About
  this Prospectus</a></font></p>
  </td>
  <td width="8%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">1</font></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#AboutOurBusiness_101410" title="Click to goto ">About
  our Business</a></font></p>
  </td>
  <td width="8%" valign="top" style="padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">1</font></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#RiskFactors_101812" title="Click to goto ">Risk Factors</a></font></p>
  </td>
  <td width="8%" valign="top" style="padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">3</font></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#SpecialNoteRegardingForwardlookin_102023" title="Click to goto ">Special Notice Regarding Forward-Looking Statements</a></font></p>
  </td>
  <td width="8%" valign="top" style="padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">8</font></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#UseOfProceeds_102048" title="Click to goto ">Use of
  Proceeds</a></font></p>
  </td>
  <td width="8%" valign="top" style="padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">9</font></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#PlanOfDistribution_102049" title="Click to goto ">Plan
  of Distribution</a></font></p>
  </td>
  <td width="8%" valign="top" style="padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">9</font></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#DescriptionOfCapitalStock_102208" title="Click to goto ">Description
  of Capital Stock</a></font></p>
  </td>
  <td width="8%" valign="top" style="padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">10</font></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#DividendPolicy_102220" title="Click to goto ">Dividend
  Policy</a></font></p>
  </td>
  <td width="8%" valign="top" style="padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">11</font></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#LegalMatters_102222" title="Click to goto ">Legal
  Matters</a></font></p>
  </td>
  <td width="8%" valign="top" style="padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">11</font></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#Experts_102223" title="Click to goto ">Experts</a></font></p>
  </td>
  <td width="8%" valign="top" style="padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">11</font></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#WhereYouCanFindMoreInformation_102227" title="Click to goto ">Where You Can Find More Information</a></font></p>
  </td>
  <td width="8%" valign="top" style="padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">12</font></p>
  </td>
 </tr>
 <tr>
  <td width="91%" valign="top" style="padding:0in .7pt 0in .7pt;width:91.98%;">
  <p style="margin:6.0pt .25in .0001pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;"><a href="a05-22096_1s3.htm#IncorporationOfCertainDocumentsBy_102306" title="Click to goto ">Incorporation of Certain Documents by Reference</a></font></p>
  </td>
  <td width="8%" valign="top" style="padding:0in .7pt 0in .7pt;width:8.02%;">
  <p align="right" style="margin:6.0pt 12.0pt .0001pt 0in;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">12</font></p>
  </td>
 </tr>
</table>

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

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

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

</font></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>

</div>
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<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="AboutThisProspectus_101402"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">ABOUT THIS PROSPECTUS</font></b></p>

<p align="left" style="font-style:italic;margin:0in 0in .0001pt;text-align:left;"><i><font size="2" face="Times New Roman" style="font-size:10.0pt;">This
prospectus is part of a registration statement that we filed with the
Securities and Exchange Commission using a &#147;shelf&#148; registration process. Under
this shelf registration process, we may, from time to time, sell common stock
in one or more offerings up to a total dollar amount of $200,000,000. This
prospectus describes the general manner in which our common stock may be
offered by this prospectus. Each time we sell common stock, we will provide a
prospectus supplement that will contain specific information about the terms of
that offering. If there is any inconsistency between the information in this
prospectus and the accompanying prospectus supplement, you should rely on the
information in the prospectus supplement. We may also add, update or change in
the prospectus supplement any of the information contained in this prospectus.
This prospectus, together with applicable prospectus supplements, includes all
material information relating to this offering.</font></i></p>

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

<p align="left" style="font-style:italic;margin:0in 0in .0001pt;text-align:left;"><i><font size="2" face="Times New Roman" style="font-size:10.0pt;">We
encourage you to read this prospectus in its entirety, including the documents
incorporated by reference. As used in this prospectus, unless otherwise
specified or the context requires otherwise, the terms &#147;Isis,&#148; &#147;we,&#148; &#147;our&#148; and &#147;us&#148;
refer to Isis Pharmaceuticals, Inc.</font></i></p>

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

<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="AboutOurBusiness_101410"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">ABOUT OUR BUSINESS</font></b></p>

<p style="margin-left:0in;margin-right:0in;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We are a biopharmaceutical company exploiting
proprietary RNA-based drug discovery technologies to identify and commercialize
novel drugs to treat important diseases. RNA, or ribonucleic acid, is a
molecule that provides to a cell the information the cell needs to produce
proteins, including those proteins implicated in disease. Interference with RNA
can keep the body from producing proteins that are involved in disease. We are
the leader in exploiting RNA as a target for drugs, and have a strong
proprietary position in RNA-based drug discovery technologies. With our primary
technology, antisense, we create inhibitors, or oligonucleotides, designed to
hybridize, with a high degree of specificity to their RNA target and modulate
the production of specific proteins associated with disease. We also use our
antisense technology internally and in collaborations with pharmaceutical
companies to rapidly and efficiently identify and prioritize attractive gene
targets for drug discovery.&#160; Within our
Ibis division, we are expanding on our RNA expertise by creating a system that
can rapidly and accurately identify a broad range of infectious organisms with
a single test.&#160; Our ongoing development
of this technology and a system related to this technology has been funded
primarily by agencies within the United States government.</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; We
successfully commercialized our first antisense drug, Vitravene. Vitravene
demonstrates our ability to meet Food and Drug Administration, or FDA, and
European regulatory requirements, and to commercially manufacture antisense
drugs. We and our partners currently have 12 antisense products in preclinical
and clinical development, the majority of which are in Phase I or Phase II
human clinical trials. Our products in development address numerous therapeutic
areas with major market potential, including inflammatory, metabolic,
cardiovascular and ocular diseases, and cancer. We are expanding the
therapeutic opportunities for antisense drugs by developing a variety of
formulations to enhance patient convenience and compliance, including
intravitrial, subcutaneous, topical cream, enema, aerosol and oral
formulations. In addition, our pipeline has matured to consist primarily of
drugs based on our proprietary second-generation chemistry.&#160; Our second-generation antisense drugs offer a
number of advantages over prior chemistries.&#160;
Specifically, these drugs offer the potential for improved safety,
increased potency and a longer half-life, which correlates with durability of
therapeutic response and the potential for less frequent dosing.&#160; Physicians may be able to dose our
second-generation drugs as infrequently as once every two weeks to once a
month. We are also making progress on developing oral formulations of our
second-generation antisense drugs.&#160; Our
oral formulations may increase the commercial value of our antisense drugs.</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;letter-spacing:-.1pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; </font><font size="2" style="font-size:10.0pt;">Within our Ibis division we have invented
technology that has the potential to revolutionize the identification of
infectious diseases.&#160; This technology is
called Triangulation Identification for Genetic Evaluation of Risks, or
TIGER.&#160; We have applied the TIGER
technology to develop a system to identify from a sample a broad range of
infectious organisms, including organisms that are newly-emerging, genetically
altered and unculturable.&#160; We have
successfully demonstrated proof-of-principle of the TIGER biosensor system with
the identification of a variety of bacteria and viruses in both environmental
and human clinical samples. In addition to bioweapons defense, Ibis has
advanced the development of our TIGER biosensor system to include
epidemiological surveillance, biological products screening and microbial
forensics screening applications. These applications represent the first </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;">&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;">1</font></p>

<div style="margin:0in 0in .0001pt;"><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 style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">of many we plan to add to the TIGER biosensor
system to enhance its commercial value and opportunity in the government,
research, medical and diagnostic markets.</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;letter-spacing:-.1pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; </font><font size="2" style="font-size:10.0pt;letter-spacing:-.1pt;">We incorporated in California in 1989, and in 1991
we reincorporated as a Delaware corporation. Our principal offices are in
Carlsbad, California. </font><font size="2" style="font-size:10.0pt;">&#160;&#160;Our executive offices are located at 1896
Rutherford Road, Carlsbad, California 92008, and our telephone number is
(760)&nbsp;931-9200.</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="3" face="Times New Roman" style="font-size:12.0pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; </font><font size="2" style="font-size:10.0pt;">Isis Pharmaceuticals<sup>TM</sup> is our
trademark.&#160; Vitravene&#174; is a registered
trademark of Novartis AG.&#160; Affinitak<sup>TM
</sup>is a trademark of Eli Lilly and Company.&#160;
This prospectus also contains trademarks and servicemarks of other
companies.</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;">2</font></p>

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</font></div>

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<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="RiskFactors_101812"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">RISK FACTORS</font></b></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Investing in our
securities involves a high degree of risk.&#160;
In addition to the other information in this prospectus, you should
carefully consider the risks described below before purchasing our securities.&#160; If any of the following risks actually occur,
our business could be materially harmed, and our financial condition and
results of operations could be materially and adversely affected.&#160; As a result, the trading price of our
securities could decline, and you might lose all or part of your investment.</font></p>

<p style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">We have incurred losses, and our business will suffer if we fail to
achieve profitability in the future.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Because drug discovery and development require
substantial lead-time and money prior to commercialization, our expenses have
exceeded our revenue since we were founded in January&nbsp;1989. As of
September 30, 2005, we had accumulated losses of approximately $762.9 million
and a stockholders&#146; equity of approximately $4.0 million.&#160; Most of the losses resulted from costs
incurred in connection with our research and development programs and from
general and administrative costs associated with our operations. Most of our
revenue has come from collaborative arrangements, with additional revenue from
interest income and research grants and the sale or licensing of patents. We
currently have only one product, Vitravene, approved for commercial use.&#160; This product has limited sales potential. We
expect to incur additional operating losses over the next several years, and
these losses may increase if we cannot increase or sustain revenue. We may not
successfully develop any additional products or services, or achieve or sustain
future profitability.</font></p>

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

<p style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">If we or our partners fail to obtain regulatory approval for our
products, we will not be able to sell them.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We and our partners must conduct time-consuming,
extensive and costly clinical trials to show the safety and efficacy of each of
our drug candidates before a drug candidate can be approved for sale. We must
conduct these trials in compliance with United States Food and Drug
Administration regulations and with comparable regulations in other countries.
If the FDA or another regulatory agency believes that we or our partners have
not sufficiently demonstrated the safety or efficacy of our drug candidates, it
will not approve them or will require additional studies, which can be time
consuming and expensive and which will delay commercialization of a drug
candidate. We and our partners may not be able to obtain necessary regulatory
approvals on a timely basis, if at all, for any of our drug candidates. Failure
to receive these approvals or delays in these approvals could prevent or delay
commercial introduction of a product and, as a result, could negatively impact
our ability to generate revenue from product sales. In addition, following
approval of a drug candidate, we and our partners must comply with
comprehensive government regulations regarding how we manufacture, market and
distribute products. If we fail to comply with these regulations, regulators
could force us to withdraw a drug candidate from the market or impose other
penalties or requirements that also could have a negative impact on our
financial results.</font></p>

<p style="margin:3.0pt 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We have only introduced one
commercial product, Vitravene. We cannot guarantee that any of our other drug
candidates will be safe and effective, will be approved for commercialization
or that our partners or we can successfully commercialize these drug
candidates.</font></p>

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

<p style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">If the results of clinical testing indicate that any of our drugs under
development are not suitable for commercial use, or if additional testing is
required to demonstrate suitability, we may need to abandon one or more of our
drug development programs.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Drug discovery and development has inherent risks,
including the risk that molecular targets prove not to be important in a
particular disease; the risk that compounds that demonstrate attractive
activity in preclinical studies do not demonstrate similar activity in human
beings; the risk that a compound is not safe or effective for use in humans;
and the risk that successful results in early human clinical trials may not be
indicative of results in late-stage clinical trials. Antisense technology in
particular is relatively new and unproven. We are applying most of our
resources to create safe and effective drugs for human use. Any of the risks
described above could prevent us from meeting this goal.&#160; In the past, we have invested in clinical
studies of drug candidates that have not met the primary clinical end points in
their initial Phase III studies.</font></p>

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><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;">In
March&nbsp;2003, we reported the results of a Phase III clinical trial of
Affinitak in patients with late stage non-small cell lung cancer and in
October&nbsp;2004, we reported the results of a second similar Phase III
clinical trial. In each case, Affinitak failed to demonstrate improved survival
sufficient enough to support an NDA filing.&#160;
In December&nbsp;2004, we reported the results of our Phase III clinical
trials of alicaforsen in patients with active Crohn&#146;s disease, in which
alicaforsen did not demonstrate statistically significant induction of clinical
remissions compared to placebo.&#160; </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;">3</font></p>

<div style="margin:0in 0in .0001pt;"><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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<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="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Similar
results could occur with the trials for our other drugs.&#160; If any of our drugs in clinical studies do
not show sufficient efficacy in patients with the targeted indication, it could
negatively impact our development and commercialization goals for this and
other drugs and our stock price could decline.</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;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">If the market does not accept our products, we are not likely to
generate revenues or become profitable.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Our success will depend upon the medical community,
patients and third-party payors accepting our products as medically useful,
cost-effective and safe. We cannot guarantee that, if approved for commercialization,
doctors will use our products to treat patients. We currently have one
commercially available product, Vitravene, a treatment for cytomegalovirus, or
CMV, retinitis in AIDS patients, which addresses a small market. Our partners
and we may not successfully commercialize additional products.</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">The degree of market acceptance for any of
our products depends upon a number of factors, including:</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">The receipt and
scope of regulatory approvals;</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">The
establishment and demonstration in the medical and patient community of the
efficacy and safety of our drug candidates and their potential advantages over
competing products;</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">The cost and
effectiveness of our drug candidates compared to other available therapies;</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">The patient
convenience of the dosing regimen for our drug candidates; and</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">Reimbursement
policies of government and third party payors.</font></p>

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

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Based on the profile of our drug candidates,
physicians, patients, patient advocates, payors or the medical community in
general may not accept and use any products that we may develop.</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;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">If any of our collaborative partners fail to fund our collaborative
programs or develop or sell any of our products under development, or if we
cannot obtain additional partners, we may have to delay or stop progress on our
product development programs.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">To date, corporate partnering has played a key role
in our strategy to fund our development programs and to add key development
resources. We plan to continue to rely on additional collaborative arrangements
to develop and commercialize our products. However, we may not be able to
negotiate additional attractive collaborative arrangements, and, even if
negotiated, the collaborative arrangements may not be successful.</font></p>

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

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We have entered into collaborative arrangements with
third parties to develop many of our product candidates. We enter into these
collaborations in order to:</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">Fund our
research and development activities;</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">Access
manufacturing by third parties;</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">Seek and obtain
regulatory approvals;</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">Conduct
clinical trials; and</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">Successfully
commercialize existing and future product candidates.</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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If any of our partners fails to develop or sell any
drug in which we have retained a financial interest, our business may suffer.
These collaborations may not continue or result in commercialized drugs. Our
collaborators can terminate their relationships with us under certain
circumstances, some of which are outside of our control. For example, in
November&nbsp;2004 based on the outcome of both Phase III trials, Lilly
discontinued its investment in Affinitak.</font></p>

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

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Other drug candidates in our development pipeline
are being developed and/or funded by corporate partners, including Antisense
Therapeutics Limited, iCo Therapeutics, Inc., OncoGenex Technologies Inc. and
Lilly. We have received significant financial support from United States
Government-funded grants and contracts for our Ibis division and the
development of our TIGER system. The United States Government can unilaterally
terminate these contracts and grants at its convenience at any time, even if we
have fully performed our obligations. If any of </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;">4</font></p>

<div style="margin:0in 0in .0001pt;"><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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<div style="font-family:Times New Roman;">

<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="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">these
pharmaceutical companies or government partners stopped funding and/or
developing these products, our business could suffer and we may not have the
resources available to develop these products on our own.</font></p>

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

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Certain of our partners are pursuing other
technologies or developing other drug candidates either on their own or in
collaboration with others, including our competitors, to develop treatments for
the same diseases targeted by our own collaborative programs. Competition may
negatively impact a partner&#146;s focus on and commitment to our drug candidate
and, as a result, could delay or otherwise negatively affect the
commercialization of a drug candidate.</font></p>

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

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">In addition, the disappointing results of the two
Affinitak trials, our Phase III clinical trials of alicaforsen in patients with
active Crohn&#146;s disease or any future clinical trial failures could impair our
ability to attract new collaborative partners. If we cannot continue to secure
additional collaborative partners, our revenues could decrease and the
development of our drug candidates could suffer.</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;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">We may not successfully develop or derive revenues from our business
based on our TIGER system to identify infectious organisms.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Our TIGER system is subject to the risks inherent in
developing tools based on innovative technologies. Our product is at an early
stage of development and requires additional research and development prior to
marketing. If our potential customers fail to purchase our TIGER system due to
competition or other factors, or if we fail to develop applications that lead
to market acceptance, we could lose our investment in this technology and our
TIGER business could fail to meet our business and financial objectives.</font></p>

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

<p style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">If we fail to obtain timely funding, we may need to curtail or abandon
some of our programs.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">All of our product candidates are still undergoing
clinical trials or are in the early stages of research and development. All of
our products under development will require significant additional research,
development, preclinical and/or clinical testing, regulatory approval and a
commitment of significant additional resources prior to their
commercialization. Based on our current operating plan with reasonable
assumptions for new sources of revenue and cash, we believe our resources will
be sufficient to meet our anticipated requirements at least through 2007.&#160; If we do not meet our goals to commercialize
our products, or to license our drugs and proprietary technologies, we will
need additional funding in the future. Our future capital requirements will
depend on many factors, such as the following:</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">the profile and
launch timing of our drugs;</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">continued
scientific progress in our research, drug discovery and development programs;</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">the size of our
programs and progress with preclinical and clinical trials;</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">the time and
costs involved in obtaining regulatory approvals;</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">competing
technological and market developments, including the introduction by others of
new therapies that address our markets;</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">success in
developing and commercializing a business based on our TIGER system to identify
infectious organisms; and</font></p>

<p style="margin:6.0pt 0in .0001pt .75in;text-autospace:none;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">changes in
existing collaborative relationships and our ability to establish and maintain
additional collaborative arrangements.</font></p>

<p style="margin:3.0pt 0in;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If we need additional funds, we may need to raise them through public
or private financing. Additional financing may not be available at all or on
acceptable terms. If we raise additional funds by issuing equity securities,
the shares of existing stockholders will be diluted and their price, as well as
the price of our other securities, may decline. If adequate funds are not
available, we may have to cut back on one or more of our research, drug
discovery or development programs.&#160; For
example, in January&nbsp;2005 we decided to terminate the development of two
lower priority drugs, ISIS 14803 and ISIS 104838.&#160; Alternatively, we may obtain funds through
arrangements with collaborative partners or others, which could require us to
give up rights to certain of our technologies, product candidates or products.</font></p>

<p align="center" style="margin:3.0pt 0in;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">5</font></p>

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</font></div>

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<p style="margin:3.0pt 0in;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">If we
cannot manufacture our products or contract with a third party to manufacture
our products at costs that allow us to charge competitive prices to buyers, we
will not be able to market products profitably.</font></b></p>

<p style="margin:3.0pt 0in;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If we successfully commercialize any of our drug candidates, we may be
required to establish large-scale commercial manufacturing capabilities. In
addition, as our drug development pipeline increases and matures, we will have
a greater need for clinical trial and commercial manufacturing capacity. We
have limited experience manufacturing pharmaceutical products of the chemical class
represented by our drug candidates, called oligonucleotides, on a commercial
scale for the systemic administration of a drug. There are a small number of
suppliers for certain capital equipment and raw materials that we use to
manufacture our drugs, and some of these suppliers will need to increase their
scale of production to meet our projected needs for commercial manufacturing.
Further, we must continue to improve our manufacturing processes to allow us to
reduce our product costs. We may not be able to manufacture at a cost or in
quantities necessary to make commercially successful products.</font></p>

<p style="margin:3.0pt 0in;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Also, manufacturers, including us, must adhere to the FDA&#146;s current
Good Manufacturing Practices regulations which the FDA enforces through its
facilities inspection program. We and our contract manufacturers may not be
able to comply or maintain compliance with Good Manufacturing Practices
regulations. Non-compliance could significantly delay our receipt of marketing
approval for potential products or result in FDA enforcement action after
approval that could limit the commercial success of our potential product.</font></p>

<p style="margin:3.0pt 0in;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">If we
fail to compete effectively, our products will not contribute significant
revenues.</font></b></p>

<p style="margin:3.0pt 0in;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Our competitors are engaged in all areas of drug discovery throughout
the world, are numerous, and include, among others, major pharmaceutical
companies and specialized biopharmaceutical firms. Other companies are engaged
in developing antisense technology or unique methods of identifying infectious
organisms. Our competitors may succeed in developing drug candidates or
technologies that are more effective than any drug candidates or technologies
that we are developing. These competitive developments could make our products
obsolete or non-competitive.</font></p>

<p style="margin:3.0pt 0in;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Many of our competitors have substantially greater financial, technical
and human resources than we do. In addition, many of these competitors have
significantly greater experience than we do in conducting preclinical testing
and human clinical trials of new pharmaceutical products and in obtaining FDA
and other regulatory approvals of products for use in health care. Accordingly,
our competitors may succeed in obtaining regulatory approval for products
earlier than we do. We will also compete with respect to marketing and sales
capabilities, areas in which we have limited or no experience.</font></p>

<p style="margin:3.0pt 0in;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">If we
cannot protect our patents or our proprietary rights, others may compete more
directly against us.</font></b></p>

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Our success depends to a significant degree upon our
ability to continue to develop and secure intellectual property rights to
proprietary products and services. However, we may not receive issued patents
on any of our pending patent applications in the United States or in other
countries. In addition, the scope of any of our issued patents may not be
sufficiently broad to provide us with a competitive advantage. Furthermore, our
issued patents or patents licensed to us may be successfully challenged,
invalidated or circumvented so that our patent rights would not create an
effective competitive barrier or revenue source.</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;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Intellectual property litigation could be expensive and prevent us from
pursuing our programs.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">It is possible that in the future we may have to
defend our intellectual property rights. In the event of an intellectual
property dispute, we may be forced to litigate to defend our rights or assert
them against others. Disputes could involve arbitration, litigation or
proceedings declared by the United States Patent and Trademark Office or the
International Trade Commission or foreign patent authorities. Intellectual
property litigation can be extremely expensive, and this expense, as well as
the consequences should we not prevail, could seriously harm our business.</font></p>

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

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If a third party claims that our products or
technology infringe their patents or other intellectual property rights, we may
have to discontinue an important product or product line, alter our products
and processes, pay license fees or cease certain activities. We may not be able
to obtain a license to such intellectual property on favorable terms, if at
all. There are many patents issued or applied for in the biotechnology
industry, and we may not be aware of patents or applications held by others
that relate to our business. This is especially true since patent applications
in the United States are filed confidentially. Moreover, the validity and
breadth of biotechnology patents involve complex legal and factual questions
for which important legal issues remain unresolved.</font></p>

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

<p style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">If we do not progress in our programs as anticipated, the price of our
securities could decrease.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">For planning purposes, we estimate the timing of a
variety of clinical, regulatory and other milestones, like when a certain
product candidate will enter the clinic, when we will complete a clinical
trial, or when we will file an </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;">6</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 style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">application
for marketing approval. We base our estimates on present facts and a variety of
assumptions. Many of the underlying assumptions are outside of our control. If
we do not achieve milestones when we expect to, investors could be disappointed
and the price of our securities would likely decrease.</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 style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">The loss of key personnel, or the inability to attract and retain
highly skilled personnel, could make it more difficult to run our business and
reduce our likelihood of success.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We are dependent on the principal members of our
management and scientific staff. We do not have employment agreements with any
of our executive officers. The loss of our management and key scientific
employees might slow the achievement of important research and development
goals. It is also critical to our success that we recruit and retain qualified
scientific personnel to perform research and development work. We may not be
able to attract and retain skilled and experienced scientific personnel on
acceptable terms because of intense competition for experienced scientists
among many pharmaceutical and health care companies, universities and
non-profit research institutions. Failure to succeed in clinical trials may
make it more challenging to recruit and retain qualified scientific personnel.</font></p>

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

<p style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">We depend on third parties in the conduct of our clinical trials for
our product candidates and any failure of those parties to fulfill their
obligations could adversely affect our development and commercialization plans.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We depend on independent clinical investigators,
contract research organizations and other third party service providers in the
conduct of our clinical trials for our product candidates and expect to
continue to do so in the future. We rely heavily on these parties for
successful execution of our clinical trials, but do not control many aspects of
their activities. For example, the investigators are not our employees.
However, we are responsible for ensuring that each of our clinical trials is
conducted in accordance with the general investigational plan and protocols for
the trial. Third parties may not complete activities on schedule, or may not
conduct our clinical trials in accordance with regulatory requirements or our
stated protocols. The failure of these third parties to carry out their
obligations could delay or prevent the development, approval and
commercialization of our product candidates.</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 style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">If the price of our securities continues to be highly volatile, this
could make it harder for you to liquidate your investment and could increase
your risk of suffering a loss.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">The market price of our common stock, like that of
the securities of many other biopharmaceutical companies, has been and is
likely to continue to be highly volatile. These fluctuations in our common
stock price may significantly affect the trading price of our securities.
During the 12 months preceding September&nbsp;30, 2005, the market price of our
common stock has ranged from $2.76 to $6.63 per share.&#160; Many factors can affect the market price of
our securities, including, for example, fluctuations in our operating results,
announcements of collaborations, clinical trial results, technological
innovations or new drug products being developed by us or our competitors,
governmental regulation, regulatory approval, developments in patent or other
proprietary rights, public concern regarding the safety of our drugs and
general market conditions.</font></p>

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

<p style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Provisions in our certificate of incorporation, other agreements and
Delaware law may prevent stockholders from receiving a premium for their
shares.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Our certificate of incorporation provides for
classified terms for the members of our board of directors. Our certificate
also includes a provision that requires at least 66% of our voting stockholders
to approve a merger or certain other business transactions with, or proposed
by, any holder of 15% or more of our voting stock, except in cases where
certain directors approve the transaction or certain minimum price criteria and
other procedural requirements are met.</font></p>

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

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Our certificate of incorporation also requires that
any action required or permitted to be taken by our stockholders must be taken
at a duly called annual or special meeting of stockholders and may not be taken
by written consent. In addition, only our board of directors, chairman of the
board or chief executive officer can call special meetings of our stockholders.
We also have implemented a stockholders&#146; rights plan, also called a poison
pill, which could make it uneconomical for a third party to acquire our company
on a hostile basis. These provisions, as well as Delaware law and other of our
agreements, may discourage certain types of transactions in which our
stockholders might otherwise receive a premium for their shares over then
current market prices, and may limit the ability of our stockholders to approve
transactions that they think may be in their best interests. In addition, our
board of directors has the authority to fix the rights and preferences of and
issue shares of preferred stock, which </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;">7</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 style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">may
have the effect of delaying or preventing a change in control of our company
without action by our stockholders.</font></p>

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

<p style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">If registration rights that we have previously granted are exercised,
then the price of our securities may be negatively affected.</font></b></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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We have granted registration rights to Eli Lilly and
Company which cover approximately 2.5 million shares of our common stock which
we issued to Lilly upon the conversion of outstanding convertible securities.
In addition, we recently registered for resale 12,000,000 shares of our common
stock and 2,999,998 shares of our common stock issuable upon the exercise of
warrants, which we issued as part of our August 2005 private placement.&#160; The addition of these shares into the market,
may have an adverse effect on the price of our securities.</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;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Our business is subject to changing regulations for corporate
governance and public disclosure that has increased both our costs and the risk
of noncompliance.</font></b></p>

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

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Each year we are required to
evaluate our internal controls systems in order to allow management to report
on, and our Independent Registered Public Accounting Firm to attest to, our
internal controls as required by Section&nbsp;404 of the Sarbanes-Oxley Act. As
a result, we will incur additional expenses and will suffer a diversion of
management&#146;s time.&#160; In addition, if we
cannot continue to comply with the requirements of Section&nbsp;404 in a timely
manner, we might be subject to sanctions or investigation by regulatory
authorities, such as the Securities and Exchange Commission, the Public Company
Accounting Oversight Board, or PCAOB, or the NASDAQ Stock Exchange. Any such
action could adversely affect our financial results and the market price of our
common stock.</font></p>

<p style="margin:0in .25in 6.0pt 0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="SpecialNoteRegardingForwardlookin_102023"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">SPECIAL
NOTE REGARDING FORWARD-LOOKING STATEMENTS</font></b></p>

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">This prospectus and the
documents incorporated herein by reference contain forward-looking statements
regarding our business, the financial position of Isis Pharmaceuticals, Inc.
and the therapeutic and commercial potential of our technologies and products
in development. Any statement describing our 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; clinical
goals. 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 technology and systems used to
identify infectious agents, and in the endeavor of building a business around
such products and services.&#160; Our
forward-looking statements also involve assumptions that, if they never
materialize or prove correct, could cause our results to differ materially from
those expressed or implied by such forward looking statements.&#160; Factors that could cause or contribute to
such differences include, but are not limited to, those discussed in the
section entitled &#147;Risk Factors&#148; in this prospectus.&#160; Although our forward-looking statements
reflect the good faith judgment of our management, these statements are based
only on facts and factors currently known by us.&#160; As a result, you are cautioned not to rely on
these forward-looking statements.</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;">8</font></p>

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

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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 style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="UseOfProceeds_102048"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">USE OF PROCEEDS</font></b></p>

<p align="left" style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:left;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Unless
otherwise provided in the applicable prospectus supplement, we intend to use the
net proceeds from the sale of our common stock under this prospectus for
research, drug discovery and product development activities, including
preclinical, clinical studies and the continued development of our TIGER
system, capital expenditures and other general corporate purposes. We will set
forth in the prospectus supplement our intended use for the net proceeds
received from the sale of our common stock. Pending the application of the net
proceeds, we intend to invest the net proceeds in investment-grade,
interest-bearing securities.</font></p>

<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="PlanOfDistribution_102049"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">PLAN OF DISTRIBUTION</font></b></p>

<p style="margin:0in 0in .0001pt;text-indent:.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We may sell our common stock
through underwriters or dealers, through agents, or directly to one or more
purchasers. The accompanying prospectus supplement will describe the terms of
the offering of our common stock, including:</font></p>

<p style="margin:6.0pt 0in .0001pt .5in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">the number of
shares of common stock we are offering;</font></p>

<p style="margin:6.0pt 0in .0001pt .5in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">the name or
names of any underwriters;</font></p>

<p style="margin:6.0pt 0in .0001pt .5in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">any securities
exchange or market on which the common stock may be listed;</font></p>

<p style="margin:6.0pt 0in .0001pt .5in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">the purchase
price of our common stock being offered and the proceeds we will receive from
the sale;</font></p>

<p style="margin:6.0pt 0in .0001pt .5in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">any
over-allotment options pursuant to which underwriters may purchase additional
shares of common stock from us;</font></p>

<p style="margin:6.0pt 0in .0001pt .5in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">any
underwriting discounts or agency fees and other items constituting underwriters&#146;
or agents&#146; compensation; and</font></p>

<p style="margin:6.0pt 0in .0001pt .5in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><font size="2" style="font-size:10.0pt;">any discounts
or concessions allowed or reallowed or paid to dealers.</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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If underwriters are used in
the sale, they will acquire the common stock for their own account and may
resell the common stock from time to time in one or more transactions at a
fixed public offering price or at varying prices determined at the time of the
sale. The obligations of the underwriters to purchase the common stock will be
subject to the conditions set forth in the applicable underwriting agreement.
We may offer the common stock to the public through underwriting syndicates
represented by managing underwriters or by underwriters without a syndicate.
Subject to certain conditions, the underwriters will be obligated to purchase
all the shares of common stock offered by the prospectus supplement. We may
change from time to time the public offering price and any discounts or
concessions allowed or reallowed or paid to dealers.</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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We may sell our common stock
directly or through agents we designate from time to time. We will name any
agent involved in the offering and sale of our common stock, and we will
describe any commissions we will pay the agent in the prospectus supplement.
Unless the prospectus supplement states otherwise, our agent will act on a best-efforts
basis for the period of its appointment.</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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We may provide underwriters
and agents with indemnification against civil liabilities related to this
offering, including liabilities under the Securities Act, or contribution with
respect to payments that the underwriters or agents may make with respect to
these liabilities. Underwriters and agents may engage in transactions with, or
perform services for, us in the ordinary course of business. We will describe
such relationships in the prospectus supplement naming the underwriter and the
nature of any such relationship.</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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Rules of the Securities and
Exchange Commission may limit the ability of any underwriters to bid for or
purchase shares of common stock before the distribution of the shares of common
stock is completed. However, underwriters may engage in the following
activities in accordance with the rules:</font></p>

<p style="margin:6.0pt 0in .0001pt .5in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><i><font size="2" style="font-size:10.0pt;font-style:italic;">Stabilizing
transactions</font></i><font size="2" style="font-size:10.0pt;"> &#151; Underwriters may make bids or purchases for the
purpose of pegging, fixing or maintaining the price of the shares, so long as
stabilizing bids do not exceed a specified maximum.</font></p>

<p style="margin:6.0pt 0in .0001pt .5in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><i><font size="2" style="font-size:10.0pt;font-style:italic;">Over-allotments
and syndicate covering transactions</font></i><font size="2" style="font-size:10.0pt;"> &#151; Underwriters may sell
more shares of our common stock than the number of shares that they have
committed to purchase in any underwritten offering. This over-allotment creates
a short position for the underwriters. This short position may involve either </font></p>

<p align="center" style="margin:6.0pt 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">9</font></p>

<div style="margin:6.0pt 0in .0001pt;"><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 style="margin:6.0pt 0in .0001pt .5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#147;covered&#148;
short sales or &#147;naked&#148; short sales. Covered short sales are short sales made in
an amount not greater than the underwriters&#146; over-allotment option to purchase
additional shares in any underwritten offering. The underwriters may close out
any covered short position either by exercising their over-allotment option or
by purchasing shares in the open market. To determine how they will close the
covered short position, the underwriters will consider, among other things, the
price of shares available for purchase in the open market, as compared to the
price at which they may purchase shares through the over-allotment option.
Naked short sales are short sales in excess of the over-allotment option. The
underwriters must close out any naked position by purchasing shares in the open
market. A naked short position is more likely to be created if the underwriters
are concerned that, in the open market after pricing, there may be downward
pressure on the price of the shares that could adversely affect investors who
purchase shares in the offering.</font></p>

<p style="margin:6.0pt 0in .0001pt .5in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font><i><font size="2" style="font-size:10.0pt;font-style:italic;">Penalty
bids</font></i><font size="2" style="font-size:10.0pt;"> &#151; If underwriters purchase shares in the open market in a stabilizing
transaction or syndicate covering transaction, they may reclaim a selling
concession from other underwriters and selling group members who sold those
shares as part of the offering.</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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Similar to other purchase
transactions, an underwriter&#146;s purchases to cover the syndicate short sales or
to stabilize the market price of our common stock may have the effect of
raising or maintaining the market price of our common stock or preventing or
mitigating a decline in the market price of our common stock. As a result, the
price of the shares of our common stock may be higher than the price that might
otherwise exist in the open market. The imposition of a penalty bid might also
have an effect on the price of shares if it discourages resales of the shares.</font></p>

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

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">If commenced, the
underwriters may discontinue any of these activities at any time.</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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Our common stock is quoted
on the Nasdaq National Market. One or more underwriters may make a market in
our common stock, but the underwriters will not be obligated to do so and may
discontinue market making at any time without notice. We cannot give any
assurance as to liquidity of the trading market for our common stock.</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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Any underwriters who are
qualified market makers on the Nasdaq National Market may engage in passive
market making transactions in the common stock on the Nasdaq National Market in
accordance with Rule 103 of Regulation M, during the business day prior to the
pricing of the offering, before the commencement of offers or sales of the common
stock. Passive market makers must comply with applicable volume and price
limitations and must be identified as passive market makers. In general, a
passive market maker must display its bid at a price not in excess of the
highest independent bid for such security; if all independent bids are lowered
below the passive market maker&#146;s bid, however, the passive market maker&#146;s bid
must then be lowered when certain purchase limits are exceeded.</font></p>

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

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">In compliance with
guidelines of the National Association of Securities Dealers, or NASD, the
maximum consideration or discount to be received by any NASD member or
independent broker dealer may not exceed 8% of the aggregate amount of the
securities offered pursuant to this prospectus and any applicable prospectus supplement.</font></p>

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

<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="DescriptionOfCapitalStock_102208"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">DESCRIPTION
OF CAPITAL STOCK</font></b></p>

<p align="left" style="margin:0in 0in 10.0pt;page-break-after:avoid;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Our authorized capital stock consists of</font></p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt 10.0pt 1.0in;page-break-after:avoid;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>Series B Convertible Exchangeable
5% Preferred Stock, 4,605 shares of which were authorized and none of which was
issued and outstanding at September 30, 2005;</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt 10.0pt 1.0in;page-break-after:avoid;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>Series C Junior Participating
Preferred Stock, 1,000,000 shares of which were authorized and none of which
was issued and outstanding at September 30, 2005; and</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt 10.0pt 1.0in;page-break-after:avoid;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>Common stock, 100,000,000 shares of
which were authorized and 72,201,505 shares of which were issues and outstanding
as of September 30, 2005.</p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">The description of our
common stock is incorporated by reference to filings with the SEC.&#160; See &#147;Incorporation by Reference.&#148;</font></p>

<p align="center" style="margin:0in 0in 10.0pt;text-align:center;text-indent:0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">10</font></p>

<div align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:0in;"><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;page-break-after:avoid;text-align:center;"><a name="DividendPolicy_102220"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">DIVIDEND POLICY</font></b></p>

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

<p style="margin:0in 0in .0001pt;page-break-after:avoid;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We have never declared or paid
any cash dividends on our capital stock. We intend to retain any future
earnings to support operations and to finance the growth and development of our
business and we do not anticipate paying cash dividends for the foreseeable
future.</font></p>

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

<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="LegalMatters_102222"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">LEGAL MATTERS</font></b></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">The validity of the
issuance of the common stock offered hereby will be passed upon for us by
Grantland E. Bryce our Vice President, Legal and General Counsel.</font></p>

<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="Experts_102223"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">EXPERTS</font></b></p>

<p style="margin:0in 0in .0001pt;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Ernst
&amp; Young LLP, independent registered public accounting firm, has audited our
consolidated financial statements included in our Annual Report on Form 10-K
for the year ended December 31, 2004, and management&#146;s assessment of the
effectiveness of our internal control over financial reporting as of December
31, 2004, as set forth in their reports, which are incorporated by reference in
this prospectus and elsewhere in the registration statement.&#160; Our financial statements and management&#146;s
assessment are incorporated by reference in reliance on Ernst &amp; Young LLP&#146;s
reports, given on their authority as experts in accounting and auditing.</font></p>

<p align="center" style="margin:0in 0in 10.0pt;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 10.0pt;text-align:center;text-indent:0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">11</font></p>

<div align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:0in;"><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 10.0pt;text-align:center;text-indent:0in;"><a name="WhereYouCanFindMoreInformation_102227"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">WHERE YOU
CAN FIND MORE INFORMATION</font></b></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">This prospectus is part
of a registration statement on Form S-3 that we filed with the Securities and
Exchange Commission. Certain information in the registration statement has been
omitted from this prospectus in accordance with the rules of the SEC. We are a
public company and file proxy statements and annual, quarterly and special
reports and other information with the SEC.&#160;
You can inspect and copy the registration statement as well as the
reports, proxy statements and other information we have filed with the SEC at
the public reference room maintained by the SEC at 100 F Street, N.E., Room
1580, Washington D.C. 20549. You can call the SEC at 1-800-732-0330 for further
information about the public reference rooms. We are also required to file
electronic versions of these documents with the SEC, which may be accessed from
the SEC&#146;s World Wide Web site at http://www.sec.gov.</font></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We make available, free
of charge, on our web site, <i><font style="font-style:italic;">www.isispharm.com</font></i>,
our reports on 10-K, 10-Q, 8-K and amendments thereto, as soon as reasonably
practical after we file such materials with the Securities and Exchange
Commission.&#160; Any information that is included
on or linked to our Internet site is not a part of this prospectus or any related
registration statement.</font></p>

<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="IncorporationOfCertainDocumentsBy_102306"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">INCORPORATION
OF CERTAIN DOCUMENTS BY REFERENCE</font></b></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">The SEC allows us to &#147;incorporate
by reference&#148; certain of our publicly-filed documents into this prospectus,
which means that information included in those documents is considered part of
this prospectus. Information that we file with the SEC after the effective date
of this prospectus will automatically update and supersede this information. We
incorporate by reference the documents listed below and any future filings made
with the SEC under Sections 13(a), 13(c), 14 or 15(d) of the Exchange Act,
until all the shares of common stock that are part of this offering are sold.</font></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">The following documents filed
with the SEC are incorporated by reference in this prospectus:</font></p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt 10.0pt 1.0in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>our Annual Report on Form 10-K for
the year ended December 31, 2004;</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt 10.0pt 1.0in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>our Quarterly Reports on Form 10-Q
for the quarters ended March 31, 2005, June 30, 2005 and September 30, 2005;</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt .0001pt 1.0in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>our Current Reports on Form&nbsp;8-K,
filed with the SEC on:</p>

<p align="left" style="font-size:10.0pt;margin:3.0pt 27.35pt .0001pt 1.5in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>April 8, 2005,</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt .0001pt 1.5in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>May 5, 2005,</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt .0001pt 1.5in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>May 24, 2005,</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt .0001pt 1.5in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>May 26, 2005,</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt .0001pt 1.5in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>June 29, 2005,</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt .0001pt 1.5in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>July 26, 2005,</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt .0001pt 1.5in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>July 27, 2005,</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt .0001pt 1.5in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>July 29, 2005,</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt .0001pt 1.5in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>August 5, 2005;</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt .0001pt 1.5in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>August 25, 2005; and</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt 10.0pt 1.5in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>December 15, 2005.</p>

<p align="left" style="font-size:10.0pt;margin:0in 27.35pt 10.0pt 1.0in;text-align:left;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#149;</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; </font>the description of our common stock
in our Registration Statement on Form 8-A filed with the SEC on April 12, 1991,
as updated by our Certificate of Amendment of our Restated Certificate of
Incorporation filed with our Quarterly Report on Form 10-Q for the period ended
June 30, 2001.</p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We will furnish without
charge to you, on written or oral request, a copy of any or all of the
documents incorporated by reference, other than exhibits to those documents.
You should direct any requests for documents to Vice President of Finance at
Isis&#146; principal executive offices at 1896 Rutherford Road, Carlsbad, California
92008, telephone number (760) 931-9200.</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;">12</font></p>

<div align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:0in;"><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 style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">You should rely only on the
information contained in this prospectus. We have not authorized anyone to
provide you with information different from that contained in this prospectus
or any prospectus supplement. This prospectus is not an offer of these securities
in any jurisdiction where an offer and sale is not permitted. The information
contained in this prospectus is accurate only as of the date of this
prospectus, regardless of the time of delivery of this prospectus or any sale
of our common stock.</font></b></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;">&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;">&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;">&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;">&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;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="4" face="Times New Roman" style="font-size:14.0pt;font-weight:bold;">$200,000,000</font></b></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="4" face="Times New Roman" style="font-size:14.0pt;font-weight:bold;">Common Stock</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;"><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;">&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;">&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;">&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;">&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;">&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;">&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;">&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;">&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;">&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;">&nbsp;</font></p>

<p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="5" face="Times New Roman" style="font-size:18.0pt;font-weight:bold;">ISIS PHARMACEUTICALS, INC.</font></b></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;">&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;">&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;">&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;">&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;">&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;">&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;">&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;">&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;">&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;">&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;">&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;">&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;">&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;">Prospectus</font></b></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;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">December
22, 2005</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;">&nbsp;</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;">&nbsp;</font></b></p>

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

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

</font></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>

</div>
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<div>

<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="PartIi_102747"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">Part II</font></b></p>

<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="InformationNotRequiredInProspectu_102749"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">INFORMATION
NOT REQUIRED IN PROSPECTUS</font></b></p>

<p align="left" style="font-weight:bold;margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:left;"><a name="Item14_102757"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;">Item
14.&#160; Other Expenses of Issuance and
Distribution</font></b></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">The following table sets
forth all expenses payable by the Registrant in connection with the sale of the
securities being registered.&#160; All the
amounts shown are estimates except for the registration fee.</font></p>

<div align="center">

<table border="0" cellspacing="0" cellpadding="0" width="80%" style="border-collapse:collapse;width:80.0%;">
 <tr>
  <td width="78%" valign="top" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:78.92%;">
  <p style="margin:0in 0in .0001pt 10.0pt;text-indent:-10.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">SEC registration fee</font></p>
  </td>
  <td width="1%" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:1.88%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" colspan="3" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:2.7%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">$</font></p>
  </td>
  <td width="14%" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:14.58%;">
  <p align="right" style="margin:0in 0in .0001pt;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">21,400</font></p>
  </td>
  <td width="1%" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:1.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="78%" valign="top" style="padding:0in .7pt 0in .7pt;width:78.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Legal fees and expenses</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.88%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" colspan="2" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.18%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">$</font></p>
  </td>
  <td width="15%" colspan="2" valign="bottom" style="padding:0in .7pt 0in .7pt;width:15.08%;">
  <p align="right" style="margin:0in 0in .0001pt;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">10,000</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="78%" valign="top" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:78.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Accounting fees and
  expenses</font></p>
  </td>
  <td width="1%" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:1.88%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="1%" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:1.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">$</font></p>
  </td>
  <td width="15%" colspan="3" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:15.34%;">
  <p align="right" style="margin:0in 0in .0001pt;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">10,000</font></p>
  </td>
  <td width="1%" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:1.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="78%" valign="top" style="padding:0in .7pt 0in .7pt;width:78.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Miscellaneous</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.88%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">$</font></p>
  </td>
  <td width="15%" colspan="3" valign="bottom" style="padding:0in .7pt 0in .7pt;width:15.34%;">
  <p align="right" style="margin:0in 0in .0001pt;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">3,600</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="78%" valign="top" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:78.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Total</font></p>
  </td>
  <td width="1%" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:1.88%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="1%" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:1.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">$</font></p>
  </td>
  <td width="15%" colspan="3" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:15.36%;">
  <p align="right" style="margin:0in 0in .0001pt;text-align:right;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">45,000</font></p>
  </td>
  <td width="1%" valign="bottom" bgcolor="#CCEEFF" style="background:#CCEEFF;padding:0in .7pt 0in .7pt;width:1.92%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr height="0">
  <td width="472" style="border:none;"></td>
  <td width="11" style="border:none;"></td>
  <td width="11" style="border:none;"></td>
  <td width="2" style="border:none;"></td>
  <td width="3" style="border:none;"></td>
  <td width="87" style="border:none;"></td>
  <td width="11" style="border:none;"></td>
 </tr>
</table>

</div>

<p align="left" style="font-weight:bold;margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:left;"><a name="Item15_102759"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;">Item
15.&#160; Indemnification of Officers and
Directors</font></b></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Under Section 145 of the
Delaware General Corporation Law, the Registrant has broad powers to indemnify
its Directors and officers against liabilities they may incur in such
capacities, including liabilities under the Securities Act of 1933.</font></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">The Registrant&#146;s
Certificate of Incorporation and Bylaws include provisions to (i) eliminate the
personal liability of its directors for monetary damages resulting from
breaches of their fiduciary duty to the extent permitted by Section 102(b)(7)
of the General Corporation Law of Delaware (the &#147;Delaware Law&#148;) and (ii)
require the Registrant to indemnify its Directors and officers to the fullest
extent permitted by Section 145 of the Delaware Law, including circumstances in
which indemnification is otherwise discretionary.&#160; Pursuant to Section 145 of the Delaware Law,
a corporation generally has the power to indemnify its present and former
directors, officers, employees and agents against expenses incurred by them in
connection with any suit to which they are, or are threatened to be made, a
party by reason of their serving in such positions so long as they acted in
good faith and in a manner they reasonably believed to be in, or not opposed
to, the best interest of the corporation, and with respect to any criminal action,
they had no reasonable cause to believe their conduct was unlawful.&#160; The Registrant believes that these provisions
are necessary to attract and retain qualified persons as Directors and
officers.&#160; These provisions do not
eliminate the Directors&#146; duty of care, and, in appropriate circumstances,
equitable remedies such as injunctive or other forms of non-monetary relief
will remain available under Delaware Law.&#160;
In addition, each Director will continue to be subject to liability for
breach of the Directors&#146; duty of loyalty to the Registrant, for acts or
omissions not in good faith or involving intentional misconduct, for knowing
violations of law, for acts or omissions that the Director believes to be
contrary to the best interests of the Registrant or its stockholders, for any
transaction from which the Director derived an improper personal benefit, for
acts or omissions involving a reckless disregard for the Directors&#146; duty to the
Registrant or its stockholders when the Director was aware or should have been
aware of a risk of serious injury to the Registrant or its stockholders, for
acts or omissions that constitute an unexcused pattern of inattention that
amounts to an abdication of the Director&#146;s duty to the Registrant or its
stockholders, for improper transactions between the Director and the Registrant
and for improper distributions to stockholders and loans to Directors and
officers.&#160; The provision also does not
affect a Director&#146;s responsibilities under any other law, such as the federal
securities law or state or federal environmental laws.</font></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">The Registrant has
entered into indemnity agreements with each of its Directors and executive
officers that require the Registrant to indemnify such persons against
expenses, judgments, fines, settlements and other amounts incurred (including
expenses of a derivative action) in connection with any proceeding, whether
actual or threatened, to which any such person may be made a party by reason of
the fact that such person is or was a Director or an executive officer of the
Registrant or any of its affiliated enterprises, provided such person acted in
good faith and in a manner such persons reasonably believed to be in or not
opposed to the best interests of the Registrant and, with respect to any
criminal proceeding, has no reasonable cause to believe his conduct was
unlawful.&#160; The indemnification agreements
also set forth certain procedures that will apply in the event of a claim for
indemnification thereunder.</font></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">At present, there is no
pending litigation or proceeding involving a Director or officer of the
Registrant as to which indemnification is being sought, nor is the Registrant
aware of any threatened litigation that may result in claims for
indemnification by any officer or Director.</font></p>

<p align="center" style="margin:0in 0in 10.0pt;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 10.0pt;text-align:center;text-indent:0in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">II-1</font></p>

<div align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:0in;"><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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<br clear="all" style="page-break-before:always;">


<div style="font-family:Times New Roman;">

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">The Registrant has an
insurance policy covering the officers and Directors of the Registrant with
respect to certain liabilities, including liabilities arising under the
Securities Act or otherwise.</font></p>

<p align="left" style="font-weight:bold;margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:left;"><a name="Item16_102805"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;">Item
16.&#160; Exhibits</font></b></p>

<table border="0" cellspacing="0" cellpadding="0" width="100%" style="border-collapse:collapse;width:100.0%;">
 <tr>
  <td width="6%" valign="bottom" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:6.72%;">
  <h6 align="left" style="font-weight:normal;line-height:normal;margin:0in 0in .0001pt;page-break-after:avoid;text-align:left;"><a name="TableHead"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">Exhibit</font></b></a><font size="1" style="font-size:8.0pt;"><br>
  <b><font style="font-weight:bold;">Number</font></b></font></h6>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <h6 align="left" style="font-weight:normal;line-height:normal;margin:0in 0in .0001pt;page-break-after:avoid;text-align:left;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></h6>
  </td>
  <td width="5%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <h6 align="left" style="font-weight:normal;line-height:normal;margin:0in 0in .0001pt;page-break-after:avoid;text-align:left;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></h6>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <h6 align="left" style="font-weight:normal;line-height:normal;margin:0in 0in .0001pt;page-break-after:avoid;text-align:left;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></h6>
  </td>
  <td width="82%" valign="bottom" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:82.56%;">
  <h6 align="center" style="font-weight:normal;line-height:normal;margin:0in 0in .0001pt;page-break-after:avoid;text-align:center;"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">Description of Document</font></b></h6>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <h6 align="left" style="font-weight:normal;line-height:normal;margin:0in 0in .0001pt;page-break-after:avoid;text-align:left;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></h6>
  </td>
 </tr>
 <tr>
  <td width="6%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:6.72%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">1.1</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="82%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:82.56%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Form
  of Underwriting Agreement (To be filed as an Exhibit to a Current Report on
  Form 8-K and incorporated herein by reference).</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="6%" valign="top" style="padding:0in .7pt 0in .7pt;width:6.72%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.1</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="82%" valign="top" style="padding:0in .7pt 0in .7pt;width:82.56%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Amended
  and Restated Certificate of Incorporation filed June 19, 1991. (1)</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="6%" valign="top" style="padding:0in .7pt 0in .7pt;width:6.72%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.2</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="3" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="82%" valign="top" style="padding:0in .7pt 0in .7pt;width:82.56%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Certificate
  of Amendment to Restated Certificate of Incorporation filed April 9, 2001.
  (2)</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="6%" valign="top" style="padding:0in .7pt 0in .7pt;width:6.72%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.3</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="3" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="82%" valign="top" style="padding:0in .7pt 0in .7pt;width:82.56%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Bylaws.
  (2)</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="6%" valign="top" style="padding:0in .7pt 0in .7pt;width:6.72%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.6</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="82%" valign="top" style="padding:0in .7pt 0in .7pt;width:82.56%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Certificate
  of Designation of the Series C Junior Participating Preferred Stock. (3)</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="6%" valign="top" style="padding:0in .7pt 0in .7pt;width:6.72%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.7</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="82%" valign="top" style="padding:0in .7pt 0in .7pt;width:82.56%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Specimen
  Common Stock Certificate. (1)</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="6%" valign="top" style="padding:0in .7pt 0in .7pt;width:6.72%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.10</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="82%" valign="top" style="padding:0in .7pt 0in .7pt;width:82.56%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Form
  of Right Certificate. (3)</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="6%" valign="top" style="padding:0in .7pt 0in .7pt;width:6.72%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">5.1</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="82%" valign="top" style="padding:0in .7pt 0in .7pt;width:82.56%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Opinion
  of Grantland E. Bryce</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="6%" valign="top" style="padding:0in .7pt 0in .7pt;width:6.72%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">23.1</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="82%" valign="top" style="padding:0in .7pt 0in .7pt;width:82.56%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Consent
  of Ernst &amp; Young LLP, Independent Registered Public Accounting Firm.
  Reference is made to page II-3</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="6%" valign="top" style="padding:0in .7pt 0in .7pt;width:6.72%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">23.2</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="82%" valign="top" style="padding:0in .7pt 0in .7pt;width:82.56%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Consent
  of Grantland E. Bryce. Reference is made to Exhibit 5.1</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="6%" valign="top" style="padding:0in .7pt 0in .7pt;width:6.72%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">24.1</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.32%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="82%" valign="top" style="padding:0in .7pt 0in .7pt;width:82.56%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Power
  of Attorney. Reference is made to page II-4</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.84%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
</table>

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

<hr size="1" width="25%" noshade color="black" align="left">

</font></div>

<p style="margin:0in 0in .0001pt 30.0pt;text-indent:-30.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(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; </font><font size="2" style="font-size:10.0pt;">Filed as an
exhibit to the Registrant&#146;s Registration Statement on Form S-1 (No. 33-39640)
or amendments thereto and incorporated herein by reference.</font></p>

<p style="margin:0in 0in .0001pt 30.0pt;text-indent:-30.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(2)</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; </font><font size="2" style="font-size:10.0pt;">Filed as an
exhibit to the Registrant&#146;s report on Form 10-Q/A for the quarter ended June
30, 2001 and incorporated herein by reference.</font></p>

<p style="margin:0in 0in .0001pt 30.0pt;text-indent:-30.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(3)</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; </font><font size="2" style="font-size:10.0pt;">Filed as an
exhibit to Registrant&#146;s Report on Form 8-K dated December 8, 2000 and
incorporated herein by reference.</font></p>

<p align="left" style="font-weight:bold;margin:12.0pt 0in 10.0pt;page-break-after:avoid;text-align:left;"><a name="Item17_102808"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;">Item 17.&#160;
Undertakings</font></b></p>

<p style="margin:0in 0in .0001pt .25in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(a)</font><font size="1" style="font-size:3.0pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; </font><font size="2" style="font-size:10.0pt;">The undersigned
registrant hereby undertakes:</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 .25in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(1)</font><font size="1" style="font-size:3.0pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; </font><font size="2" style="font-size:10.0pt;">To file, during
any period in which offers or sales are being made, a post-effective amendment
to this registration statement</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 .75in;text-indent:-.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(i)</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; </font><font size="2" style="font-size:10.0pt;">to include any
prospectus required by Section 10(a)(3) of the Securities Act of 1933;</font></p>

<p style="margin:0in 0in .0001pt .25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt .75in;text-indent:-.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(ii)</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; </font><font size="2" style="font-size:10.0pt;">to reflect in
the prospectus any facts or events arising after the effective date of the
registration statement (or the most recent post-effective amendment thereof)
which, individually or in the aggregate, represent a fundamental change in the
information set forth in the registration statement. Notwithstanding the
foregoing, any increase or decrease in volume of securities offered (if the
total dollar value of securities offered would not exceed that which was registered)
and any deviation from the low or high end of the estimated maximum offering
range may be reflected in the form of prospectus filed with the Commission
pursuant to Rule 424(b) if, in the aggregate, the changes in volume and price
represent no more than a 20 percent change in the maximum aggregate offering
price set forth in the &#147;Calculation of Registration Fee&#148; table in the effective
registration statement;</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 .75in;text-indent:-.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(iii)</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; </font><font size="2" style="font-size:10.0pt;">to include any
material information with respect to the plan of distribution not previously
disclosed in the registration statement or any material change to such
information in the registration statement;</font></p>

<p style="margin:0in 0in .0001pt .25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt .25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">provided, however, that the
undertakings set forth in paragraphs (1)(i), (1)(ii) and (1)(iii) above do not
apply if the information required to be included in a post-effective amendment
by those paragraphs is contained in reports filed with or furnished to the
Commission by the registrant pursuant to Section 13 or 15(d) of the Securities
Exchange Act of 1934 that are incorporated by reference in the registration
statement, or is contained in a form of prospectus filed pursuant to Rule
424(b) that is a part of the registration statement.</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;">II-2</font></p>

<div style="margin:0in 0in .0001pt;"><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 style="font-family:Times New Roman;">

<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="margin:0in 0in .0001pt .25in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(2)</font><font size="1" style="font-size:3.0pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; </font><font size="2" style="font-size:10.0pt;">That, for the
purpose of determining any liability under the Securities Act of 1933, each
such post-effective amendment shall be deemed to be a new registration
statement relating to the securities offered therein, and the offering of such
securities at that time shall be deemed to be the initial bona fide offering
thereof.</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 .25in;text-indent:-.25in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(3)</font><font size="1" style="font-size:3.0pt;">&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; </font><font size="2" style="font-size:10.0pt;">To remove from
registration by means of a post-effective amendment any of the securities being
registered which remain unsold at the termination of the offering.</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;">(4)&#160;&#160; That, for the purpose of determining liability under the Securities
Act of 1933 to any purchaser:</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;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(A) Each prospectus filed by
the registrant pursuant to Rule 424(b)(3) shall be deemed to be part of the
registration statement as of the date the filed prospectus was deemed part of
and included in the registration statement; and</font></p>

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

<p style="margin:0in 0in .0001pt;text-indent:.5in;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(B) Each prospectus required
to be filed pursuant to Rule 424(b)(2), (b)(5), or (b)(7) as part of a
registration statement in reliance on Rule 430B relating to an offering made
pursuant to Rule 415(a)(1)(i), (vii), or (x) for the purpose of providing the
information required by section 10(a) of the Securities Act of 1933 shall be
deemed to be part of and included in the registration statement as of the
earlier of the date such form of prospectus is first used after effectiveness
or the date of the first contract of sale of securities in the offering
described in the prospectus. As provided in Rule 430B, for liability purposes
of the issuer and any person that is at that date an underwriter, such date
shall be deemed to be a new effective date of the registration statement
relating to the securities in the registration statement to which that
prospectus relates, and the offering of such securities at that time shall be
deemed to be the initial bona fide offering thereof. Provided, however, that no
statement made in a registration statement or prospectus that is part of the
registration statement or made in a document incorporated or deemed
incorporated by reference into the registration statement or prospectus that is
part of the registration statement will, as to a purchaser with a time of
contract of sale prior to such effective date, supersede or modify any
statement that was made in the registration statement or prospectus that was
part of the registration statement or made in any such document immediately
prior to such effective date.</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 the purpose of determining liability of
the registrant under the Securities Act to any purchaser in the initial
distribution of the securities, the undersigned registrant undertakes that in a
primary offering of securities of the undersigned registrant pursuant to this
registration statement, regardless of the underwriting method used to sell the
securities to the purchaser, if the securities are offered or sold to such
purchaser by means of any of the following communications, the undersigned
registrant will be a seller to the purchaser and will be considered to offer or
sell such securities to such purchaser:</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 45.0pt;text-indent:-27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(i)</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; </font><font size="2" style="font-size:10.0pt;">Any preliminary prospectus
or prospectus of the undersigned registrant relating to the offering required
to be filed pursuant to Rule 424;</font></p>

<p style="margin:0in 0in .0001pt 45.0pt;text-indent:-27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt 45.0pt;text-indent:-27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(ii)</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; </font><font size="2" style="font-size:10.0pt;">Any free writing prospectus
relating to the offering prepared by or on behalf of the undersigned registrant
or used or referred to by the undersigned registrant;</font></p>

<p style="margin:0in 0in .0001pt 45.0pt;text-indent:-27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt 45.0pt;text-indent:-27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(iii)</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; </font><font size="2" style="font-size:10.0pt;">The portion of any other free writing
prospectus relating to the offering containing material information about the
undersigned registrant or its securities provided by or on behalf of the
undersigned registrant; and</font></p>

<p style="margin:0in 0in .0001pt 45.0pt;text-indent:-27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt 45.0pt;text-indent:-27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(iv)</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; </font><font size="2" style="font-size:10.0pt;">Any other communication that is an offer in
the offering made by the undersigned registrant to the purchaser.</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;">The undersigned registrant hereby undertakes
that, for purposes of determining any liability under the Securities Act of
1933, each filing of the registrant&#146;s annual report pursuant to Section 13(a)
or 15(d) of the Securities Exchange Act of 1934 (and, where applicable, each
filing of an employee benefit plan&#146;s annual report pursuant to Section 15(d) of
the Securities Exchange Act of 1934) that is incorporated by reference in the
registration statement shall be deemed to be a new registration statement
relating to the securities offered therein, and the offering of such securities
at that time shall be deemed to be the initial bona fide offering thereof.</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;">Insofar as indemnification for liabilities
arising under the Securities Act of 1933 may be permitted to directors,
officers, and controlling persons of the registrant pursuant to the foregoing
provisions, or otherwise, the registrant has been advised that in the opinion
of the Securities and Exchange Commission such indemnification is against
public policy as expressed in the Securities Act and is, therefore,
unenforceable. In the event that a claim for indemnification against such
liabilities (other than the payment by the registrant of expenses incurred or
paid by a director, officer, or controlling person of the registrant in the
successful defense of any action, suit or proceeding) </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;">II-3</font></p>

<div style="margin:0in 0in .0001pt;"><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="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">is asserted by such director, officer, or
controlling person in connection with the securities being registered, the
registrant will, unless in the opinion of its counsel the matter has been
settled by controlling precedent, submit to a court of appropriate jurisdiction
the question whether such indemnification by it is against public policy as
expressed in the Securities Act and will be governed by the final adjudication
of such issue.</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;">The undersigned registrant hereby undertakes
that:</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;">(1)&#160;&#160; For purposes of determining any liability under the Securities Act
of 1933, the information omitted from the form of prospectus filed as part of
this registration statement in reliance upon Rule 430A and contained in a form
of prospectus filed by the registrant pursuant to Rule 424(b)(1) or (4) or
497(h) under the Securities Act shall be deemed to be part of this registration
statement as of the time it was declared effective.</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;">(2)&#160;&#160; For purposes of determining any liability under the Securities Act
of 1933, each post-effective amendment that contains a form of prospectus shall
be deemed to be a new registration statement relating to the securities offered
therein, and the offering of such securities at that time shall be deemed to be
the initial bona fide offering thereof.</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;">The undersigned registrant hereby undertakes
to file an application for the purpose of determining the eligibility of the
trustee to act under subsection (a) of Section 310 of the Trust Indenture Act
in accordance with the rules and regulations prescribed by the Securities and
Exchange Commission under Section 305(b)(2) of the Trust Indenture Act.</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;">II-4</font></p>

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

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

</font></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>

</div>
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<div>

<p style="margin:0in 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="Signatures_104057"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">SIGNATURES</font></b></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Pursuant to the
requirements of the Securities Act of 1933, the registrant certifies that it
has reasonable grounds to believe that it meets all of the requirements for
filing on Form S-3 and has duly caused this Registration Statement to be signed
on its behalf by the undersigned thereunto duly authorized, in the city of
Carlsbad, County of San Diego, State of California, on the 20th day of
December, 2005.</font></p>

<table border="0" cellspacing="0" cellpadding="0" width="100%" style="border-collapse:collapse;width:100.0%;">
 <tr>
  <td width="50%" valign="top" style="padding:0in .7pt 0in .7pt;width:50.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="50%" colspan="2" valign="top" style="padding:0in .7pt 0in .7pt;width:50.0%;">
  <p style="margin:0in 0in .0001pt;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">ISIS PHARMACEUTICALS, INC.</font></b></p>
  </td>
 </tr>
 <tr>
  <td width="50%" valign="top" style="padding:0in .7pt 0in .7pt;width:50.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="44%" valign="top" style="padding:0in .7pt 0in .7pt;width:44.76%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="50%" valign="top" style="padding:0in .7pt 0in .7pt;width:50.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">By:</font></p>
  </td>
  <td width="44%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:44.76%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">/s/ B. Lynne Parshall</font></p>
  </td>
 </tr>
 <tr>
  <td width="50%" valign="top" style="padding:0in .7pt 0in .7pt;width:50.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="44%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:44.76%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">B. Lynne Parshall</font></p>
  </td>
 </tr>
 <tr>
  <td width="50%" valign="top" style="padding:0in .7pt 0in .7pt;width:50.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="5%" valign="top" style="padding:0in .7pt 0in .7pt;width:5.24%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="44%" valign="top" style="padding:0in .7pt 0in .7pt;width:44.76%;">
  <p style="margin:0in 0in .0001pt;"><i><font size="2" face="Times New Roman" style="font-size:10.0pt;font-style:italic;">Executive Vice President and
  Chief Financial Officer</font></i></p>
  </td>
 </tr>
</table>

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

<p style="margin:0in 0in 10.0pt;page-break-after:avoid;text-align:center;"><a name="PowerOfAttorney_105242"></a><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">POWER OF ATTORNEY</font></b></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">KNOW ALL PERSONS BY THESE
PRESENTS, that each person whose signature appears below constitutes and
appoints STANLEY T. CROOKE and B. LYNNE PARSHALL, and each of them, as his or
her true and lawful attorney-in-fact and agents, with full power of
substitution and resubstitution, for the undersigned and in his or her name,
place and stead, in any and all capacities, to sign any or all amendments
(including post-effective amendments) to this Registration Statement and to
sign any Registration Statement that is to be effective on filing pursuant to
Rule 462(b) promulgated under the Securities Act of 1933, and all
post-effective amendments thereto, and to file the same, with all exhibits
thereto, and all documents in connection therewith, with the Securities and
Exchange commission, granting unto said attorneys-in-fact and agents, and each
of them, full power of authority to do and perform each and every act and thing
requisite and necessary to be done in connection therewith, as fully to all
intents and purposes as he or she might or could do in person, hereby ratifying
and confirming all that said attorneys-in-fact and agents, each acting alone,
or his or her substitute or substitutes, may lawfully do or cause to be done by
virtue hereof.</font></p>

<p align="left" style="margin:0in 0in 10.0pt;text-align:left;text-indent:27.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Pursuant to the
requirements of the Securities Act of 1933, this Registration Statement has
been signed below by the following persons in the capacities indicated and on
the dates indicated.</font></p>

<table border="0" cellspacing="0" cellpadding="0" width="100%" style="border-collapse:collapse;width:100.0%;">
 <tr>
  <td width="35%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">Signatures</font></b></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></p>
  </td>
  <td width="41%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:41.46%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">Title</font></b></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></p>
  </td>
  <td width="17%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">Date</font></b></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:17.72%;">
  <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>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">/s/
  Stanley T. Crooke</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Stanley
  T. Crooke</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Chairman of the Board and
  Chief&nbsp;Executive Officer (Principal&nbsp;executive officer)</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">December
  20, 2005</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">/s/
  B. Lynne Parshall</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">B.
  Lynne Parshall</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Executive Vice President,
  Chief Financial Officer and Director (Principal financial and accounting
  officer)</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">December
  20, 2005</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">/s/
  Spencer R. Berthelsen</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Spencer
  R. Berthelsen</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Director</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">December
  20, 2005</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="padding:0in .7pt 0in .7pt;width:35.58%;">
  <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>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <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>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">/s/
  Richard D. DiMarchi</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Richard
  D. DiMarchi</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Director</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">December
  20, 2005</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="padding:0in .7pt 0in .7pt;width:35.58%;">
  <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>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <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>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">/s/
  Christopher F.O. Gabrieli</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Christopher
  F.O. Gabrieli</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Director</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">December
  20, 2005</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="padding:0in .7pt 0in .7pt;width:35.58%;">
  <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>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <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>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">/s/
  Frederick T. Muto</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Frederick
  T. Muto</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Director</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">December
  20, 2005</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="padding:0in .7pt 0in .7pt;width:35.58%;">
  <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>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <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>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;page-break-after:avoid;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">/s/ John C. Reed</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;page-break-after:avoid;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;page-break-after:avoid;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;page-break-after:avoid;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;page-break-after:avoid;text-align:center;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">John
  C. Reed</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Director</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">December
  20, 2005</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="padding:0in .7pt 0in .7pt;width:35.58%;">
  <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>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <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>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">/s/
  Joseph H. Wender</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
 </tr>
 <tr>
  <td width="35%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:35.58%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Joseph
  H. Wender</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="41%" valign="top" style="padding:0in .7pt 0in .7pt;width:41.46%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Director</font></p>
  </td>
  <td width="2%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:2.62%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="17%" valign="top" style="padding:0in .7pt 0in .7pt;width:17.72%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">December
  20, 2005</font></p>
  </td>
 </tr>
</table>

<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;">&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;">II-5</font></p>

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

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

</font></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>

</div>
<!-- SEQ.=1,FOLIO='II-5',FILE='C:\JMS\mvreela\05-22096-1\task715179\22096-1-jc.htm',USER='mvreela',CD='Dec 20 10:58 2005' -->



<br clear="all" style="page-break-before:always;">

<div style="font-family:Times New Roman;">

<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">EXHIBIT INDEX</font></b></p>

<table border="0" cellspacing="0" cellpadding="0" width="100%" style="border-collapse:collapse;width:100.0%;">
 <tr>
  <td width="7%" valign="bottom" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:7.3%;">
  <h6 align="left" style="font-weight:normal;line-height:normal;margin:0in 0in .0001pt;page-break-after:avoid;text-align:left;"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">Exhibit</font></b><font size="1" style="font-size:8.0pt;"><br>
  <b><font style="font-weight:bold;">Number</font></b></font></h6>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <h6 align="left" style="font-weight:normal;line-height:normal;margin:0in 0in .0001pt;page-break-after:avoid;text-align:left;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></h6>
  </td>
  <td width="4%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <h6 align="left" style="font-weight:normal;line-height:normal;margin:0in 0in .0001pt;page-break-after:avoid;text-align:left;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></h6>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <h6 align="left" style="font-weight:normal;line-height:normal;margin:0in 0in .0001pt;page-break-after:avoid;text-align:left;"><b><font size="1" face="Times New Roman" style="font-size:1.0pt;font-weight:bold;">&nbsp;</font></b></h6>
  </td>
  <td width="86%" valign="bottom" style="border:none;border-bottom:solid windowtext 1.0pt;padding:0in .7pt 0in .7pt;width:86.26%;">
  <h6 align="center" style="font-weight:normal;line-height:normal;margin:0in 0in .0001pt;page-break-after:avoid;text-align:center;"><b><font size="1" face="Times New Roman" style="font-size:8.0pt;font-weight:bold;">Description of Document</font></b></h6>
  </td>
 </tr>
 <tr>
  <td width="7%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:7.3%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">1.1</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="4%" valign="top" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="86%" valign="top" style="border:none;padding:0in .7pt 0in .7pt;width:86.26%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Form of Underwriting
  Agreement (To be filed as an Exhibit to a Current Report on Form 8-K and
  incorporated herein by reference).</font></p>
  </td>
 </tr>
 <tr>
  <td width="7%" valign="top" style="padding:0in .7pt 0in .7pt;width:7.3%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.1</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="4%" valign="top" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="86%" valign="top" style="padding:0in .7pt 0in .7pt;width:86.26%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Amended and Restated
  Certificate of Incorporation filed June 19, 1991. (1)</font></p>
  </td>
 </tr>
 <tr>
  <td width="7%" valign="top" style="padding:0in .7pt 0in .7pt;width:7.3%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.2</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="3" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="4%" valign="top" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="86%" valign="top" style="padding:0in .7pt 0in .7pt;width:86.26%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Certificate of Amendment
  to Restated Certificate of Incorporation filed April 9, 2001. (2)</font></p>
  </td>
 </tr>
 <tr>
  <td width="7%" valign="top" style="padding:0in .7pt 0in .7pt;width:7.3%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.3</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="3" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="4%" valign="top" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="86%" valign="top" style="padding:0in .7pt 0in .7pt;width:86.26%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Bylaws. (2)</font></p>
  </td>
 </tr>
 <tr>
  <td width="7%" valign="top" style="padding:0in .7pt 0in .7pt;width:7.3%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.6</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="4%" valign="top" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="86%" valign="top" style="padding:0in .7pt 0in .7pt;width:86.26%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Certificate of Designation
  of the Series C Junior Participating Preferred Stock. (3)</font></p>
  </td>
 </tr>
 <tr>
  <td width="7%" valign="top" style="padding:0in .7pt 0in .7pt;width:7.3%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.7</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="4%" valign="top" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="86%" valign="top" style="padding:0in .7pt 0in .7pt;width:86.26%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Specimen Common Stock
  Certificate. (1)</font></p>
  </td>
 </tr>
 <tr>
  <td width="7%" valign="top" style="padding:0in .7pt 0in .7pt;width:7.3%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">4.10</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="4%" valign="top" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="86%" valign="top" style="padding:0in .7pt 0in .7pt;width:86.26%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Form of Right Certificate.
  (3)</font></p>
  </td>
 </tr>
 <tr>
  <td width="7%" valign="top" style="padding:0in .7pt 0in .7pt;width:7.3%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">5.1</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="4%" valign="top" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="86%" valign="top" style="padding:0in .7pt 0in .7pt;width:86.26%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Opinion of Grantland E.
  Bryce</font></p>
  </td>
 </tr>
 <tr>
  <td width="7%" valign="top" style="padding:0in .7pt 0in .7pt;width:7.3%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">23.1</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="4%" valign="top" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="86%" valign="top" style="padding:0in .7pt 0in .7pt;width:86.26%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Consent of Ernst &amp;
  Young LLP, Independent Registered Public Accounting Firm. Reference is made
  to page II-3</font></p>
  </td>
 </tr>
 <tr>
  <td width="7%" valign="top" style="padding:0in .7pt 0in .7pt;width:7.3%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">23.2</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="4%" valign="top" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="86%" valign="top" style="padding:0in .7pt 0in .7pt;width:86.26%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Consent of Grantland E.
  Bryce. Reference is made to Exhibit 5.1</font></p>
  </td>
 </tr>
 <tr>
  <td width="7%" valign="top" style="padding:0in .7pt 0in .7pt;width:7.3%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">24.1</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.0%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="4%" valign="top" style="padding:0in .7pt 0in .7pt;width:4.08%;">
  <p align="center" style="margin:0in 0in .0001pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#151;</font></p>
  </td>
  <td width="1%" valign="bottom" style="padding:0in .7pt 0in .7pt;width:1.38%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:1.0pt;">&nbsp;</font></p>
  </td>
  <td width="86%" valign="top" style="padding:0in .7pt 0in .7pt;width:86.26%;">
  <p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Power of Attorney.
  Reference is made to page II-4</font></p>
  </td>
 </tr>
</table>

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

<hr size="1" width="25%" noshade color="black" align="left">

</font></div>

<p style="margin:0in 0in .0001pt 24.0pt;text-indent:-24.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(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; </font><font size="2" style="font-size:10.0pt;">Filed as an exhibit to the
Registrant&#146;s Registration Statement on Form S-1 (No. 33-39640) or
amendments thereto and incorporated herein by reference.</font></p>

<p style="margin:0in 0in .0001pt 24.0pt;text-indent:-24.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(2)</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; </font><font size="2" style="font-size:10.0pt;">Filed as an exhibit to the
Registrant&#146;s report on Form 10-Q/A for the quarter ended June 30, 2001 and
incorporated herein by reference.</font></p>

<p style="margin:0in 0in .0001pt 24.0pt;text-indent:-24.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">(3)</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; </font><font size="2" style="font-size:10.0pt;">Filed as an exhibit to
Registrant&#146;s Report on Form 8-K dated December 8, 2000 and incorporated herein
by reference.</font></p>

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

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

</font></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>

</div>
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<DOCUMENT>
<TYPE>EX-5.1
<SEQUENCE>2
<FILENAME>a05-22096_1ex5d1.htm
<DESCRIPTION>OPINION REGARDING LEGALITY
<TEXT>
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<body lang="EN-US">

<div>

<p align="right" style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:right;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">EXHIBIT
5.1</font></b></p>

<p style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:center;"><b><font size="2" face="Times New Roman" style="font-size:10.0pt;font-weight:bold;">OPINION OF GRANTLAND E. BRYCE</font></b></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">December 20, 2005</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;">Isis Pharmaceuticals, Inc.<br>
1896 Rutherford Road<br>
Carlsbad, CA 92008</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;">Ladies and Gentlemen:</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;">This opinion is furnished to you in
connection with the Registration Statement on Form S-3 (the &#147;Registration
Statement&#148;) to be filed with the Securities and Exchange Commission (the &#147;Commission&#148;)
under the Securities Act of 1933, as amended (the &#147;Securities Act&#148;), for the
registration of common stock, $.001 par value per share (the &#147;Common Stock&#148;),
of Isis Pharmaceuticals, Inc. (the &#147;Company&#148;), which may be issued from time to
time on a delayed or continuous basis pursuant to Rule 415 under the Securities
Act at an aggregate initial offering price not to exceed $200,000,000 (the &#147;Shares&#148;).</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;">I am acting as counsel for the Company in
connection with the registration for sale by the Company of the Shares. I have
examined a signed copy of the Registration Statement to be filed with the
Commission. I have also examined and relied upon the minutes of meetings of the
Board of Directors of the Company, as provided to me by the Company, the
Certificate of Incorporation and By-Laws of the Company, each as amended to
date (collectively, the &#147;Charter Documents&#148;), and such other documents as I
have deemed necessary for purposes of rendering the opinions hereinafter set
forth.</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;">In my examination of the foregoing documents,
I have assumed the genuineness of all signatures, the authenticity of all
documents submitted to me as originals, the conformity to original documents of
all documents submitted to me as copies, the authenticity of the originals of
such latter documents and the legal competence of all signatories to such
documents.</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;">I assume that appropriate action will be
taken, prior to the offer and sale of the Shares, to register and qualify the
Shares for sale under all applicable state securities or &#147;blue sky&#148; laws.</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;">I express no opinion herein as to the laws of
any state or jurisdiction other than the state laws of the Commonwealth of
Massachusetts, the General Corporation Law of the State of Delaware and the
federal laws of the United States of America.</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;">Based upon and subject to the foregoing, I am
of the opinion that the Shares, when (i) specifically authorized for issuance
by the Company&#146;s Board of Directors or an authorized committee thereof (the &#147;Authorizing
Resolutions&#148;), (ii) the Registration Statement, as finally amended, has become
effective under the Securities Act, (iii) an appropriate prospectus supplement
with respect to the Shares has been prepared, filed and delivered in compliance
with the Securities Act and the applicable rules promulgated thereunder, (iv)
the terms of the sale of the Shares have been duly established in conformity
with the Charter Documents and do not violate any applicable law or result in a
default under or breach of any agreement or instrument binding on the Company
and comply with any requirement or restriction imposed by any court or
governmental body having jurisdiction over the Company, (v) the Shares have
been issued and sold as contemplated by the Registration Statement, and (vi)
the Company has received the consideration provided for in the Authorizing
Resolutions and such consideration is not less than the par value of the
Shares, will be validly issued, fully paid and nonassessable.</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;">It is understood that this opinion is to be
used only in connection with the offer and sale of the Shares while the
Registration Statement is in effect.</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;">Please note that I am opining only as to the
matters expressly set forth herein, and no opinion should be inferred as to any
other matters. This opinion is based upon currently existing statutes, rules,
regulations and judicial decisions, and we disclaim any obligation to advise
you of any change in any of these sources of law or subsequent legal or factual
developments which might affect any matters or opinions set forth herein.</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;">I consent to the reference to myself under
the caption &#147;Legal Matters&#148; in the Prospectus included in the Registration
Statement and to the filing of this opinion as an exhibit to the Registration
Statement.</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;">Sincerely,</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;">/s/ Grantland E. Bryce</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;">Grantland E. Bryce</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">Vice President, Legal and</font></p>

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

<div style="margin:0in 0in .0001pt;"><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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<DOCUMENT>
<TYPE>EX-23.1
<SEQUENCE>3
<FILENAME>a05-22096_1ex23d1.htm
<DESCRIPTION>CONSENTS OF EXPERTS AND COUNSEL
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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
23.1</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;">&nbsp;</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;">CONSENT
OF ERNST &amp; YOUNG LLP, INDEPENDENT REGISTERED PUBLIC ACCOUNTING&nbsp;FIRM</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="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">We consent to the reference to our firm under
the caption &#147;Experts&#148; in the Registration Statement (Form S-3) to be filed on
December 22, 2005, and related Prospectus of Isis Pharmaceuticals, Inc. for the
registration of up to $200,000,000 worth of its common stock and to the
incorporation by reference therein of our reports dated March 3, 2005, with
respect to the consolidated financial statements of Isis Pharmaceuticals, Inc.,
Isis Pharmaceuticals, Inc. management&#146;s assessment of the effectiveness of
internal control over financial reporting, and the effectiveness of internal
control over financial reporting of Isis Pharmaceuticals, Inc. included in its
Annual Report (Form 10-K) for the year ended December 31, 2004, filed with the
Securities and Exchange Commission.</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;">&nbsp;</font></p>

<p style="margin:0in 0in .0001pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&#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;&#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;&#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; /s/&#160; ERNST
&amp; YOUNG LLP</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;">San Diego, California</font></p>

<p align="left" style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

<p align="left" style="margin:5.0pt 0in 10.0pt;page-break-after:avoid;text-align:left;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">December
20, 2005</font></p>

<div style="margin:0in 0in 6.0pt;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">

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

</font></div>

<p align="center" style="margin:0in 0in 6.0pt;text-align:center;"><font size="2" face="Times New Roman" style="font-size:10.0pt;">&nbsp;</font></p>

</div>
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