OLIGONUCLEOTIDE MANUFACTURING AND

                                SUPPLY AGREEMENT





                                 By and between





                           ISIS PHARMACEUTICALS, INC.



                     2292 Faraday Avenue, Carlsbad, CA 92008

                       - Hereinafter referred to as ISIS -



                                       and



                        INTEGRATED DNA TECHNOLOGIES, INC.



                   1710 Commercial Park, Coralville, IA 52241

                       - Hereinafter referred to as IDT -





                                TABLE OF CONTENTS

{Table}



     {S}                                                                {C}

     Recitals.............................................................2

     Article 1  Definitions...............................................2

     Article 2  Oligonucleotide Supply Period and Deposit.................4

     Article 3  Program Oligonucleotide Specifications Committee..........5

     Article 4  Ordering, Pricing and Invoicing...........................6

     Article 5  Intellectual Property.....................................8

     Article 6  Representations and Warranties ...........................9

     Article 7  Confidential Information.................................12

     Article 8  Term and Termination.....................................13

     Article 9  Indemnification..........................................15

     Article 10 General..................................................15

     Appendix A.........................................................A-1

     Appendix B.........................................................B-1



{/Table}



                                       1

{Page}



                                    RECITALS



         WHEREAS, ISIS and its GeneTrove Division have a need for a reliable

supply of quality-controlled oligonucleotides for use in its antisense

functional genomics and target validation program; and



         WHEREAS, IDT has the expertise and manufacturing capacity sufficient

to supply ISIS quality controlled oligonucleotides at required volumes; and



         WHEREAS, both IDT and ISIS are willing to collaborate in continuous

efforts to refine IDT's oligonucleotides manufacturing, purification and quality

controlled techniques to ensure that ISIS receives optimized oligonucleotides

for use in its functional genomics program;



         NOW THEREFORE, IDT and ISIS agree to the following Oligonucleotide

Manufacturing and Supply Agreement according to the terms and conditions as

stated herein.





                                   ARTICLE 1:

                                  DEFINITIONS



For purposes of this Oligonucleotide Manufacturing and Supply Agreement, the

following words, phrases, or terms shall have the meanings as herein defined:



1.0      "Agreement" shall mean this Oligonucleotide Manufacturing and Supply

         Agreement, including Appendices A and B, as originally executed and as

         properly amended from time to time according to Article 10.



1.1      "Antisense Oligonucleotides" shall mean a polynucleotide,

         oligonucleotide or oligonucleotide analog, which hybridizes in a

         sequence specific manner under physiological conditions to RNA forming

         an RNA-DNA duplex, which duplex acts to modulate the production of a

         targeted gene product. An antisense oligonucleotide analog may include

         naturally occurring or non-natural heterocycles, sugar and/or backbone

         linkages, and may be a molecule in which the sugar may be absent, in

         which the backbone linkage may be phosphate based, amide based, or

         based on other chemistries and which may or may not include stem loop

         or structural units.



1.2      "Assigned Supply Period" shall mean the [***] year period immediately

         following the Effective Date.



1.3      "Assigned Systems" shall mean oligonucleotide synthesizers,

         purification and analytical instruments, and other supporting equipment

         assigned by IDT to support the manufacture and delivery of ISIS's

         requirements of Program Oligonucleotides.





                                       2

{Page}



1.4      "Business Day(s)" shall mean those days from Monday through Friday,

         which are not declared as national holidays in the United States, or as

         holidays routinely recognized by one or more of the Parties.



1.5      "Calendar Days" shall mean all days Sunday through Saturday, which

         appear on the calendar from January 1 through December 31.



1.6      "Customer Deposit" shall mean the credit for dedicated Program

         Oligonucleotide supply and Program Oligonucleotide purchases obtained

         by ISIS under this Agreement, which will be credited to the benefit of

         ISIS against Program Oligonucleotide purchases by ISIS at a rate of

         [***] of the monthly Program Oligonucleotide invoice described in

         section 4.8 herein.



1.7      "Dedicated Data Management System" shall mean the components of an

         integrated hardware and software system designed to support the

         isolated processing, tracking and storage of all information related to

         ISIS Program Oligonucleotide orders, with access limited to authorized

         personnel of IDT and/or ISIS.



1.8      "Effective Date" shall mean the execution date of the last signature on

         the signature page of this Agreement.



1.9      "IDT" shall mean Integrated DNA Technologies, Inc., and its affiliates,

         if any.



1.10     "IDT List Price" shall mean the then current IDT Catalog price for a

         specified product or service as displayed in IDT's World Wide Web

         On-line Catalog at (www.idtdna.com) or any successive Internet URL.



1.11     "Intellectual Property" shall mean and includes, but is not limited to,

         inventions (whether patentable or unpatentable), trade secrets, all

         present improvements thereto and future improvements thereto, and all

         United States, and foreign patents, patent applications, patent

         disclosures, and patentable inventions, together with all reissuances,

         continuations, continuations-in-part, divisionals, revisions,

         extensions and reexaminations thereof.



1.12     "ISIS" shall mean ISIS Pharmaceuticals, Inc., its and its divisions,

         including specifically GeneTrove-TM-.



1.13     "ISIS Supplied Reagent" shall mean those reagents to be supplied by

         ISIS to IDT that are necessary for the specific and limited purpose of

         enabling or optimizing IDT's manufacture and supply of MOE

         Oligonucleotides or Antisense Oligonucleotides to ISIS.





                                       3

{Page}



1.14     "MOE Oligonucleotides" shall mean oligonucleotides ordered from IDT by

         ISIS, which contain one or more of ISIS's proprietary 2'methoxy-ethoxy

         modifications (or any combination of an alkyl, alkoxy or thioalkoxy

         together with an ether, ester, amino or aminohydroxy substituent). With

         the exception of Appendix A and paragraph 4.2 herein, and at ISIS's

         sole discretion, MOE Oligonucleotide may also mean any Antisense

         Oligonucleotide ordered by ISIS from IDT.



1.15     "Parties" shall refer collectively to ISIS and IDT, each individually

         referred to as a "Party".



1.16     "Primers" shall refer to unmodified oligonucleotides used to promote

         amplification of a targeted sequence.



1.17     "Probes" shall refer to dye-labeled or similarly modified

         oligonucleotides used to detect and/or quantify the presence of a

         targeted sequence in a sample.



1.18     "Program Oligonucleotide" means a MOE Oligonucleotide and/or a

         Quantification Oligonucleotide conforming to the specifications and

         criteria set forth in Appendix A (as amended from time to time) for

         supply and delivery to ISIS.



1.19     "Quantification Oligonucleotide" shall mean Primers and Probes, either

         ordered individually by ISIS, or as 96-well plate combinations referred

         to as "Primer-Probes Sets" as defined in Appendix A (as amended from

         time to time).





                                    ARTICLE 2

                    OLIGONUCLEOTIDE SUPPLY PERIOD AND DEPOSIT



2.1      SUPPLY PERIOD. For the duration of the Assigned Supply Period, IDT will

         utilize the Assigned Systems to manufacture and sell Program

         Oligonucleotides ordered by ISIS according to the terms and conditions

         as described in this Agreement. This commitment by IDT includes the

         obligations of IDT to individually staff, train, and fully compensate,

         the personnel needed to operate the Assigned Systems for ISIS, and to

         otherwise fully manage the production and delivery of Program

         Oligonucleotides to ISIS.



2.2      SUPPLY DEPOSIT. ISIS shall advance IDT five million dollars

         ($5 million) to IDT within five (5) Business Days of the effective date

         of the Amended and Restated IDT-ISIS Licensing Agreement, in the form

         of Customer Deposit.



2.3      ASSIGNMENT OF MANUFACTURING CAPACITY. IDT will utilize the

         Customer Deposit to assign within its facility sufficient Program

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