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<P ALIGN="CENTER"><FONT SIZE=2><B>As filed with the Securities and Exchange Commission on June&nbsp;28, 2002  </B></FONT></P>

<P ALIGN="RIGHT"><FONT SIZE=2><B> Registration No.&nbsp;333-&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</B></FONT></P>

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<P ALIGN="CENTER"><FONT SIZE=5><B>SECURITIES AND EXCHANGE COMMISSION<BR>  </B></FONT><FONT SIZE=2><B>Washington, D.C. 20549  </B></FONT></P>

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<P ALIGN="CENTER"><FONT SIZE=5><B>FORM S-8<BR>  </B></FONT><FONT SIZE=2><B>REGISTRATION STATEMENT<BR>
UNDER<BR>
THE SECURITIES ACT OF 1933  </B></FONT></P>

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<P ALIGN="CENTER"><FONT SIZE=5><B>ISIS PHARMACEUTICALS,&nbsp;INC.<BR>  </B></FONT><FONT SIZE=2>(Exact name of registrant as specified in its charter) </FONT></P>

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<TD WIDTH="50%" ALIGN="CENTER"><FONT SIZE=2><B>Delaware</B></FONT></TD>
<TD WIDTH="50%" ALIGN="CENTER"><FONT SIZE=2><B>33-0336973</B></FONT></TD>
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<TD WIDTH="50%" ALIGN="CENTER"><FONT SIZE=2>(State of Incorporation)</FONT></TD>
<TD WIDTH="50%" ALIGN="CENTER"><FONT SIZE=2>(I.R.S. Employer Identification No.)<BR></FONT>
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<P ALIGN="CENTER"><FONT SIZE=2><B>2292 Faraday Avenue<BR>
Carlsbad, CA 92008<BR>  </B></FONT><FONT SIZE=2>(Address of principal executive offices) </FONT></P>

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<P ALIGN="CENTER"><FONT SIZE=2><B>2000 BROAD BASED EQUITY INCENTIVE PLAN<BR>
2000 EMPLOYEE STOCK PURCHASE PLAN<BR>
2002 NON-EMPLOYEE DIRECTORS' STOCK OPTION PLAN<BR>  </B></FONT><FONT SIZE=2>(Full title of the plans) </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><B>B. Lynne Parshall, Esq.<BR>
Executive Vice President, Chief Financial Officer and Secretary<BR>
ISIS PHARMACEUTICALS,&nbsp;INC.<BR>
2292 Faraday Avenue<BR>
Carlsbad, California 92008<BR>
(760)&nbsp;931-9200<BR>  </B></FONT><FONT SIZE=2>(Name, address, including zip code, and telephone number, including area code, of agent for service) </FONT></P>

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<P ALIGN="CENTER"><FONT SIZE=2>Copies
to:<BR></FONT> <FONT SIZE=2><B>Julie M. Robinson, Esq.<BR>
COOLEY GODWARD LLP<BR>
4401 Eastgate Mall<BR>
San Diego, CA 92121<BR>
(858)&nbsp;550-6000  </B></FONT></P>

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<P ALIGN="CENTER"><FONT SIZE=2><B> CALCULATION OF REGISTRATION FEE  </B></FONT></P>

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<TD WIDTH="34%" ALIGN="CENTER" VALIGN="BOTTOM"><FONT SIZE=1><B>Title of Securities<BR>
to be Registered</B></FONT></TD>
<TD WIDTH="1%" VALIGN="BOTTOM"><FONT SIZE=1>&nbsp;</FONT></TD>
<TD WIDTH="19%" ALIGN="CENTER" VALIGN="BOTTOM"><FONT SIZE=1><B>Amount to be Registered(1)</B></FONT></TD>
<TD WIDTH="1%" VALIGN="BOTTOM"><FONT SIZE=1>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="CENTER" VALIGN="BOTTOM"><FONT SIZE=1><B>Proposed Maximum<BR>
Offering<BR>
Price per Share(2)</B></FONT></TD>
<TD WIDTH="1%" VALIGN="BOTTOM"><FONT SIZE=1>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="CENTER" VALIGN="BOTTOM"><FONT SIZE=1><B>Proposed Maximum<BR>
Aggregate<BR>
Offering Price (2)</B></FONT></TD>
<TD WIDTH="1%" VALIGN="BOTTOM"><FONT SIZE=1>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="CENTER" VALIGN="BOTTOM"><FONT SIZE=1><B>Amount of<BR>
Registration Fee</B></FONT></TD>
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<TD WIDTH="34%"><FONT SIZE=2>Common Stock, par value $.001 per share</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="19%" ALIGN="CENTER"><FONT SIZE=2>2,972,000 shares</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="CENTER"><FONT SIZE=2>$7.94</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="CENTER"><FONT SIZE=2>$23,597,680</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="14%" ALIGN="CENTER"><FONT SIZE=2>$2,171</FONT></TD>
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<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>(1)</FONT></DT><DD><FONT SIZE=2>Includes
2,000,000 shares issuable pursuant to the Registrant's 2000 Broad Based Equity Incentive Plan (the "Equity Plan"), 400,000 shares issuable pursuant to the Registrant's 2000
Employee Stock Purchase Plan
(the "ESPP"), and 572,000 shares issuable pursuant to the Registrant's 2002 Non-Employee Directors' Stock Purchase Plan (the "NED Plan").
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>(2)</FONT></DT><DD><FONT SIZE=2>Estimated
solely for the purpose of calculating the amount of the registration fee pursuant to Rule&nbsp;457(h)(1) of the Securities Act of 1933, as amended, (the "Securities Act").
The price per share and the aggregate offering price are calculated on the basis of $7.94, the average of the high and low sales prices of Registrant's Common Stock on June&nbsp;24, 2002, as
reported on the NASDAQ National Market for the remainder of the shares subject to the Equity Plan and the NED Plan registered hereunder, as well as the shares subject to the ESPP. </FONT></DD></DL>
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<BR></FONT><FONT SIZE=2><B>INCORPORATION OF CERTAIN DOCUMENTS BY REFERENCE    <BR>  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The SEC allows us to "incorporate by reference" certain of our publicly-filed documents into this prospectus, which means that information included in those
documents is considered part of this prospectus. Information that we file with the SEC after the effective date of this prospectus will automatically update and supersede this information. We
incorporate by reference the documents listed below and any future filings made with the SEC under Sections 13(a), 13(c), 14 or 15(d) of the Exchange Act, until all the shares of common stock that are
part of this offering are sold. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The
following documents filed with the SEC are incorporated by reference in this prospectus: </FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>our
Annual Report on Form&nbsp;10-K for the year ended December&nbsp;31, 2001;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>our
Quarterly Report on Form&nbsp;10-Q for the quarter ended March&nbsp;31, 2002;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>our
Current Report on Form&nbsp;8-K, filed with the SEC on January&nbsp;4, 2002;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>our
Current Report on Form&nbsp;8-K, filed with the SEC on January&nbsp;7, 2002;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>our
Current Report on Form&nbsp;8-K, filed with the SEC on April&nbsp;23, 2002;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>our
Current Report on Form&nbsp;8-K, filed with the SEC on April&nbsp;24, 2002;
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>our
Current Report on Form&nbsp;8-K, filed with the SEC on April&nbsp;24, 2002; and
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>&#149;</FONT></DT><DD><FONT SIZE=2>the
description of our common stock in our Registration Statement on Form&nbsp;8-A filed with the SEC on April&nbsp;12, 1991, as updated by
our Certificate of Amendment of our Restated Certificate of Incorporation filed with our Quarterly Report on Form&nbsp;10-Q for the period ended June&nbsp;30, 2001. </FONT></DD></DL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
will furnish without charge to you, on written or oral request, a copy of any or all of the documents incorporated by reference, other than exhibits to those documents. You should
direct any requests for documents to Vice President of Finance at Isis' principal executive offices at 2292 Faraday Avenue, Carlsbad, California 92008, telephone number
(760)&nbsp;931-9200. </FONT></P>

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

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<BR></FONT><FONT SIZE=2><B>SIGNATURES    <BR>  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Pursuant to the requirements of the Securities Act of 1933, as amended, the Registrant certifies that it has reasonable grounds to believe that it meets all of
the requirements for filing on Form&nbsp;S-8 and has duly caused this Registration Statement to be signed on its behalf by the undersigned, thereunto duly authorized, in the City of
Carlsbad, State of California, on June&nbsp;27, 2002. </FONT></P>

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<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD COLSPAN=3><FONT SIZE=2>ISIS PHARMACEUTICALS,&nbsp;INC.</FONT></TD>
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<TD WIDTH="47%"><FONT SIZE=2><BR>
&nbsp;</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="5%"><FONT SIZE=2><BR>
By:</FONT></TD>
<TD WIDTH="1%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="45%" ALIGN="CENTER"><FONT SIZE=2><BR>
/s/&nbsp;&nbsp;</FONT><FONT SIZE=2>B. LYNNE PARSHALL</FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> B. Lynne Parshall<BR></FONT> <FONT SIZE=2><I>Executive Vice President, Chief Financial Officer and Secretary
</I></FONT><FONT SIZE=2>(Principal Financial and Accounting Officer)</FONT></TD>
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<P ALIGN="CENTER"><FONT SIZE=2><A
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<A NAME="toc_jc1574_2"> </A>
<BR></FONT><FONT SIZE=2><B>POWER OF ATTORNEY    <BR>  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Know
All Persons By These Presents, that each person whose signature appears below constitutes and appoints Stanley T. Crooke and B. Lynne Parshall, and each or any one of them, his true
and lawful attorney-in-fact and agent, with full power of substitution and resubstitution, for him and in his name, place and stead, in any and all capacities, to sign any and
all amendments (including post-effective amendments) to this Registration Statement, and to file the same, with all exhibits thereto, and other documents in connection therewith, with the
Securities and Exchange Commission, granting unto said attorneys-in-fact and agents, and each of them, full power and authority to do and perform each and every act and thing
requisite and necessary to be done in connection therewith, as fully to all intents
and purposes as he might or could do in person, hereby ratifying and confirming all that said attorneys-in-fact and agents, or any of them, or their or his substitutes or
substitute, may lawfully do or cause to be done by virtue hereof. </FONT></P>

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

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<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Pursuant
to the requirements of the Securities Act of 1933, this Registration Statement has been signed by the following persons in the capacities and on the dates indicated. </FONT></P>

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<TH WIDTH="28%" ALIGN="CENTER"><FONT SIZE=1><B>Title</B></FONT><HR NOSHADE></TH>
<TH WIDTH="3%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="20%" ALIGN="CENTER"><FONT SIZE=1><B>Date</B></FONT><HR NOSHADE></TH>
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<TR VALIGN="BOTTOM">
<TD WIDTH="46%" ALIGN="CENTER" VALIGN="CENTER"><BR><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="28%" VALIGN="CENTER"><FONT SIZE=2><BR>
&nbsp;</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="20%" VALIGN="CENTER"><FONT SIZE=2><BR>
&nbsp;</FONT></TD>
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<TD WIDTH="46%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2>/s/&nbsp;&nbsp;</FONT><FONT SIZE=2>STANLEY T. CROOKE</FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> Stanley T. Crooke, M.D., Ph.D.</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="28%" VALIGN="CENTER"><FONT SIZE=2>Chairman of the Board, Chief Executive Officer and President (Principal Executive Officer)</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="20%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2>June 27, 2002</FONT></TD>
</TR>
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<TD WIDTH="46%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
/s/&nbsp;&nbsp;</FONT><FONT SIZE=2>B. LYNNE PARSHALL</FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> B. Lynne Parshall</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="28%" VALIGN="CENTER"><FONT SIZE=2><BR>
Executive Vice President and Chief Financial Officer (Principal Financial and Accounting Officer)</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="20%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
June 27, 2002</FONT></TD>
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<TD WIDTH="46%" ALIGN="CENTER" VALIGN="CENTER"><BR><HR NOSHADE><FONT SIZE=2> Spencer R. Berthelsen</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="28%" VALIGN="CENTER"><FONT SIZE=2><BR>
Director</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="20%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
June&nbsp;&nbsp;&nbsp;&nbsp;, 2002</FONT></TD>
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<TD WIDTH="46%" ALIGN="CENTER" VALIGN="CENTER"><BR><HR NOSHADE><FONT SIZE=2> Christopher F. O. Gabrieli</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="28%" VALIGN="CENTER"><FONT SIZE=2><BR>
Director</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="20%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
June&nbsp;&nbsp;&nbsp;&nbsp;, 2002</FONT></TD>
</TR>
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<TD WIDTH="46%" ALIGN="CENTER" VALIGN="CENTER"><BR><HR NOSHADE><FONT SIZE=2> William R. Miller</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="28%" VALIGN="CENTER"><FONT SIZE=2><BR>
Director</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="20%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
June&nbsp;&nbsp;&nbsp;&nbsp;, 2002</FONT></TD>
</TR>
<TR VALIGN="BOTTOM">
<TD WIDTH="46%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
/s/&nbsp;&nbsp;</FONT><FONT SIZE=2>FREDERICK T. MUTO</FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> Frederick T. Muto</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="28%" VALIGN="CENTER"><FONT SIZE=2><BR>
Director</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="20%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
June 27, 2002</FONT></TD>
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<TD WIDTH="46%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
/s/&nbsp;&nbsp;</FONT><FONT SIZE=2>JOHN C. REED</FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> John C. Reed</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="28%" VALIGN="CENTER"><FONT SIZE=2><BR>
Director</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="20%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
June 27, 2002</FONT></TD>
</TR>
<TR VALIGN="BOTTOM">
<TD WIDTH="46%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
/s/&nbsp;&nbsp;</FONT><FONT SIZE=2>MARK B. SKALETSKY</FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> Mark B. Skaletsky</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="28%" VALIGN="CENTER"><FONT SIZE=2><BR>
Director</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="20%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
June 27, 2002</FONT></TD>
</TR>
<TR VALIGN="BOTTOM">
<TD WIDTH="46%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
/s/&nbsp;&nbsp;</FONT><FONT SIZE=2>JOSEPH H. WENDER</FONT><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><HR NOSHADE><FONT SIZE=2> Joseph H. Wender</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="28%" VALIGN="CENTER"><FONT SIZE=2><BR>
Director</FONT></TD>
<TD WIDTH="3%" VALIGN="CENTER"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="20%" ALIGN="CENTER" VALIGN="CENTER"><FONT SIZE=2><BR>
June 27, 2002</FONT></TD>
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<P ALIGN="CENTER"><FONT SIZE=2>7</FONT></P>

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<P ALIGN="CENTER"><FONT SIZE=2><A
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<A NAME="toc_ka1574_1"> </A>
<BR></FONT><FONT SIZE=2><B>EXHIBIT INDEX    <BR>  </B></FONT></P>

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<TH WIDTH="10%" ALIGN="CENTER"><FONT SIZE=1><B>Exhibit<BR>
Number<BR> </B></FONT><HR NOSHADE></TH>
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<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>5.1</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2>Opinion of Grantland E. Bryce</FONT></TD>
</TR>
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<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>23.1</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2>Consent of Ernst &amp; Young LLP, Independent Auditors</FONT></TD>
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<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>23.2</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2>Consent of Grantland E. Bryce is contained in Exhibit 5.1 to this Registration Statement</FONT></TD>
</TR>
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<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>24</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2>Power of Attorney is contained on the signature pages.</FONT></TD>
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<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>99.1</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2>2000 Broad Based Equity Incentive Plan</FONT></TD>
</TR>
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<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>99.2</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>*</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2>2000 Employee Stock Purchase Plan</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>99.3</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>**</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2>2002 Non-Employee Directors' Stock Option Plan</FONT></TD>
</TR>
</TABLE>
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<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>*</FONT></DT><DD><FONT SIZE=2>Filed
as an exhibit to the Registrant's Annual Report on Form&nbsp;10-K for the year ended December&nbsp;31, 1999, and incorporated herein by reference.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>**</FONT></DT><DD><FONT SIZE=2>Filed
as an exhibit to the Registrant's Annual Report on Form&nbsp;10-K for the year ended December&nbsp;31, 2001, and incorporated herein by reference. </FONT></DD></DL>
<P ALIGN="CENTER"><FONT SIZE=2>8</FONT></P>

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<A NAME="toc_la1574_1"> </A>
<BR></FONT><FONT SIZE=2><B>DESCRIPTION OF SECURITIES    <BR>  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Not applicable. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="la1574_interests_of_named_experts_and_counsel"> </A>
<A NAME="toc_la1574_2"> </A>
<BR></FONT><FONT SIZE=2><B>INTERESTS OF NAMED EXPERTS AND COUNSEL    <BR>  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The validity of the issuance of the common stock offered in this prospectus will be passed upon for Isis by Grantland E. Bryce, Vice President and General Counsel
of Isis. Mr.&nbsp;Bryce is the beneficial owner of options to purchase 102,500 shares of Isis common stock. As of June&nbsp;21, 2002, Mr.&nbsp;Bryce will be vested as to options to purchase
65,876 shares of Isis common stock. </FONT></P>

<P ALIGN="CENTER"><FONT SIZE=2><A
NAME="la1574_indemnification_of_directors_and_officers"> </A>
<A NAME="toc_la1574_3"> </A>
<BR></FONT><FONT SIZE=2><B>INDEMNIFICATION OF DIRECTORS AND OFFICERS    <BR>  </B></FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Under Section&nbsp;145 of the Delaware General Corporation Law, we have broad powers to indemnify our directors and officers against liabilities they may incur
in such capacities, including liabilities under the Securities Act of 1933. </FONT></P>

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

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
have entered into indemnity agreements with each of our directors and executive officers that require us to indemnify such persons against expenses, judgments, fines, settlements and
other amounts incurred (including expenses of a derivative action) in connection with any proceeding, whether actual or threatened, to which any such person may be made a party by reason of the fact
that such person is or was a director or an executive officer of Isis or any of our affiliated enterprises, provided such person acted in good faith and in a manner such persons reasonably believed to
be in, or not opposed to, the best interests of Isis and, with respect to any criminal proceeding, has no reasonable cause to believe his conduct was unlawful. The indemnification agreements also set
forth procedures that will apply in the event of a claim for indemnification thereunder. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;We
have an insurance policy covering our officers and directors with respect to certain liabilities, including liabilities arising under the Securities Act or otherwise. </FONT></P>

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

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<P ALIGN="CENTER"><FONT SIZE=2><A
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<A NAME="toc_lc1574_1"> </A>
<BR></FONT><FONT SIZE=2><B>EXHIBITS    <BR>  </B></FONT></P>

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<TABLE WIDTH="100%" BORDER=0 CELLSPACING=0 CELLPADDING=0>
<TR VALIGN="BOTTOM">
<TH WIDTH="10%" ALIGN="CENTER"><FONT SIZE=1><B>Exhibit<BR>
Number<BR> </B></FONT><HR NOSHADE></TH>
<TH WIDTH="3%"><FONT SIZE=1>&nbsp;</FONT></TH>
<TH WIDTH="88%" ALIGN="LEFT"><FONT SIZE=1>&nbsp;</FONT><BR></TH>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2>5.1</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2>&nbsp;</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2>Opinion of Grantland E. Bryce</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2><BR>
23.1</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2><BR>
Consent of Ernst &amp; Young LLP, Independent Auditors</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2><BR>
23.2</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2><BR>
Consent of Grantland E. Bryce is contained in Exhibit 5.1 to this Registration Statement</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2><BR>
24</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2><BR>
Power of Attorney is contained on the signature pages.</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2><BR>
99.1</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>&nbsp;</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2><BR>
2000 Broad Based Equity Incentive Plan</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2><BR>
99.2</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>*</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2><BR>
2000 Employee Stock Purchase Plan</FONT></TD>
</TR>
<TR VALIGN="TOP">
<TD WIDTH="10%" ALIGN="RIGHT"><FONT SIZE=2><BR>
99.3</FONT></TD>
<TD WIDTH="3%"><FONT SIZE=2><BR>**</FONT></TD>
<TD WIDTH="88%"><FONT SIZE=2><BR>
2002 Non-Employee Directors' Stock Option Plan</FONT></TD>
</TR>
</TABLE>
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<HR NOSHADE ALIGN="LEFT" WIDTH="120">
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>*</FONT></DT><DD><FONT SIZE=2>Filed
as an exhibit to the Registrant's Annual Report on Form&nbsp;10-K for the year ended December&nbsp;31, 1999, and incorporated herein by reference.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>**</FONT></DT><DD><FONT SIZE=2>Filed
as an exhibit to the Registrant's Annual Report on Form&nbsp;10-K for the year ended December&nbsp;31, 2001, and incorporated herein by reference. </FONT></DD></DL>
<P ALIGN="CENTER"><FONT SIZE=2>4</FONT></P>

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<A NAME="toc_le1574_1"> </A>
<BR></FONT><FONT SIZE=2><B>UNDERTAKINGS    <BR>  </B></FONT></P>

<UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>1.</FONT></DT><DD><FONT SIZE=2>The
undersigned registrant hereby undertakes: </FONT></DD></DL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;(a)&nbsp;&nbsp;To
file, during any period in which offers or sales are being made, a post-effective amendment to this registration statement: </FONT></P>

<UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;(i)&nbsp;&nbsp;To
include any prospectus required by section&nbsp;10(a)(3) of the Securities Act; </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;(ii)&nbsp;&nbsp;To
reflect in the prospectus any facts or events arising after the effective date of the registration statement (or the most recent post-effective amendment
thereof) which, individually or in the aggregate, represent a fundamental change in the information set forth in the registration statement. Notwithstanding the foregoing, any increase or decrease in
volume of securities offered (if the total dollar value of securities offered would not exceed that which was registered) and any deviation from the low or high end of the estimated maximum offering
range may be reflected in the form of prospectus filed with the Commission pursuant to Rule&nbsp;424(b) (&sect; 230.424(b) of this chapter) if, in the aggregate, the changes in volume and
price represent no more than a 20% change in the maximum aggregate offering price set forth in the "Calculation of Registration Fee" table in the effective registration statement. </FONT></P>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;(iii)&nbsp;&nbsp;To
include any material information with respect to the plan of distribution not previously disclosed in the registration statement or any material change to such
information in the registration statement; </FONT></P>

</UL>
</UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</FONT><FONT
SIZE=2><I>Provided, however,</I></FONT><FONT SIZE=2> that paragraphs (a)(i)&nbsp;and (a)(ii)&nbsp;do not apply if the information required to be included in a
post-effective amendment by those paragraphs is contained in periodic reports filed by the issuer pursuant to section&nbsp;13 or section&nbsp;15(d) of the Exchange Act that are
incorporated by reference herein. </FONT></P>

<UL>

<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;(b)&nbsp;&nbsp;That,
for the purpose of determining any liability under the Securities Act, each such post-effective amendment shall be deemed to be a new registration
statement relating to the securities offered herein, and the offering of such securities at that time shall be deemed to be the initial bona fide offering thereof. </FONT></P>


<P><FONT SIZE=2>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;(c)&nbsp;&nbsp;To
remove from registration by means of a post-effective amendment any of the securities being registered which remain unsold at the termination of the
offering. </FONT></P>

</UL>
<DL compact>
<DT style='margin-bottom:-11pt;'><FONT SIZE=2>2.</FONT></DT><DD><FONT SIZE=2>The
undersigned registrant hereby undertakes that, for purposes of determining any liability under the Securities Act, each filing of the registrant's annual report pursuant to
Section&nbsp;13(a) or Section&nbsp;15(d) of the Exchange Act (and, where applicable, each filing of an employee benefit plan's annual report pursuant to section&nbsp;15(d) of the Exchange Act)
that is incorporated by reference in the Registration Statement shall be deemed to be a new registration statement relating to the securities offered herein, and the offering of such securities at
that time shall be deemed to be the initial bona fide offering thereof.
<BR><BR></FONT></DD><DT style='margin-bottom:-11pt;'><FONT SIZE=2>3.</FONT></DT><DD><FONT SIZE=2>Insofar
as indemnification for liabilities arising under the Securities Act may be permitted to directors, officers and controlling persons of the registrant pursuant to the foregoing
provisions, or otherwise, the registrant has been advised that in the opinion of the Securities and Exchange Commission such indemnification is against public policy as expressed in the Securities Act
and is, therefore, unenforceable. In the event that a claim for indemnification against such liabilities (other than the payment by the registrant of expenses incurred or paid by a director, officer
or controlling person of the registrant in the successful defense of any action, suit or proceeding) is asserted by such director, officer or controlling person in connection with the securities being
registered, the registrant will, unless in the opinion of its counsel the matter has been settled by controlling precedent, submit to a court of appropriate jurisdiction the question whether such
indemnification by it is against public policy as expressed in the Securities Act and will be governed by the final adjudication of such issue. </FONT></DD></DL>
<P ALIGN="CENTER"><FONT SIZE=2>5</FONT></P>

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<P><br><A NAME="02SAN1574_1">QuickLinks</A><br></P><!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_be1574_1">INCORPORATION OF CERTAIN DOCUMENTS BY REFERENCE</A></FONT><BR>
<!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_jc1574_1">SIGNATURES</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_jc1574_2">POWER OF ATTORNEY</A></FONT><BR>
<!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_ka1574_1">EXHIBIT INDEX</A></FONT><BR>
<!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_la1574_1">DESCRIPTION OF SECURITIES</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_la1574_2">INTERESTS OF NAMED EXPERTS AND COUNSEL</A></FONT><BR>
<FONT SIZE=2><A HREF="#toc_la1574_3">INDEMNIFICATION OF DIRECTORS AND OFFICERS</A></FONT><BR>

<!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_lc1574_1">EXHIBITS</A></FONT><BR>
<!-- TOC_BEGIN -->
<FONT SIZE=2><A HREF="#toc_le1574_1">UNDERTAKINGS</A></FONT><BR>

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QuickLinks
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As filed with the Securities and Exchange Commission on June 28, 2002
Registration No. 333-
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM S-8
REGISTRATION STATEMENT
UNDER
THE SECURITIES ACT OF 1933
ISIS PHARMACEUTICALS, INC.
(Exact name of registrant as specified in its charter)
Delaware
33-0336973
(State of Incorporation)
(I.R.S. Employer Identification No.)
2292 Faraday Avenue
Carlsbad, CA 92008
(Address of principal executive offices)
2000 BROAD BASED EQUITY INCENTIVE PLAN
2000 EMPLOYEE STOCK PURCHASE PLAN
2002 NON-EMPLOYEE DIRECTORS' STOCK OPTION PLAN
(Full title of the plans)
B. Lynne Parshall, Esq.
Executive Vice President, Chief Financial Officer and Secretary
ISIS PHARMACEUTICALS, INC.
2292 Faraday Avenue
Carlsbad, California 92008
(760) 931-9200
(Name, address, including zip code, and telephone number, including area code, of agent for service)
Copies
to:
Julie M. Robinson, Esq.
COOLEY GODWARD LLP
4401 Eastgate Mall
San Diego, CA 92121
(858) 550-6000
CALCULATION OF REGISTRATION FEE
Title of Securities
to be Registered
Amount to be Registered(1)
Proposed Maximum
Offering
Price per Share(2)
Proposed Maximum
Aggregate
Offering Price (2)
Amount of
Registration Fee
Common Stock, par value $.001 per share
2,972,000 shares
$7.94
$23,597,680
$2,171
(1)
Includes
2,000,000 shares issuable pursuant to the Registrant's 2000 Broad Based Equity Incentive Plan (the "Equity Plan"), 400,000 shares issuable pursuant to the Registrant's 2000
Employee Stock Purchase Plan
(the "ESPP"), and 572,000 shares issuable pursuant to the Registrant's 2002 Non-Employee Directors' Stock Purchase Plan (the "NED Plan").
(2)
Estimated
solely for the purpose of calculating the amount of the registration fee pursuant to Rule 457(h)(1) of the Securities Act of 1933, as amended, (the "Securities Act").
The price per share and the aggregate offering price are calculated on the basis of $7.94, the average of the high and low sales prices of Registrant's Common Stock on June 24, 2002, as
reported on the NASDAQ National Market for the remainder of the shares subject to the Equity Plan and the NED Plan registered hereunder, as well as the shares subject to the ESPP.
INCORPORATION OF CERTAIN DOCUMENTS BY REFERENCE
The SEC allows us to "incorporate by reference" certain of our publicly-filed documents into this prospectus, which means that information included in those
documents is considered part of this prospectus. Information that we file with the SEC after the effective date of this prospectus will automatically update and supersede this information. We
incorporate by reference the documents listed below and any future filings made with the SEC under Sections 13(a), 13(c), 14 or 15(d) of the Exchange Act, until all the shares of common stock that are
part of this offering are sold.
The
following documents filed with the SEC are incorporated by reference in this prospectus:
•
our
Annual Report on Form 10-K for the year ended December 31, 2001;
•
our
Quarterly Report on Form 10-Q for the quarter ended March 31, 2002;
•
our
Current Report on Form 8-K, filed with the SEC on January 4, 2002;
•
our
Current Report on Form 8-K, filed with the SEC on January 7, 2002;
•
our
Current Report on Form 8-K, filed with the SEC on April 23, 2002;
•
our
Current Report on Form 8-K, filed with the SEC on April 24, 2002;
•
our
Current Report on Form 8-K, filed with the SEC on April 24, 2002; and
•
the
description of our common stock in our Registration Statement on Form 8-A filed with the SEC on April 12, 1991, as updated by
our Certificate of Amendment of our Restated Certificate of Incorporation filed with our Quarterly Report on Form 10-Q for the period ended June 30, 2001.
We
will furnish without charge to you, on written or oral request, a copy of any or all of the documents incorporated by reference, other than exhibits to those documents. You should
direct any requests for documents to Vice President of Finance at Isis' principal executive offices at 2292 Faraday Avenue, Carlsbad, California 92008, telephone number
(760) 931-9200.
2
SIGNATURES
Pursuant to the requirements of the Securities Act of 1933, as amended, the Registrant certifies that it has reasonable grounds to believe that it meets all of
the requirements for filing on Form S-8 and has duly caused this Registration Statement to be signed on its behalf by the undersigned, thereunto duly authorized, in the City of
Carlsbad, State of California, on June 27, 2002.
ISIS PHARMACEUTICALS, INC.
By:
/s/
B. LYNNE PARSHALL
B. Lynne Parshall
Executive Vice President, Chief Financial Officer and Secretary
(Principal Financial and Accounting Officer)
POWER OF ATTORNEY
Know
All Persons By These Presents, that each person whose signature appears below constitutes and appoints Stanley T. Crooke and B. Lynne Parshall, and each or any one of them, his true
and lawful attorney-in-fact and agent, with full power of substitution and resubstitution, for him and in his name, place and stead, in any and all capacities, to sign any and
all amendments (including post-effective amendments) to this Registration Statement, and to file the same, with all exhibits thereto, and other documents in connection therewith, with the
Securities and Exchange Commission, granting unto said attorneys-in-fact and agents, and each of them, full power and authority to do and perform each and every act and thing
requisite and necessary to be done in connection therewith, as fully to all intents
and purposes as he might or could do in person, hereby ratifying and confirming all that said attorneys-in-fact and agents, or any of them, or their or his substitutes or
substitute, may lawfully do or cause to be done by virtue hereof.
6
Pursuant
to the requirements of the Securities Act of 1933, this Registration Statement has been signed by the following persons in the capacities and on the dates indicated.
Signature
Title
Date
/s/
STANLEY T. CROOKE
Stanley T. Crooke, M.D., Ph.D.
Chairman of the Board, Chief Executive Officer and President (Principal Executive Officer)
June 27, 2002
/s/
B. LYNNE PARSHALL
B. Lynne Parshall
Executive Vice President and Chief Financial Officer (Principal Financial and Accounting Officer)
June 27, 2002
Spencer R. Berthelsen
Director
June    , 2002
Christopher F. O. Gabrieli
Director
June    , 2002
William R. Miller
Director
June    , 2002
/s/
FREDERICK T. MUTO
Frederick T. Muto
Director
June 27, 2002
/s/
JOHN C. REED
John C. Reed
Director
June 27, 2002
/s/
MARK B. SKALETSKY
Mark B. Skaletsky
Director
June 27, 2002
/s/
JOSEPH H. WENDER
Joseph H. Wender
Director
June 27, 2002
7
EXHIBIT INDEX
Exhibit
Number
5.1
Opinion of Grantland E. Bryce
23.1
Consent of Ernst & Young LLP, Independent Auditors
23.2
Consent of Grantland E. Bryce is contained in Exhibit 5.1 to this Registration Statement
24
Power of Attorney is contained on the signature pages.
99.1
2000 Broad Based Equity Incentive Plan
99.2
*
2000 Employee Stock Purchase Plan
99.3
**
2002 Non-Employee Directors' Stock Option Plan
*
Filed
as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 1999, and incorporated herein by reference.
**
Filed
as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2001, and incorporated herein by reference.
8
DESCRIPTION OF SECURITIES
Not applicable.
INTERESTS OF NAMED EXPERTS AND COUNSEL
The validity of the issuance of the common stock offered in this prospectus will be passed upon for Isis by Grantland E. Bryce, Vice President and General Counsel
of Isis. Mr. Bryce is the beneficial owner of options to purchase 102,500 shares of Isis common stock. As of June 21, 2002, Mr. Bryce will be vested as to options to purchase
65,876 shares of Isis common stock.
INDEMNIFICATION OF DIRECTORS AND OFFICERS
Under Section 145 of the Delaware General Corporation Law, we have broad powers to indemnify our directors and officers against liabilities they may incur
in such capacities, including liabilities under the Securities Act of 1933.
Our
certificate of incorporation and by-laws include provisions to (i) eliminate the personal liability of its directors for monetary damages resulting from breaches
of their fiduciary duty to the extent permitted by Section 102(b)(7) of the General Corporation Law of Delaware and (ii) require us to indemnify our directors and officers to the fullest
extent permitted by Section 145 of the Delaware Law, including circumstances in which indemnification is otherwise discretionary. Pursuant to Section 145 of the Delaware Law, a
corporation generally has the power to indemnify its present and former directors, officers, employees and agents against expenses incurred by them in connection with any suit to which they are, or
are threatened to be made, a party by reason of their serving in such positions so long as they acted in good faith and in a manner they reasonably believed to be in, or not opposed to, the best
interest of the corporation, and with respect to any criminal action, they had no reasonable cause to believe their conduct was unlawful. We believe that these provisions are necessary to attract and
retain qualified persons as directors and officers. These provisions do not eliminate the directors' duty of care, and, in appropriate circumstances, equitable remedies such as injunctive or other
forms of non-monetary relief will remain available under Delaware law. In addition, each director will continue to be subject to liability for breach of the directors' duty of loyalty to
us, for acts or omissions not in good faith or
involving intentional misconduct, for knowing violations of law, for acts or omissions that the director believes to be contrary to the best interests of Isis or our stockholders, for any transaction
from which the director derived an improper personal benefit, for acts or omissions involving a reckless disregard for the directors' duty to Isis or our stockholders when the director was aware or
should have been aware of a risk of serious injury to Isis or our stockholders, for acts or omissions that constitute an unexcused pattern of inattention that amounts to an abdication of the
director's duty to Isis or our stockholders, for improper transactions between the director and us and for improper distributions to stockholders and loans to directors and officers. The provision
also does not affect a director's responsibilities under any other law, such as the federal securities law or state or federal environmental laws.
We
have entered into indemnity agreements with each of our directors and executive officers that require us to indemnify such persons against expenses, judgments, fines, settlements and
other amounts incurred (including expenses of a derivative action) in connection with any proceeding, whether actual or threatened, to which any such person may be made a party by reason of the fact
that such person is or was a director or an executive officer of Isis or any of our affiliated enterprises, provided such person acted in good faith and in a manner such persons reasonably believed to
be in, or not opposed to, the best interests of Isis and, with respect to any criminal proceeding, has no reasonable cause to believe his conduct was unlawful. The indemnification agreements also set
forth procedures that will apply in the event of a claim for indemnification thereunder.
We
have an insurance policy covering our officers and directors with respect to certain liabilities, including liabilities arising under the Securities Act or otherwise.
3
EXHIBITS
Exhibit
Number
5.1
Opinion of Grantland E. Bryce
23.1
Consent of Ernst & Young LLP, Independent Auditors
23.2
Consent of Grantland E. Bryce is contained in Exhibit 5.1 to this Registration Statement
24
Power of Attorney is contained on the signature pages.
99.1
2000 Broad Based Equity Incentive Plan
99.2
*
2000 Employee Stock Purchase Plan
99.3
**
2002 Non-Employee Directors' Stock Option Plan
*
Filed
as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 1999, and incorporated herein by reference.
**
Filed
as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2001, and incorporated herein by reference.
4
UNDERTAKINGS
1.
The
undersigned registrant hereby undertakes:
(a)  To
file, during any period in which offers or sales are being made, a post-effective amendment to this registration statement:
(i)  To
include any prospectus required by section 10(a)(3) of the Securities Act;
(ii)  To
reflect in the prospectus any facts or events arising after the effective date of the registration statement (or the most recent post-effective amendment
thereof) which, individually or in the aggregate, represent a fundamental change in the information set forth in the registration statement. Notwithstanding the foregoing, any increase or decrease in
volume of securities offered (if the total dollar value of securities offered would not exceed that which was registered) and any deviation from the low or high end of the estimated maximum offering
range may be reflected in the form of prospectus filed with the Commission pursuant to Rule 424(b) (§ 230.424(b) of this chapter) if, in the aggregate, the changes in volume and
price represent no more than a 20% change in the maximum aggregate offering price set forth in the "Calculation of Registration Fee" table in the effective registration statement.
(iii)  To
include any material information with respect to the plan of distribution not previously disclosed in the registration statement or any material change to such
information in the registration statement;
Provided, however,
that paragraphs (a)(i) and (a)(ii) do not apply if the information required to be included in a
post-effective amendment by those paragraphs is contained in periodic reports filed by the issuer pursuant to section 13 or section 15(d) of the Exchange Act that are
incorporated by reference herein.
(b)  That,
for the purpose of determining any liability under the Securities Act, each such post-effective amendment shall be deemed to be a new registration
statement relating to the securities offered herein, and the offering of such securities at that time shall be deemed to be the initial bona fide offering thereof.
(c)  To
remove from registration by means of a post-effective amendment any of the securities being registered which remain unsold at the termination of the
offering.
2.
The
undersigned registrant hereby undertakes that, for purposes of determining any liability under the Securities Act, each filing of the registrant's annual report pursuant to
Section 13(a) or Section 15(d) of the Exchange Act (and, where applicable, each filing of an employee benefit plan's annual report pursuant to section 15(d) of the Exchange Act)
that is incorporated by reference in the Registration Statement shall be deemed to be a new registration statement relating to the securities offered herein, and the offering of such securities at
that time shall be deemed to be the initial bona fide offering thereof.
3.
Insofar
as indemnification for liabilities arising under the Securities Act may be permitted to directors, officers and controlling persons of the registrant pursuant to the foregoing
provisions, or otherwise, the registrant has been advised that in the opinion of the Securities and Exchange Commission such indemnification is against public policy as expressed in the Securities Act
and is, therefore, unenforceable. In the event that a claim for indemnification against such liabilities (other than the payment by the registrant of expenses incurred or paid by a director, officer
or controlling person of the registrant in the successful defense of any action, suit or proceeding) is asserted by such director, officer or controlling person in connection with the securities being
registered, the registrant will, unless in the opinion of its counsel the matter has been settled by controlling precedent, submit to a court of appropriate jurisdiction the question whether such
indemnification by it is against public policy as expressed in the Securities Act and will be governed by the final adjudication of such issue.
5
QuickLinks
INCORPORATION OF CERTAIN DOCUMENTS BY REFERENCE
SIGNATURES
POWER OF ATTORNEY
EXHIBIT INDEX
DESCRIPTION OF SECURITIES
INTERESTS OF NAMED EXPERTS AND COUNSEL
INDEMNIFICATION OF DIRECTORS AND OFFICERS
EXHIBITS
UNDERTAKINGS