<SUBMISSION>
<ACCESSION-NUMBER>0001047469-05-010713
<TYPE>DEF 14A
<PUBLIC-DOCUMENT-COUNT>2
<PERIOD>20050526
<FILING-DATE>20050419
<DATE-OF-FILING-DATE-CHANGE>20050419
<EFFECTIVENESS-DATE>20050419
<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>DEF 14A
<ACT>34
<FILE-NUMBER>000-19125
<FILM-NUMBER>05759760
</FILING-VALUES>
<BUSINESS-ADDRESS>
<STREET1>2292 FARADAY AVE
<CITY>CARLSBAD
<STATE>CA
<ZIP>92008
<PHONE>7609319200
</BUSINESS-ADDRESS>
<MAIL-ADDRESS>
<STREET1>2292 FARADAY AVE
<CITY>CARLSBAD
<STATE>CA
<ZIP>92008
</MAIL-ADDRESS>
</FILER>
<DOCUMENT>
<TYPE>DEF 14A
<SEQUENCE>1
<FILENAME>a2155960zdef14a.htm
<DESCRIPTION>DEF 14A
<TEXT>
<HTML>
<HEAD>
</HEAD>
<BODY BGCOLOR="#FFFFFF" LINK=BLUE  VLINK=PURPLE>
<BR>
<FONT SIZE=3 ><A HREF="#05SAN1096_1">QuickLinks</A></FONT>
<font size=3> -- Click here to rapidly navigate through this document</font>
<P ALIGN="CENTER"><FONT SIZE=2><B>UNITED STATES<BR>
SECURITIES AND EXCHANGE COMMISSION<BR>
Washington, D.C. 20549  </B></FONT></P>

<P ALIGN="CENTER"><FONT SIZE=4><B> SCHEDULE 14A</B></FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>Proxy
Statement Pursuant to Section 14(a) of<BR>
the Securities Exchange Act of 1934 (Amendment No.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;) </FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="73%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD COLSPAN=3><FONT SIZE=2>Filed by the Registrant <FONT FACE="WINGDINGS">&#253;</FONT></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD COLSPAN=3><BR><FONT SIZE=2>Filed by a Party other than the Registrant <FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD COLSPAN=3><FONT SIZE=2><BR>
Check the appropriate box:</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2><BR>
<FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="95%"><FONT SIZE=2><BR>
Preliminary Proxy Statement</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2><BR>
<FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="95%"><BR><FONT SIZE=2><B>Confidential, for Use of the Commission Only (as permitted by Rule 14a-6(e)(2))</B></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2><BR>
<FONT FACE="WINGDINGS">&#253;</FONT></FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="95%"><FONT SIZE=2><BR>
Definitive Proxy Statement</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2><BR>
<FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="95%"><FONT SIZE=2><BR>
Definitive Additional Materials</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2><BR>
<FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="95%"><FONT SIZE=2><BR>
Soliciting Material Pursuant to &sect;240.14a-12<BR></FONT>
</TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="77%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD COLSPAN=5 ALIGN="CENTER"><BR><FONT SIZE=2><B>Isis Pharmaceuticals, Inc.</B></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD COLSPAN=5 ALIGN="CENTER"><HR NOSHADE><FONT SIZE=2> (Name of Registrant as Specified In Its Charter)</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD COLSPAN=5 ALIGN="CENTER"><BR><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD COLSPAN=5 ALIGN="CENTER"><HR NOSHADE><FONT SIZE=2> (Name of Person(s) Filing Proxy Statement, if other than the Registrant)</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="4%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="89%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD COLSPAN=5><FONT SIZE=2>Payment of Filing Fee (Check the appropriate box):</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2><BR>
<FONT FACE="WINGDINGS">&#253;</FONT></FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD COLSPAN=3><FONT SIZE=2><BR>
No fee required.</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2><BR>
<FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD COLSPAN=3><FONT SIZE=2><BR>
Fee computed on table below per Exchange Act Rules 14a-6(i)(1) and&nbsp;0-11.</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="4%"><FONT SIZE=2>(1)</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="89%"><FONT SIZE=2>Title of each class of securities to which transaction applies:<BR>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="4%"><FONT SIZE=2>(2)</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="89%"><FONT SIZE=2>Aggregate number of securities to which transaction applies:<BR>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="4%"><FONT SIZE=2>(3)</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="89%"><FONT SIZE=2>Per unit price or other underlying value of transaction computed pursuant to Exchange Act Rule 0-11 (set forth the amount on which the filing fee is calculated and state how it was determined):<BR>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="4%"><FONT SIZE=2>(4)</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="89%"><FONT SIZE=2>Proposed maximum aggregate value of transaction:<BR>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="4%"><FONT SIZE=2>(5)</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="89%"><FONT SIZE=2>Total fee paid:<BR>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2><BR>
<FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD COLSPAN=3><FONT SIZE=2><BR>
Fee paid previously with preliminary materials.</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2><BR>
<FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD COLSPAN=3><FONT SIZE=2><BR>
Check box if any part of the fee is offset as provided by Exchange Act Rule&nbsp;0-11(a)(2) and identify the filing for which the offsetting fee was paid previously. Identify the previous filing by registration statement number, or the Form or
Schedule and the date of its filing.</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2><BR>
&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="4%"><FONT SIZE=2><BR>
(1)</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="89%"><FONT SIZE=2><BR>
Amount Previously Paid:<BR>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="4%"><FONT SIZE=2>(2)</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="89%"><FONT SIZE=2>Form, Schedule or Registration Statement No.:<BR>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="4%"><FONT SIZE=2>(3)</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="89%"><FONT SIZE=2>Filing Party:<BR>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="4%"><FONT SIZE=2>(4)</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="89%"><FONT SIZE=2>Date Filed:<BR>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2><BR>
&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="4%"><FONT SIZE=2><BR>
&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="89%"><BR><FONT SIZE=2><B>Persons who are to respond to the collection of information contained in this form are not required to respond unless the form displays a currently valid OMB control number.</B></FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=1,SEQ=1,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=414765,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]BA1096A.;3',USER='JHILL',CD='19-APR-2005;14:21' -->
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->
<P ALIGN="CENTER"><FONT SIZE=4><B>ISIS PHARMACEUTICALS,&nbsp;INC.<BR>  </B></FONT><FONT SIZE=2><B>1896 Rutherford Road<BR>
Carlsbad, CA 92008  </B></FONT></P>

<HR NOSHADE ALIGN="CENTER" WIDTH="120">
<P ALIGN="CENTER"><FONT SIZE=3><B>NOTICE OF<BR>
2005 ANNUAL MEETING OF STOCKHOLDERS<BR>
AND PROXY STATEMENT  </B></FONT></P>

<HR NOSHADE ALIGN="CENTER" WIDTH="120">

<P><FONT SIZE=2>Dear Stockholders, </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;I
am pleased to invite you to Isis Pharmaceuticals' 2005 Annual Meeting of Stockholders. We will host the meeting at our offices in Carlsbad, California on Thursday, May&nbsp;26, 2005
at 9:30&nbsp;a.m. Pacific Time. In addition to covering the formal items on the agenda, we will review the major developments of the past year and answer your questions. Please note if you wish to
attend the meeting in person that, although we have moved our corporate headquarters, we will hold the Annual Meeting in the same place as previous years. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;This
booklet includes the agenda for this year's Annual Meeting and the Proxy Statement. The Proxy Statement explains the matters we will discuss in the meeting and provides general
information about Isis. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Your
vote is very important. Whether or not you plan to attend the meeting, please complete, date, sign and return the enclosed proxy as soon as possible to ensure your representation at
the meeting. We have provided a postage-paid envelope for your convenience. If you plan to attend the meeting and prefer to vote in person, you may still do so even if you have already
returned your proxy. If you are unable to attend, please note that a web cast and copy of the slides presented will be available at www.isispharm.com.(1) </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;If
you are a stockholder of record (that is, if your stock is registered with us in your own name), you may vote by telephone, or electronically through the Internet, by following the
instructions included with your proxy card. If your shares are registered in the name of a broker or other nominee, your nominee may be participating in a program provided through ADP Investor
Communication Services that allows you to vote by phone or through the Internet. If so, the voting form your nominee sends you will provide telephone and Internet instructions. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT
SIZE=2><B>PLEASE NOTE, HOWEVER, THAT IF A BROKER, BANK OR OTHER NOMINEE HOLDS YOUR SHARES OF RECORD AND YOU WISH TO VOTE AT THE MEETING, YOU MUST OBTAIN A PROXY ISSUED IN
YOUR NAME FROM THE BROKER, BANK OR OTHER NOMINEE.</B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
look forward to seeing you at the meeting. </FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="100%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>Sincerely,</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>B. Lynne Parshall<BR>
Secretary</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<HR NOSHADE ALIGN="LEFT" WIDTH="120">
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>(1)</FONT></DT><DD><FONT SIZE=2>Any
information that is included on or linked to our website is not part of this proxy statement or any registration statement or report that incorporates this proxy statement by
reference. </FONT></DD></DL>
<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=1,SEQ=2,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=798970,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]BC1096A.;5',USER='JHILL',CD='19-APR-2005;14:21' -->
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->
<P ALIGN="CENTER"><FONT SIZE=4><B>ISIS PHARMACEUTICALS,&nbsp;INC.<BR>  </B></FONT><FONT SIZE=2><B>1896 Rutherford Road<BR>
Carlsbad, CA 92008  </B></FONT></P>

<HR NOSHADE ALIGN="CENTER" WIDTH="120">
<P ALIGN="CENTER"><FONT SIZE=3><B>NOTICE OF 2005 ANNUAL MEETING OF STOCKHOLDERS  </B></FONT></P>

<HR NOSHADE ALIGN="CENTER" WIDTH="120">

<!-- User-specified TAGGED TABLE -->
<DIV ALIGN="CENTER"><TABLE WIDTH="31%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="18%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="76%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="18%"><FONT SIZE=2><U>Date</U>:</FONT></TD>
<TD WIDTH="6%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="76%"><FONT SIZE=2>Thursday, May&nbsp;26, 2005</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="18%"><FONT SIZE=2><BR>
<U>Time</U>:</FONT></TD>
<TD WIDTH="6%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="76%"><FONT SIZE=2><BR>
9:30&nbsp;a.m., Pacific Time</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="18%"><FONT SIZE=2><BR>
<U>Place</U>:</FONT></TD>
<TD WIDTH="6%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="76%"><FONT SIZE=2><BR>
Isis&nbsp;Pharmaceuticals,&nbsp;Inc.<BR>
1896 Rutherford Road<BR>
Carlsbad, CA 92008</FONT></TD>
</TR>
</TABLE></DIV>
<!-- end of user-specified TAGGED TABLE -->


<P><FONT SIZE=2>Dear
Stockholders, </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;At
our 2005 Annual Meeting, we will ask you to: </FONT></P>

<UL>
<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>elect
three Directors to serve for a three-year term each and one Director to serve for a one year term;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>ratify
the Audit Committee of the Board of Directors' selection of Ernst&nbsp;&amp; Young LLP as independent auditors for our fiscal year ending December&nbsp;31, 2005; and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>transact
any other business that may be properly presented at the Annual Meeting. </FONT></DD></DL>
</UL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
foregoing items of business are more fully described in the enclosed Proxy Statement. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;If
you were an Isis stockholder of record at the close of business on March&nbsp;28, 2005 you may vote at the Annual Meeting. </FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="100%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>By order of the Board of Directors,</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>B. Lynne Parshall<BR>
Secretary</FONT></TD>
</TR>
<TR VALIGN="BOTTOM">
<TD WIDTH="49%" VALIGN="TOP"><FONT SIZE=2>Carlsbad, California<BR>
April&nbsp;19, 2005</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->


<P><FONT SIZE=2><B>ALL STOCKHOLDERS ARE CORDIALLY INVITED TO ATTEND THE MEETING IN PERSON. WHETHER OR NOT YOU EXPECT TO ATTEND THE MEETING, PLEASE COMPLETE, DATE, SIGN AND RETURN THE ENCLOSED
PROXY AS PROMPTLY AS POSSIBLE IN ORDER TO ENSURE YOUR REPRESENTATION AT THE MEETING. A RETURN ENVELOPE (WHICH IS POSTAGE PREPAID IF MAILED IN THE UNITED STATES) IS ENCLOSED FOR THAT PURPOSE.
ALTERNATIVELY, YOU MAY VOTE BY PHONE OR INTERNET BY FOLLOWING THE INSTRUCTIONS INCLUDED IN THIS PROXY STATEMENT AND WITH YOUR PROXY CARD.
EVEN IF YOU HAVE GIVEN YOUR PROXY, YOU MAY STILL VOTE IN PERSON IF YOU ATTEND THE MEETING. PLEASE NOTE, HOWEVER, THAT IF YOUR SHARES ARE HELD OF RECORD BY A BROKER, BANK OR OTHER NOMINEE AND YOU WISH
TO VOTE AT THE MEETING, YOU MUST OBTAIN FROM THE RECORD HOLDER A PROXY ISSUED IN YOUR NAME.</B></FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=1,SEQ=3,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=789190,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]BE1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->
<!-- TOC_END -->
<P ALIGN="CENTER"><FONT SIZE=4><B>ISIS PHARMACEUTICALS,&nbsp;INC.<BR>  </B></FONT><FONT SIZE=2><B>1896 Rutherford Road<BR>
Carlsbad, CA 92008  </B></FONT></P>

<HR NOSHADE ALIGN="CENTER" WIDTH="120">
<P ALIGN="CENTER"><FONT SIZE=3><B>PROXY STATEMENT<BR>
INFORMATION ABOUT THE 2005 ANNUAL MEETING AND VOTING  </B></FONT></P>

<HR NOSHADE ALIGN="CENTER" WIDTH="120">

<P><FONT SIZE=2><B>General  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The enclosed proxy card has been sent to you by the Board of Directors of Isis Pharmaceuticals,&nbsp;Inc., a Delaware corporation, for use at the 2005 Annual
Meeting of Stockholders to be held on Thursday, May&nbsp;26, 2005, at 9:30&nbsp;a.m. Pacific Time, or at any adjournment or postponement of the meeting, for the purposes stated in this document.
The Annual Meeting will be held at 1896 Rutherford Road, Carlsbad, California. This Proxy Statement summarizes the information you will need to know to vote in an informed manner. </FONT></P>

<P><FONT SIZE=2><B>Voting Rights, Outstanding Shares and Quorum  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We will begin mailing this Proxy Statement and the accompanying proxy card on or about April&nbsp;19, 2005 to all stockholders who are entitled to vote. Only
stockholders who owned our common stock at the close of business on March&nbsp;28, 2005 are entitled to vote at the Annual Meeting. On this record date, we had 57,527,999 shares of our common stock
outstanding. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;A
quorum of stockholders is necessary to hold a valid meeting. A quorum will be present if at least a majority of the outstanding shares are represented by stockholders at the meeting in
person or by
proxy. Your shares will be counted towards the quorum only if you submit a valid proxy vote or vote at the meeting. Abstentions and broker non-votes will be counted towards the quorum
requirement. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Each
share of our common stock that you own entitles you to one vote. The proxy card indicates the number of shares of our common stock that you own. The inspector of election will count
votes for the meeting, and will separately count "For" and "Against" votes, abstentions and broker non-votes. With respect to the election of directors, stockholders do not affirmatively
vote "Against" certain directors. Instead, if a stockholder does not want to elect a particular director, the stockholder may simply withhold their "For" vote. Abstentions will be counted towards the
vote total for each proposal, and will have the same effect as "Against" votes. Broker non-votes have no effect and will not be counted towards the vote total for any proposal. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;If
your broker holds your shares as your nominee (that is, in "street name"), you will need to obtain a proxy form from the institution that holds your shares and follow the instructions
included on that form regarding how to instruct your broker to vote your shares. If you do not give instructions to your broker, your broker can vote your shares with respect to "discretionary" items,
but not with respect to "non-discretionary" items. Discretionary items are proposals considered routine under the rules of the New York Stock Exchange on which a broker may vote shares
held in street name in the absence of your voting instructions. On non-discretionary items for which you do not give your broker instructions, the shares will be treated as broker
non-votes. Proposals 1 and 2 are considered discretionary items. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;You
may vote in one of the following ways: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>attend
the 2005 Annual Meeting and vote in person;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>complete,
sign, date and return the enclosed proxy card; or
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>vote
by phone or through the Internet by following the instructions included with your proxy card. </FONT></DD></DL>
</UL>
<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=1,SEQ=4,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=113600,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]DE1096A.;5',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_de1096_1_2"> </A>
<UL>
<UL>
</UL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
will announce preliminary voting results at the annual meeting and publish final voting results in our quarterly report on Form&nbsp;10-Q for the second quarter of 2005. </FONT></P>


<P><FONT SIZE=2><B>Solicitation  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We will bear the entire cost of soliciting proxies, including preparing, assembling, printing and mailing this Proxy Statement, the proxy card and any additional
information furnished to stockholders. Copies of solicitation materials will be furnished to banks, brokerage houses, fiduciaries and custodians holding in their names shares of our common stock
beneficially owned by others, to forward to such beneficial owners. We may reimburse persons representing beneficial owners of common stock for their costs of forwarding solicitation materials to such
beneficial owners. Original solicitation of proxies by mail may be supplemented by telephone, telegram or personal solicitation by Directors, officers or other employees of Isis. We will not pay our
Directors and employees any additional compensation for soliciting proxies. </FONT></P>

<P><FONT SIZE=2><B>General Information for all Shares Voted by Phone or Through the Internet  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Votes submitted by phone or through the Internet must be received by 11:59&nbsp;p.m., Eastern Time, on May&nbsp;25, 2005. Submitting your proxy by phone or
through the Internet will not affect your right to vote in person should you decide to attend the Annual Meeting. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
provide Internet proxy voting to allow you to vote your shares on-line, with procedures designed to ensure the authenticity and correctness of your proxy vote
instructions. However, please be aware that you must bear any costs associated with your Internet access, such as usage charges from Internet access providers or telephone companies. </FONT></P>

<P><FONT SIZE=2><B><I>For Shares Registered in Your Name  </I></B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;If you are a stockholder of record, you may go to http://www.voteproxy.com to vote your shares through the Internet. The votes represented by such proxy will be
generated on the computer screen and you
will be prompted to submit or revise your votes as desired. If you are using a touch-tone telephone you may also vote your shares by calling 1-800-PROXIES
(1-800-776-9437) and following the recorded instructions. Please have your proxy card available at the time you are voting. </FONT></P>

<P><FONT SIZE=2><B><I>For Shares Registered in the Name of a Broker or Bank  </I></B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Most beneficial owners whose stock is held in street name receive instructions for voting their shares from their bank, broker or other agent, rather than from
our proxy card. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;A
number of brokers and banks are participating in an ADP Investor Communications program which allows proxies to vote shares by means of the telephone and Internet. If your shares are
held in an account with a broker or bank participating in the ADP Investor Communication Services program, you may vote your shares by phone or through the Internet (have the voting form in hand) and
call the number or go to the website indicated on the form and follow the instructions. </FONT></P>

<P><FONT SIZE=2><B>Revocability of Proxies  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Once you have submitted your proxy by mail, Internet or telephone, you may revoke it at any time before we exercise it at the Annual Meeting. You may revoke your
proxy by any one of the following four ways: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>you
may mail another proxy marked with a later date;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>you
may revoke it through the Internet; </FONT></DD></DL>
</UL>
<P ALIGN="CENTER"><FONT SIZE=2>2</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=2,SEQ=5,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=214690,FOLIO='2',FILE='DISK014:[05SAN6.05SAN1096]DE1096A.;5',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_de1096_1_3"> </A>
<UL>
<UL>
</UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>you
may notify our Secretary in writing that you wish to revoke your proxy before the Annual Meeting takes place; or
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>you
may vote in person at the Annual Meeting. </FONT><FONT SIZE=2><I>Attendance</I></FONT><FONT SIZE=2> at the meeting </FONT><FONT SIZE=2><I>will
not</I></FONT><FONT SIZE=2>, by itself, revoke a proxy. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2><B>Stockholder Proposals  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;If you have a proposal or director nomination that you would like included in our proxy statement and form of proxy for, or to be presented at, the 2006 Annual
Meeting of Stockholders, you must send the proposal to Isis by no later than December&nbsp;20, 2005. Stockholders wishing to submit proposals or director nominations that are not to be included in
such proxy statement and proxy must do so no earlier than the close of business on January&nbsp;26, 2006 and no later than the close of business on February&nbsp;25, 2006. Stockholders are also
advised to review our Bylaws, which contain additional requirements with respect to advance notice of stockholder proposals and director nominations. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>3</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=3,SEQ=6,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=141974,FOLIO='3',FILE='DISK014:[05SAN6.05SAN1096]DE1096A.;5',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_de1096_1_4"> </A>
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="de1096_proposal_1_election_of_directors"> </A>
<A NAME="toc_de1096_1"> </A>
<BR></FONT><FONT SIZE=2><B>PROPOSAL 1    <BR>    <BR>    ELECTION OF DIRECTORS    <BR>    </B></FONT></P>

<P><FONT SIZE=2><B>Information about our Board of Directors  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The Board is divided into three classes, each consisting of one third of our total number of Directors. Presently, the Board has nine members with each class
consisting of three Directors. Each class serves a three-year term and we hold elections each year at the Annual Meeting to elect the Directors whose terms are expiring. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
Board represents the interests of our stockholders by overseeing the Chief Executive Officer and other senior management in the operation of the Company. The Board's goal is to
optimize long-term value by providing the Company guidance and strategic oversight on our stockholders' behalf. Therefore, on April&nbsp;16, 2004, the Board adopted membership standards
and believes that the Board members should meet the minimum membership requirements listed below. In addition to these minimum standards, the Board will consider a member or nominee's diversity,
maturity and such other factors as the Board deems appropriate based on its current needs. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
minimum membership requirements are as follows: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>members
must be able to read and understand basic financial statements;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>members
must demonstrate high personal integrity and ethics;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>members
cannot serve as a director on the board of more than seven other publicly traded companies;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>members
cannot serve more than ten consecutive terms on the Board; and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>members
cannot run for re-election or serve on the Board once they have reached the age of 80&nbsp;years old. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;During
a term, the Board may elect a new Director to fill any vacant spot, including a vacancy caused by an increase in the size of the Board. However, the Board believes it is important
for our stockholders to ratify any member of the Board who has been appointed by the Board. As a result, whenever the Board appoints a new member, such as Dr.&nbsp;DiMarchi, the Board will submit
such new member's directorship for approval at the next regularly scheduled Annual Meeting of stockholders. If elected by the stockholders, such Board member will serve the remaining term of the class
of Directors to which he or she was elected. </FONT></P>

<P><FONT SIZE=2><B>Information about the 2005 Elections  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The Board has nominated four Directors for election at the 2005 Annual Meeting. Each of the nominees currently serves as one of our Directors and, except for Drs.
DiMarchi and Berthelsen, each was previously elected by our stockholders. Based on the recommendation of our Chief Executive Officer and the unanimous nomination of our Nominating, Governance and
Review Committee, Dr.&nbsp;DiMarchi and Dr.&nbsp;Berthelsen were appointed to the Board by the then current members of the Board in December&nbsp;2004 and May&nbsp;2002, respectively. If
re-elected, three of the nominees, Dr.&nbsp;Berthelsen, Ms.&nbsp;Parshall and Mr.&nbsp;Wender, will serve until the 2008 Annual Meeting and Dr.&nbsp;DiMarchi will serve until the
2006 Annual Meeting or, in each case, until his or her successor is elected and has qualified, or in the case of their death, resignation or removal. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Our
stockholders elect Directors by a plurality of the votes of the shares present in person or represented by proxy at the meeting and entitled to vote in the election of Directors.
Shares represented by executed proxies will be voted for the election of the four nominees listed below, unless authority to vote in favor of the nominees is withheld. Each person nominated for
election has agreed </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>4</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=4,SEQ=7,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=455757,FOLIO='4',FILE='DISK014:[05SAN6.05SAN1096]DE1096A.;5',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_de1096_1_5"> </A>
<BR>

<P><FONT SIZE=2>to
serve if elected, and we have no reason to believe that any of the nominees will be unable to serve. However, if any nominee cannot serve, your proxy may be voted for another nominee proposed by
the Board, or the Board may reduce the number of authorized Directors. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
provide below a short biography of each of the nominees and of each Director whose term of office will continue after the Annual Meeting. </FONT></P>

<P><FONT SIZE=2><B>Biographies of Nominees for Election for a Three-year Term Expiring at the 2008 Annual Meeting  </B></FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT SIZE=2><B><I>Spencer R. Berthelsen</I></B></FONT><FONT SIZE=2>, M.D., age 53, has served as a Director of Isis since May&nbsp;2002. Since 1980, he has
practiced Internal Medicine with the Kelsey Seybold Clinic, a 280 physician medical group based in the Texas Medical Center in Houston. Dr.&nbsp;Berthelsen has served in various senior leadership
positions at Kelsey Seybold, including Chairman of the Department of Internal Medicine and Medical Director, and has been Chairman of the Board of Directors since October&nbsp;2001. He is a Clinical
Professor of Medicine at the University of Texas Health Science Center at Houston and of Baylor College of Medicine. Dr.&nbsp;Berthelsen has served on the Board of the Texas Academy of Internal
Medicine in the past and the Caremark National Pharmacy and Therapeutics Committee since 1999. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT
SIZE=2><B><I>B. Lynne Parshall</I></B></FONT><FONT SIZE=2>, age 50, has served as a Director of Isis since September&nbsp;2000. She has served as our Executive Vice President
since December&nbsp;1995, our Chief Financial Officer since June&nbsp;1994, and our Secretary since November&nbsp;1991. From February&nbsp;1993 to December&nbsp;1995, she was a Senior Vice
President of Isis, and from November&nbsp;1991 to February&nbsp;1993, she was a Vice President of Isis. Prior to joining Isis, Ms.&nbsp;Parshall practiced law at Cooley Godward LLP, outside
counsel to Isis, where she was a partner from 1986 to 1991. Ms.&nbsp;Parshall is on the Board of Trustees of the Bishops School and is also a member of the American, California and San Diego bar
associations. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT
SIZE=2><B><I>Joseph H. Wender</I></B></FONT><FONT SIZE=2>, age 60, has served as a Director of Isis since January&nbsp;1994. Mr.&nbsp;Wender is currently an Advisory Director
and Senior Director of the Financial Institutions Group at Goldman, Sachs&nbsp;&amp; Co., an investment banking firm. He joined Goldman, Sachs&nbsp;&amp; Co. in 1971 and became a General Partner of that
firm in 1982 and a Limited Partner in 1992. He is also a Director of First Coastal Bancshares, a bank holding company, and Affinity Financial, an Internet financial institution. </FONT></P>

<P><FONT SIZE=2><B>Biography of Nominee for Election for a One-Year Term Expiring at the 2006 Annual Meeting  </B></FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Dr.&nbsp;DiMarchi, appointed on December&nbsp;14, 2004 by our Board of Directors, is a Class&nbsp;III Director in the class whose term expires upon the 2006
Annual Meeting. However, in accordance with our membership requirements, as set forth on page 4 above, he is nominated for election this year. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT
SIZE=2><B><I>Richard D. DiMarchi</I></B></FONT><FONT SIZE=2>, Ph.D., age 52, has served as a Director of Isis since December&nbsp;2004. Dr.&nbsp;DiMarchi is a professor and
the Jack and Linda Gill Distinguished Chair in Biomolecular Science at Indiana University, Bloomington, Indiana. Prior to joining Indiana University, Dr.&nbsp;DiMarchi worked for 22&nbsp;years at
Eli Lilly and Company in several senior management positions, including Group Vice President, Biotechnology and Product Development, from 1996 to 2003, and Vice President, Endocrine Research and
Clinical Investigation, from 1992 to 1996. He is a co-founder and Chairman of Ambrx,&nbsp;Inc., a biotechnology company started in 2003, which focuses on protein therapeutics. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="de1096_the_board_of_directors_recomme__the04083"> </A>
<A NAME="toc_de1096_2"> </A>
<BR></FONT><FONT SIZE=2><B><I>THE BOARD OF DIRECTORS RECOMMENDS THAT YOU VOTE IN FAVOR OF THE ELECTION OF<BR>  EACH OF THE ABOVE NOMINEES    <BR>    </I></B></FONT></P>

<P><FONT SIZE=2><B>Biographies of additional Directors Whose Terms Expire at the 2007 Annual Meeting  </B></FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT SIZE=2><B><I>Stanley T. Crooke</I></B></FONT><FONT SIZE=2>, M.D., Ph.D., age 60, was a founder of Isis and has been Chief Executive Officer and a Director
since January&nbsp;1989. He was elected Chairman of the Board in February&nbsp;1991. Prior to founding Isis from 1980 until January&nbsp;1989, Dr.&nbsp;Crooke was employed by SmithKline
Beckman Corporation, a pharmaceutical company, where his titles included President of Research and </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>5</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=5,SEQ=8,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=721048,FOLIO='5',FILE='DISK014:[05SAN6.05SAN1096]DE1096A.;5',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_de1096_1_6"> </A>
<BR>

<P><FONT SIZE=2>Development
of SmithKline and French Laboratories. He serves as a Director of Antisense Therapeutics&nbsp;Ltd., a biopharmaecutical company, and EPIX Pharmaceuticals,&nbsp;Inc., a developer of
magnetic resonance imaging contrast agents. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT
SIZE=2><B><I>John C. Reed</I></B></FONT><FONT SIZE=2>, M.D., Ph.D., age 46, has served as a Director of Isis since February&nbsp;2002. Dr.&nbsp;Reed has been the President and
Chief Executive Officer of The Burnham Institute, an independent, nonprofit, public benefit organization dedicated to basic biomedical research, since January&nbsp;2002. Dr.&nbsp;Reed has been
with The Burnham Institute for the past ten years, serving as the Deputy Director of the Cancer Center beginning in 1994, as Scientific Director of the Institute beginning in 1995, and as Cancer
Center Director in 2002. He also currently serves as adjunct professor in the University of California, San Diego's (UCSD) Department of Molecular Pathology and in San Diego State University's Biology
department. In addition, Dr.&nbsp;Reed is an associate member of UCSD's Cancer Center. Prior to these positions, from 1989 to 1992, Dr.&nbsp;Reed worked as Assistant Director, Laboratory of
Molecular Diagnosis at the hospital of the University of Pennsylvania and Assistant Professor, Department of Pathology and Laboratory Medicine at the University of Pennsylvania School of Medicine. In
June&nbsp;2004, Dr.&nbsp;Reed joined the Board of Stratagene,&nbsp;Inc., a biopharmaceutical company. In December&nbsp;2004, Dr.&nbsp;Reed was appointed to the Independent Citizen's
Oversight Committee of the California Institute for Regenerative Medicine. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT
SIZE=2><B><I>Mark B. Skaletsky</I></B></FONT><FONT SIZE=2>, age 56, has served as a Director of Isis since January&nbsp;1989. Mr.&nbsp;Skaletsky has been the Chairman, Chief
Executive Officer and President of Trine Pharmaceuticals,&nbsp;Inc., a biopharmaceutical company, formerly known as Essential Therapeutics since March&nbsp;2001. On May&nbsp;1, 2003, Essential
Therapeutics filed a voluntary petition for relief under Chapter 11 of the U.S. Bankruptcy Code. From May&nbsp;1993 to January&nbsp;2001, Mr.&nbsp;Skaletsky served as President and Chief
Executive Officer of GelTex Pharmaceuticals,&nbsp;Inc., a biopharmaceutical company. Mr.&nbsp;Skaletsky is also a Director of ImmunoGen,&nbsp;Inc. and Alkermes&nbsp;Inc., both
biopharmaceutical companies. He is a Director and past Chairman of the Biotechnology Industry Organization. </FONT></P>

<P><FONT SIZE=2><B>Biographies of Directors Whose Terms Expire at the 2006 Annual Meeting  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT SIZE=2><B><I>Christopher F.O. Gabrieli</I></B></FONT><FONT SIZE=2>, age 45, has served as a Director of Isis since May&nbsp;1994. Mr.&nbsp;Gabrieli
also served as a Director of Isis from January&nbsp;1989 to May&nbsp;1992. He is the Chairman of Massachusetts 2020, a non-profit public policy organization. He is also a member of the
general partner of Bessemer Venture Partners III L.P., Bessemer Venture Partners IV L.P., and related venture capital partnerships, where he worked from 1986 to 2000. He is also Chairman of the Board
of EPIX Medical,&nbsp;Inc., a developer of magnetic resonance imaging contrast agents. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT
SIZE=2><B><I>Frederick T. Muto</I></B></FONT><FONT SIZE=2>, age 51, has served as a Director of Isis since March&nbsp;2001. Mr.&nbsp;Muto joined the law firm of Cooley Godward
LLP, outside counsel to Isis, in 1980 and became a partner in 1986. He is a founding partner of Cooley Godward's San Diego office and serves as the partner in charge of that office. Mr.&nbsp;Muto
also serves on that firm's firmwide management committee. </FONT></P>

<P><FONT SIZE=2><B>Independence of the Board of Directors  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;As required under The Nasdaq Stock Market ("Nasdaq") listing standards, a majority of the members of a listed Company's Board of Directors must qualify as
"independent," as affirmatively determined by the Board of Directors. The Board consults with our counsel to ensure that the Board's determinations are consistent with all relevant securities and
other laws and regulations regarding the definition of "independent," including those set forth in the Nasdaq listing standards, as in effect from time to time. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>6</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=6,SEQ=9,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=79249,FOLIO='6',FILE='DISK014:[05SAN6.05SAN1096]DE1096A.;5',USER='JHILL',CD='19-APR-2005;14:21' -->
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->

<P><FONT SIZE=2><A
NAME="page_dg1096_1_7"> </A> </FONT> <FONT SIZE=2>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Consistent with these considerations, after review of all relevant transactions or relationships between each Director, or any of his or her family members, and Isis, its senior
management and its independent auditors, the Board affirmatively has determined that all of our Directors are independent Directors within the meaning of the applicable Nasdaq listing standards,
except for Dr.&nbsp;Crooke and Ms.&nbsp;Parshall, our Chief Executive Officer and Executive Vice President, respectively. With respect to Mr.&nbsp;Muto who is a partner of Cooley Godward LLP,
our outside counsel, he is independent for purposes other than serving on the Audit Committee, of which he is not a member. </FONT></P>

<P><FONT SIZE=2><B>Information Regarding the Board of Directors and its Committees  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;As part of each Board meeting, our independent Directors meet in executive session without the presence of our employee Directors. The Chairpersons of the Audit
Committee, the Compensation Committee and the Nominating, Governance and Review Committee will each preside over at least one executive session. Persons interested in communicating with the
independent Directors about their concerns or issues may address correspondence to a particular Director or to the independent Directors generally, in care of Isis Pharmaceuticals,&nbsp;Inc., 1896
Rutherford Road, Carlsbad, CA 92008. If no particular Director is named, letters will be forwarded, depending on the subject matter, to the Chair of the Audit, Compensation, or Nominating, Governance
and Review Committee. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
Board has three committees: an Audit Committee, a Compensation Committee, and a Nominating, Governance and Review Committee. Below is a description of each committee of our Board.
Each of the committees has authority to engage legal counsel or other experts or consultants, as it deems appropriate to carry out its responsibilities. The Board has determined that each member of
each committee meets the applicable rules and regulations regarding "independence" and that each member is free of any relationship that would interfere with his or her individual exercise of
independent judgment with regard to Isis. </FONT></P>

<P><FONT SIZE=2><B>Audit Committee  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The Audit Committee of the Board of Directors oversees our corporate accounting and financial reporting process. For this purpose, the Audit Committee performs
several functions. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
Audit Committee: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>reviews
the annual and quarterly financial statements and oversees the annual and quarterly financial reporting processes;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>selects
and hires our independent auditors;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>oversees
the independence of our independent auditors;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>evaluates
our independent auditors' performance; and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>has
the authority to hire its own outside consultants and advisors if necessary. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
addition to the responsibilities listed above, the Audit Committee charter codifies the following Audit Committee functions: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>reviewing
our annual budget with management and, if acceptable, recommending the budget to the Board for approval;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>receiving
and considering our independent auditors' comments as to internal controls, adequacy of staff and management performance and procedures in connection with internal
controls;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>reviewing
and, if appropriate, approving related party transactions;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>establishing
and enforcing procedures for the receipt, retention and treatment of complaints regarding accounting or auditing improprieties; and </FONT></DD></DL>
</UL>
<P ALIGN="CENTER"><FONT SIZE=2>7</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=1,SEQ=10,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=717065,FOLIO='7',FILE='DISK014:[05SAN6.05SAN1096]DG1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dg1096_1_8"> </A>
<UL>
<UL>
</UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>pre-approving
all audit and non-audit services provided by our independent auditors that are not prohibited by law. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2004, the Audit Committee met seven times and its members were Mr.&nbsp;Wender (Chairman), Dr.&nbsp;Berthelsen and Mr.&nbsp;Skaletsky. For 2005, the Audit Committee is composed
of Mr.&nbsp;Wender (Chairman), Dr.&nbsp;Berthelsen and Mr.&nbsp;Gabrieli. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Our
Audit Committee charter requires that each member must be independent. We consider the members to be independent as long as they: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>do
not accept any consulting, advisory or other compensatory fee from us, except in connection with their service as a director;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>are
not an affiliate of Isis or one of its subsidiaries; and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>meet
all of the other Nasdaq independence requirements. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
addition, all Audit Committee members must be financially literate and at least one member must be a "financial expert," as defined by Securities and Exchange Commission ("SEC")
regulations. Our Board has determined that the Audit Committee's financial expert is Mr.&nbsp;Wender based on, among other things, his over 30&nbsp;years of experience as an investment banker with
Goldman, Sachs&nbsp;&amp; Co. We provide the Audit Committee with the funding it needs to perform its duties. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2004, the members met the membership criteria set forth in the Audit Committee charter. None of the members of our Audit Committee are officers or employees of Isis and all are
independent Directors under currently applicable rules. Our Audit Committee charter can be found on our corporate website at www.isispharm.com. Any information that is included on or linked to our
website is not part of this proxy statement or any registration statement or report that incorporates this proxy statement by reference. </FONT></P>

<P><FONT SIZE=2><B>Compensation Committee  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The Compensation Committee of the Board of Directors reviews, modifies (as needed) and approves the overall compensation strategy and policies of Isis. The
Compensation Committee reviews and approves corporate performance goals and objectives relevant to the compensation of our executive officers and other senior management; reviews and approves the
compensation for our Directors and reviews and approves the compensation and other terms of employment of our executive officers, including our Chief Executive Officer; and administers our stock
option and purchase plans. We also have a Non-Management Stock Option Committee that may award stock options to employees who are below director level which consists of one member,
Dr.&nbsp;Crooke. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2004, three Directors comprised the Compensation Committee: Mr.&nbsp;Skaletsky (Chairman), Dr.&nbsp;Reed and Mr.&nbsp;Wender. For 2005, the members are Mr.&nbsp;Wender
(Chairman), Drs. Berthelsen and Reed. All members of our Compensation Committee are independent, as independence is currently defined in Rule&nbsp;4200(a)(15) of the Nasdaq listing standards. The
committee met one time in 2004 and acted by unanimous written consent fifteen times. Our Compensation Committee charter can be found on our corporate website at www.isispharm.com. Any information that
is included on or linked to our website is not part of this proxy statement or any registration statement or report that incorporates this proxy statement by reference. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>8</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=2,SEQ=11,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=898755,FOLIO='8',FILE='DISK014:[05SAN6.05SAN1096]DG1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dg1096_1_9"> </A>
<BR>

<P><FONT SIZE=2><B>Nominating, Governance and Review Committee  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The Nominating, Governance and Review Committee of the Board of Directors is responsible for: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>interviewing,
evaluating, nominating and recommending individuals for membership on Isis' Board of Directors. As part of this process, the Nominating, Governance and Review
Committee will consider nominees recommended by Isis' stockholders;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>on
an annual basis, reviewing the performance of the Board and its committees, including evaluating the Board's ability to function as a group and the integrity and
competency of the individual Board members;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>annually
reviewing and assessing the adequacy of Isis' corporate governance guidelines and recommending any proposed changes to the Board for approval; and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>performing
such other functions as may be necessary or convenient for the efficient discharge of the foregoing. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Two
Directors currently comprise the Nominating, Governance and Review Committee: Dr.&nbsp;Berthelsen and Mr.&nbsp;Gabrieli. Mr.&nbsp;Muto serves as counsel to the Committee. Both
members of the Nominating, Governance and Review Committee are independent, as independence is currently defined in Rule&nbsp;4200(a)(15) of the Nasdaq listing standards. Our Nominating, Governance
and Review Committee charter can be found on our corporate website at www.isispharm.com. Any information that is included on or linked to our website is not part of this proxy statement or any
registration statement or report that incorporates this proxy statement by reference. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
Nominating, Governance and Review Committee met once during 2004. In addition, the Nominating, Governance and Review Committee met in March&nbsp;2005 to recommend to the Board the
candidates for election at the 2005 Annual Meeting. The Nominating, Governance and Review Committee believes that candidates for Director should have certain minimum qualifications, including the
ability to read and understand basic financial statements, and having the highest personal integrity and ethics. The Committee also considers such factors as: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>possessing
relevant expertise to offer advice and guidance to management;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>having
sufficient time to devote to the affairs of Isis;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>demonstrating
excellence in his or her field;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>having
sound business judgment; and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>having
the commitment to represent rigorously the long-term interests of our stockholders. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;New
candidates for Director nominees are reviewed in the context of the current composition of the Board, the operating requirements of Isis and the long-term interests of
our stockholders. In conducting this assessment, the Committee considers diversity, maturity, skills, the minimum membership requirements discussed on page 4, and such other factors as it deems
appropriate given the current needs of the Board and Isis, to maintain a balance of knowledge, experience and capability. In the case of incumbent Directors whose terms of office are set to expire,
the Nominating, Governance and Review Committee reviews such Directors' overall service to Isis during their term, including the number of meetings attended, level of participation, quality of
performance, and any other relationships and transactions that might impair such Directors' independence. In the case of new Director candidates, the Committee also determines whether the nominee is
independent, which determination is based upon applicable Nasdaq listing standards, applicable SEC rules and regulations and the advice of counsel, if necessary. The Committee then uses its network of
contacts to compile a list of potential candidates, but may also engage, if it deems appropriate, a professional search firm. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>9</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=3,SEQ=12,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=723023,FOLIO='9',FILE='DISK014:[05SAN6.05SAN1096]DG1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dg1096_1_10"> </A>
<BR>

<P><FONT SIZE=2>The
Committee conducts any appropriate and necessary inquiries into the backgrounds and qualifications of possible candidates after considering the function and needs of the Board. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
Committee meets to discuss and consider the candidates' qualifications and then selects a nominee for recommendation to the Board by majority vote. To date, the Nominating,
Governance and Review Committee has not paid a fee to any third party to assist in the process of identifying or evaluating Director candidates. In December&nbsp;2004, the Nominating, Governance and
Review Committee met and reviewed the appointment of Dr.&nbsp;DiMarchi who was identified by Dr.&nbsp;Crooke and determined it was in the best interest of the Company and its stockholders to
appoint Dr.&nbsp;DiMarchi to the Board. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
Nominating, Governance and Review Committee will consider Director candidates recommended by stockholders. The Committee does not intend to alter the manner in which it evaluates
candidates, including the minimum criteria set forth above, based on whether the candidate was recommended by a stockholder or not. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Stockholders
who wish to recommend individuals for consideration by the Nominating, Governance and Review Committee to become nominees for election to the Board may do so by delivering a
written recommendation to the Nominating, Governance and Review Committee at the following address: 1896 Rutherford Road, Carlsbad, CA 92008, by December&nbsp;20, 2005. Submissions must include the
full name of the proposed nominee, a description of the proposed nominee's business experience for at least the previous five years, complete biographical information, a description of the proposed
nominee's qualifications as a Director and a representation that the nominating stockholder is a beneficial or record owner of our stock. Any such submission must be accompanied by the written consent
of the proposed nominee to be named as a nominee and to serve as a Director if elected. </FONT></P>

<P><FONT SIZE=2><B>Meetings and Attendance  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The Board of Directors met four times in 2004, all at regularly scheduled meetings, and acted by unanimous written consent five times. During 2004, all Directors
attended at least 80% of the meetings of the Board and the committees on which they served. We encourage each member of the Board to attend the Annual Meeting of Stockholders. Mr.&nbsp;Muto,
Dr.&nbsp;Berthelsen and Dr.&nbsp;Reed attended our 2004 Annual Meeting of Stockholders. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
following table provides membership and meeting information for fiscal 2004 for each of the Board committees: </FONT></P>

<!-- User-specified TAGGED TABLE -->
<DIV ALIGN="CENTER"><TABLE WIDTH="74%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="BOTTOM">
<TH WIDTH="42%" ALIGN="LEFT"><FONT SIZE=1><B>Name<BR> </B></FONT><HR NOSHADE></TH>
<TH WIDTH="3%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="6%" ALIGN="CENTER"><FONT SIZE=1><B>Audit</B></FONT><HR NOSHADE></TH>
<TH WIDTH="3%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="15%" ALIGN="CENTER"><FONT SIZE=1><B>Compensation</B></FONT><HR NOSHADE></TH>
<TH WIDTH="3%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="27%" ALIGN="CENTER"><FONT SIZE=1><B>Nominating, Governance<BR>
and Review</B></FONT><HR NOSHADE></TH>
<TH WIDTH="2%"><FONT SIZE=1>&nbsp;</FONT></TH>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="42%"><FONT SIZE=2>Dr. Spencer R. Berthelsen</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="CENTER"><FONT SIZE=2>X</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="15%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%" ALIGN="CENTER"><FONT SIZE=2>X</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="42%"><FONT SIZE=2>Dr. Stanley T. Crooke</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="15%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="42%"><FONT SIZE=2>Dr. Richard D. DiMarchi</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="15%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="42%"><FONT SIZE=2>Mr. Christopher F. O. Gabrieli</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="15%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%" ALIGN="CENTER"><FONT SIZE=2>X</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>*</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="42%"><FONT SIZE=2>Mr. Frederick T. Muto</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="15%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="42%"><FONT SIZE=2>Ms. B. Lynne Parshall</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="15%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="42%"><FONT SIZE=2>Dr. John C. Reed</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="15%" ALIGN="CENTER"><FONT SIZE=2>X</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="42%"><FONT SIZE=2>Mr. Mark B. Skaletsky</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="CENTER"><FONT SIZE=2>X</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="15%" ALIGN="CENTER"><FONT SIZE=2>X</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>*</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="42%"><FONT SIZE=2>Mr. Joseph H. Wender</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="CENTER"><FONT SIZE=2>X</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>*</FONT></TD>
<TD WIDTH="15%" ALIGN="CENTER"><FONT SIZE=2>X</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%" ALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="42%"><FONT SIZE=2>Total meetings in fiscal year 2004</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="CENTER"><FONT SIZE=2>7</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="15%" ALIGN="CENTER"><FONT SIZE=2>1</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>**</FONT></TD>
<TD WIDTH="27%" ALIGN="CENTER"><FONT SIZE=2>1</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
</TABLE></DIV>
<!-- end of user-specified TAGGED TABLE -->

<HR NOSHADE ALIGN="LEFT" WIDTH="120">
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>*</FONT></DT><DD><FONT SIZE=2>Committee
Chairperson
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>**</FONT></DT><DD><FONT SIZE=2>Acted
by written consent 15 times as well </FONT></DD></DL>
<P ALIGN="CENTER"><FONT SIZE=2>10</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=4,SEQ=13,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=583901,FOLIO='10',FILE='DISK014:[05SAN6.05SAN1096]DG1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dg1096_1_11"> </A>


<P><FONT SIZE=2><B>Stockholder Communications with the Board of Directors  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We make every effort to ensure that the views of stockholders are heard by the Board or individual Directors, as applicable, and that appropriate responses are
provided to stockholders in a timely manner. Stockholders who wish to communicate with the Board, or individual Directors, may do so by sending written communications addressed to the Secretary of
Isis at 1896 Rutherford Road, Carlsbad, CA 92008. Communications will be compiled by the Secretary and submitted to the Board or the individual Directors on a periodic basis. These communications will
be reviewed by one or more employees of Isis designated by the Board, who will determine whether they should be presented to the Board. The purpose of this screening is to allow the Board to avoid
having to consider irrelevant or
inappropriate communications (such as advertisements, solicitations and hostile communications). All communications directed to the Audit Committee in accordance with our Code of Ethics policy that
relate to questionable accounting or auditing matters involving Isis will be promptly and directly forwarded to the Audit Committee. Our Board has not adopted a formal process for stockholder
communications with the Board. We believe our Board's responsiveness to stockholder communications has been excellent. The Nominating, Governance and Review Committee is drafting a formal process for
stockholder communications with the Board and, if adopted, we will promptly publish the policy and post it to our website. </FONT></P>


<P><FONT SIZE=2><B>Code of Ethics  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Isis has adopted a Code of Ethics that applies to all officers, Directors and employees. We filed the Code of Ethics as an exhibit to our Annual Report on
Form&nbsp;10-K for the fiscal year ended December&nbsp;31, 2003 and posted the Code of Ethics on our website. If we make any substantive amendments to the Code of Ethics or grant any
waiver from a provision of the Code of Ethics to any executive officer or Director, we will promptly disclose the nature of the amendment or waiver on our website at www.isispharm.com. Any information
that is included on or linked to our website is not part of this proxy statement or any registration statement or report that incorporates this proxy statement by reference. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>11</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=5,SEQ=14,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=907380,FOLIO='11',FILE='DISK014:[05SAN6.05SAN1096]DG1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="page_di1096_1_12"> </A> </FONT></P>

<!-- TOC_END -->
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="di1096_proposal_2_ratification__di102458"> </A>
<A NAME="toc_di1096_1"> </A>
<BR></FONT><FONT SIZE=2><B>PROPOSAL 2    <BR>    <BR>    RATIFICATION OF SELECTION OF INDEPENDENT AUDITORS    <BR>    </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The Audit Committee of the Board of Directors has selected Ernst&nbsp;&amp; Young LLP as our independent registered public accounting firm for the fiscal year
ending December&nbsp;31, 2005, and has requested management to ask for stockholder ratification at the Annual Meeting. Ernst&nbsp;&amp; Young LLP has audited our financial statements since we were
founded in 1989. Representatives of Ernst&nbsp;&amp; Young LLP will be at the 2005 Annual Meeting to answer any questions and make a statement should they be asked to do so. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Although
our Bylaws do not require stockholders to approve our independent registered public accounting firm, the Audit Committee of the Board would like our stockholders' opinion as a
matter of good corporate practice. If the stockholders vote against Ernst&nbsp;&amp; Young LLP, the Audit Committee of the Board will reconsider whether to keep the firm. However, even if the
stockholders ratify the selection, the Audit Committee of the Board may choose to appoint a different independent accounting firm at any time during the year if it believes that a change would be in
the best interests of our stockholders and Isis. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
require the affirmative vote of the holders of a majority of the shares present in person or represented by proxy and entitled to vote at the annual meeting to ratify the selection of
Ernst&nbsp;&amp; Young LLP. Abstentions will be counted toward the tabulation of votes cast on proposals presented to the stockholders and will have the same effect as negative votes. Broker
non-votes are counted towards a quorum, but are not counted for any purpose in determining whether this matter has been approved. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;As
of December&nbsp;31, 2004, none of our finance or accounting employees had been employed by Ernst&nbsp;&amp; Young LLP during the past six years. </FONT></P>

<P><FONT SIZE=2><B>Independent Auditors' Fees  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The Audit Committee has adopted a policy and procedures for the pre-approval of audit and permissible non-audit services rendered by our
independent registered public accounting firm, Ernst&nbsp;&amp; Young LLP. The policy generally pre-approves specific services in the defined categories of audit services, audit-related
services, and tax services up to pre-determined amounts. Pre-approval may also be given as part of the Audit Committee's approval of the scope of the engagement of the
independent auditor or on an individual explicit case-by-case basis before the independent registered public accounting firm is engaged to provide each service. All fees
described below were pre-approved by the Audit Committee. </FONT></P>

<P><FONT SIZE=2><B>Audit Fees  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;For the fiscal years ended December&nbsp;31, 2004 and 2003, the aggregate fees billed by Ernst&nbsp;&amp; Young LLP related to the audit of our financial
statements for such fiscal years and for the reviews of our interim financial statements were $290,970 and $134,647, respectively. $161,068 of the fees billed during fiscal 2004 were primarily for
services related to Sarbanes-Oxley 404 internal controls test work. </FONT></P>


<P><FONT SIZE=2><B>Audit Related Fees  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;During the fiscal years ended December&nbsp;31, 2004 and 2003, the aggregate fees billed by Ernst&nbsp;&amp; Young LLP for assurance and related services that
were reasonably related to the performance of the audit or review of our financial statements that are not included under "Audit Fees" above were $24,904 and $17,140, respectively. The fees billed
during such fiscal years were primarily for services related to Ernst&nbsp;&amp; Young LLP's consultations related to accounting for a number of our business transactions. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>12</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=1,SEQ=15,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=418831,FOLIO='12',FILE='DISK014:[05SAN6.05SAN1096]DI1096A.;9',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_di1096_1_13"> </A>
<BR>

<P><FONT SIZE=2><B>Tax Fees:  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;During the fiscal years ended December&nbsp;31, 2004 and 2003, the aggregate fees billed by Ernst&nbsp;&amp; Young LLP for professional services rendered for tax
compliance, tax advice and tax planning were $6,800 and
$31,905, respectively. These fees were for services related to the preparation of our tax returns and other filings we made with the Internal Revenue Service for 2003 and consultations regarding the
application of various provisions of the Internal Revenue Code (the "Code") for each year. In 2004, we utilized Deloitte&nbsp;&amp; Touche LLP for the majority of our tax services. </FONT></P>

<P><FONT SIZE=2><B>Financial Information Systems Design and Implementation Fees:  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;During the fiscal years ended December&nbsp;31, 2004 and 2003, there were no fees billed by Ernst&nbsp;&amp; Young LLP for information technology consulting. </FONT></P>

<P><FONT SIZE=2><B>All Other Fees:  </B></FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;During the fiscal years ended December&nbsp;31, 2004 and 2003, all other fees billed by Ernst&nbsp;&amp; Young LLP were $790 and $1,616, respectively. These fees
were for a subscription to an online accounting and tax information service. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
Audit Committee has determined that the rendering of all non-audit services by Ernst&nbsp;&amp; Young LLP is compatible with maintaining the auditor's independence. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;During
the fiscal year ended December&nbsp;31, 2004, none of the total hours expended on our financial audit by Ernst&nbsp;&amp; Young LLP were provided by persons other than
Ernst&nbsp;&amp; Young LLP's full-time permanent employees. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="di1096_the_board_of_directors_recomme__the02491"> </A>
<A NAME="toc_di1096_2"> </A>
<BR></FONT><FONT SIZE=2><B><I>THE BOARD OF DIRECTORS RECOMMENDS A VOTE IN FAVOR OF PROPOSAL&nbsp;2    <BR>    </I></B></FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>13</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=2,SEQ=16,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=451143,FOLIO='13',FILE='DISK014:[05SAN6.05SAN1096]DI1096A.;9',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_di1096_1_14"> </A>
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="di1096_security_ownership_of_certain___sec02525"> </A>
<A NAME="toc_di1096_3"> </A>
<BR></FONT><FONT SIZE=2><B>SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT    <BR>    </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;This table outlines the ownership of our common stock as of February&nbsp;28, 2005 by: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>each
Director and nominee for Director;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>each
executive officer named in the Summary Compensation Table under "Executive Compensation&#151;Compensation of Executive Officers";
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>all
Directors and executive officers as a group; and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>every
entity that we know beneficially owns more than five percent of our common stock. </FONT></DD></DL>
</UL>
<BR>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="100%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="BOTTOM">
<TH WIDTH="66%" ALIGN="LEFT"><FONT SIZE=2>&nbsp;</FONT><BR></TH>
<TH WIDTH="3%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=3 ALIGN="CENTER"><FONT SIZE=1><B>Beneficial Ownership(1)</B></FONT><HR NOSHADE></TH>
</TR>
<TR VALIGN="BOTTOM">
<TH WIDTH="66%" ALIGN="LEFT"><FONT SIZE=1><B>Beneficial Owner<BR> </B></FONT><HR NOSHADE></TH>
<TH WIDTH="3%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="14%" ALIGN="CENTER"><FONT SIZE=1><B>Number of Shares</B></FONT><HR NOSHADE></TH>
<TH WIDTH="3%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="14%" ALIGN="CENTER"><FONT SIZE=1><B>Percent of Total(2)</B></FONT><HR NOSHADE></TH>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>Citigroup&nbsp;Inc.(3)<BR>
&nbsp;&nbsp;&nbsp;&nbsp;399 Park Avenue<BR>
&nbsp;&nbsp;&nbsp;&nbsp;New York, NY 10043</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>5,385,335</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>9.4</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2><BR>
Eli Lilly and Company(4)<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Lilly Corporate Center<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Indianapolis, IN 46285</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2><BR>
4,166,167</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2><BR>
7.2</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2><BR>
Federated Investors,&nbsp;Inc.(5)<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Federated Investors Tower<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Pittsburgh, PA 15222-3779</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2><BR>
4,029,478</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2><BR>
7.0</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2><BR>
Mazama Capital Management,&nbsp;Inc.(6)<BR>
&nbsp;&nbsp;&nbsp;&nbsp;One S. W. Columbia, Suite 1500<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Portland, Oregon 97258</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2><BR>
4,372,702</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2><BR>
7.6</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2><BR>
Spencer R. Berthelsen(7)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2><BR>
46,870</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2><BR>
*</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>Stanley T. Crooke(8)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>1,456,487</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>2.5</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>Richard D. DiMarchi</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>0</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>*</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>Christopher F. O. Gabrieli(9)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>201,671</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>*</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>Frederick T. Muto(10)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>30,000</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>*</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>B. Lynne Parshall(11)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>346,565</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>*</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>John C. Reed(12)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>32,500</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>*</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>Mark B. Skaletsky(13)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>67,500</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>*</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>Joseph H. Wender(14)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>76,500</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>*</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>C. Frank Bennett(15)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>163,912</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>*</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>Richard K. Brown(16)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>54,004</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>*</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>David J. Ecker(17)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>192,998</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>*</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="BOTTOM">
<TD WIDTH="66%" VALIGN="TOP"><FONT SIZE=2>All Directors and executive officers as a group (16 persons)(18)</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>3,002,119</FONT></TD>
<TD WIDTH="3%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT" VALIGN="TOP"><FONT SIZE=2>5.1</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<HR NOSHADE ALIGN="LEFT" WIDTH="120">
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>*</FONT></DT><DD><FONT SIZE=2>Less
than one percent.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(1)</FONT></DT><DD><FONT SIZE=2>This
table is based upon information supplied by officers, Directors, principal stockholders and Schedules&nbsp;13D and 13G filed with the SEC. Unless otherwise
indicated in the footnotes to this table and subject to community property laws where applicable, we believe that each of the stockholders named in this table has sole voting and investment power with
respect to the shares indicated as beneficially owned.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(2)</FONT></DT><DD><FONT SIZE=2>Applicable
percentages are based on 57,527,898 shares of common stock outstanding on February&nbsp;28, 2005, adjusted as required by rules promulgated by the SEC. </FONT></DD></DL>
<P ALIGN="CENTER"><FONT SIZE=2>14</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=3,SEQ=17,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=266915,FOLIO='14',FILE='DISK014:[05SAN6.05SAN1096]DI1096A.;9',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_di1096_1_15"> </A>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>(3)</FONT></DT><DD><FONT SIZE=2>Includes
3,546,264 shares held by Citigroup Global Markets&nbsp;Inc. ("CGM"), 3,546,264 shares held by Citigroup Financial Products&nbsp;Inc. ("CFP"), 5,322,818
shares held by Citigroup Global Markets Holdings&nbsp;Inc. ("CGM Holdings") and 5,385,335 shares held by Citigroup&nbsp;Inc. CFP is the sole stockholder of CGM. CGM Holdings is the sole
stockholder of CFP. Citigroup&nbsp;Inc. is the sole stockholder of CGM Holdings. As a result of the foregoing, the holdings reported for CGM Holdings and Citigroup&nbsp;Inc. include the shares
held by their respective wholly-owned subsidiaries.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(4)</FONT></DT><DD><FONT SIZE=2>Includes
3,541,875 with sole voting and dispositive power, and 624,791 shares with shared voting and dispositive power. Based on information contained in their
Schedule&nbsp;13G, Amendment&nbsp;1.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(5)</FONT></DT><DD><FONT SIZE=2>Federated
Investors,&nbsp;Inc. (the "Parent") is the parent holding company of Federated Equity Management Company of Pennsylvania and Federated Global Investment
Management Corp. (the "Investment Advisers"), which act as investment advisers to registered investment companies and separate accounts that own shares of our common stock. The Investment Advisers are
wholly owned subsidiaries of FII Holdings,&nbsp;Inc., which is a wholly owned subsidiary of the Parent. All of the Parent's outstanding voting stock is held in the Voting Shares Irrevocable Trust
(the "Trust") for which John&nbsp;F. Donahue, Rhodora&nbsp;J. Donahue and J.&nbsp;Christopher Donahue act as trustees. Based on information contained in their Schedule&nbsp;13G.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(6)</FONT></DT><DD><FONT SIZE=2>Mazama
Capital Management,&nbsp;Inc. has sole voting authority over 2,466,150 shares and sole dispositive power over 4,372,702 shares.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(7)</FONT></DT><DD><FONT SIZE=2>Includes
70 shares owned by Dr.&nbsp;Berthelsen's daughter for which he disclaims beneficial ownership. Includes 17,500 shares of common stock issuable upon exercise
of options held by Dr.&nbsp;Berthelsen that are exercisable on or before April&nbsp;29, 2005.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(8)</FONT></DT><DD><FONT SIZE=2>Includes
508,625 shares of common stock issuable upon exercise of options held by Dr.&nbsp;Crooke that are exercisable on or before April&nbsp;29, 2005. Also
includes 24,571 shares of common stock issuable upon exercise of options held by Rosanne Crooke, Dr.&nbsp;Crooke's wife, that are exercisable on or before April&nbsp;29, 2005, and 1,050 shares
owned by her. Dr.&nbsp;Crooke disclaims beneficial ownership of the shares of common stock owned and issuable upon exercise of options held by his wife.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(9)</FONT></DT><DD><FONT SIZE=2>Includes
740 shares of common stock held of record by the Gabrieli Family Foundation ("GFF"). Mr.&nbsp;Gabrieli is a trustee of GFF and disclaims beneficial ownership
of the shares of common stock held of record by or issuable to GFF. Also includes 45,500 shares of common stock issuable upon exercise of options held by Mr.&nbsp;Gabrieli that are exercisable on or
before April&nbsp;29, 2005.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(10)</FONT></DT><DD><FONT SIZE=2>Includes
1,500 shares of common stock indirectly beneficially owned through the Cooley Godward LLP Salary Deferral and Profit Sharing Plan and 28,500 shares of common
stock issuable upon exercise of options held by Mr.&nbsp;Muto that are exercisable on or before April&nbsp;29, 2005.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(11)</FONT></DT><DD><FONT SIZE=2>Includes
276,321 shares of common stock issuable upon exercise of options held by Ms.&nbsp;Parshall that are exercisable on or before April&nbsp;29, 2005, and an
aggregate of 60,090 shares of common stock issuable upon exercise of options which Ms.&nbsp;Parshall transferred to her two daughters that are exercisable on or before April&nbsp;29, 2005.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(12)</FONT></DT><DD><FONT SIZE=2>Includes
32,500 shares of common stock issuable upon exercise of options held by Dr.&nbsp;Reed that are exercisable on or before April&nbsp;29, 2005.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(13)</FONT></DT><DD><FONT SIZE=2>Includes
45,500 shares of common stock issuable upon exercise of options held by Mr.&nbsp;Skaletsky that are exercisable on or before April&nbsp;29, 2005.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(14)</FONT></DT><DD><FONT SIZE=2>Includes
45,500 shares of common stock issuable upon exercise of options held by Mr.&nbsp;Wender that are exercisable on or before April&nbsp;29, 2005. </FONT></DD></DL>
<P ALIGN="CENTER"><FONT SIZE=2>15</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=4,SEQ=18,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=986688,FOLIO='15',FILE='DISK014:[05SAN6.05SAN1096]DI1096A.;9',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_di1096_1_16"> </A>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>(15)</FONT></DT><DD><FONT SIZE=2>Includes
162,854 shares of common stock issuable upon exercise of options held by Dr.&nbsp;Bennett that are exercisable on or before April&nbsp;29, 2005.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(16)</FONT></DT><DD><FONT SIZE=2>Includes
51,656 shares of common stock issuable upon exercise of options held by Dr.&nbsp;Brown that are exercisable on or before April&nbsp;29, 2005.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(17)</FONT></DT><DD><FONT SIZE=2>Includes
37,493 shares of common stock held by the Ecker Family Revocable Trust in which Dr.&nbsp;Ecker is a trustee. Also includes 155,505 shares of common stock
issuable upon exercise of options held by Dr.&nbsp;Ecker that are exercisable on or before April&nbsp;29, 2005.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(18)</FONT></DT><DD><FONT SIZE=2>Includes
an aggregate of 1,785,210 shares issuable upon exercise of options held by all current Directors and executive officers as a group that are exercisable on or
before April&nbsp;29, 2005. </FONT></DD></DL>
<BR>

<P><FONT SIZE=2><B>Section&nbsp;16(a) Beneficial Ownership Reporting Compliance  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Section&nbsp;16(a) of the Securities Exchange Act of 1934, as amended (the "Exchange Act"), requires our Directors, executive officers, and persons who own more
than ten percent of a registered class of our equity securities, to file with the SEC initial reports of ownership and reports of changes in ownership of common stock and other equity securities of
Isis. Officers, Directors and greater than ten percent stockholders are required by SEC regulation to furnish us with copies of all Section&nbsp;16(a) forms they file. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;To
our knowledge, based solely on a review of the copies of such reports furnished to us and written representations that no other reports were required, during the fiscal year ended
December&nbsp;31, 2004, all Section&nbsp;16(a) filing requirements applicable to our officers, Directors and greater than ten percent beneficial owners were complied with except Dr.&nbsp;Arthur
A. Levin, who was four days late reporting shares sold under a Rule&nbsp;10b5-1 Plan because the broker administering his plan failed to notify Dr.&nbsp;Levin within the
two-day reporting requirement of the trade. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="di1096_executive_compensation"> </A>
<A NAME="toc_di1096_4"> </A>
<BR></FONT><FONT SIZE=2><B>EXECUTIVE COMPENSATION    <BR>    </B></FONT></P>

<P><FONT SIZE=2><B>Compensation of Directors  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We pay our non-employee Directors a fee of $25,000 per year. We do not pay additional compensation for attending Board or Board committee meetings,
but we do reimburse Board members for the expenses they incur to attend the meetings. For the fiscal year ending December&nbsp;31, 2004, we paid total fees of $18,750 to each of our
non-employee Directors plus an additional payment of $6,250 paid in December&nbsp;2003, excluding Dr.&nbsp;DiMarchi who was elected in December&nbsp;2004. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2004, each non-employee Director also received automatic stock option grants under our 2002 Non-Employee Directors' Stock Option Plan. On July&nbsp;1, 2004,
under the 2002 Non-Employee Directors' Stock Option Plan, each of our non-employee Directors at that time received an option to purchase 10,000 shares of our common stock, at
an exercise price of $5.72 per share, the fair market value of the common stock on the date of the grant, based on the closing sales price reported on the Nasdaq National Market. In
December&nbsp;2004, in connection with his appointment to the Board, Dr.&nbsp;DiMarchi received an option to purchase 20,000 shares of our common stock, at an exercise price of $6.09 the fair
market value on the date of grant. The options vest over a four-year period in equal annual installments. </FONT></P>

<P><FONT SIZE=2><B>Compensation of Executive Officers  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The following table outlines the compensation paid to or earned by our Chief Executive Officer and each of our four other highest paid executive officers whose
total annual salary and bonus exceeded $100,000, for the fiscal years ending December&nbsp;31, 2004, 2003, and 2002. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>16</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=5,SEQ=19,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=72868,FOLIO='16',FILE='DISK014:[05SAN6.05SAN1096]DI1096A.;9',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_di1096_1_17"> </A>
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="di1096_summary_compensation_table"> </A>
<A NAME="toc_di1096_5"> </A>
<BR></FONT><FONT SIZE=2><B>Summary Compensation Table    <BR>    </B></FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="97%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="BOTTOM">
<TH WIDTH="33%" ALIGN="LEFT"><FONT SIZE=2>&nbsp;</FONT><BR></TH>
<TH WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TH>
<TH WIDTH="5%" ALIGN="LEFT"><FONT SIZE=2>&nbsp;</FONT><BR></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=5 ALIGN="CENTER"><FONT SIZE=1><B>Annual Compensation</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="13%" ALIGN="CENTER"><FONT SIZE=1><B>Long-Term<BR>
Compensation<BR>
Awards</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="13%" ALIGN="LEFT"><FONT SIZE=1>&nbsp;</FONT><BR></TH>
</TR>
<TR VALIGN="BOTTOM">
<TH WIDTH="33%" ALIGN="LEFT"><FONT SIZE=1><B>Name and<BR>
Principal Position<BR> </B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="5%" ALIGN="CENTER"><FONT SIZE=1><B>Year</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="8%" ALIGN="CENTER"><FONT SIZE=1><B>Salary<BR>
($)</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="8%" ALIGN="CENTER"><FONT SIZE=1><B>Bonus<BR>
($)(1)</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="13%" ALIGN="CENTER"><FONT SIZE=1><B>Other&nbsp;Annual<BR>
Compensation<BR>
($)(2)</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="13%" ALIGN="CENTER"><FONT SIZE=1><B>Securities<BR>
Underlying<BR>
Options<BR>
(#)</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="13%" ALIGN="CENTER"><FONT SIZE=1><B>All Other<BR>
Compensation<BR>
($)</B></FONT><HR NOSHADE></TH>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="33%"><FONT SIZE=2><BR>
Stanley T. Crooke<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Chairman, CEO and<BR>
&nbsp;&nbsp;&nbsp;&nbsp;President</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="5%" ALIGN="RIGHT"><FONT SIZE=2><BR>
2004<BR>
2003<BR>
2002</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="8%" ALIGN="RIGHT"><FONT SIZE=2><BR>
539,499<BR>
510,300<BR>
486,000</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="8%" ALIGN="RIGHT"><FONT SIZE=2><BR>
122,651<BR>
191,363<BR>
205,286</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
&#151;<BR>
&#151;<BR>
&#151;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
80,000<BR>
117,333<BR>
55,000</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR><BR>(3)<BR></FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
&#151;<BR>
&#151;<BR>
&#151;</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="33%"><FONT SIZE=2><BR>
B. Lynne Parshall<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Director, Executive VP<BR>
&nbsp;&nbsp;&nbsp;&nbsp;&amp; Chief Financial Officer</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="5%" ALIGN="RIGHT"><FONT SIZE=2><BR>
2004<BR>
2003<BR>
2002</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="8%" ALIGN="RIGHT"><FONT SIZE=2><BR>
422,305<BR>
405,089<BR>
385,799</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="8%" ALIGN="RIGHT"><FONT SIZE=2><BR>
84,989<BR>
127,603<BR>
136,650</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
&#151;<BR>
&#151;<BR>
&#151;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
38,400<BR>
81,466<BR>
35,000</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR><BR>(4)<BR></FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
&#151;<BR>
&#151;<BR>
&#151;</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="33%"><FONT SIZE=2><BR>
C. Frank Bennett<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Vice President, Antisense<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Research</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="5%" ALIGN="RIGHT"><FONT SIZE=2><BR>
2004<BR>
2003<BR>
2002</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="8%" ALIGN="RIGHT"><FONT SIZE=2><BR>
287,311<BR>
274,939<BR>
261,847</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="8%" ALIGN="RIGHT"><FONT SIZE=2><BR>
49,561<BR>
77,327<BR>
76,040</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
&#151;<BR>
&#151;<BR>
&#151;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
28,800<BR>
46,099<BR>
19,000</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR><BR>(5)<BR></FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
&#151;<BR>
&#151;<BR>
&#151;</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="33%"><FONT SIZE=2><BR>
Richard K. Brown<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Vice President,<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Business Development</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="5%" ALIGN="RIGHT"><FONT SIZE=2><BR>
2004<BR>
2003<BR>
2002</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="8%" ALIGN="RIGHT"><FONT SIZE=2><BR>
317,710<BR>
305,490<BR>
290,943</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="8%" ALIGN="RIGHT"><FONT SIZE=2><BR>
33,360<BR>
72,172<BR>
49,926</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
&#151;<BR>
&#151;<BR>
&#151;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
18,000<BR>
65,500<BR>
12,000</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR><BR>(6)<BR></FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
&#151;<BR>
&#151;<BR>
&#151;</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="33%"><FONT SIZE=2><BR>
David J. Ecker<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Vice President, and<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Scientific Head of Ibis<BR>
&nbsp;&nbsp;&nbsp;&nbsp;Division</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="5%" ALIGN="RIGHT"><FONT SIZE=2><BR>
2004<BR>
2003<BR>
2002</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="8%" ALIGN="RIGHT"><FONT SIZE=2><BR>
317,805<BR>
271,765<BR>
257,597</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="8%" ALIGN="RIGHT"><FONT SIZE=2><BR>
51,119<BR>
79,491<BR>
81,607</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
&#151;<BR>
&#151;<BR>
&#151;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
32,640<BR>
92,865<BR>
23,200</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR><BR>(7)<BR>(8)</FONT></TD>
<TD WIDTH="13%" ALIGN="RIGHT"><FONT SIZE=2><BR>
&#151;<BR>
&#151;<BR>
&#151;</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<HR NOSHADE ALIGN="LEFT" WIDTH="120">
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>(1)</FONT></DT><DD><FONT SIZE=2>Bonuses
are included here in the years they were earned, not in the year in which they were paid. Bonuses represent compensation for achievements and are not necessarily paid in the
year they are earned; i.e., bonuses for 2004 were paid in January&nbsp;2005.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(2)</FONT></DT><DD><FONT SIZE=2>As
permitted by rules promulgated by the SEC, no amounts are shown for any executive officers where the amounts constitute perquisites and do not exceed the lesser of 10% of the sum
of the aggregate amount in the Salary and Bonus columns or $50,000.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(3)</FONT></DT><DD><FONT SIZE=2>Includes
67,333 options issued in a stock exchange offered to all employees in which 147,500 options previously granted to Dr.&nbsp;Crooke were cancelled.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(4)</FONT></DT><DD><FONT SIZE=2>Includes
56,466 options issued in a stock exchange offered to all employees in which 128,000 options previously granted to Ms.&nbsp;Parshall were cancelled.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(5)</FONT></DT><DD><FONT SIZE=2>Includes
34,599 options issued in a stock exchange offered to all employees in which 71,000 options previously granted to Dr.&nbsp;Bennett were cancelled.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(6)</FONT></DT><DD><FONT SIZE=2>Includes
49,000 options issued in a stock exchange offered to all employees in which 102,000 options previously granted to Dr.&nbsp;Brown were cancelled.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(7)</FONT></DT><DD><FONT SIZE=2>Includes
80,365 options issued in a stock exchange offered to all employees in which 148,200 options previously granted to Dr.&nbsp;Ecker were cancelled.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(8)</FONT></DT><DD><FONT SIZE=2>Includes
10,000 options granted to Dr.&nbsp;Ecker in January&nbsp;2002 in association with his promotion. </FONT></DD></DL>
<BR>

<P><FONT SIZE=2><B>Stock Option Grants and Exercises  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Executive officers are granted stock options under our 2000 Broad-Based Equity Incentive Plan (the "2000 Plan") and our 1989 Stock Option Plan (the "1989 Plan").
During 2004, options to purchase a total of 498,850 shares and 1,583,641 shares of our common stock had been granted under the 2000 Plan and 1989 Plan, respectively. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>17</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=6,SEQ=20,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=526068,FOLIO='17',FILE='DISK014:[05SAN6.05SAN1096]DI1096A.;9',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_di1096_1_18"> </A>
<BR>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
implemented a stock trading program for our Board of Directors, corporate executive officers and other insiders, under Rule&nbsp;10b5-1 of the Exchange Act in 2002. When
there is no material non-public information available, Rule&nbsp;10b5-1 allows corporate insiders to establish plans that permit prearranged future sales of their securities.
With respect to our insiders who participate in our 10b5-1 trading program, we do not allow them to buy or sell our stock outside of the 10b5-1 trading program. All of our
executive officers who have vested stock options and/or own shares of our stock currently participate in our 10b5-1 trading program. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
following tables show certain information regarding options granted to, exercised by, and held at December&nbsp;31, 2004 by each of the executive officers named in the Summary
Compensation Table: </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="di1096_option_grants_in_last_fiscal_year"> </A>
<A NAME="toc_di1096_6"> </A>
<BR></FONT><FONT SIZE=2><B>Option Grants in Last Fiscal Year    <BR>    </B></FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="94%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="BOTTOM">
<TH WIDTH="36%" ALIGN="LEFT"><FONT SIZE=2>&nbsp;</FONT><BR></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=7 ALIGN="CENTER"><FONT SIZE=1><B>Individual Grants</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%" ROWSPAN=3><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=5 ROWSPAN=3 ALIGN="CENTER"><FONT SIZE=1><B>Potential Realizable Value at Assumed Annual Rates of Stock Price Appreciation for Option Term(3)</B></FONT><HR NOSHADE></TH>
</TR>
<TR VALIGN="BOTTOM">
<TH WIDTH="36%" ALIGN="LEFT"><FONT SIZE=1>&nbsp;</FONT><BR></TH>
<TH WIDTH="1%" ROWSPAN=3><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="10%" ROWSPAN=3 ALIGN="CENTER"><FONT SIZE=1><B>Number of Securities<BR>
Underlying<BR>
Options<BR>
Granted (#)(1)</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%" ROWSPAN=3><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="10%" ROWSPAN=3 ALIGN="CENTER"><FONT SIZE=1><B>% of Total<BR>
Options Granted to<BR>
Employees<BR>
in Fiscal Year(2)</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="7%" ALIGN="LEFT"><FONT SIZE=1>&nbsp;</FONT><BR></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="9%" ALIGN="LEFT"><FONT SIZE=1>&nbsp;</FONT><BR></TH>
</TR>
<TR VALIGN="BOTTOM">
<TH WIDTH="36%" ROWSPAN=2 ALIGN="LEFT"><FONT SIZE=1><B>Name<BR> </B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%" ROWSPAN=2><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="7%" ROWSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>Exercise<BR>
Price<BR>
($/Sh)</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%" ROWSPAN=2><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="9%" ROWSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>Expiration<BR>
Date</B></FONT><HR NOSHADE></TH>
</TR>
<TR VALIGN="BOTTOM">
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>5% ($)</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>10% ($)</B></FONT><HR NOSHADE></TH>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="36%"><FONT SIZE=2>Stanley T. Crooke</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>80,000</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>3.84</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%" ALIGN="RIGHT"><FONT SIZE=2>6.81</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>1/1/14</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>342,503</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>867,902</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="36%"><FONT SIZE=2>B. Lynne Parshall</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>38,400</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>1.84</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%" ALIGN="RIGHT"><FONT SIZE=2>6.81</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>1/1/14</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>164,402</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>416,593</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="36%"><FONT SIZE=2>C. Frank Bennett</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>28,800</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>1.38</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%" ALIGN="RIGHT"><FONT SIZE=2>6.81</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>1/1/14</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>123,301</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>312,445</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="36%"><FONT SIZE=2>Richard K. Brown</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>18,000</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>.86</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%" ALIGN="RIGHT"><FONT SIZE=2>6.81</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>1/1/14</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>77,063</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>195,278</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="36%"><FONT SIZE=2>David J. Ecker</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>32,640</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>1.57</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%" ALIGN="RIGHT"><FONT SIZE=2>6.81</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>1/1/14</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>139,741</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="9%" ALIGN="RIGHT"><FONT SIZE=2>354,104</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<HR NOSHADE ALIGN="LEFT" WIDTH="120">
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>(1)</FONT></DT><DD><FONT SIZE=2>All
options granted in 2004 vest over a four-year period: 25% after the first year and 2.08% per month thereafter.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(2)</FONT></DT><DD><FONT SIZE=2>Based
on options to purchase an aggregate of 2,082,491 shares granted in 2004 to employees only under our 2000 Plan and 1989 Plan. This is not necessarily indicative of the number of
options that will be granted in the future.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(3)</FONT></DT><DD><FONT SIZE=2>The
potential realizable value is calculated based on the term of the option at its time of grant, based on the assumption that the market value of the underlying stock increases at
the stated values, compounded annually. Actual gains, if any, on stock option exercises are dependent on the future performance of the common stock, overall market conditions and the option holders
continued employment through the vesting periods. The amounts reflected in this table may not necessarily be achieved. </FONT></DD></DL>
<P ALIGN="CENTER"><FONT SIZE=2>18</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=7,SEQ=21,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=500125,FOLIO='18',FILE='DISK014:[05SAN6.05SAN1096]DI1096A.;9',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_di1096_1_19"> </A>
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="di1096_aggregated_option_exercises_in__agg02858"> </A>
<A NAME="toc_di1096_7"> </A>
<BR></FONT><FONT SIZE=2><B>Aggregated Option Exercises in Last Fiscal Year and FY-End Option Values    <BR>    </B></FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="97%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="BOTTOM">
<TH WIDTH="37%" ALIGN="LEFT"><FONT SIZE=2>&nbsp;</FONT><BR></TH>
<TH WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TH>
<TH WIDTH="11%" ALIGN="LEFT"><FONT SIZE=2>&nbsp;</FONT><BR></TH>
<TH WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TH>
<TH COLSPAN=2 ALIGN="LEFT"><FONT SIZE=2>&nbsp;</FONT><BR></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="17%" ALIGN="CENTER"><FONT SIZE=1><B>Number of Securities<BR>
Underlying Unexercised<BR>
Options at<BR>
Fiscal Year End</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="18%" ALIGN="CENTER"><FONT SIZE=1><B>Value of<BR>
Unexercised In-the-Money Options at Fiscal Year End(2)</B></FONT><HR NOSHADE></TH>
<TH WIDTH="2%"><FONT SIZE=1>&nbsp;</FONT></TH>
</TR>
<TR VALIGN="BOTTOM">
<TH WIDTH="37%" ALIGN="LEFT"><FONT SIZE=1><B>Name<BR> </B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="11%" ALIGN="CENTER"><FONT SIZE=1><B>Shares<BR>
Acquired on<BR>
Exercise</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>Value<BR>
Realized(1)</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="17%" ALIGN="CENTER"><FONT SIZE=1><B>Exercisable/<BR>
Unexercisable</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="18%" ALIGN="CENTER"><FONT SIZE=1><B>Exercisable/<BR>
Unexercisable</B></FONT><HR NOSHADE></TH>
<TH WIDTH="2%"><FONT SIZE=1>&nbsp;</FONT></TH>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="37%"><FONT SIZE=2>Stanley T. Crooke</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="11%" ALIGN="RIGHT"><FONT SIZE=2>50,000</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>70,890</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="17%" ALIGN="RIGHT"><FONT SIZE=2>470,934/131,399</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="18%" ALIGN="RIGHT"><FONT SIZE=2>$32,264/$18,236</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="37%"><FONT SIZE=2>B. Lynne Parshall</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="11%" ALIGN="RIGHT"><FONT SIZE=2>&#151;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>&#151;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="17%" ALIGN="RIGHT"><FONT SIZE=2>315,470/72,396</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>(3)</FONT></TD>
<TD WIDTH="18%" ALIGN="RIGHT"><FONT SIZE=2>$27,056/$15,293</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>(3)</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="37%"><FONT SIZE=2>C. Frank Bennett</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="11%" ALIGN="RIGHT"><FONT SIZE=2>&#151;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>&#151;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="17%" ALIGN="RIGHT"><FONT SIZE=2>147,051/52,848</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="18%" ALIGN="RIGHT"><FONT SIZE=2>$16,578/$&nbsp;&nbsp;9,371</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="37%"><FONT SIZE=2>Richard K. Brown</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="11%" ALIGN="RIGHT"><FONT SIZE=2>&#151;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>&#151;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="17%" ALIGN="RIGHT"><FONT SIZE=2>39,211/44,289</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="18%" ALIGN="RIGHT"><FONT SIZE=2>$23,479/$13,271</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="37%"><FONT SIZE=2>David J. Ecker</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="11%" ALIGN="RIGHT"><FONT SIZE=2>12,150</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>59,261</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="17%" ALIGN="RIGHT"><FONT SIZE=2>134,958/68,547</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="18%" ALIGN="RIGHT"><FONT SIZE=2>$38,508/$21,766</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<HR NOSHADE ALIGN="LEFT" WIDTH="120">
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>(1)</FONT></DT><DD><FONT SIZE=2>Fair
market value of our common stock on the date of exercise minus the exercise price.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(2)</FONT></DT><DD><FONT SIZE=2>Fair
market value of our common stock at December&nbsp;31, 2004 ($5.90) multiplied by the applicable number of shares minus the aggregate exercise price of the options for the
number of shares.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(3)</FONT></DT><DD><FONT SIZE=2>Includes
an aggregate of 60,090 options transferred to Ms.&nbsp;Parshall's two daughters. </FONT></DD></DL>
<P ALIGN="CENTER"><FONT SIZE=2>19</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=8,SEQ=22,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=739957,FOLIO='19',FILE='DISK014:[05SAN6.05SAN1096]DI1096A.;9',USER='JHILL',CD='19-APR-2005;14:21' -->
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="page_dk1096_1_20"> </A> </FONT></P>

<!-- TOC_END -->
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="dk1096_equity_compensation_plan_information"> </A>
<A NAME="toc_dk1096_1"> </A>
<BR></FONT><FONT SIZE=2><B>EQUITY COMPENSATION PLAN INFORMATION    <BR>    </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The following table sets forth information regarding outstanding options and shares reserved for future issuance under our equity compensation plans as of
December&nbsp;31, 2004. </FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="91%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="BOTTOM">
<TH COLSPAN=2 ALIGN="LEFT"><FONT SIZE=1><B>Plan Category<BR> </B></FONT><HR NOSHADE></TH>
<TH WIDTH="2%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="14%" ALIGN="CENTER"><FONT SIZE=1><B>Number of Shares to be<BR>
Issued Upon Exercise of<BR>
Outstanding Options</B></FONT><HR NOSHADE></TH>
<TH WIDTH="3%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>Weighted Average<BR>
Exercise Price of<BR>
Outstanding Options</B></FONT><HR NOSHADE></TH>
<TH WIDTH="2%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="19%" ALIGN="CENTER"><FONT SIZE=1><B>Number of Shares<BR>
Remaining Available<BR>
for Future Issuance</B></FONT><HR NOSHADE></TH>
<TH WIDTH="2%"><FONT SIZE=1>&nbsp;</FONT></TH>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="BOTTOM">
<TD COLSPAN=2 VALIGN="TOP"><FONT SIZE=2>Equity compensation plans approved by stockholders</FONT></TD>
<TD WIDTH="2%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT"><FONT SIZE=2>3,863,000</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>(a)</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="20%" ALIGN="RIGHT"><FONT SIZE=2>8.92</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="19%" ALIGN="RIGHT"><FONT SIZE=2>5,108,000</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>(c)</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="BOTTOM">
<TD COLSPAN=2 VALIGN="TOP"><FONT SIZE=2>Equity compensation plans not approved by stockholders</FONT></TD>
<TD WIDTH="2%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT"><FONT SIZE=2>4,804,000</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>(b)</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="20%" ALIGN="RIGHT"><FONT SIZE=2>7.88</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="19%" ALIGN="RIGHT"><FONT SIZE=2>792,000</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD COLSPAN=2><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT"><HR NOSHADE></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD COLSPAN=2 ALIGN="RIGHT"><HR NOSHADE></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="19%" ALIGN="RIGHT"><HR NOSHADE></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="BOTTOM">
<TD WIDTH="2%"><FONT SIZE=0>&nbsp;</FONT></TD>
<TD WIDTH="33%" VALIGN="TOP"><FONT SIZE=2>Total</FONT></TD>
<TD WIDTH="2%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="RIGHT"><FONT SIZE=2>8,667,000</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="20%" ALIGN="RIGHT"><FONT SIZE=2>8.34</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="19%" ALIGN="RIGHT"><FONT SIZE=2>5,900,000</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<HR NOSHADE ALIGN="LEFT" WIDTH="120">
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>(a)</FONT></DT><DD><FONT SIZE=2>Consists
of two Isis plans: the 1989 Plan and the 2002 Non-Employee Directors' Stock Option Plan.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(b)</FONT></DT><DD><FONT SIZE=2>Consists
of the 2000 Plan only.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(c)</FONT></DT><DD><FONT SIZE=2>Of
these shares, 72,993 remain available for purchase under the 2000 Employee Stock Purchase Plan. The 2000 Employee Stock Purchase Plan incorporates an evergreen formula, which was
approved by our stockholders, pursuant to which on each January&nbsp;1 for the first nine anniversaries, the aggregate number of shares reserved for issuance under the plan will be increased
automatically by the lesser of (i)&nbsp;1% of the total number of shares of common stock outstanding on such anniversary date or (ii)&nbsp;200,000 shares. </FONT></DD></DL>

<P><FONT SIZE=2><B>Description of 2000 Broad-Based Equity Incentive Plan  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We adopted the 2000 Plan to provide our employees, officers, Directors and consultants an opportunity to benefit from increases in the value of our common stock
through the granting of nonstatutory stock options, stock bonuses and rights to purchase restricted stock. At the time we adopted the 2000 Plan, we were not required to seek the approval of our
stockholders. We will request stockholder approval for future share increases to the 2000 Plan. The Board has delegated administration of the 2000 Plan to the Compensation Committee of the Board, and
the Compensation Committee has delegated administration of the 2000 Plan to the Non-Management Stock Option Committee with respect to certain option grants to employees who are not our
executive officers. The Compensation Committee has the power to construe and interpret the 2000 Plan and, subject to the provisions of the 2000 Plan, to select the persons to whom stock awards are to
be made, to designate the number of shares to be covered by each stock award, to establish vesting schedules, to specify the exercise price and the type of consideration to be paid to us upon exercise
or purchase. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;As
of February&nbsp;28, 2005, there were 5,592,286 shares reserved for issuance under the 2000 Plan, options to purchase an aggregate of 4,711,468 shares had been granted and were
outstanding under the 2000 Plan, options to purchase an aggregate of 397,714 shares had been exercised under the 2000 Plan, and 880,818 shares remained available for grant thereunder. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Options
granted under the 2000 Plan generally have a term of ten years, have an exercise price equal to the fair market value at the time of grant, can only be exercised with a cash
payment and vest at the rate of 25% per year after the first year and then at the rate of 2.08% per month thereafter for 36&nbsp;months during the optionee's employment or service as a consultant or
an affiliate. Options granted pursuant to the April&nbsp;2003 stock option exchange program vested 33.34% on January&nbsp;1, 2004 and then at the rate of 2.78% per month thereafter for
24&nbsp;months during the optionee's employment or service. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>20</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=1,SEQ=23,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=957372,FOLIO='20',FILE='DISK014:[05SAN6.05SAN1096]DK1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dk1096_1_21"> </A>
<BR>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;If
any change is made in the common stock subject to the 2000 Plan, or subject to any stock award, without the receipt of consideration by us (through merger, consolidation,
reorganization, recapitalization, reincorporation, stock dividend, dividend in property other than cash, stock split, liquidating dividend, combination of shares, exchange of shares, change in
corporate structure or other transaction not involving the receipt of consideration by us), the 2000 Plan will be appropriately adjusted in the class(es) and maximum number of securities subject to
the 2000 Plan, and the outstanding stock awards will be appropriately adjusted in the class(es) and number of securities and price per share of common stock subject to such outstanding stock awards.
Our Board will make such adjustments, and its determination will be final, binding and conclusive. The conversion of any of our convertible securities will not be treated as a transaction without
receipt of consideration. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
the event of our dissolution or liquidation, then all outstanding stock awards will terminate immediately prior to such event. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
the event of: </FONT></P>

<UL>
<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>a
sale, lease or other disposition of all or substantially all of our assets;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>a
merger or consolidation in which we are not the surviving corporation; or
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>a
reverse merger in which we are the surviving corporation but the shares of common stock outstanding immediately preceding the merger are converted by virtue of the merger
into other property, whether in the form of securities, cash or otherwise, </FONT></DD></DL>
</UL>
</UL>
<BR>

<P><FONT SIZE=2>then
any surviving corporation or acquiring corporation will assume any stock awards outstanding under the 2000 Plan or will substitute similar stock awards (including an award to acquire the same
consideration paid to the stockholders in the transaction for those outstanding under the 2000 Plan). In the event any surviving corporation or acquiring corporation refuses to assume such stock
awards or to substitute similar stock awards for those outstanding under the 2000 Plan, then with respect to stock awards held by participants whose continuous service has not terminated, the vesting
of such stock awards (and, if applicable, the time during which such stock awards may be exercised) will be accelerated in full, and the stock awards will terminate if not exercised (if applicable) at
or prior to such event. With respect to any other stock awards outstanding under the 2000 Plan, such stock awards will terminate if not exercised (if applicable) prior to such event. In addition, as
of December&nbsp;31, 2004, approximately 4,803,647stock awards granted under the 2000 Plan will be accelerated in full if a transaction described above occurs, even if the surviving corporation
assumes such award. </FONT></P>

<P><FONT SIZE=2><B>Employment, Severance and Change of Control Agreements  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;To continue the employee retention program we started in 2000, in April&nbsp;2003, we entered into agreements with certain key employees, including each of our
named executive officers then employed by Isis, pursuant to which we agreed to provide the covered employees with severance benefits under the following conditions: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>In
the event that a covered employee's employment is terminated without "cause," as defined in the agreement, by Isis on or before December&nbsp;31, 2005 (the "Severance
Period"), the employee will be eligible to receive a severance payment equal to a minimum of nine months and up to a maximum of 24&nbsp;months of his or her then current base salary depending on his
or her position with Isis, less payroll deductions and withholdings.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>In
the event that the covered employee's employment is terminated on or before December&nbsp;31, 2005 as a result of a change in control as defined in the agreement, the
employee's severance payment will be increased so that he or she will receive a minimum of 13.5&nbsp;months and up to a maximum of 36&nbsp;months of his or her then current base salary, depending
on his or her position with Isis, less payroll deductions and withholdings. </FONT></DD></DL>
</UL>
<P ALIGN="CENTER"><FONT SIZE=2>21</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=2,SEQ=24,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=437975,FOLIO='21',FILE='DISK014:[05SAN6.05SAN1096]DK1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dk1096_1_22"> </A>
<UL>
<UL>
</UL>
</UL>

<P><FONT SIZE=2><B>Compensation Committee Interlocks and Insider Participation  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;As noted above, during the fiscal year ended December&nbsp;31, 2004, our Compensation Committee was composed of Mr.&nbsp;Skaletsky, Dr.&nbsp;Reed and
Mr.&nbsp;Wender. None of the members of the Committee has ever been an employee or officer of Isis. None of our executive officers serves as a member of the Board of Directors or Compensation
Committee of any other entity that has one or more executive officers serving as a member of our Board of Directors or Compensation Committee. </FONT></P>

<P><FONT SIZE=2><B>Compensation Committee Report(2)  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In 2004, the Compensation Committee of the Board of Directors consisted of Mark B. Skaletsky, Chairman, John Reed and Joseph H. Wender, none of whom has ever been
an officer or employee of Isis. The Compensation Committee's responsibilities include: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>overall
compensation strategy;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>reviewing
and approving corporate performance goals and objectives relevant to the compensation of Isis' executive officers;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>evaluating
and recommending to the Board the compensation plans and programs advisable for Isis, as well as modifying or terminating existing plans and programs;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>establishing
policies with respect to equity compensation arrangements;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>reviewing
and approving compensation arrangements for Isis' executive officers, including its Chief Executive Officer;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>reviewing
and approving compensation arrangements for Isis' Directors;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>administering
Isis' benefit plans, including stock option and employee stock purchase plans;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>performing
other functions as may be necessary or convenient in the efficient discharge of the foregoing; and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>reporting
to the Board of Directors from time to time, or whenever it shall be called upon to do so. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
full Board of Directors reviews and approves the Compensation Committee's recommendations regarding the compensation of executive officers. </FONT></P>

<P><FONT SIZE=2><B>Executive Compensation  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We design our executive compensation programs to attract and retain executives who can help us meet our business objectives and to motivate them to enhance
long-term stockholder value. The executive officers' annual compensation consists of three elements: cash salary, a cash incentive bonus and stock option grants. The Compensation Committee
approves the total compensation for each of the executive officers. </FONT></P>

<HR NOSHADE ALIGN="LEFT" WIDTH="120">
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>(2)</FONT></DT><DD><FONT SIZE=2>The
material in this report is not "soliciting material," is not deemed filed with the SEC and is not to be incorporated by reference in any filing of Isis under the Securities Act of
1933, as amended (the "1933 Act"), or the Exchange Act. </FONT></DD></DL>
<P ALIGN="CENTER"><FONT SIZE=2>22</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=3,SEQ=25,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=618917,FOLIO='22',FILE='DISK014:[05SAN6.05SAN1096]DK1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dk1096_1_23"> </A>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;To
determine fair compensation, the Compensation Committee reviews historical and current salary, bonus and stock award information for other comparable companies in similar geographic
areas and at similar stages of growth and development. The group of comparable companies is different from the companies included in the market indices included in the performance graph in this Proxy
Statement. The Compensation Committee also reviews a variety of industry surveys throughout the year, which provide additional information about short and long-term executive compensation
in comparable companies. Based in part on this information, the Compensation Committee generally sets salaries, including that of our Chief Executive Officer, at levels comparable to competitive
companies of similar size in similar industries. We structure our management bonus program around both the individual's and Isis' performance. The Compensation Committee assesses Isis' achievement
against our key corporate objectives, and determines the corporate bonus guideline for all participants in the bonus program. Individual bonus guidelines are determined by an individual's manager and
approved by the CEO. The Compensation Committee reviews all bonus grants and approves all executive officer bonuses. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
use our stock option program to give all employees, including Isis' executive officers, an economic interest in the long-term appreciation of our common stock. We grant
existing employees new options on an annual basis to provide a continuing financial incentive. The size of the individual annual option grant is related to the employee's position and performance in
the previous year. For 2004, the Compensation Committee did not consider the number of options held by executive officers when awarding new grants. </FONT></P>

<P><FONT SIZE=2><B>Taxes  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Under Section&nbsp;162(m) of the Code, we can only deduct up to $1&nbsp;million of compensation we pay to certain executive officers each taxable year.
However, we may deduct compensation above $1&nbsp;million if it is "performance based compensation" within the meaning of the Internal Revenue Code. The Compensation Committee has determined that
stock options granted under the 1989 Plan and the 2000 Plan with an exercise price at least equal to the fair market value of our common stock on the date of grant is performance-based compensation. </FONT></P>


<P><FONT SIZE=2><B>Assessment of 2004  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We set very challenging objectives for 2004. In achieving most of those objectives, we made significant progress in the areas discussed below. However, 2004 had
its disappointments. Most notably, the results of Isis' Phase III clinical trials of alicaforsen in patients with Crohn's disease that did not demonstrate statistically significant induction of
clinical remission compared to placebo. Further, the price of Isis' stock suffered a significant decline over the year. We also failed to achieve some of our partnering objectives. Therefore, in
addition to the substantial reduction in force which the Board approved, the Compensation Committee recommended to the Board a corporate performance bonus guideline of 50%, with the guideline for a
year in which all objectives were achieved by the Company being 100%, and a reduction of salary increase guideline from 4% to 3% for all employees at director level or above, including Isis' executive
officers. </FONT></P>

<UL>

<P><FONT SIZE=2><B> Advanced Isis' Drugs in Development with Focus on Second-Generation Drugs  </B></FONT></P>

</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Inflammatory Disease: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>Ulcerative Colitis (ISIS 2302)</I></FONT><FONT SIZE=2>&#151;In December&nbsp;2004, Isis released results of three Phase II studies of
alicaforsen (ISIS 2302) enema to treat patients with ulcerative colitis. In the trials, alicaforsen enema produced significant and long-lasting disease improvement, as measured by changes
in the Disease Activity Index and out-performed both placebo and the enema standard of care. Isis </FONT></DD></DL>
</UL>
<P ALIGN="CENTER"><FONT SIZE=2>23</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=4,SEQ=26,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=694675,FOLIO='23',FILE='DISK014:[05SAN6.05SAN1096]DK1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dk1096_1_24"> </A>
<UL>
<UL>

<P><FONT SIZE=2>plans
to find a strong commercial partner for alicaforsen enema, while planning a Phase III program for the drug. </FONT></P>

</UL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Cardiovascular
Diseases: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>ISIS 301012</I></FONT><FONT SIZE=2> is a second-generation compound which targets apoB-100. Isis initiated a Phase I study in late 2003
in volunteers with borderline elevated cholesterol. In 2004, Isis announced data from this trial, which demonstrated that ISIS 301012 produced dose-dependent, rapid and prolonged
reductions of its target, in LDL and VLDL, and in
total cholesterol levels. Isis has also demonstrated that an oral formulation of ISIS 301012 reduces cholesterol in animals. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Metabolic
Diseases: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>ISIS 113715</I></FONT><FONT SIZE=2>&#151;In May&nbsp;2003, Isis initiated a Phase I clinical trial in healthy volunteers. In
September&nbsp;2003, Isis reported results from this Phase I study in which ISIS 113715 increased insulin sensitivity in normal volunteers. In addition, subjects treated with ISIS 113715 did not
experience hypoglycemia or excessively low blood sugar. A Phase II study was initiated in 2004. Isis intends to report the results from this trial mid-2005. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Cancer: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>ISIS 345794</I></FONT><FONT SIZE=2> emerged from Isis' internal oncology research program and is in preclinical development for cancer. This second
generation drug targets Signal Transducer and Activator of Transcription 3, or STAT-3, a protein that regulates cell division and growth and prevents cell death. In preclinical studies,
Isis has demonstrated that antisense inhibition of STAT-3 significantly delayed tumor growth and increased the rate of cancer cell death in multiple cell and animal models of cancer. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Recently
Discontinued Products: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>alicaforsen (ISIS 2302) for Crohn's Disease</I></FONT><FONT SIZE=2>&#151;administered intravenously (IV)&nbsp;did not demonstrate
statistically significant induction of clinical remissions in patients with Crohn's disease compared to placebo in two Phase 3 clinical trials. As a result of these trials, Isis will not invest
further in the development of alicaforsen for Crohn's disease.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>Affinitak&#153; (ISIS 3521, LY900003)</I></FONT><FONT SIZE=2>&#151;in combination with Gemzar&reg; (gemcitabine HCI) and
cisplatin did not demonstrate statistically significant improvement in median survival in patients with non-small cell lung cancer in a Phase III study sponsored by Eli Lilly and Co
("Lilly"). As a result of these trials, neither Lilly nor Isis will invest further in the development of Affinitak.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>ISIS 104838</I></FONT><FONT SIZE=2>&#151;produced positive disease responses in patients with rheumatoid arthritis, according to results of
two Phase II studies. While Isis was encouraged by the performance of this drug, in light of the strong competition in this market and the significant investment required to bring the first oral
anti-TNF product to market, Isis elected to discontinue development of this drug, and focus its resources on its two most promising second generation products ISIS 301012 and ISIS 113715.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>ISIS 14803</I></FONT><FONT SIZE=2>&#151;is a first generation antisense drug to treat Hepatitis C which Isis will not continue to develop. </FONT></DD></DL>
</UL>
<UL>

<P><FONT SIZE=2><B> Isis' Partnered Second-Generation Development Pipeline Continued to Expand  </B></FONT></P>

<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>LY2181308</I></FONT><FONT SIZE=2>, the first drug from the Isis-Lilly drug discovery alliance to advance to the clinic, entered Phase 1
clinical trials in patients with cancer in November&nbsp;2004. The compound targets survivin, which plays a role in cancer cell death, or apoptosis. For the accomplishment of this milestone, Isis
earned a $1.5&nbsp;million payment from Lilly. </FONT></DD></DL>
</UL>
<P ALIGN="CENTER"><FONT SIZE=2>24</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=5,SEQ=27,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=452545,FOLIO='24',FILE='DISK014:[05SAN6.05SAN1096]DK1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dk1096_1_25"> </A>
<UL>
<UL>
</UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>LY2275796</I></FONT><FONT SIZE=2> was licensed to Lilly in September&nbsp;2004. Isis earned a $750,000 payment from Lilly for the license. This
second-generation antisense drug targets eukaryotic initiation factor 4E, or eIF-4E, a protein involved in tumor progression, angiogenesis and metastasis. LY2275796 ended the year in
preclinical studies and is the second antisense anti-cancer drug to emerge from the Isis-Lilly collaboration.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>OGX-011</I></FONT><FONT SIZE=2>, formerly called ISIS 112989, is a second generation antisense inhibitor of clusterin, which Isis is
co-developing and commercializing OGX-011 with OncoGenex, a Canadian oncology-focused research and development company. In June&nbsp;2004, the partnership reported results of
a Phase I study of OGX-011
in prostate cancer. Results from the trial demonstrated OGX-011 was well-tolerated, achieved excellent drug concentration in its target tissue, the prostate, and produced up to
a 91&nbsp;percent dose-dependent reduction of its target. This drug ended the year in the process of completing a second Phase I clinical trial.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>ATL1102</I></FONT><FONT SIZE=2> entered into a Phase IIa clinical trial in patients with multiple sclerosis (MS) in December&nbsp;2004. Results of
a dose-escalating Phase I study of the second-generation antisense drug showed that six mg/kg/week of ATL1102 appeared well-tolerated. In March&nbsp;2005, ATL announced that,
although it and the trial investigators are confident that the current ATL 1102 Phase II trial is safe, in light of the recently announced safety issues associated with one other VLA-4
inhibitor that works through a different mechanism, ATL decided to halt the current trial and convene an advisory group to consider the potential development path for ATL 1102 which may include
restarting a Phase II trial program in multiple sclerosis and exploring ATL 1102 as an inhaled asthma treatment.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2><I>ATL1101</I></FONT><FONT SIZE=2> entered a Phase I study in patients with mild to moderate psoriasis. The drug is designed to block the synthesis of
the IGF-1 receptor, a protein involved in the regulation of cell overgrowth in psoriasis. </FONT></DD></DL>

<P><FONT SIZE=2><B> Furthered TIGER Biosensor Program  </B></FONT></P>

<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Entered
into a two-year contract providing up to $19.5&nbsp;million to further the development of Isis' TIGER biosensor system to identify infectious agents in
potential biological warfare attacks.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Received
three new government contracts valued at up to $10&nbsp;million for the continued development of its TIGER biosensor technology.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Hired
an experienced business head for Ibis Technologies to help lead it to commercialization.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Isis
did not complete a commercial transaction for the TIGER biosensor system that was a source of revenue in 2004. </FONT></DD></DL>
</UL>
<UL>

<P><FONT SIZE=2><B> Advanced Antisense Research Programs  </B></FONT></P>

<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Reported
positive data from multiple preclinical studies that demonstrated the utility of four second-generation antisense inhibitors in identifying new diabetes and related
metabolic disease targets for drug discovery and as potential innovative treatments for these conditions.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Announced
positive data from preclinical studies evaluating an antisense drug that suppressed the production of the mutant protein Cu/Zn superoxide dismutase (SOD1), a
molecule associated with an aggressive form of amyotrophic lateral sclerosis (ALS). </FONT></DD></DL>
</UL>
<UL>

<P><FONT SIZE=2><B> Other Business Developments  </B></FONT></P>

<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Formed
a strategic alliance with Alnylam to accelerate the development and commercialization of RNAi therapeutics. Isis earned a $5.0&nbsp;million technology access fee
and a $500,000 payment from Isis' participation in Alnylam's partnering program. </FONT></DD></DL>
</UL>
<P ALIGN="CENTER"><FONT SIZE=2>25</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=6,SEQ=28,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=138381,FOLIO='25',FILE='DISK014:[05SAN6.05SAN1096]DK1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dk1096_1_26"> </A>
<UL>
<UL>
</UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Earned
$4.0&nbsp;million in milestone payments from Eyetech associated with Eyetech's filing of an NDA for Macugen&reg; and receipt of marketing clearance for the
drug. Isis also sold a portion of its royalty rights in Macugen to Drug Royalty USA,&nbsp;Inc. in exchange for aggregate payments of $24.0&nbsp;million over the next three years.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Jointly
developed a new high performance solid support for the manufacture of oligonucleotides with Nitto Denko Corporation of Osaka, Japan. The new solid support has the
potential to decrease manufacturing costs of oligonucleotide-based drugs, including antisense.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Extended
its anti-cancer antisense drug discovery collaboration with Lilly.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Acquired
Elan Corporation plc's minority interest in Orasense and HepaSense, joint ventures arising out of prior collaborations between Isis and Elan, and eliminated all
future royalty obligations to Elan related to the oral delivery platform developed within the Orasense collaboration and to ISIS 14803.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Failed
to achieve its objective to outlicense at least one of the drugs in its development pipeline. </FONT></DD></DL>
</UL>
<UL>

<P><FONT SIZE=2><B> Patents and Proprietary Rights  </B></FONT></P>

</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Isis expanded its strong intellectual property position in RNA-based drug discovery by licensing core intellectual property regarding all therapeutic
uses of miRNA from the Max Planck Society. </FONT></P>

<P><FONT SIZE=2><B>Overall Accomplishment of Objectives  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;As a result of the foregoing factors and based on a combination of the accomplishment of major research and drug development objectives and the success of
alicaforsen enema in Phase II trials for
ulcerative colitis, the failure of alicaforsen in patients with Crohn's disease to demonstrate statistically significant induction of clinical remission compared to placebo, and the significant
decline in the price of Isis' stock in 2004, the Compensation Committee recommended to the Board a corporate performance bonus guideline of 50%, with the guideline for a year in which all objectives
were achieved by the Company being 100%, which, together with individual performance, formed the basis for cash bonus awards for 2004. Individual executive officer base salary increases were based on
individual executive officer performance; however, merit salary increases for executive officers were reduced by 25% as a result of the significant disappointments for the year. </FONT></P>

<P><FONT SIZE=2><B>Compensation for Isis' CEO  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Dr.&nbsp;Crooke's compensation is determined in accordance with the criteria described above for all executive officers. The Compensation Committee reviewed
published salary survey data for chief executive officers in comparable biotechnology companies and assessed Dr.&nbsp;Crooke's performance in light of Isis' objectives achieved and not achieved, as
discussed above. As a result, the Compensation Committee recommended that Dr.&nbsp;Crooke receive a base salary increase of 3%, to $549,262 for 2005. Dr.&nbsp;Crooke received a base salary
increase in 2004 of 4.5% and an increase of 5% in 2003. In January&nbsp;2005, Dr.&nbsp;Crooke received a bonus of $122,651 for accomplishments in 2004, likewise based on the assessment of
corporate objectives achieved and not achieved. On January&nbsp;2, 2004, the Committee approved an option grant of 80,000 shares of common stock for performance in 2003 for Dr.&nbsp;Crooke,
pursuant to Isis' 1989 Plan, at an exercise price of $6.81 per share, the fair market value on the date of grant. In January&nbsp;2005, the Committee approved an option grant of 75,720 shares of
common stock for performance in 2004 for Dr.&nbsp;Crooke, pursuant to Isis' 1989 Plan, at an exercise price of $5.80 per share, the fair market value on the date of grant. The options vest over a
four-year period; 25% after the first year and 2.08% per month for the remaining 36&nbsp;months. </FONT></P>

<UL>

<P><FONT SIZE=2>Mark
B. Skaletsky, Chairman<BR>
John C. Reed<BR>
Joseph H. Wender </FONT></P>

</UL>
<P ALIGN="CENTER"><FONT SIZE=2>26</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=7,SEQ=29,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=615362,FOLIO='26',FILE='DISK014:[05SAN6.05SAN1096]DK1096A.;8',USER='JHILL',CD='19-APR-2005;14:21' -->
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="page_dm1096_1_27"> </A> </FONT></P>

<!-- TOC_END -->
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="dm1096_audit_committee_report(3)"> </A>
<A NAME="toc_dm1096_1"> </A>
<BR></FONT><FONT SIZE=2><B>AUDIT COMMITTEE REPORT(3)    <BR>    </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The Audit Committee oversees our financial reporting process on behalf of the Board of Directors. Management has the primary responsibility for the financial
statements and the reporting process, including the systems of internal controls. In fulfilling its oversight responsibilities, the Audit Committee reviewed the audited financial statements in our
Annual Report on Form&nbsp;10-K for the fiscal year ended December&nbsp;31, 2004 with management, including a discussion of the quality, not just the acceptability, of the accounting
principles, the reasonableness of significant judgments, and the clarity of disclosures in the financial statements. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
Audit Committee reviewed with our independent auditors, who are responsible for expressing an opinion on the conformity of our audited financial statements with generally accepted
accounting principles, their judgments as to the quality, not just the acceptability, of our accounting principles and any other matters as are required to be discussed with the Audit Committee under
generally accepted auditing principles. In addition, the Audit Committee has discussed with the independent auditors the auditors' independence from management and Isis, including the matters in the
written disclosures required by the Independence Standards Board. The Audit Committee received from Ernst&nbsp;&amp; Young LLP written disclosure and the letter regarding its independence as required by
Independence Standards Board Standard No.&nbsp;1. The Audit Committee also discussed with our independent auditors the matters required by the Statement on Auditing Standards No.&nbsp;61. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
Audit Committee discussed with our independent auditors the overall scope and plans for their audit. The Audit Committee met with the independent auditors, with and without
management present, to discuss the results of their examinations, their evaluations of our internal controls, and the overall quality of our financial reporting. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
reliance on the reviews and discussions referred to above, the Audit Committee recommended to the Board of Directors, and the Board has approved, that the audited financial statements
be included in our Annual Report on Form&nbsp;10-K for the fiscal year ended December&nbsp;31, 2004 for filing with the SEC. The Audit Committee and the Board have also recommended,
subject to stockholder approval, the selection of Ernst&nbsp;&amp; Young LLP as our independent auditors. </FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="100%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>Joseph H. Wender, Chairman<BR>
Spencer R. Berthelsen<BR>
Christopher F. O. Gabrieli</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<HR NOSHADE ALIGN="LEFT" WIDTH="120">
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>(3)</FONT></DT><DD><FONT SIZE=2>This
Section is not "soliciting material," is not deemed filed with the SEC and is not to be incorporated by reference in any filing of Isis under the 1933 Act or the Exchange Act. </FONT></DD></DL>
<P ALIGN="CENTER"><FONT SIZE=2>27</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=1,SEQ=30,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=692675,FOLIO='27',FILE='DISK014:[05SAN6.05SAN1096]DM1096A.;9',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dm1096_1_28"> </A>

<P><FONT SIZE=2><B>Performance Measurement Comparison(4)  </B></FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="dm1096_comparison_of_5_year_cumulativ__com05631"> </A>
<A NAME="toc_dm1096_2"> </A>
<BR></FONT><FONT SIZE=2><B>COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN AMONG ISIS PHARMACEUTICALS,&nbsp;INC.,<BR>  THE NASDAQ COMPOSITE INDEX (TOTAL RETURN) AND<BR>  THE AMEX BIOTECH INDEX    <BR>    </B></FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT> <FONT SIZE=2><B>
<IMG SRC="g911319.jpg" ALT="CHART" WIDTH="601" HEIGHT="283">
  </B></FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="101%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="BOTTOM">
<TH WIDTH="46%" ALIGN="LEFT"><FONT SIZE=2>&nbsp;</FONT><BR></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>Dec-99</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>Dec-00</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>Dec-01</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>Dec-02</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>Dec-03</B></FONT><HR NOSHADE></TH>
<TH WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH COLSPAN=2 ALIGN="CENTER"><FONT SIZE=1><B>Dec-04</B></FONT><HR NOSHADE></TH>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="46%"><FONT SIZE=2><B>Isis Pharmaceuticals Inc.</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>100</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>170</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>355</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>105</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>104</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>94</FONT></TD>
</TR>
<TR BGCOLOR="White" VALIGN="TOP">
<TD WIDTH="46%"><FONT SIZE=2><B>AMEX Biotech Index</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>100</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>162</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>148</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>86</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>125</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>139</FONT></TD>
</TR>
<TR BGCOLOR="#CCEEFF" VALIGN="TOP">
<TD WIDTH="46%"><FONT SIZE=2><B>Nasdaq U.S.</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>100</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>60</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>48</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>33</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>49</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>$</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>54</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The above table and chart assume $100 invested on December&nbsp;31, 1999 in our common stock, the NASDAQ Composite Index (Total Return) and the
AMEX Biotech Index. Total return assumes reinvestment of dividends. </FONT></P>

<HR NOSHADE ALIGN="LEFT" WIDTH="120">
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>(4)</FONT></DT><DD><FONT SIZE=2>This
Section is not "soliciting material," is not deemed filed with the SEC and is not to be incorporated by reference in any filing of Isis under the 1933 Act or the Exchange Act. </FONT></DD></DL>
<P ALIGN="CENTER"><FONT SIZE=2>28</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=2,SEQ=31,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=907919,FOLIO='28',FILE='DISK014:[05SAN6.05SAN1096]DM1096A.;9',USER='JHILL',CD='19-APR-2005;14:21' -->
<A NAME="page_dm1096_1_29"> </A>

<P><FONT SIZE=2><B>Certain Relationships and Related Transactions  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Rosanne Crooke, the wife of Dr.&nbsp;Crooke, our Chairman and Chief Executive Officer, is a non-executive employee of Isis and earns more than
$60,000 per year in compensation. However, Mrs.&nbsp;Crooke's compensation is commensurate with the compensation with that of other employees at the same level at Isis. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;One
of our Directors, Mr.&nbsp;Muto, who was elected by the Board in March&nbsp;2001, is a partner at Cooley Godward LLP, our outside counsel. However, the fees we paid to Cooley
Godward did not exceed five percent of its gross revenues for its 2004 fiscal year. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2003, we entered into the transactions described in this Proxy Statement under "Employment, Severance and Change of Control Arrangements." </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
have entered into indemnity agreements with each of our executive officers and Directors and certain non-executive officers which provide, among other things, that we will
indemnify such officer or Director, under the circumstances and to the extent provided for therein, for expenses, damages, judgments, fines and settlements he or she may be required to pay in actions
or proceedings which he or she is or may be made a party by reason of his or her position as a Director, officer or other agent of Isis, and otherwise to the fullest extent permitted under Delaware
law and our bylaws. Our bylaws provide that we will indemnify our Directors and executive officers to the fullest extent not prohibited by Delaware law or any other applicable law, except that we will
generally not be required to indemnify a Director or executive officer in connection with any proceeding initiated by such Director or executive officer. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Our
policies and procedures specifically prohibit personal loans to our executive officers and any officer with a title of Vice President or higher. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>29</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=3,SEQ=32,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=140723,FOLIO='29',FILE='DISK014:[05SAN6.05SAN1096]DM1096A.;9',USER='JHILL',CD='19-APR-2005;14:21' -->
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="page_do1096_1_30"> </A> </FONT></P>

<!-- TOC_END -->
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="do1096_householding_of_proxy_materials"> </A>
<A NAME="toc_do1096_1"> </A>
<BR></FONT><FONT SIZE=2><B>HOUSEHOLDING OF PROXY MATERIALS    <BR>    </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The SEC has adopted rules that permit companies and intermediaries (e.g. brokers) to satisfy the delivery requirements for proxy statements and annual reports
with respect to two or more stockholders sharing the same address by delivering a single proxy statement addressed to those stockholders. This process, which is commonly referred to as "householding,"
potentially means extra convenience for stockholders and cost savings for companies. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;This
year, a number of brokers with account holders who are Isis stockholders will be "householding" our proxy materials. A single proxy statement will be delivered to multiple
stockholders sharing an address unless contrary instructions have been received from the affected stockholders. Once you have received notice from your broker that they will be "householding"
communications to your address, "householding" will continue until you are notified otherwise or until you revoke your consent. If, at any time, you no longer wish to participate in "householding" and
would prefer to receive a separate proxy statement and annual report, please notify your broker; direct your written request to Isis Pharmaceuticals,&nbsp;Inc., Attn: Linda Powell, Assistant
Corporate Secretary, 1896 Rutherford Road, Carlsbad, California 92008 or contact Linda Powell at (760)&nbsp;603-2471. Stockholders who currently receive multiple copies of the proxy
statement at their address and would like to request "householding" of their communications should contact their broker. </FONT></P>

<P><FONT SIZE=2><B>Other Matters  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The Board of Directors knows of no other matters that will be presented for consideration at the Annual Meeting. If any other issues are properly brought before
the meeting, we will ask our proxy holders to vote on the matters using their best judgment. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;For
further information about Isis Pharmaceuticals,&nbsp;Inc., please request a copy of our Annual Report. The report includes our Form&nbsp;10-K for the year ended
December&nbsp;31, 2004 that we filed with the SEC, and is available free of charge. Please send written requests to: </FONT></P>

<UL>

<P><FONT SIZE=2>B.
Lynne Parshall, Secretary<BR>
Isis Pharmaceuticals,&nbsp;Inc.<BR>
1896 Rutherford Road<BR>
Carlsbad, CA 92008 </FONT></P>

</UL>

<P><FONT SIZE=2>You
may also visit the Company's website (www.isispharm.com) to view our 2004 Annual Report. Any information that is included on or linked to our website is not part of this proxy statement or any
registration statement or report that incorporates this proxy statement by reference. </FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="100%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>By Order of the Board of Directors</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>B. Lynne Parshall<BR>
Secretary</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="49%"><FONT SIZE=2>April&nbsp;19, 2005</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="49%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<P ALIGN="CENTER"><FONT SIZE=2>30</FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=1,SEQ=33,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=552366,FOLIO='30',FILE='DISK014:[05SAN6.05SAN1096]DO1096A.;5',USER='JHILL',CD='19-APR-2005;14:22' -->
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->
<!-- TOC_END -->
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="ma1096_annual_meeting_of_stockholders__ann02424"> </A>
<A NAME="toc_ma1096_1"> </A>
<BR></FONT><FONT SIZE=2><B>ANNUAL MEETING OF STOCKHOLDERS OF    <BR>    <BR>    ISIS PHARMACEUTICALS,&nbsp;INC.    <BR>    <BR>    May&nbsp;26, 2005    <BR>    </B></FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>Please
date, sign and mail<BR>
your proxy card in the<BR>
envelope provided as soon<BR>
as possible. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2>V
Please detach along perforated line and mail in the envelope provided. V </FONT></P>

<HR NOSHADE>
<P ALIGN="CENTER"><BR><FONT SIZE=2><B>THE BOARD OF DIRECTORS RECOMMENDS A VOTE "FOR" THE ELECTION OF DIRECTORS AND "FOR" PROPOSAL&nbsp;2.  </B></FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><B> PLEASE SIGN, DATE AND RETURN PROMPTLY IN THE ENCLOSED ENVELOPE. PLEASE MARK YOUR VOTE IN BLUE OR BLACK INK AS SHOWN HERE <FONT FACE="WINGDINGS">&#253;</FONT></B></FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="100%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="20%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="16%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%" ALIGN="CENTER"><FONT SIZE=1><B>FOR</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="CENTER"><FONT SIZE=1><B>AGAINST</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="CENTER"><FONT SIZE=1><B>ABSTAIN</B></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>1.</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD COLSPAN=5><FONT SIZE=2>To elect three directors to hold office until the 2008 Annual Meeting of Stockholders and elect Dr.&nbsp;DiMarchi to hold office until the 2006 Annual Meeting of Stockholders.</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>2.</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>To ratify the selection of Ernst&nbsp;&amp; Young LLP as independent auditors of the Company for its fiscal year ending December&nbsp;31, 2005</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD COLSPAN=7 ALIGN="CENTER"><FONT SIZE=2><B>NOMINEES:</B></FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="20%"><FONT SIZE=2><B>FOR ALL NOMINEES</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT><BR>
<FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="16%"><FONT SIZE=2>Spencer&nbsp;R.&nbsp;Berthelsen<BR>
Richard D. DiMarchi</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="20%"><FONT SIZE=2><B>WITHHOLD&nbsp;AUTHORITY<BR>
FOR ALL NOMINEES</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT><BR>
<FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="16%"><FONT SIZE=2>B. Lynne Parshall<BR>
Joseph H. Wender</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD COLSPAN=9><FONT SIZE=2><B>Please vote, date and promptly return this proxy in the enclosed return envelope which is postage prepaid if mailed in the United States.</B></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="20%"><FONT SIZE=2><B>FOR ALL EXCEPT<BR>
(See instructions below)</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="16%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="20%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="16%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="20%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="16%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="27%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="87%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="18%"><FONT SIZE=2><B>INSTRUCTION:</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD COLSPAN=5><FONT SIZE=2>To withhold authority to vote for any individual nominee(s), mark </FONT><FONT SIZE=2><B>"FOR ALL EXCEPT"</B></FONT><FONT SIZE=2> and fill in the circle next to each nominee you wish to withhold, as shown here:&nbsp;<FONT
FACE="WINGDINGS">&#111;</FONT></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="18%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="38%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="38%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="18%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="38%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="38%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="BOTTOM">
<TD COLSPAN=3 VALIGN="TOP"><FONT SIZE=2>To change the address on your account, please check the box at right and indicate your new address in the address space above. Please note that changes to the registered name(s) on the account may not be
submitted via this method.</FONT></TD>
<TD WIDTH="1%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%" ALIGN="CENTER" VALIGN="TOP"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="2%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="38%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="100%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="22%"><FONT SIZE=2>Signature of Stockholder</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>Date:</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%" ALIGN="RIGHT"><FONT SIZE=2>Signature of Stockholder</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>Date:</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><HR NOSHADE></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><HR NOSHADE></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%" ALIGN="RIGHT"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><HR NOSHADE></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><HR NOSHADE></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2><B>Note:</B></FONT></DT><DD><FONT SIZE=2>Please sign exactly as your name or names appear on this Proxy. When shares are held jointly, each holder should sign. When signing
as executor, administrator, attorney, trustee or guardian, please give full title as such. If the signer is a corporation, please sign full corporate name by duly authorized officer, giving full title
as such. If signer is a partnership, please sign in partnership name by authorized person. </FONT></DD></DL>
</UL>
<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=1,SEQ=34,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=647557,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MA1096A.;24',USER='JHILL',CD='19-APR-2005;14:22' -->
<UL>
<UL>
</UL>
</UL>
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="ma1096_isis_pharmaceuticals,_inc._thi__isi05575"> </A>
<A NAME="toc_ma1096_2"> </A>
<BR></FONT><FONT SIZE=2><B>ISIS PHARMACEUTICALS,&nbsp;INC.<BR>  THIS PROXY IS SOLICITED ON BEHALF OF THE BOARD OF DIRECTORS<BR>  FOR THE ANNUAL MEETING OF STOCKHOLDERS TO BE HELD ON MAY&nbsp;26, 2005    <BR>    </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The undersigned hereby appoints STANLEY T. CROOKE and B. LYNNE PARSHALL, and each of them, as attorneys and proxies of the undersigned, with full power of
substitution, to vote all of the shares of stock of Isis Pharmaceuticals,&nbsp;Inc. (the "Company") which the undersigned may be entitled to vote at the Annual Meeting of Stockholders of the Company
to be held at the Company's offices at 1896 Rutherford Road, Carlsbad, California 92008 on Thursday, May&nbsp;26, 2005 at 9:30&nbsp;a.m. PT, and at any and all continuations and adjournments
thereof, with all powers that the undersigned would possess if personally present, upon and in respect of the following matters and in accordance with the following instructions, with discretionary
authority as to any and all other matters that may properly come before the meeting. </FONT></P>

<P><FONT SIZE=2><B>UNLESS A CONTRARY DIRECTION IS INDICATED, THIS PROXY WILL BE VOTED FOR PROPOSALS&nbsp;1 AND 2 AS MORE SPECIFICALLY DESCRIBED IN THE PROXY STATEMENT. IF SPECIFIC INSTRUCTIONS
ARE INDICATED, THIS PROXY WILL BE VOTED IN ACCORDANCE THEREWITH.</B></FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><B>(Continued and to be signed on the reverse side)</B></FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=2,SEQ=35,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=281196,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MA1096B.;11',USER='JHILL',CD='19-APR-2005;14:22' -->
<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="ma1096_annual_meeting_of_stockholders__ann02424_1"> </A>
<A NAME="toc_ma1096_3"> </A>
<BR></FONT><FONT SIZE=2><B>ANNUAL MEETING OF STOCKHOLDERS OF    <BR>    <BR>    ISIS PHARMACEUTICALS,&nbsp;INC.    <BR>    <BR>    May&nbsp;26, 2005    <BR>    </B></FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="ma1096_proxy_voting_instructions"> </A>
<A NAME="toc_ma1096_4"> </A></FONT> <FONT SIZE=2><B>PROXY VOTING INSTRUCTIONS    <BR>    </B></FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="100%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="BOTTOM">
<TD WIDTH="52%" VALIGN="TOP"><FONT SIZE=2><B>MAIL</B></FONT><FONT SIZE=2>&#151;Date, sign and mail your proxy card in the envelope provided as soon as possible.</FONT></TD>
<TD WIDTH="2%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="21%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="21%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="52%" ALIGN="CENTER"><FONT SIZE=2>&#151;OR&#151;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="21%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="21%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="52%"><FONT SIZE=2><B>TELEPHONE</B></FONT><FONT SIZE=2>&#151;Call toll-free </FONT><FONT SIZE=2><B>1-800-PROXIES</B></FONT><FONT SIZE=2> (1-800-776-9437) from any touch-tone telephone and follow the instructions. Have your proxy card
available when you call.</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="21%"><FONT SIZE=2><B>COMPANY NUMBER</B></FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="21%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="52%" ALIGN="CENTER"><FONT SIZE=2>&#151;OR&#151;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="21%"><FONT SIZE=2><B>ACCOUNT NUMBER</B></FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="21%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="BOTTOM">
<TD WIDTH="52%" VALIGN="TOP"><FONT SIZE=2><B>INTERNET</B></FONT><FONT SIZE=2>&#151;Access "</FONT><FONT SIZE=2><B>www.voteproxy.com</B></FONT><FONT SIZE=2>" and follow the on-screen instructions. Have your proxy card available when you access the web
page.</FONT></TD>
<TD WIDTH="2%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="21%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="21%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->


<P><FONT SIZE=2>You
may enter your voting instructions at 1-800-PROXIES or www.voteproxy.com up until 11:59 PM Eastern Time the day before the cut-off or meeting date. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><B>V Please detach along perforated line and mail in the envelope provided <U>IF</U><BR>
you are not voting via telephone or the Internet. V</B></FONT></P>

<HR NOSHADE>
<P ALIGN="CENTER"><BR><FONT SIZE=2><B>THE BOARD OF DIRECTORS RECOMMENDS A VOTE "FOR" THE ELECTION OF DIRECTORS AND "FOR" PROPOSAL&nbsp;2.  </B></FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><B> PLEASE SIGN, DATE AND RETURN PROMPTLY IN THE ENCLOSED ENVELOPE. PLEASE MARK YOUR VOTE IN BLUE OR BLACK INK AS SHOWN HERE <FONT FACE="WINGDINGS">&#253;</FONT></B></FONT></P>

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="100%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="23%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="18%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%" ALIGN="CENTER"><FONT SIZE=1><B>FOR</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="CENTER"><FONT SIZE=1><B>AGAINST</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=1>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="CENTER"><FONT SIZE=1><B>ABSTAIN</B></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>1.</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD COLSPAN=5><FONT SIZE=2>To elect three directors to hold office until the 2008 Annual Meeting of Stockholders and elect Dr.&nbsp;DiMarchi to hold office until the 2006 Annual Meeting of Stockholders.</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>2.</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%"><FONT SIZE=2>To ratify the selection of Ernst&nbsp;&amp; Young LLP as independent auditors of the Company for its fiscal year ending December&nbsp;31, 2005</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD COLSPAN=7 ALIGN="CENTER"><FONT SIZE=2><B>NOMINEES:</B></FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="23%"><FONT SIZE=2><B>FOR ALL NOMINEES</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT><BR>
<FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="18%"><FONT SIZE=2>Spencer&nbsp;R.&nbsp;Berthelsen<BR>
Richard D. DiMarchi</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="23%"><FONT SIZE=2><B>WITHHOLD&nbsp;AUTHORITY<BR>
FOR ALL NOMINEES</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT><BR>
<FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="18%"><FONT SIZE=2>B. Lynne Parshall<BR>
Joseph H. Wender</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD COLSPAN=9><FONT SIZE=2><B>Please vote, date and promptly return this proxy in the enclosed return envelope which is postage prepaid if mailed in the United States.</B></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%" ALIGN="CENTER"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="23%"><FONT SIZE=2><B>FOR ALL EXCEPT<BR>
(See instructions below)</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="18%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="23%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="18%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="23%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="18%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="9%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="87%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="18%"><FONT SIZE=2><B>INSTRUCTION:</B></FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD COLSPAN=5><FONT SIZE=2>To withhold authority to vote for any individual nominee(s), mark </FONT><FONT SIZE=2><B>"FOR ALL EXCEPT"</B></FONT><FONT SIZE=2> and fill in the circle next to each nominee you wish to withhold, as shown here:&nbsp;<FONT
FACE="WINGDINGS">&#111;</FONT></FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="18%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="38%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="38%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="18%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="38%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="2%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="38%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="BOTTOM">
<TD COLSPAN=3 VALIGN="TOP"><FONT SIZE=2>To change the address on your account, please check the box at right and indicate your new address in the address space above. Please note that changes to the registered name(s) on the account may not be
submitted via this method.</FONT></TD>
<TD WIDTH="1%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%" ALIGN="CENTER" VALIGN="TOP"><FONT SIZE=2><FONT FACE="WINGDINGS">&#111;</FONT></FONT></TD>
<TD WIDTH="2%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="38%" VALIGN="TOP"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<!-- User-specified TAGGED TABLE -->
<TABLE WIDTH="100%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="TOP">
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="22%"><FONT SIZE=2>Signature of Stockholder</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>Date:</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%" ALIGN="RIGHT"><FONT SIZE=2>Signature of Stockholder</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>Date:</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><FONT SIZE=2>&nbsp;</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="22%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><HR NOSHADE></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><HR NOSHADE></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="22%" ALIGN="RIGHT"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="12%"><HR NOSHADE></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="6%" ALIGN="RIGHT"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="7%"><HR NOSHADE></TD>
</TR>
</TABLE>
<!-- end of user-specified TAGGED TABLE -->

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2><B>Note:</B></FONT></DT><DD><FONT SIZE=2>Please sign exactly as your name or names appear on this Proxy. When shares are held jointly, each holder should sign. When signing
as executor, administrator, attorney, trustee or guardian, please give full title as such. If the signer is a corporation, please sign full corporate name by duly authorized officer, giving full title
as such. If signer is a partnership, please sign in partnership name by authorized person. </FONT></DD></DL>
</UL>
<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=3,SEQ=36,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=131975,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MA1096B.;11',USER='JHILL',CD='19-APR-2005;14:22' -->
<UL>
<UL>
</UL>
</UL>
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->

<P><FONT SIZE=2>
DEAR STOCKHOLDERS, </FONT></P>

<P><FONT SIZE=2>ISIS
AND OUR GROWING LIST OF PARTNERS HAVE LED IN THE ADVANCEMENT OF ALL AREAS OF ANTISENSE DRUG DEVELOPMENT, FROM BASIC RESEARCH TO DRUG DISCOVERY TO CLINICAL DEVELOPMENT TO COMMERCIAL- SCALE
MANUFACTURING. </FONT></P>

<P><FONT SIZE=2>THESE
ADVANCES ARE EVIDENCED BY THE: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Number
of antisense drugs in development;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Number
of companies participating in development of these drugs;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Range
of diseases in which we are studying antisense drugs;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Significant
reductions in the cost to deliver antisense drugs;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Invention
of improved second-generation chemistries, and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>Development
of many routes of administration for antisense drugs, including the potential for oral and aerosol delivery. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Through
our investment, innovation and passion, we have created antisense technology; a technology that allows us to efficiently generate drugs for ourselves and our partners. Our
second-generation drugs represent the future of Isis and the technology. We are committed to broadening the applications for antisense, while taking advantage of the technology's productivity and
capitalizing on the drug assets that arise from our drug discovery and development programs. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Our
business strategy is designed to take advantage of our knowledge and expertise in RNA-based drug development and the strengths of our technology, patent position,
employees and management team to advance multiple drug candidates toward the market. We plan to execute this strategy by licensing our drugs as early in the clinical development process as we can on
the best terms possible. This strategy allows us to participate in the progress of many drugs as they move through the clinic, while decreasing our investment in any one product. Further, by
increasing the number of antisense drugs in development, we significantly increase the probability of multiple commercial successes. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;As
we enter 2005, we have all the elements in place to continue to implement this strategy. We have an exciting pipeline, excellent partners, and more than 1,500 issued or exclusively
licensed patents, all of which provide us with a sound leadership position in oligonucleotide-based therapeutics. We have built the infrastructure necessary to efficiently and effectively discover and
develop antisense drugs. And, along the way, we have advanced our TIGER biosensor system to an important stage in its development. We are optimistic about the prospects of the Company and the
therapeutic and commercial potential of each one of our products in development. What remains is for us to execute our 2005-2006 plan by achieving the following objectives: </FONT></P>

<P><FONT SIZE=2>FIRST,
WE MUST FIND A STRONG PARTNER FOR ALICAFORSEN ENEMA, AND AGGRESSIVELY MOVE THIS NEAR-TERM PRODUCT OPPORTUNITY TOWARDS THE MARKET. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
late 2004, we announced data from three Phase 2 clinical trials of alicaforsen enema involving more than 300 patients with ulcerative colitis (UC). These trials demonstrate the drug
improves signs and symptoms of UC and is well-tolerated. In the Phase 2 studies, alicaforsen enema outperformed both placebo and the enema standard-of-care. As a
result, we now have the information we need to plan a Phase 3 development program. We believe alicaforsen enema represents an attractive commercial opportunity for Isis. If the activity, durability
and safety results demonstrated in the Phase 2 trials are replicated in late-stage trials, we believe alicaforsen enema will be an important new drug for patients with this disease. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Our
goal in 2005 is to meet with the U.S. Food and Drug Administration to discuss Phase 3 clinical trial plans for alicaforsen enema, identify the best marketing partner with
late-stage development and commercial expertise, and work with that partner to develop and implement a successful Phase 3 program. This strategy should allow us to benefit from a partner's
clinical trial </FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=1,SEQ=37,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=303449,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MC1096A.;2',USER='JHILL',CD='19-APR-2005;14:24' -->
<BR>

<P><FONT SIZE=2>experience
and knowledge, and avoid the significant costs associated with late-stage development. In turn, we will focus our resources and unique strengths on advancing our second-
generation drugs. </FONT></P>

<P><FONT SIZE=2>SECOND,
WE PLAN TO ADVANCE OUR TWO KEY SECOND-GENERATION DRUGS, ISIS 301012 AND ISIS 113715, TO CLINICAL PROOF-OF-VALUE. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT
SIZE=2><I>ISIS 301012</I></FONT><FONT SIZE=2>, a drug that inhibits apoB-100 for the treatment of high cholesterol, is an important asset. ISIS 301012
administered subcutaneously is completing Phase 1 studies. Last year, we reported data from this Phase 1 trial that showed ISIS 301012 produces dose-dependent, rapid and prolonged
reductions of its target, and in LDL, VLDL and total cholesterol levels in volunteers with borderline elevated cholesterol. Further, these data demonstrate that ISIS 301012 is working as designed; it
inhibits and reduces its intended target, resulting in the predicted therapeutic pharmacological outcome, the lowering of cholesterol. Importantly, we have also demonstrated that an oral form of the
drug reduces cholesterol in animals. These results gave us the confidence to initiate a Phase 1 trial of the oral formulation of ISIS 301012 in March&nbsp;2005. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2005-2006, through our development of both the subcutaneous injection and oral formulations of ISIS 301012, we plan to: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>define
the optimal dose and schedule for ISIS 301012 as a single agent;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>prepare
for the initiation of combination studies with oral lipid-lowering drugs;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>define
the oral bioavailability of ISIS 301012 and demonstrate reduction of apoB-100 and cholesterol in man;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>advance
ISIS 301012 into additional clinical trials to evaluate longer-term dosing, and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>explore
other indications, such as therapeutic apheresis, that may offer shortened routes to commercialization. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Consistent
with these goals, we plan to: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>report
final results from the ongoing Phase 1 single agent study in normal volunteers with borderline elevated cholesterol;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>initiate
a Phase 2 trial to evaluate dose and dose schedule in patients with high cholesterol;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>initiate
a pharmacokinetic study to evaluate the addition of ISIS 301012 to statin therapy, and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>initiate
a Phase 2 study in patients with high cholesterol who are also taking statins. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT
SIZE=2><I>ISIS 113715</I></FONT><FONT SIZE=2>, a drug that inhibits PTP-1B for the treatment of type 2 diabetes, represents another significant product
opportunity. This drug is in Phase 2 clinical trials. In a Phase1 study, ISIS 113715 increased insulin sensitivity in normal volunteers. Subjects treated with ISIS 113715 did not experience
hypoglycemia, or excessively low blood sugar, which is an adverse effect observed with many currently available type 2 diabetes treatments. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
goals of our ISIS 113715 development program in 2005-2006 are to: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>demonstrate
the safety of the drug as a single agent in patients with type 2 diabetes to support longer-term dosing;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>define
the optimal dose and schedule to support future clinical trials;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>advance
ISIS 113715 into additional clinical trials to evaluate longer-term dosing, and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>explore
the drug in patients who are also taking oral anti-diabetic therapies. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
line with these goals, we plan to: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>report
results from the ongoing Phase 2 single agent trial in patients with type 2 diabetes;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>report
results following 12 weeks of dosing in patients with this disease, and </FONT></DD></DL>
</UL>
<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=2,SEQ=38,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=1011795,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MC1096A.;2',USER='JHILL',CD='19-APR-2005;14:24' -->
<UL>
<UL>
</UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>initiate
dosing in patients with type 2 diabetes who are also taking oral anti-diabetic therapy. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>THIRD,
WE INTEND TO CAPTURE VALUE FROM OUR PORTFOLIO OF SECOND-GENERATION ANTISENSE PRODUCT OPPORTUNITIES AND CONTINUE OUR ADVANCEMENT OF THE TECHNOLOGY. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
our internal development initiatives, we plan to focus our drug discovery efforts on molecular targets that give us early clinical proof-of-value and have the
potential to be exciting new drugs that address numerous therapeutic areas with major market potential. Specific areas we are concentrating on include inflammatory, metabolic and cardiovascular
diseases, and cancer. In 2005-2006, we intend to advance at least two new drug candidates from our drug discovery programs into development. </FONT></P>

<P><FONT SIZE=2>FOURTH,
WE PLAN TO EXPAND OUR PARTNERS' DEVELOPMENT PIPELINES AND SUPPORT THE CONTINUED ADVANCEMENT OF CURRENTLY PARTNERED SECOND-GENERATION DRUGS. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
are pleased with the progress made within our current collaborations and our achievements in establishing new ones. Our overall goal in working with partners is to participate in
advancing their products through the clinical development process and toward the market. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2004, we extended our anti-cancer drug discovery collaboration with Eli Lilly and Company and reported continued progress within our alliance throughout the year. Lilly
initiated a Phase 1 trial of LY2181308 in patients with cancer. LY2181308 is the first drug from our alliance to enter the clinic. This second-generation antisense drug targets survivin, a molecule
that allows cells that would normally undergo programmed cell death to survive. We also licensed LY2275796 to Lilly in September&nbsp;2004, the second antisense anti-cancer drug to
emerge from the Isis-Lilly collaboration. LY2275796 targets eukaryotic initiation factor-4E, a protein involved in the growth and progression of tumors. This drug is in
preclinical development. For these accomplishments we earned $2.25&nbsp;million in milestone payments from Lilly. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2005-2006, our goal is to support the continuation of Lilly's anti-cancer antisense research and development programs. Further, we are optimistic we will add
new antisense drug candidates to Lilly's oncology franchise, and plan to continue to discover and advance additional compounds for licensing consideration by Lilly. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
have also successfully engaged in other strategic drug discovery and development collaborations, which we call our satellite company partnerships. Satellite companies allow us to
benefit from our partners' expertise and highly focused research efforts. In turn, partners gain from our experience and expertise in RNA-based drug discovery and development and access to
our proprietary antisense chemistries and leading intellectual property. We currently work with high-quality life sciences companies such as OncoGenex Technologies,&nbsp;Inc., Antisense
Therapeutics Limited (ATL), Alnylam Pharmaceuticals,&nbsp;Inc., Santaris Pharma A/S and Sarissa,&nbsp;Inc. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;OncoGenex
has been a partner since 2001. This collaboration combines OncoGenex's proprietary antisense position in inhibitors to the cancer target clusterin, with our proprietary
second-generation antisense chemistry. The lead drug in this collaboration is OGX-011 which targets clusterin, a cell survival protein that when overproduced, prevents cancer cell death
and counters the effectiveness of standard anti-tumor treatments. Currently, we are supporting OncoGenex's OGX-011 development initiatives. In June&nbsp;2004, the partnership
reported that OGX-011 was well-tolerated, achieved excellent drug concentration in its target tissue, the prostate, and produced up to a 91% dose-dependent
reduction of its target in a Phase 1 trial. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2003, we expanded our partnership with OncoGenex to include the development of OGX-225, the first bi-specific antisense inhibitor to enter development. A
bi-specific inhibitor is a single-stranded antisense drug designed to inhibit the production of two proteins simultaneously. OGX-225 targets both insulin-like
growth factor binding protein-5 and insulin-like growth factor binding protein-2, two molecules involved in the development of metastatic disease in hormone-
regulated tumors. OGX-225 is </FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=3,SEQ=39,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=392671,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MC1096A.;2',USER='JHILL',CD='19-APR-2005;14:24' -->
<BR>

<P><FONT SIZE=2>in
the research phase of development. Recently, we again expanded our collaboration with OncoGenex to allow for the development of two additional second-generation antisense drug candidates for
cancer. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2005-2006, we will support OncoGenex's expansion of OGX-011 development into additional cancer therapeutic areas through the completion of a second Phase 1
trial evaluating OGX-011 in combination with TAXOTERE&reg; in solid tumors, and the initiation of Phase 2 clinical trials of the drug in patients with lung, breast and prostate
cancers. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;ATL
is an Australian-based antisense company we helped found in 2001. We are supporting ATL's development efforts to determine the potential of ATL 1102 as an effective
treatment for multiple sclerosis (MS). ATL 1102 is an antisense inhibitor of VLA-4. ATL 1102 entered a Phase 2a clinical trial in patients with MS after positive findings from an earlier
trial. In March&nbsp;2005, ATL announced that, although it and the trial investigators are confident that the current ATL 1102 Phase 2a trial is safe, in light of recently announced safety issues
associated with another VLA-4 inhibitor that works through a different mechanism, ATL decided to halt the current trial. ATL plans to convene an advisory group to consider the potential
development path for ATL 1102. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2004, ATL also initiated a proof-of-concept study to explore the activity of ATL 1101 in patients with psoriasis. ATL 1101 is a second-generation antisense
drug designed to block the synthesis of the insulin-like growth factor-1 receptor, a protein involved in the regulation of cell growth in psoriasis. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
2005-2006, we will support ATL's ongoing development efforts to determine the potential of ATL 1102 for MS and to explore the activity of ATL 1101 in
psoriasis. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Alnylam
is a partnership focused on a particular antisense mechanism of action called RNAi or siRNA. Alnylam is widely considered to be the center of excellence for RNAi research and
therapeutic development. In 2004, we formed a strategic alliance with Alnylam to accelerate the development and commercialization of RNAi therapeutics. This alliance combines our expertise in
antisense drug
development, antisense mechanisms of action and oligonucleotide chemistry with Alnylam's expertise in RNAi therapeutics. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
this transaction, we licensed to Alnylam our patent estate relating to antisense mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics in exchange for a
$5&nbsp;million technology access fee, participation in fees from Alnylam's partnering programs and downstream milestone and royalty payments. We have already realized value from this alliance
through the receipt of a $500,000 license fee from Alnylam related to Alnylam's partnership with Merck to develop and commercialize RNAi therapeutics for ocular diseases. Recently, we and Alnylam
expanded our strong patent positions in RNA-based drug discovery by licensing core intellectual property regarding all therapeutic uses of microRNA. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Sarissa,
a Canadian biotechnology company emerging from the University of Western Ontario, is our most recent satellite company relationship. In February&nbsp;2005, we licensed an
anti-cancer antisense drug to Sarissa. The licensed drug is an antisense inhibitor of thymidylate synthase, a well-known drug target that protects cancer cells from the effects
of several chemotherapy treatments. In preclinical studies, antisense inhibition of thymidylate synthase suppressed human tumor cell growth and overcame tumor cell resistance to marketed thymidylate
synthase-targeted drugs. This drug is in the research phase of development. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
will support Sarissa's development efforts by providing them with access to our RNA-based drug discovery and development expertise. This partnership, similar to the one we
have with OncoGenex, combines our second-generation chemistry and experience in antisense discovery and development with Sarissa's deep understanding of the biological role of thymidylate synthase and
oncology expertise. </FONT></P>

<P><FONT SIZE=2>FIFTH,
OUR GOAL IS TO CONTINUE THE DEVELOPMENT OF OUR TIGER BIOSENSOR SYSTEM, AND IMPLEMENT A BUSINESS PLAN TO TAKE ADVANTAGE OF THE MANY COMMERCIAL PRODUCT OPPORTUNITIES AVAILABLE FOR TIGER. </FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=4,SEQ=40,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=214083,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MC1096A.;2',USER='JHILL',CD='19-APR-2005;14:24' -->
<BR>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
have continued to make excellent progress in advancing core TIGER (</FONT><FONT SIZE=2><B>T</B></FONT><FONT SIZE=2>riangulation </FONT> <FONT SIZE=2><B>I</B></FONT><FONT SIZE=2>dentification </FONT><FONT SIZE=2><B>G</B></FONT><FONT SIZE=2>enetic
</FONT><FONT SIZE=2><B>E</B></FONT><FONT SIZE=2>valuation of </FONT> <FONT SIZE=2><B>R</B></FONT><FONT SIZE=2>isks) technology, and in creating new applications for the TIGER biosensor system. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;During
2004, the TIGER team made remarkable technology and system engineering advances that strengthened the potential commercial opportunities for this system. Our scientists added
application development for epidemiological surveillance and biological products screening, and continued to
expand our microbial agent database to support broader uses of the TIGER biosensor system. The bioweapons defense, epidemiological surveillance and biological products screening applications of our
TIGER technology represent the first of many we plan to develop for the TIGER system to enhance its commercial value and opportunity in the government, research, and medical and diagnostic markets. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Our
goals for the TIGER program in 2005-2006 are to continue to: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>secure
government contracts;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>deploy
TIGER biosensor systems to our government partners, and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>execute
a business plan to successfully market TIGER's products and services to both government and non-government commercial customers. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>SIXTH,
WE PLAN TO CONTINUE TO CAPITALIZE ON OUR INTELLECTUAL PROPERTY ESTATE. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
most important aspect of our patent estate is that it protects our drugs in development, while supporting substantial long-term control of oligonucleotide-based
therapeutics. We have been very successful in licensing our patent estate and have used it wisely to enter into a number of strategic relationships. To date, we have generated nearly
$70&nbsp;million from licensings, which helps fund our drug discovery and clinical development programs. Our highly productive oligonucleotide chemistry program and patents arising from it should
continue to provide significant licensing opportunities in the future. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
conclusion, we have created the right chemistry for success. The ideal mix of: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>exciting
drugs in various stages of development with significant commercial potential;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>a
sustainable portfolio of new product opportunities waiting to be developed;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>a
strong blend of partnerships that encompass all areas of our business and are dedicated to increasing the use of our technologies in the marketplace;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>deep
antisense drug discovery and development expertise;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>a
strong management team, and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>a
leadership position in RNA-based technology development that is unmatched. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
ongoing advancement of a technology that could significantly improve the efficiency of drug discovery and development and yield fundamentally different, improved drugs for patients
is a substantial challenge. We have made great progress, but we have more to do. As we achieve our goals in the coming year, we will be significantly closer to bringing RNA-based products
to market. We thank you for your continued interest in Isis and your support of our endeavors. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;In
an additional effort to contain costs, we are providing this letter along with our Annual Report on Form&nbsp;10-K as a simplified version of our 2004 Annual Report. An
on-line version of the Isis 2004 Annual Report is available on our web site at </FONT><FONT SIZE=2><B>www.isispharm.com</B></FONT><FONT SIZE=2>. The online version of our Annual Report is
an interactive, multimedia discussion of the Company and its businesses. I hope you enjoy reading it. </FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=5,SEQ=41,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=643477,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MC1096A.;2',USER='JHILL',CD='19-APR-2005;14:24' -->
<BR>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;You
may also contact our Investor Relations and Corporate Communications Department at 760-603-2331, or by email at </FONT> <FONT SIZE=2><B>info@isisph.com</B></FONT><FONT SIZE=2>, to request the Isis 2004 Annual Report, either on a CD-Rom or in hard
copy, be sent to you free of charge. Please send
written requests to: </FONT></P>

<P><FONT SIZE=2>B.
Lynne Parshall, Secretary<BR>
Isis Pharmaceuticals,&nbsp;Inc.<BR>
1896 Rutherford Road<BR>
Carlsbad, CA 92008 </FONT></P>

<P><FONT SIZE=2>Sincerely,
</FONT></P>

<P><FONT SIZE=2>Stanley
T. Crooke, M.D., Ph.D.<BR>
Chairman and CEO </FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=6,SEQ=42,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=910296,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MC1096A.;2',USER='JHILL',CD='19-APR-2005;14:24' -->

<P><FONT SIZE=2>FORWARD-LOOKING
STATEMENT </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;This
annual report contains forward-looking statements regarding our business, the financial position of Isis Pharmaceuticals, 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' 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. 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. Although our forward-looking statements reflect the good faith judgment of our management,
these statements can only be based on facts and factors currently known by us. As a result, you are cautioned not to rely on these forward-looking statements. Factors that could cause or contribute to
such differences include but are not limited to, those discussed in Isis' Annual Report on Form&nbsp;10-K for the year ended December&nbsp;31, 2004, which is on file with the U.S.
Securities and Exchange Commission, and available from the company. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Taxotere&reg;
is a registered trademark of Aventis Pharmaceuticals&nbsp;Inc. </FONT></P>

<P><FONT SIZE=2>Board
of Directors<BR>
STANLEY T. CROOKE, M.D., PH.D.<BR></FONT> <FONT SIZE=2><I>Chairman of the Board and Chief Executive Officer</I></FONT><FONT SIZE=2><BR>
Isis Pharmaceuticals,&nbsp;Inc. </FONT></P>

<P><FONT SIZE=2>SPENCER
R. BERTHELSEN, M.D.<BR></FONT> <FONT SIZE=2><I>Chairman, Executive Administration</I></FONT><FONT SIZE=2><BR>
Kelsey-Seybold Clinic </FONT></P>

<P><FONT SIZE=2>RICHARD
DIMARCHI, PH.D.<BR></FONT> <FONT SIZE=2><I>Professor and the Jack and Linda Gill Distinguished Chair</I></FONT><FONT SIZE=2><BR>
Biomolecular Science, Indiana University </FONT></P>

<P><FONT SIZE=2>CHRISTOPHER
F.O. GABRIELI<BR></FONT> <FONT SIZE=2><I>Chairman</I></FONT><FONT SIZE=2><BR>
Massachusetts 2020 </FONT></P>

<P><FONT SIZE=2>FREDERICK
T. MUTO, J.D.<BR></FONT> <FONT SIZE=2><I>Partner</I></FONT><FONT SIZE=2><BR>
Cooley Godward LLP </FONT></P>

<P><FONT SIZE=2>B.
LYNNE PARSHALL, J.D.<BR></FONT> <FONT SIZE=2><I>Executive Vice President,<BR>
Chief Financial Officer and Secretary</I></FONT><FONT SIZE=2><BR>
Isis Pharmaceuticals,&nbsp;Inc. </FONT></P>

<P><FONT SIZE=2>JOHN
C. REED, M.D., PH.D.<BR></FONT> <FONT SIZE=2><I>President and Chief Executive Officer</I></FONT><FONT SIZE=2><BR>
Burnham Institute </FONT></P>

<P><FONT SIZE=2>MARK
B. SKALETSKY<BR></FONT> <FONT SIZE=2><I>Chairman and Chief Executive Officer</I></FONT><FONT SIZE=2><BR>
Trine Pharmaceuticals,&nbsp;Inc. </FONT></P>


<P><FONT SIZE=2>JOSEPH
H. WENDER<BR></FONT> <FONT SIZE=2><I>Senior Director, Financial Institutions Group</I></FONT><FONT SIZE=2><BR>
Goldman, Sachs&nbsp;&amp; Co. </FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=7,SEQ=43,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=307194,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MC1096A.;2',USER='JHILL',CD='19-APR-2005;14:24' -->
<BR>

<P><FONT SIZE=2>EXECUTIVE
OFFICERS<BR>
STANLEY T. CROOKE, M.D., PH.D.<BR></FONT> <FONT SIZE=2><I>Chairman of the Board and Chief Executive Officer</I></FONT></P>

<P><FONT SIZE=2>B.
LYNNE PARSHALL, J.D.<BR></FONT> <FONT SIZE=2><I>Executive Vice President,<BR>
Chief Financial Officer and Secretary</I></FONT></P>

<P><FONT SIZE=2>C.
FRANK BENNETT, PH.D.<BR></FONT> <FONT SIZE=2><I>Vice President, Antisense Research</I></FONT></P>

<P><FONT SIZE=2>RICHARD
K. BROWN, PH.D.<BR></FONT> <FONT SIZE=2><I>Vice President, Business Development</I></FONT></P>

<P><FONT SIZE=2>DAVID
J. ECKER, PH.D.<BR></FONT> <FONT SIZE=2><I>Vice President, Scientific Head of Ibis,<BR>
a division of Isis</I></FONT></P>

<P><FONT SIZE=2>ARTHUR
A. LEVIN, PH.D.<BR></FONT> <FONT SIZE=2><I>Vice President, Development</I></FONT></P>

<P><FONT SIZE=2>PATRICIA
LOWENSTAM<BR></FONT> <FONT SIZE=2><I>Vice President, Human Resources and Operations</I></FONT></P>


<P><FONT SIZE=2>JOHN
MCNEIL<BR></FONT> <FONT SIZE=2><I>Vice President, Ibis Product Development</I></FONT></P>

<P><FONT SIZE=2>MICHAEL
TREBLE<BR></FONT> <FONT SIZE=2><I>Vice President, Head of Ibis,<BR>
a division of Isis</I></FONT></P>

<P><FONT SIZE=2>CORPORATE
HEADQUARTERS<BR>
Isis Pharmaceuticals,&nbsp;Inc.<BR>
1896 Rutherford Road<BR>
Carlsbad, CA 92008<BR>
TEL: 760.931.9200<BR>
ONLINE: www.isispharm.com<BR>
EMAIL: </FONT><FONT SIZE=2><I>info@isisph.com</I></FONT><FONT SIZE=2><BR>
COMMON STOCK SYMBOL NASDAQ: ISIS </FONT></P>

<P><FONT SIZE=2>TRANSFER
AGENT<BR>
American Stock<BR>
Transfer&nbsp;&amp; Trust<BR>
59 Maiden Lane<BR>
New York, NY 10038 </FONT></P>

<P><FONT SIZE=2>OUTSIDE
LEGAL COUNSEL<BR>
Cooley Godward LLP<BR>
4401 Eastgate Mall<BR>
San Diego, CA 92121 </FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=8,SEQ=44,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=173224,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MC1096A.;2',USER='JHILL',CD='19-APR-2005;14:24' -->

<P><FONT SIZE=2>CHIEF
PATENT COUNSEL<BR>
Woodcock Washburn LLP<BR>
One Liberty Place<BR>
46th Floor<BR>
Philadelphia, PA 19103 </FONT></P>

<P><FONT SIZE=2>INDEPENDENT
REGISTERED<BR>
PUBLIC ACCOUNTING FIRM<BR>
Ernst&nbsp;&amp; Young LLP<BR>
501 W. Broadway,<BR>
Suite 1100<BR>
San Diego, CA 92101 </FONT></P>

<HR NOSHADE>
<P style='page-break-before:always'></p>
<!-- ZEQ.=9,SEQ=45,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1",CHK=267367,FOLIO='blank',FILE='DISK014:[05SAN6.05SAN1096]MC1096A.;2',USER='JHILL',CD='19-APR-2005;14:24' -->
<!-- THIS IS THE END OF A COMPOSITION COMPONENT -->
<BR>
<P><br><A NAME="05SAN1096_1">QuickLinks</A><br></P><!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_de1096_1">PROPOSAL 1 ELECTION OF DIRECTORS</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_de1096_2">THE BOARD OF DIRECTORS RECOMMENDS THAT YOU VOTE IN FAVOR OF THE ELECTION OF EACH OF THE ABOVE NOMINEES</A></FONT><BR>

<!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_di1096_1">PROPOSAL 2 RATIFICATION OF SELECTION OF INDEPENDENT AUDITORS</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_di1096_2">THE BOARD OF DIRECTORS RECOMMENDS A VOTE IN FAVOR OF PROPOSAL 2</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_di1096_3">SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_di1096_4">EXECUTIVE COMPENSATION</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_di1096_5">Summary Compensation Table</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_di1096_6">Option Grants in Last Fiscal Year</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_di1096_7">Aggregated Option Exercises in Last Fiscal Year and FY-End Option Values</A></FONT><BR>
<!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_dk1096_1">EQUITY COMPENSATION PLAN INFORMATION</A></FONT><BR>
<!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_dm1096_1">AUDIT COMMITTEE REPORT(3)</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_dm1096_2">COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN AMONG ISIS PHARMACEUTICALS, INC., THE NASDAQ COMPOSITE INDEX (TOTAL RETURN) AND THE AMEX BIOTECH INDEX</A></FONT><BR>
<!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_do1096_1">HOUSEHOLDING OF PROXY MATERIALS</A></FONT><BR>
<!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_ma1096_1">ANNUAL MEETING OF STOCKHOLDERS OF ISIS PHARMACEUTICALS, INC. May 26, 2005</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_ma1096_2">ISIS PHARMACEUTICALS, INC. THIS PROXY IS SOLICITED ON BEHALF OF THE BOARD OF DIRECTORS FOR THE ANNUAL MEETING OF STOCKHOLDERS TO BE HELD ON MAY 26, 2005</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_ma1096_3">ANNUAL MEETING OF STOCKHOLDERS OF ISIS PHARMACEUTICALS, INC. May 26, 2005</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_ma1096_4">PROXY VOTING INSTRUCTIONS</A></FONT><BR>
<!-- SEQ=,FILE='QUICKLINK',USER=SFLORES,SEQ=,EFW="2155960",CP="ISIS PHARMACEUTICALS, INC.",DN="1" -->
<!-- TOCEXISTFLAG -->
</BODY>
</HTML>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>GRAPHIC
<SEQUENCE>2
<FILENAME>g911319.jpg
<DESCRIPTION>G911319.JPG
<TEXT>
begin 644 g911319.jpg
M_]C_X``02D9)1@`!`0$!KP&O``#__@`U1$E32S`Q-#I;,#5304XV+C`U4T%.
M,3`Y-BY/5510551=,3`Y-E]015)&7TQ)3D4N15!3_]L`0P`'!08&!@4'!@8&
M"`@'"0L2#`L*"@L7$!$-$AL7'!P:%QH9'2$J)!T?*"`9&B4R)2@L+2\P+QTC
M-#@T+C<J+B\N_\``"P@!.@*;`0$1`/_$`!P``0`"`P$!`0`````````````%
M!@,$!P(!"/_$`%<0```%`P`$"0D$!P0'!@4%```!`@,$!081$A8A5@<3%3%1
M5925TQ07(D%35)/1TF%QDN,R-W6!H;/4(T)2D20S-D-REL,(-$1BLL&"@Z*Q
M\24F97.C_]H`"`$!```_`+]3;YKLGA'E4!XJ5'CM2%,>02-)F4;19P^A:CT7
M,XTM%)?HGSY(Q&U+A7J<2H7`^W2X[E(CTU$NEF>DER4:I!1TK4><$VI9F9;,
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M;]HC\1!QK?M$?B(.-;]HC\1!QK?M$_B(>P`<T/@Q.1<S,ZHU^9-H\9XY,>$^
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M(LW=6C=B;^0:D6;NK1NQ-_(-2+-W5HW8F_D/J;)LY*B4FUJ.2B/)&4)O8?\`
MD+$````*L_\`K)@_L:1_/9%I````````````````````````````````````
M````````````````&(I,<Y!Q2?;.0E)+-HE%I$D]A'CGQ]H^H>:6:R0ZA1H/
M"B)1'H_?T#ZIUM*36I:22G:9F>PAZ0I*TDM"B4DRR1D>2,5=_P#63!_8TC^>
MR+2````````````````````````````````````````````````````/SC$F
M4ECA/-YI":D],J;J=)O3CU6$X9.:1*27^L:))8+."P:=F2$0X5O)DU=%NSX;
M%)FVX\VM]M+KCL?+J-)<Y*24HUY-1$9%LST;1FCG263.E+31GK78N&"F?4Z:
MV;424VII:B0[E2BT4+T2,]+&TL[1UC@96I-HU(XB5.TUNJS2I:4J]%48G#T"
M09_W<Z1$,;M:KQW[#>.SYI/%27TDQY7'R9&\UE6=/&"P1<^=HL7+UQ[CS^W1
M?$#EZX]QY_;HOB!R]<>X\_MT7Q`Y>N/<>?VZ+X@<O7'N//[=%\0.7KCW'G]N
MB^('+UQ[CS^W1?$#EZX]QY_;HOB!R]<>X\_MT7Q`Y>N/<>?VZ+X@<O7'N//[
M=%\0.7KCW'G]NB^('+UQ[CS^W1?$#EZX]QY_;HOB!R]<>X\_MT7Q`Y>N/<>?
MVZ+X@<O7'N//[=%\0.7KCW'G]NB^('+UQ[CS^W1?$#EZX]QY_;HOB!R]<>X\
M_MT7Q`Y>N/<>?VZ+X@<O7'N//[=%\0.7KCW'G]NB^('+UQ[CS^W1?$#EZX]Q
MY_;HOB!R]<>X\_MT7Q`Y>N/<>?VZ+X@<O7'N//[=%\04NKWY=-PNSK=LJWWF
MZI',DS)RWV7&HA'SDE1*T%.\_HF>S&W[/MJ7G=5)ELV;<U`ERZXE"G(C_E#*
M#F,%S&:E+T3<(OTB29\V1<^7KCW'G]NB^('+UQ[CS^W1?$#EZX]QY_;HOB!R
M]<>X\_MT7Q`Y>N/<>?VZ+X@<O7'N//[=%\0.7KCW'G]NB^('+UQ[CS^W1?$#
MEZX]QY_;HOB!R]<>X\_MT7Q`Y>N/<>?VZ+X@<O7'N//[=%\0.7KCW'G]NB^(
M'+UQ[CS^W1?$#EZX]QY_;HOB!R]<>X\_MT7Q`Y>N/<>?VZ+X@<O7'N//[=%\
M0.7KCW'G]NB^('+UQ[CS^W1?$#EZX]QY_;HOB!R]<>X\_MT7Q`Y>N/<>?VZ+
MX@<O7'N//[=%\0.7KCW'G]NB^('+UQ[CS^W1?$#EZX]QY_;HOB!R]<>X\_MT
M7Q`Y>N/<>?VZ+X@<O7'N//[=%\0.7KCW'G]NB^('+UQ[CS^W1?$#EZX]QY_;
MHOB!R]<>X\_MT7Q`Y>N/<>?VZ+X@<O7'N//[=%\0.7KCW'G]NB^('+UQ[CS^
MW1?$#EZX]QY_;HOB!R]<>X\_MT7Q`Y>N/<>?VZ+X@<O7'N//[=%\0.7KCW'G
M]NB^('+UQ[CS^W1?$'I-=N(U)([)GI(S(C/RV+L^W_6"S@`U4T^"FH*J28K1
M35-DVI_1+3-)'G&?WCTU"ALF\;45ALWSRZ:6R+C/^+!;?WCXB!!1$.&B''3%
M/)&R3220?_PXP,S33;+2&F6TMMH+"4)+!$701$*R_P#K)@_L:1_/9%I`````
M````````````!Y<6AM"G'%$E"2,U*4>"(NDQR^=6:MPBRGJ/:4EV!;32S;G5
MU'Z4C&Q34;_W<]7J^V_6[0J7;E*8I5'B(C1&BV)3SJ/UJ4?.I1^LSVB.OBU8
MUU4I,<WE1:A&63\"<V7]I%>+F472727K+]PT+`NJ55BE4*X6$P[HIF$S(Y?H
MO)_NOM]*%;/N,\=`N@`````````````````````````````````*L_\`K)@_
ML:1_/9%I`````````````````:U1GPZ9!?GU"2U&B,)-;CKJM%*"Z3,<R2BK
M<*CFD\4FEV(2LI;VMR*OCUGZT,_9SJ_^W3H,.+3XC,*%':CQF4DAMII))2A)
M<Q$1<PV`%+O^U9=6\EKUO/)B713,JAOGL2\G^\PYTH5M^XSSTB0LBZ8UTTI4
MA+2HM0C+-B=!</\`M(KQ<Z3^SH/UE^\60```````````````````````````
M```<_@<(3LZZYM)C6_*>IT20N*[+9<)QQMQ.EE2V2])*#-)D2ONV8,A&EPLM
MQ"GJKMLU"EDQ!.<PVXXA;KJ.,2VE*T%M:6I2DX2KI^P;!\)RV6Y$"9;4IFY6
MYK$)%**0A7&+>0:VU<:7HDG12K)XV8P+79MQM7/2%3BB.0Y#,AR+*BN*)2F'
MFU:*DY+8?3GH,:K_`.LB#^QI'\]D6D````````````````1-R7!2;:I3M5K$
MM$>,WLR>U2U>I*2YU*/H(42FT.KW_,9KEZ15PJ&TKC*?0%'^GT.R?\1^LD<Q
M>OUYZ@DDI224D1)(L$1>H?0`-@YW?%!J5,JR;[M)HW*JP@DU"`D\)J4<O[N/
M:)+]$_W;=A"WVU7J;<M%BUBE/D[%D)R6=BD'ZTJ+U*(]AD)4````````````
M`````````````````''RX/[HD<(,>M2YU-0B*\I]-6C-<5+>0>F265H21(5C
M)$:CSDDI^T:<W@NNBNN5!ZN5*D1Y;D$X_E=/:4E=0=2XA;;LA."3LXM.PL\_
MV$0WGK`NR9/D77*F4ENYCJ,68S':-PXF@RTIO0-1ITO2):CSC8>!<K#MN70J
M#,C5.2VY4*A,D39:HIJ2A#CJLF2#/!X(L8/G$`[:L8K]AQ>5Z\:3I+Z],ZH]
MIY)YHL:6EG&WF^X6/4V+UW<??#_U!J;%Z[N/OA_Z@U-B]=W'WP_]0:FQ>N[C
M[X?^H-38O7=Q]\/_`%!J;%Z[N/OA_P"H-38O7=Q]\/\`U!J;%Z[N/OA_Z@U-
MB]=W'WP_]0:FQ>N[C[X?^H-38O7=Q]\/_4&IL7KNX^^'_J#4V+UW<??#_P!0
M:FQ>N[C[X?\`J#4V+UW<??#_`-0:FQ>N[C[X?^H-38O7=Q]\/_4&IL7KNX^^
M'_J#4V+UW<??#_U!J;%Z[N/OA_Z@U-B]=W'WP_\`4&IL7KNX^^'_`*@U-B]=
MW'WP_P#4&IL7KNX^^'_J%<O%JA6K";<E5JYI$V2KBX<%BKOJ>E.'S)2G2_S/
MF+^`C[:X-9M34U6[YJ52=J*'.-@PD5%Q:::1[2(G,Y4YS95S='2+GJ;%Z[N/
MOA_Z@U-B]=W'WP_]0:FQ>N[C[X?^H-38O7=Q]\/_`%!J;%Z[N/OA_P"H-38O
M7=Q]\/\`U!J;%Z[N/OA_ZASVZ[358T[66E2JVNW75FJM1(LYU+J5'_XI)D>5
M&7]XC]6W[KU`MJEU"$Q.A7%7WXKZ"<:=;K+YI6DRR1D>D-C4V+UW<??#_P!0
M:FQ>N[C[X?\`J#4V+UW<??#_`-0:FQ>N[C[X?^H-38O7=Q]\/_4&IL7KNX^^
M'_J#4V+UW<??#_U!J;%Z[N/OA_Z@U-B]=W'WP_\`4&IL7KNX^^'_`*@U-B]=
MW'WP_P#4&IL7KNX^^'_J#4V+UW<??#_U!J;%Z[N/OA_Z@U-B]=W'WP_]0:FQ
M>N[C[X?^H-38O7=Q]\/_`%!J;%Z[N/OA_P"H-38O7=Q]\/\`U!J;%Z[N/OA_
MZ@U-B]=W'WP_]0:FQ>N[C[X?^H-38O7=Q]\/_4&IL7KNX^^'_J#4V+UW<??#
M_P!0:FQ>N[C[X?\`J#4V+UW<??#_`-0:FQ>N[C[X?^H-38O7=Q]\/_4&IL7K
MNX^^'_J#4V+UW<??#_U!J;%Z[N/OA_Z@U-B]=W'WP_\`4&IL7KNX^^'_`*@U
M-B]=W'WP_P#4&IL7KNX^^'_J#4V+UW<??#_U!J;%Z[N/OA_Z@U-B]=W'WP_]
M0:FQ>N[C[X?^H?4V?%2HE<M7$>#(\'5WS+_U"S@```"K/_K)@_L:1_/9%I``
M`````````````4Z\[S11'V:+2(AU6YIA?Z+3VSYB]HX?]Q!<^3Y_5TEBLVS'
M*;.=N.XIA56Z)*<.2C+^SC(]DPD_T4%T\Y_O%V`````>7$(<0IMQ)*0HC)25
M%DC+H,<K2M7!56TLKTCL6IOX;4>TJ1(4?Z)]#*CYO4D_X]52HE))23(R,LD9
M#Z```````````````````````````````JS_`.LF#^QI'\]D6D``````````
M````4"ZKQG/59=HV4RU-N$R_TB0YMCTU)_WW3]:NA'/T]!R]EV=`M=E]XGG9
MU7F'ISJE)/+LE?VGZDEZDEL(6@``````:M2@0ZI`D4^H1VY$20@VW6G"R2DG
MSD.=6Q49MC5Z/8U??<>I,DS*A5)T\FHO=G#_`,:?[I^LL%T$.G@`````````
M``````````````````#A,6JSV>$CRB37IZV*A/5&@3H<DI$)1'IDB.XP9EQ9
MI-/.1&>D1GG;D:S:[C;B5R1;ETU6J1&Z<['D52?,2S'?GFXE*3C&M1$@DY5M
M(]'81$9F,:*G6F)J+.FU6N0IK];AQ9SRZKY49,.-+<23+NBDVS4:<'LSL+`Z
M-P55*8_;E4:GS)$Y-+JDN&S)=,W'7F6U^B9GSJ/&S/.>!J.W73#OV%+*-6.+
M*D/HP=(E:>3>:/\`1XO.-G/C'J]8L6N=)]TKG<LOPPUSI/NE<[EE^&&N=)]T
MKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI
M/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&
MN=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LO
MPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPQ0KAX1)-S
M/)H]E'468"E&B?76Z:^[Y-TMM(2@SXW[3(B+^)6.U9MI6K2D4VDTVN(;SIN.
M+HTM3CRSYUK5Q>5*/_\`&"$UKG2?=*YW++\,-<Z3[I7.Y9?AAKG2?=*YW++\
M,-<Z3[I7.Y9?AAKG2?=*YW++\,-<Z3[I7.Y9?AAKG2?=*YW++\,-<Z3[I7.Y
M9?AAKG2?=*YW++\,-<Z3[I7.Y9?AAKG2?=*YW++\,-<Z3[I7.Y9?AB'NJI6O
M=%$D4>IP*ZIETLI6FC2R6TLOT5I/B]BB/:7R$)9/"&Y"4=LW<BI+JS&2ARBI
MDC2J3!<SI-Z&D2B(O2R7V](N>N=(]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LO
MPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[
MEE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]T
MKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI
M/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&
MN=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LO
MPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[
MEE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]TKG<LOPPUSI/NE<[EE^&&N=)]T
MKG<LOPPUSI/NE<[EE^&/J;RI*E$DHE;R9XVT:61?RQ90`59%A6HBX7K@31V"
MJ#J5$I9$9%I*(R4LD\Q*,C,C5SC#$X-[&AF\<:V8*..:4RYZ)F2D*YR/)C,S
M8-GL41^AMT&,5/?<)UQL](S4LN96F9Z62]1YV>H3=%I-.H=-9IE)B-Q83)&3
M;39;"R>3/I,S,S,S/:8A'_UD0?V-(_GLBT@```````````#%(?9BL.2)#J&F
M6DFM;BU:*4I+:9F9\Q#E[\VK\)\A<.CNR*99*%&B14$D:'JGC8:&?\+7J-?.
M?-TD.D4BET^BTYBF4N(W%AL)T6VFRP22_P#<^DSVF-T````````!5[[M1JZ*
M:TEJ0J%5H:^/I\]LO3C.ES']J3YC+UE]Q#6L*ZGJVU)I-:83"N:F&3<^)G8?
M0ZCI0KG(_5G'1FX@`````````````````````````````JS_`.LF#^QI'\]D
M6D```````````&A6JM3J'3'ZI59;<6&PG2<=</!%]GVF?J(MICG+%-J_";);
MGUYA^FV8A1.1:4OT'JAC:3C^-J4>LD>OG/I/J3#+3#*&6&T-M-I)*$(224I(
MN8B(N8A[``````````%(OZUIE0=BW+;;J8UT4PC..L]B)3?.J.YTI5MQT&8E
M;*NB%==(*;'0IB4RLV9D-S_617B_2;47V>H_60L0````````````````````
M``````JB+^MI5Q+H!S'$2$N*9XY;*TL*=21FIHG3+1-9$1Y+/J,N<C(:\'A+
MLV:F6MNK&VW&CJDFX^PXVEQE)Z)K;-22TRSL]'(]-\(MJ+I+]4\M>0VQ(1%6
MRN*XE_C5EE"":-.D9J+:6"VEGH$_0*W3;@I;54I4CCHKAJ(C-)I4E23PI*DG
M@R,C+!D8B'_UDP?V-(_GLBT@``````````(.[+GI-JTPY]5>,B4HD,L-EI.R
M'#YD-I_O*/\`_(J%&MBK794X]SWXPEMME7&4V@YTFHO0X[_C=^P]B?X%TL``
M``````````<YO6B5"A5@[^M2.IV:A))JM.1G%18+UD7M4EM(_7S?8=SMVMTV
MXJ/%K%)D$_#DHTD*+G+I(R]1D>PRZ1)@`````````````````````````X9%
MIETQ^$52H=!EPFW)*WJFTEU#U/E1S-PS6@EGE+JST=A$6TSS@A&U.VKLNJF5
M-52M29"J:8IMTR,1L(A1&4.H<XE.BK24M9(P:C(B]6"(;\RB7-4;DDWZFV9S
M33=7@R$TMWB_*7&66%MK61:6CI97L(SVD0OO!C2:K3[>J;T^.<"75*G+GHCN
M$2E1TNJR@E$1XS@B,RSZ\"-=IUUE?L-L[EA')Y)?,G>2]A)XYK):/&\YG@\Y
M]0L7)=Y;V0.Y_P`X.2[RWL@=S_G!R7>6]D#N?\X.2[RWL@=S_G!R7>6]D#N?
M\X.2[RWL@=S_`)P<EWEO9`[G_.#DN\M[('<_YP<EWEO9`[G_`#@Y+O+>R!W/
M^<')=Y;V0.Y_S@Y+O+>R!W/^<')=Y;V0.Y_S@Y+O+>R!W/\`G!R7>6]D#N?\
MX.2[RWL@=S_G"K7G7KEMA$>,BY(E1K4P]"%3(](RZ^KI/^V]%!>M1["&.D6%
M=DFK,W9<%Q0'*^;1)0TNG\>S`+GT6?[1)$?J-6,GMV^L[;R7>6]<#N?\X.2[
MRWL@=S_G!R7>6]D#N?\`.#DN\M[('<_YP<EWEO9`[G_.#DN\M[('<_YP<EWE
MO9`[G_.#DN\M[('<_P"<')=Y;V0.Y_S@Y+O+>R!W/^<')=Y;V0.Y_P`X.2[R
MWL@=S_G!R7>6]D#N?\X.2[RWL@=S_G!R7>6]D#N?\X.2[RWL@=S_`)P<EWEO
M9`[G_.#DN\M[('<_YP<EWEO9`[G_`#@Y+O+>R!W/^<')=Y;V0.Y_SASJN4FZ
M>#>3)N*FU9AVBSY!+J[3--]&(9X+RA#7&?BP9=..B_Q(EU38K,N)>5,>CO()
M;;K=)RE:3+)&1\=M(9N2[RWL@=S_`)P<EWEO9`[G_.#DN\M[('<_YP<EWEO9
M`[G_`#@Y+O+>R!W/^<')=Y;V0.Y_S@Y+O+>R!W/^<')=Y;V0.Y_S@Y+O+>R!
MW/\`G!R7>6]D#N?\X.2[RWL@=S_G!R7>6]D#N?\`.#DN\M[('<_YP<EWEO9`
M[G_.#DN\M[('<_YP<EWEO9`[G_.#DN\M[('<_P"<')=Y;V0.Y_S@Y+O+>R!W
M/^<')=Y;V0.Y_P`X.2[RWL@=S_G!R7>6]D#N?\X.2[RWL@=S_G!R7>6]D#N?
M\X.2[RWL@=S_`)P<EWEO9`[G_.#DN\M[('<_YP<EWEO9`[G_`#@Y+O+>R!W/
M^<')=Y;V0.Y_S@Y+O+>R!W/^<')=Y;V0.Y_S@Y+O+>R!W/\`G!R7>6]D#N?\
MX>DTN\24DU75`-.2R7)&,E\86<``,$&`%6?_`%DP?V-(_GLBT@`````````H
M]Y7F]"G(MJUXB:K=$A.4L:7]E$1[5]7]U)<^.<]G2-FS+,9H+K]6J4M55N.:
M69=2>3Z1_P#D;+^XV7J271]Q%;P`````````````!X=;;>:6TZA+C:R-*D*+
M)*(^<C+UD.6177>"ZNMTZ0I2K'J;^(CRSSR4^H\\4H_9*/F/U'S^LSZL1D99
M(```````````````````````````%6?_`%DP?V-(_GLBT@```````9%3N#A!
MM&@.^33JRPN89Z*8D7+[YGT:",F7[\"OR;BONYV%1K9ME^@QGL)*JUE24.-D
M9[5(CEDS/'-D\"UV=:E,M2`N/"XQZ4^KC)<U]6F_*<]:EJ]?.>"YB%A#)=(`
M`````````````#3JU-A5BFR:948Z)$.2@VW6E\RB/_[??ZAS^TJE/LZN,V)<
MDE;\1[/(53=/:^@O_#N'[1/JZ2Q]@Z8````````````````````````.11+J
MN5'">Y2*K4FH##LHVHU/E0S2S)C^EHK9?+.DX>"/!F1<Z<;![;NV]$,<(K<F
M-&<JE&3'*#%@-J?2E3C>D6,I)2^<C/)=.-@BXM[70ZVW0^6#;KTNK,0%^64A
M,9R`VMM;G&<63BTN:1)]')EC!Y%\X.:_/JU"GG6WF5S*74),!^2A)-H=XI6.
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MF.Q`GRHEJ7185K4@E:+4J*;<B:ZG']XUJ(B_B-Y%M<',Q1/7/?6L3_/F?6TD
MVD__`"MMJ221?7+FL]<140KGI"&S;-OT*@V1I+&-AZ6P_M%#.@68@\Q.%JLQ
M<?HDW<R%$GIV*R0W:4S1J;4(\DN&.7+8962CCRZG%<2X7K2H\9,C%DKMRT:9
M2GX]'OJB4V<K1XN4M]E\F\&1GZ!J(CR62Y_6*@57N9C'%\*]E2O5_I#"$9^W
MT'>?^`E;;NNJ(J"BN:[[$=@<69).GRC0[IY+!GIK,L8SG]PW[HOJ-$885;D^
MW*DZI9DZB166F"0G&PR/;G:*TGA6K22/C;6HZ_\`^BZH:O\`U&6W[A9K:X0Z
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M;54HDIN:CF9G@B*<UM/\0G``4&%P8T6'<K=81+GJBLOG+8IJGLL-2#-1FX18
MS_>,R+.",S$O*LRDRG+B=6Y,0Y7>).2II\T&A3222A39EM298(_7M^S8(CS8
MT9<-],BIU>14WI+4OE9V01RD.-$:6S2HDZ)$DC,L:.-IY%DM>W8%M4=-*A&\
MZ@UK==>D*TW'W%GE2UG@LF9GT"'>@02X183?D<?0Y'D'H\4G&>/9]6!9N3*=
M[A%^"GY!R93O<(OP4_(.3*=[A%^"GY!R93O<(OP4_(.3*=[A%^"GY!R93O<(
MOP4_(?%4ZFI(S.#%(BYSXI.S^`IU=O;@^HSYQ%O0YL_:10Z?'*2\9]&B@CP?
MWF0Y]6>%$WWO)*50Z-2C6HDI.H)*5*5GU%&8)1D?_$9#/;%IS;UGD=Y0;C>I
M:4&M)R6VJ;'6K)83Y.V?&'LR>D:O5MYQ?JCP;T=V)'I]&DOV_`3I>4-4I#;2
MY/-C2<-)JV;?7ZQGH'!G9%"63L.@1G9)'GRB41ON9Z<KS@_NP+0=.IYGDX,8
MS^UI/R'SDRG>X1?@I^0<F4[W"+\%/R#DRG>X1?@I^0<F4[W"+\%/R#DRG>X1
M?@I^0<F4[W"+\%/R#DRG>X1?@I^0<F4[W"+\%/R#DRG>X1?@I^0<F4[W"+\%
M/R#DRG>X1?@I^0^E3:>7-!C%_P#*3\A]\@@^YQ_A)^0^'3:>9Y.#&,_M:3\A
MK2+?H4DC*31:>\1GDR<BH5G_`#(1DBP;(D&9NVC1#49Y-106R,S^\B$P5'I1
M,DP5.BDT2-`DDRDL)QC'-T"@GP41J8:EVA<-1HAGS1UDF9&+_P"6Z1G_`!&U
M1H5[PJI'AUJC6U5*:M>BN?$3Y.ZTG!^DIM1&1[?4D_6+-6Y%LT&&F;6>3X49
M3B6R=?0E*=(^8LX^PQL0$4"HQTR:>BG2V%<SC!(<2?[RV#9Y-IWN$7X*?D')
ME.]PB_!3\@Y,IWN$7X*?D')E.]PB_!3\@Y,IWN$7X*?D')E.]PB_!3\@Y,IW
MN$7X*?D')E.]PB_!3\A6;YL>#<=-:\B)JGU>$YY1`F-MD7%.EZE%CTD'S&1_
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MK39;+$2VZRYQJR2ATJ&X2-IXTLFG81>L_5@=%````%6?_63!_8TC^>R+2`#X
MI24)-2E$22+)F?,0I=8X3+1ITGR%B>JJU$]B85*;.4ZH^CT-A']YD.:U/AAO
M6MS'Z99-B3.-:<-IQZ6TIQ3:B/!D:4X2DR/I48PQ>#[A2NR2S(O:KLHA::5.
M0GY"E),LY,N*9-*"V;-JC,=D19MK-4:31&:%"9ITE.@\RRV3?&%G/I&G!GS%
MZQNT6WZ)0F>)HU)AP4&6TH[*4&K[S(LG^\2@``````````````#%)CL2F5,2
M66WF5EA2'$DI)_>1[!2)_!9:+SZIE,C2:%./_P`31Y"HRB_^%/H_P$S:E%K=
M&.4U5+ID5J,K1*,4F.A#C)%G.DM/Z>=G.18Q]HU[GO-FVIZ&9]"K3L%39+54
M(D7CF6SR?HJT3TBYL\WK&Q;]ZVI<1)*CUZ%)</\`W).:+I?>A6%%_D+&```"
MBW[;$V1*C7;:YI9N>FI,D$9X1-9YU,.=)'ZC]1]'.4W9MSP+KHR*E");3B5&
MU)BNEAR,\G])M9=)'_GSB?````````'EQQ#:#6XLD)+G4H\$0$M)HTR,C299
M(R]9"@'PJ4-[)TFCW'5TD>-.#275)S]ZB2,T*^ZC,E,LM\']U,M..)0IV3';
M;)O)X-1EIYP7/DA;:R_4(M,DR*7`3/FH3EJ,IXF2=//-IF1DD4PJWPH/_P"K
MLBD13,\%Y16-/1^T]!&W]PDK?>X0W:H@Z_!MUBEFE6D420\X^E6-GZ22299$
MM<T6X)<1INWJK%IT@G,K<D1>/)2,'L(M(L'G&T5;5GA(>/+W"6TR1[=&-0VM
MA]&5*/)"Q6M1JS22DG5[HEUM3NCHF^PVT31EG.B2"+GR7/T#!=%I(N&4S(7<
M%P4[BF]`FZ;/..A6W.5$1;3]61#>:NW%_P#>IU?E;,%QU7?/'3C"B%KMV@4N
MVZ:FF4>.MB(E:EDA3JW#R?/M69G_`!&C4;(M"ISW:A4+:IDJ8ZHE.//1DK4L
MR(BVF?/L(AEC6=:47'DUL49G!Z1:$%HL'T_HB<;;0TVAII"4-H(DI2DL$1%Z
MB(>L!@``1C=>HCE970VZM#554)TU0R>2;I%S_HYSS;?NP8V2J,`W9;138_&0
MR)4E/&%E@C+2(UE_=R6W;ZAIM7';[U+<J[-<ISE,:/#DM,I!M(/H-><%SEZQ
MOPI<6?%:F09+,F,ZG2;>962T++I(RV&*Z_\`K)@_L:1_/9%G<<;:0IQQ:4(2
M634H\$1?:8I56X3K2@23@Q)KM8J/JATEHY3A_9Z/HE^\R%<J]R\+E46ABV['
M9I3+J<E+JDE"EI+I-!'Z)_8>D(I?!)=USF3E_7]+D-F>50H!:+1?=G"?_H'4
MK1M:D6E1F:31V-!AO.5KP;CAF9GE2B(LGM$Y@B]0^@``````````````````
M&!7+@LFU+BRJLT&%)=/_`'QMZ+I?<M.%?Q$K1J9%H],C4R$3A1HZ=!LG'%.*
MQG.U2C,SYQ3)%=X1J/(=.H6C"K,'34:7J/*T74(R>,M._I*QCF,;-*X3K6FS
MF:9,=ET>INJ)*(=5C+CN&9G@B(S+1,\[-AB\``#FUYTBH6S65W]:T53ZS215
MJFM_^.9+_>)+VJ"VETE_&\T*KT^O4F+5Z7(2_#DHTVW$_P`2/H,CV&7J,A(`
M```#P3K9N&T2TFX19-.=I%]P@+IO"B6NN,U5')/'RM+B&H\5QY3F,9QH)/'.
M7/@5X[_K<XC*@\'5Q23]2YR6X2#^W*SSC]PMEM2ZW,IQO5^EL4V8;AD3#,GC
MR)&"P9JP6WGV?8(.N6I7:O5'WCONKP*:O'%PX#332F]A$?\`:X-1Y/)_9D:+
M?!-9[BDN59NHUEY/,Y4Z@Z\?^6D1?P%[AQH\*(S#B-(9CL(2VTV@L)0DBP1$
M701#+LZ0]'[!]```````````?GNFOH:X56HT*FO252*JMZ1`J$(TR("C-9JD
MMOIV&CF,M(SR2M'U#U6[:?@TWA:I=!ITDHYN4]QMI!K6IYLDI6\25*,S5DM/
M.W[!'S/()=P3+FI]/<.QFZ[3G7="(I+1DB.M+CG%:.32E:D$>SGZ1T[@=:?;
MM2I2&(RFHDJJS)--9<2;1%'4O+>PRRE)[3YN8\B`NM_A,>O2FLT*FT.)4':8
M\A3JI:GT,MF\WI+])"-I'H[,*V&>P5^O69<,>GNUKA&E.7$PT:36PBJOH9(S
M/&QEJ.9^OU&+?P>.D=(\NLFU+8:AN*-M;K,YYM:E)YTJ-48E'C/K%M*;>N3(
MJ#0LE_\`RSG]./OEE[=04/O9W^G#RR]^H*'WL[_3AY9>_4%#[V=_IP\LO?J"
MA][._P!.'EE[]04/O9W^G#RR]^H*'WL[_3AY9>_4%#[V=_IP\LO?J"A][._T
MX>67OU!0^]G?Z</++WZ@H?>SO].'EE[]04/O9W^G#RR]^H*'WL[_`$X>67OU
M!0^]G?Z</++WZ@H?>SO].'EE[]04/O9W^G#RR]^H*'WL[_3AY9>_4%#[V=_I
MP\LO?J"A][._TX>67OU!0^]G?Z</++WZ@H?>SO\`3AY9>_4%#[V=_IP\LO?J
M"A][._TX>67OU!0^]G?Z</++WZ@H?>SO].'EE[]04/O9W^G#RR]^H*'WL[_3
MAY9>_4%#[V=_IP\LO?J"A][._P!.'EE[]04/O9W^G#RR]^H*'WL[_3AY9>_4
M%#[V=_IP\LO?J"A][._TX>67OU!0^]G?Z</++WZ@H?>SO].'EE[]04/O9W^G
M#RR]NH*'WL[_`$XQ/.7>_H<=;5ON:"B6G3JCBM%1<QEF/L,:E<:OJJTN1`;@
MT^G+=(L2H=9<2ZV9&1^B9QS+U8/[#,0%*B\-5)TSDR[=K<=/Z+;[BVWS+U%I
MI;2G/VF0DJ/==_5&IOT^1P>(IJFF]/CY=3/B5[<:*5H:41GZ\=`F55.\$O(8
M51:`3JR,TH.L.:2B+G,BXC;SC)Y9>W4%#[V=_IQ25V'5TR9+\&FG2TR73><C
MTVZI,9G3/G42$L8+(:CW)[6J?\ZR_`'Q=DW&A)K6]4TI+:9G>TLB+_\`P&"9
M9-R(85(5/J[#3:36M2;SE*V$6<[8Y_P'/4U27+,BH1WW7,G@E4^O2S1]^DN,
MDL"Q4JV[\J*V]*E7A`:4>UR;>9IP7_"EHU?P$G4^#J^WHAHIEP56'*-23)UZ
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M\;#2U4G$&K[2TD;`.X.$UH]%7!Y`?SMTFJXA)%]GI(R-5V\.$MM)J5P4*41'
MCT*VRHS_`'8&F[?_``B-*)*N".:9F6?0J*%%_F21I*X4KY;R;W!'6$((\&HG
M%KQ^XFLF">%NX2V/\'E3CK]27&I.3+IV,&/A\,KB"TGZ*S'3_>4]Y8DDGT'_
M`**8)X:H!YXQV@LG_A>F2T&?VD1Q!NL\+41XTDBHV>1J+):=:>1_GF,6!OQ.
M$;RIYMIFH62M2UD@DIN,])1F>,$DV",S^P=)`!X)ILG3>)">,-))-6-ID6TB
MST;3'L`%6?\`UDP?V-(_GLBT@1$7,0K!V-;6LQ70B`MNK\9QBWVY#B2</&/2
M3I:)[/L$C<D*L3Z8;%#K*:3-):5%(5&3(+1+G2:5&7/TC)0&:NQ2F6J[,C2Z
M@DU<8]'9-I"BR>CZ)F>#QC/VB)AW%5W+E71YEHU*/%4XXEFI)6VXPI*2,R4K
M!Y1I8V$99R9"5KE=H]`C-2JU48\&.ZX32''UZ*369&9%G[B/_(;<";#J,1J;
M`E,RHKI:3;S*R6A9=)&6PQL```````````````````````*]=%G6Y=1,G6Z:
MB0ZP1DR\E:FW&MN?16DR,MHK>I%ST<LVM?E02TG:4.L(*:T?_E)1X6DON,Q<
M+<.OG2T:R)IZ:D2E$LX!K-HTY]$RTMI&9<Y"NU:T[GJE2E.N\(%2ATUQ9FS$
MI\9IE32>CC3(U&?VC53P36H\9+K*ZM6W"_OU.HNN_P`",B_@+\RTVPRVPR@D
M--I)"4ES$1%@B'O!<WJ`````````````,%T!@@#`^&E)GDR(S^TAJNTVGO)-
M#T&,XDSR9+929'_F0U#MRWS?;D'0J:;S9D:'#B-Z23(\D9'C)8,2P````JS_
M`.LF#^QI'\]D6D```&&5&C2V38E1VGVCYT.H)23_`'&$2+&A1FXL..U'CMEA
M#3*"0E)=!$6PA7J3:+=+K[U88K]==2\:S7!D33=C94><DA1;,>K![!M72=U%
M&85:I4A4@EF;R:EQA)4C',DT<QYZ1)4M<]=.C+JC3#4XVR-]#"C4A*_623/:
M9""M^\H5;JKU*12ZS"EM)4LTSX"V4J2DR+)*/8><EC;D6"3-AQ7&FY,MAEQT
MS)M+CA)->.?!&>T;!&1EDCR0````````````````````````````````````
M```````/+J^+;4LTJ5HD9X263/[AR:E<*TZ50JU7WJ)#53HD54AKR>>2UMJ(
MDX9?+1RA9Z7.1&1&1EZLGL1>$^;+I33\6CTV1-F5!JG0FHE5)]M3BB4I1N+)
M!:!)).>8\YV"X6/<:KFH[LIZ'Y',BRG8<N.2],FWFU841*P62YCSCUC"_P#K
M(@_L:1_/9%IR&0R&0R&0R&0R&0R/FP0]PVU0+D9;9KM)BST-YXOCF\FC.,Z)
M\Y9P7-T"0BQ&(4!F!#1Q,=AHFFDIVZ"2+!$6>@B(0%KT*OT>8^JI7?+K,%39
M):8E16TK;5G]+C$D1JV;,&0R725ZJ<CZINT-"-%7'\IMNJ,SV:.CH&6SGSG[
M!/-G(**DW2;5)XLM(DY)!KQMQG;C(@K:G7;)DR$7%0H-/92DN*<C33?TU9VD
M9:)8+`^W-6+@IC\5%&M1^M-.$HWEM3&F#9,L8+"S+2SMYN@3B'E^2I><86AS
MB])3184HCQDT[-AGZA`6M=+E???:<MFOTCBD$HEU.*327,GC"3)1Y,N@9;FN
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MTQ]%0=-LD-IB/+29K/"?32DTE_GL%F`!CD-J>8=:2ZII2T&DG$<Z3,N<OM(<
MA@\&%P*J-3J%0KM/*>J*J*Q,:IR35+SQ9\9(0LU)7^AC&.<S5GF&T?!M6WI,
MFX7ZS3T7,NH1IS1L1%)B)-EM39(4C2TC)25'D\YYL"X63;"[?H4F%-EE+F3I
M+\R8ZV1MI4ZZK*M$LY(B+!%MSLR*X[9U!3?L.&34WB3I+ZS+E&1G)/-$7I<9
MG&T]F<"QZBVY[&?WG*\0-1;<]C/[SE>(&HMN>QG]YRO$#46W/8S^\Y7B!J+;
MGL9_><KQ`U%MSV,_O.5X@:BVY[&?WG*\0-1;<]C/[SE>(&HMN>QG]YRO$#46
MW/8S^\Y7B!J+;GL9_><KQ`U%MSV,_O.5X@:BVY[&?WG*\0-1;<]C/[SE>(&H
MMN>QG]YRO$#46W/8S^\Y7B!J+;GL9_><KQ`U%MSV,_O.5X@:BVY[&?WG*\0-
M1;<]C/[SE>(&HMN>QG]YRO$'TK'MY/Z+=0+[JI*+_J#YJ+;GL9_>DKQ!X38-
MKI6I:(DM*U?I*349)&?WGQFT:L[@QLBHJ0NH494Q2"P@Y$Q]PTET%I+/`V]0
MK9XOBRC32;T='0Y2DXQC&,<9S8&I!X,+(IREKI]&5#4LL*5'F/MFHN@]%99'
MJ=P;VM-T>,;J:33S&BJR2_Z@V%6%;IM&VE%10>CHDI-4DY3LQDO[3G&A2^#6
MBP5.&_5+@J!+(B(IE5>,D8]9:!IYQ'W)P6,5.0P[2;FKE&0VDR6VQ+==2X>=
MAGIK/[A.KL.A%&4ALIO'Z&$K7491EI8V&9$X7K]0A;<L"4T[)UDDL2FL)XCR
M&5,9,CVY-6D\>?5S#%<UFSF9$<K:I#$I@TGQQS:[-:42L["+14>S`GG;)H:(
MBW$PI[CZ6S432:M)+25C]$C-SIV9$':UOLU54A%:LVKT-31)-)N5YU]+AGG)
M$:'?5@N?I'BZ(-LV](897;5W5'C4&K3IKLN0E.W&%&3NPQ.R;0M:+!=FR&JB
MVRTT;KAG4I1FE)%D]A.'ZO40AK6C<'EU^4\A/5.1Y-H\;IRYS6CI9Q^FHL\Q
M\PV*O3.#JBRVHE8JQ0)#J--")5;?;-2<XR67>DA,'8]M$DUFW.))%DS.J2<8
M^(,;-FVJ_GB?*W,<^A5I)X_R=&74:W/8S^\Y7B!J+;GL9_>DKQ`U&MSV,_O2
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M_P#5)6/Y@LP````JS_ZR8/[&D?SV1:0`````````````````````````:-0I
M-+J1I.HTV)+-)8+RAA+F/7ZR,;4AAF3'=C/M(<8=0;:VU%E*DF6#(RZ,"(MV
MU;>MHY!T*DQX'E&CQO$I,M/1SC/W9/\`S&M<5G4>X9S$ZH*GI?81H(.--=8(
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M7C23%82T2L<V=$BR-XTI,\F19^X?0``````````````````'E*TK22D*)23]
M9'D>A5G_`-9,']C2/Y[(M(``````````````````````````````````````
M``````````````"J<)RVT6+6.,JW)25M);\L,EF39J6E)$K0](DF9Z)F7,1F
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M[FW'\)CQ1KLWL;\N3#:M2X5R(VAQS9-,Y1I%E/\`O?60V-:I>YMQ_"8\4-:I
M>YMQ_"8\4-:I>YMQ_"8\4-:I>YMQ_"8\4-:I>YMQ_"8\4-:I>YMQ_"8\4-:I
M>YMQ_"8\4-:I>YMQ_"8\4-:I>YMQ_"8\4-:I>YMQ_"8\4-:I>YMQ_"8\4-:I
M>YMQ_"8\4-:I>YMQ_"8\4-:I>YMQ_"8\4:\B]51GHK+]IW"AR4X;3*399]-9
M)4K!?VO^%*C_`'#8UJE[FW'\)CQ0UJE[FW'\)CQ0UJE[FW'\)CQ0UJE[FW'\
M)CQ0UJE[FW'\)CQ0UJE[FW'\)CQ0UJE[FW'\)CQ0UJE[FW'\)CQ0UJE[FW'\
M)CQ0UJE[FW'\)CQ0UJE[FW'\)CQ0UJE[FW'\)CQ0UJE[FW'\)CQ0UJE[FW'\
M)CQ1AE7DY#BO2Y5I7"U'80IQUQ3+.$(263,\.YV$1BULN(>:0ZV>4+22DGTD
M99(>P`8Y##,EAR/)9;>9<(TK;<22DJ+UD9'SD(J):]NPZ.NB,46`FF.&:G(O
M$)-M9F><J3C!GS<_00DH42+`BM0X49J-&:+1;9902$(+H(BV$,*J;%55VZL:
M5>5-QU1TGG9H*4E1[.G*2&[@N@,%T!@N@,%T!@N@,%T!@N@,%T!@N@,%T!@N
M@,%T!@N@,%T#3J=.C5.,B/*)1MH>:?+1/'I-K2M/\4D-S!=`8+H#!=`8+H#!
M=`8+H#!=`8+H#!=`8+H#!=`8+H#!=`8+H#!=`TJ138M(ID:FPTJ*/&;)MLE'
MD\%TF-W!=`8+H#!=`8+H#!=`8+H#!=`8+H#!=`8+H#!=`8+H#!=`8+H&C%ID
M6+49U0:2KCYO%\:9JR1Z"=%."]6PQO8+H#!=`8+H#!=`8+H#!=`8+H#!=`8+
MH#!=`8+H#!=`8+H#!=`TYM.C3)$"0\2C<A/&^S@\$2C0I&WI]%:AN8+H#!=`
M8+H#!=`8+H#!=`8+H#!=`8+H#!=`8+H#!=`8+H#!=`UJC"8J-/E4^21FQ)96
MRX23P>BI)D>#]6PQF8:0PRVRWG0;224YZ"+`]@`'S#D=3NN^$G>=5ILBCG3[
M<E+0<-^,O3>;0VEQ7]H2]AX,\;!))X6:.JJ1XOD$DHBE1VGY9NMDEAUY*5(3
MH&K341:1$I1%@C&_1.$.-5)ZM*C3XM%6N0ABL.Z'DZS9,R6:C(\MEL/!JP1X
MZ17+]X2Y=*JCB*-4J$W3X],.H(>EJ-PJDLEFDV&5)419+1/:63R?-@C&E-X6
M*@U7#=)REQZ<B5#832WR5Y;(:?0E1O(5G&$Z?^$R/!Y,LD.UD``````*)>%8
MN1N\*';M`EP(GET62^X[+C*>P;>A@B(E)Y](Q`0N%1^+#.G5:EHE7&S4)4%;
M,-U#+3A,$DU.DIU1$DC):<$9Y,]A"4<X48,@H*J'0ZI6$OP"J+Y14I)4=@UF
MC:DSRI>D2BT4Y/8-R\+V;BPX,6VYD"35I]18IZ4N+TRB*<SZ3K9&2BP25>B>
M#R*M%ON[JE-8M:$FEM5YN9.CRICC*U,&F.23(TMZ6<KXQ);3V;><="L*X%73
M9])KSC!,N2V=)QM)[$K(S2K'V9(\?8+"`````"I<)]>J%M65/K%+XGRQE;*&
M^.0:D>FZA!Y(C+.Q1^L5F7?-8LVKSH-ZNPIL5%-5/CR:='4TM1I<2V;1H4H]
MIFI.#SC_`-MEOA5@*I\C2H\OEEJ8Q"33&WFG5.N/$9M:+B5&C!D2LGG9HF1B
M<8OFG<C/S*BRNEU%E#RE4N:M+;ZU-$9J)!9]-)Z)X4G)&*O:MZW?+F1&)\"F
MS'*M1>5Z>Q'4IC0/227$K6HU9]%:3TL<^=@M/!I7ZC<MK(JE5:8:EG)D-*;9
MSHI)#JDD63Y]A<_K%M``````,<88O>]8]O%>,IVD2*.W4U1'X2(RVWB;\HXD
ME)<TS(U9P>,"PTWA6HDVL'#5%?8@N*D)C3E.-J2\;!&;GH$HUH+"5&1J(LX&
M[;7"#&JK7E53I,RAP78R)<69/4A+#[*E:*3TR/12H]GH*/.#R617;@X0ZU%J
M=8J-,*G.6Y1)4*/((TFMV63^CI+;62M%))):<;#SM&]`NJ[F+YI=$K#5)--2
M7(-5/C&:I$!E!&;;KBR4:3)6"+F+:>SUD.F@`````#G=;J]XR[[G6[;TVE16
MHM-:EEY9$4Z;BUK4G1RE98+T2]1B%A\,T,Z+394FD/.3%0US*@VP\VA,9M#B
MFU*3IJ+3,S0HR0G)X%C:X1(TJN*A4ZB5*=3&WF6'ZG'22FVG'4$M.49TS21&
M6DK&$YVC'<MX2)-5H5!LVH4I^95''R5,6KRAJ.EELEJ(TH465'I)+GV<XJ%3
MX2;M*R8%W,,TF%"\G43I/-./')EI<4A3222?]FCT#/34>-I$.T0WE2(C#ZT$
MA3C:5FE*B41&9$>,ES_>,P`````*9PD5NL4=B@,41V*U*JE69@&Y)9-U*$K2
ML\Z)*+.U)>L5PN$6HVY*K-(NMF--J,1Z*B&NGEQ*9?E!*T2,G%809:*LF9XQ
M_'<;X5(DN/":I="GSZQ(?D,+IS+C6DR;!$;IFYI:!EA2<&1GI9V"1N3A"I=+
ML^96XZD'46H1244R2LFY"35@B);>=(B(U%G[!$T^]:]3'Z]2+B:A3*M#3$.#
MY"@VTRG)!&2&M%2CP9+(\GG]')^H9++O"N52W8\RIG!\M-U]MWB$&2#-#RT;
M,GS820Z6`Y[4>#.//F5@W+CK#5.J\GRB;`84VAMX\$1I-6CID1DDB/!\PR/\
M&\`[E56(=2D0XSSS3\B$TRT:5K;(B+1<-)K0DR264I/:/=$X/(U+FF2JS/E4
M5M3ZH]'=T?)V^.,S62B(LN%M/!+R19Z1[NC@^AUMMF+%J4FE4XF51W8,1IKB
M5MJ,S5HI-)\6L\F1K3@S(\#S4>#R'/K4:6[59A4MA;#A4O10;1&R1<6E*C+3
M2C*2,T$>#/:+T``````*I=%H'7*Q3JQ&KD^E38+3K+;D1+9Y2YC2SII5_A(0
M<G@KI7D%.;I]2EQJA"<?=\O=;;DKD*>QQIN)<2:5&9D1YQLQL&67P:MJ<B.4
MZY:O3W4P4T^6ZRI!N2F24:MJC+T%9,_23@\'@2M>L6B5."341E-,G-R&I;4^
M*T@GDOMF9I6HS+TSVGG2SG)B$\UT=J+&=AW!4(U<:D29+E52ALW'E2"(G24@
MRT<&1%C'Z."P+I;=%AV[0H-$IY**+#:)I!K/*E=)G]IF9F?WB4`````!!WE;
ML>ZK=E4*5(>CLR#;4;K.--)H6E98R1ESI(5I_@QIM18JO+U8J=6FU",F+Y7)
M4@EQVTK)9$V24DE/ID2N;:9#&7!FVNEJ8?N":NHIF,S8\YMAEKR=UK)(-+2$
MDC&%*SDO2SM$[3+,I3$`FJMFM3E&X;D^>A*WCXS.D23Q_9IVF1)3@B&A9]@1
M[;J:*@NKS:BN-#*!!3(2@BBQ]+2T"T2+2/)%Z1[<%@3MJ6_&MJD\F17G7F^/
M>?TG<9RXLUF6SU$:A-``````#G4+@OAL*88DW!5I5)8FG.33%FVEDW36:RTM
M%)*41*/.#/`]TK@QIM.J+SB:E*<I:C?-%/-II*4\<2B61N$G36GTU8(SV#:M
MO@_C4ILXU4JTRN06HR(D6'/0@V&&4JRDM`BT5J+!>FHLX+`UZKP9TR=6'934
M^3$IDIR,[-I;*$$Q)4QCB_5E!8(B,DX(\$,]N6&[0:Y)JS-T51\Y<A4B4RZV
MSB0HR,B)2B1IX+.PLX+&P7D``````4JOV,JJ7!(KD2Y*K2I$F(B&\4+BRTFT
MFH^=23,C](]I",G\%%(5Y`5'J$FE%&A%`7Q333INLDHU<[B3T7,J4>FG![1O
M(X/FF:\N?#K]4BT]Y]J5)I[2R)#[K:221FO&G@R(M))'A7K&Q7;#IDPX$FAN
M%;]1@NK=8E4^.VG!K1H+)2#3HJRG'/MV$(=_@IAHI<>E4NX*I3X?D!T^8VV:
M%E+:-1J49DHC)*S-2LJ26=N!T*!$8@08T&,G18CM):;3G.$I(B(L_<0V````
M``5R\K7;NB+3VE5&5`>@3436'XQ(-27$I41?I$9?WC]0KTG@MIDJGRTRJM4)
M-7D2VIJJI(XM;I.M$9-EHZ.@:"(S+1QC!F"N#71CT]Z)<U1BUB(M\RJ#331&
MI+Q$2T$WHZ"4X26"(O1QDA,RK$MV907:1+B$^MV'Y(Y/=PJ6M."+)NF6D9Y(
MCZ-A;,;!&4_@RHIIG+N5YRXI4Q;*G'IR$IP3232V1)01$6"4>3]><F-2F\#M
MFPHA1U0N/,EK5IN$6EA2C41;/46<%]A$.D@`````````````````````````
M````````````````````````````````````````````````````````````
M````````````````````````````"LURKUIJOQ*+18<!YQV(Y*6N8^MLDDE:
M$X+12K)^G_`>.-OWJ^W.VO\`A!QM^]7VYVU_P@XV_>K[<[:_X0<;?O5]N=M?
M\(.-OWJ^W.VO^$'&W[U?;G;7_"#C;]ZOMSMK_A!QM^]7VYVU_P`(.-OWJ^W.
MVO\`A!QM^]7VYVU_P@XV_>K[<[:_X0<;?O5]N=M?\(.-OWJ^W.VO^$'&W[U?
M;G;7_"#C;]ZOMSMK_A!QM^]7VYVU_P`(.-OWJ^W.VO\`A!QM^]7VYVU_P@XV
M_>K[<[:_X0<;?O5]N=M?\(.-OWJ^W.VO^$'&W[U?;G;7_"#C;]ZOMSMK_A!Q
MM^]7VYVU_P`(.-OWJ^W.VO\`A!QM^]7VYVU_P@XV_>K[<[:_X0<;?O5]N=M?
M\(.-OWJ^W.VO^$'&W[U?;G;7_"#C;]ZOMSMK_A!QM^]7VYVU_P`(.-OWJ^W.
MVO\`A!QM^]7VYVU_P@XV_>K[<[:_X0<;?O5]N=M?\(.-OWJ^W.VO^$'&W[U?
M;G;7_"#C;]ZOMSMK_A!QM^]7VYVU_P`(.-OWJ^W.VO\`A!QM^]7VYVU_P@XV
M_>K[<[:_X0<;?O5]N=M?\(.-OWJ^W.VO^$'&W[U?;G;7_"#C;]ZOMSMK_A!Q
MM^]7VYVU_P`(.-OWJ^W.VO\`A!QM^]7VYVU_P@XV_>K[<[:_X0<;?O5]N=M?
M\(.-OWJ^W.VO^$'&W[U?;G;7_"#C;]ZOMSMK_A!QM^]7VYVU_P`(.-OWJ^W.
MVO\`A!QM^]7VYVU_P@XV_>K[<[:_X0<;?O5]N=M?\(.-OWJ^W.VO^$'&W[U?
M;G;7_"#C;]ZOMSMK_A!QM^]7VYVU_P`(.-OWJ^W.VO\`A!QM^]7VYVU_P@XV
M_>K[<[:_X0<;?O5]N=M?\(.-OWJ^W.VO^$'&W[U?;G;7_"#C;]ZOMSMK_A!Q
MM^]7VYVU_P`(.-OWJ^W.VO\`A!QM^]7VYVU_P@XV_>K[<[:_X0U*M4[YIE+F
MU)ZF6^MN(PM]2437M)1)2:C(LM<^P3MN7!2;B@%,I-0C2T)PEPV'"63:S21Z
M)F7KVB7```!5G_UDP?V-(_GLBT@`9#(9#(9$56ZY`HJZ:B<IPCJ,Q$)C01I9
M=61F6>@O1/:/,FX:2S%J;[,QF8Y3FENR(\5Q+CJ-$C,RT2/8>SF/&T>XU>I3
M_D*%36&),UE+S$5]U*'E)462]#.<_<-*ZKKIUL^0IFL3I#LYU34=F%&4^XM1
M)TC(DIV\PC87"/:TOR#_`$MV.<M]^/B4T;/$.,H);B7=+&@9$9<_2+)(K-(B
MLQGY-4A,LR<<0MR0A*7<\VB9GZ7.7,,CU2IS#QL/3XS;Q%DVUO))1%HFKF,^
M@C/[BR,)5RBGS5>`?]JEC9)1_K#+)(Y_TC+:1<XR\ITWE'DSE"+Y?HZ7DO')
MXW&,YT,YQ^X(]3ITF5(B1Y\5Z3'_`-<TV\E2VO\`B(CRG]X\QZO2I3'E$:IP
MWF.,XKC&WTJ3I\VCDCQG[.<:-;NFA4,HYU&HLM<?+1"3A6EAU7,2L?H^K)GS
M9+(1+GI+T6;+DO<GL1)CD);DY264J6@\929G@TGZC]8WI56I41<=$JI1&%R?
M]0EU]*3=_P"$C/TN<N8:,:Z:*\=6-R8B,W2I7DLEV2HFD)<T25^D9XQA1#<G
MU>#!HDJN./$Y`CQUR5.,^F2FTI-1FG'/L(88UPT61'A/<I1FCF(;4RVZZE"U
M::24DM$SSDR/F&V=2IQ5`J:<^,4\TZ91N-3QIIZ=#.<?;@;8```&0R`9`!79
M]XT.!=D"TY$E2:I-;XQI!(RG'I8(U>HST%8+UX&LF_+>.N5RB*?=1,HL=4F6
M2FS))-I21F:3]>"47^8C4<*-N/4ZD3XD>K3$U4WRBLQ8*W75<29$YZ"=I8R0
MDDWQ1T+I29[%0IO*9NI8.H1%,$E399-*]+]`S(C,L\Y<PWJ9<]-J5L+N=A,E
M--)IQ\E.M&A2VT9,U$D]N#(C,NDA#T3A&H58F0XC4:JQ7)S*GH1S("V42DI3
MI'Q:CV*]';L/F$S3[GH\ND4ZJO24T]JH))3#<]:67%&?]W!GS_861Z9N:B/5
MRH4-$]OR^`RE^0A1X)"#SMR>S9C;T;,C;*L4A5..J)JD(Z>7/*)]/%<^/T\X
MY_M$=+N^WXE3BP)%19;.3%5+;D*<23)MDHDYXS.-IJ+'2-NXJ[3[>H4JNU!:
M_(8R26M32=,\&9$6"]>TR&P=6I92T0E5&(4IQ1I0P;R2<4HBR9$G.3,B/.!'
MU6ZJ'3)L2`_-;7+DS&X1,LJ):VW%D9ITR(\I(]$]IC>36*2I4I":G#-<3_O"
M2?3EG_CV^C^\;+4J,\ZMEJ0TXXA)*4A*R,TD?,9ET'ZAF```````5]=V45N[
MT6@Y(4BK.1O*6VU)PE:<GL)73L,\=!!2KOM^I4>)6$U)F-$EN.-L'+6EDUJ0
MLT*(B4>T\D8E'*I36Y[=-<J$5$YQ.DB,IY).J+I).<F7[A'56ZJ'3)L2`_-;
M7+DS&X1,LJ):VW%D9ITR(\I(]$]IB0BU6ES'9#42HQ'W(^QY#3R5FU_Q$1^C
MS'SCY"JU*GJ)$&I0Y2C0:R)A]*S-)'HF>P^;.S/3L$7(N^CL,7$\XI[0H'_?
M<-\WH$OT?\6PQZKMUTNBTF%4Y"93Q3E(;B1XS)N//K4G2)*4%Z\9/]P]VM<]
M.N:/)<A-RH[\5WB9,68R;3S"\9PI)])&1Y+)"=`0EZ_['7!^SI'\I0Y)_P!E
M+_8^L?M'_I('=@```59_]9,']C2/Y[(M("OW1:\.Y/)O*YU4C>3Z6CY#-7'T
MM+'Z6CS\VSHVB`\U]'Z\N?OE[YAYKZ/UY<_?+WS#S7T?KRY^^7OF'FOH_7ES
M]\O?,/-?1^O+G[Y>^8]W=;4YV+9<.DMO2VZ368TAY;[^DLF4(61J4I1Y4>3+
MI/:.9TBQ;ICHJD*-;[S+"J-48I%-5'4I#KJ3T$-/MF2GB4HR,S=26"Z#&:H6
M1="*M"<A4!Y4A35,2XIY4=Z*LV&T$HU*REU@T&1[&S42L?;@=&X0[;J=P5BT
MU0'I<5F)-=<DRXCJ$.QTFTHB4G2(\Y/!<Q\XA9G!M'8KMHM,PUU6F,3ILRJO
MU!:'5/.N-$25K(\:1FI*2P18+!"A3+!O%5N4RCNVYQBFJ9-CMK:..XMMU<A:
MD(4IU1DVC0-)DILM/U9+U6:)8-6=:NR;.HK:ZE(MR+"IKKBT*63Y1%-NI(\^
MB>E@C,^<O7C(C*GP73ET^J-Q;8B$\NV8D>/H\4D_+4G_`&AD>=B\$65^OI,9
M56A=C]]Q*J[0%-\17VI3DAKR<FUQB02=/C#4;RE_XD;$EZB,SV8Z58=PZOR:
M&5JLPJRQ!GL.5Y4HDG-6ZHS21$@\K)1<YN%Z/JP,46R;B;I$R9#MN7&=:>IK
MOD+CD5LY!L.&I>@AHB3DB/!+4>5%ZM@WI]H7'5(TVIRK3TGG+K8JB(3KS"W%
M120DEEDU:)&>C@TF?J]8/V;7XM0:J<RU^6(#-PU66NF<8T9O-OI23+N%'HG@
MR/8>TLYP(J[K#N>?`:@Q;20UH45N/%3$>9>2RLG%+4TMV0HUI).=AMX,S/&E
M@A.5JSZ^]%JKKE'FN*7<+=185&=86ZE)1TH)SBG,H<PK)&A1I/UD+%0[>KS?
M`W5:!)IK+%4D0YK;$9K11DW-/0TB)1H2HS5DR2>B6?4*;4^#>NRZ3<ZET)EV
MINTFDQZ:XI;9K2ZTA)/$E1GZ!D:2V[,XV9$['M:J,WU.=E6BU/7)KJ*DS7')
M!-^31R01:!:*M,U)P9$C&B>=NP=1H4NH3:>E^J4I5,DFM:3C*>2Z9))1DD])
M.S:6#QZLB1```4)S@QI"UJ6=;N8C49G@JP\1;?WCZQP:4AA]IY-:N52FUDLB
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M_4DL>O`MU.C5^;P8R*75*4B'6>3GH?D[:T<6M1-FA*DF1X)*MAX/&,X]0YW9
M5E7+%JMMO.V]/IQ4V"ZS,>G51$I#VDSH:#+9*5Q>58/9HD1%C[!K(LBX(5,I
M:*A9B*XI5M\F)CJ?:_T"3IK/2/2/!$9*+TTF9EHC[4^#BYDQ*O$9I34B5)HM
M/:.<AQI/'O,*2;S1FH]+*R(BR98/1+2&5%E5I-.\N3;,IV(FO1YSU&D+C(.0
MTAHT*4339):2>3(]$S/2T<GCU[[%@RITV`]*LZ)#@(I=02W!4\EY$9YUS2;3
MA1GA1D9GZ/HI,]F!-UFV*]+X"&[71#-=;*FQV#CFZG.FE2,EI9T=A$?K]0B:
MC8=3>JU7JR*&TN>Y=,2;'DZ3?&>2(T-,R5G*2_2]'89]![!%L63<"*Y36=5$
ME)B7*Y4'Z\3K67HZU*-)[5:9F6D64^K1+'.,%H6+7J6HN4+6DR7H5.F1Y"3>
MC(9J1N'A*-)):;A*V*RX9:&#Y^87?@9MFLVK"J5/KL!/E;BVG"J*'^,*0CBR
M236T](N*QHEG89;2'3```%9DV?!DW(FX%U&KID)<0YQ")[B6#-)$1%Q>='&S
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MX:;*9H#_`!QNTYV0N2J.]'5Q+:$J6;F2>:4G1/T4Z1*Z3(\#TBRKC9K$!#5I
M-KFPKC=J+M<4\T7E+*C4:2/TM,^=.2QLT=G.(VC<']W*:FI;H;E-=DT"5`69
M^3--D^I:5$A/%F:U(,B,B6X:CVGG!"R\'$7R3A3D,ZKIMT]6V2.(2FS-9D]H
MFX>@9EM,C+I/1R?.,UST6[&95^4NGVXY4&+G)OR:8W);0VQEHFU<82C(RQC.
MPCR)2[Z36JE0V:0[9Y5&-2I,8FW$SB:>D()HR4ZP9*(VUI5LPH]I9'NQ&KTH
MT>24JF529`DU%IN)'J50;<DPHVB?&.K7DR41*QA!&9X_CTX!"7K_`+'7!^SI
M'\I0Y)_V4O\`8ZL?M'_I('=@```4>X*Q2Z'?M/FU><S"C*I,A!.OJT4Z7',G
MC/W$9C:\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M
M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;W4?M20\Y%
MA;W4?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?
MM20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y
M%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;WT
M?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\
MY%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;W
MT?M20\Y%A;WT?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20
M\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;
MW4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;WT?M20\Y%A;WT?M2
M0\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A
M;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M20\Y%A;WT?M
M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M20\Y%A;W4?M21C\X/!X4@Y.M-#X
M\T:'&>4(TM'.<9Y\9]0R><BPM[J/VI(><BPM[J/VI(><BPM[J/VI(><BPM[Z
M/VI(><BPM[Z/VI(B+LX0;(E6M6HT>ZJ2X\[!?0VA,E)FI1MJ(B(NDS%._P"R
ME_L?6/VC_P!)`[L```"H<*_ZM[H_9KW_`*1^##,\GM'S)](9/I#)](9/I#)]
M(9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I
M#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](
M9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#
M)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9/I#)](9
7/I#)](_5G_92_P!CJQ^T?^D@=W`?_]D_
`
end
</TEXT>
</DOCUMENT>
</SUBMISSION>
