Document:

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                                                CONFIDENTIAL TREATMENT REQUESTED
                              UNDER 17 C.F.R. SECTIONS 200.80(b)4, AND 240.24b-2

                           [ISIS PHARMACEUTICALS LOGO]

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                        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>

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                                    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.

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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.

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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
         Oligonucleotide synthesis, processing and purification capacity to
         manufacture [***] MOE Oligonucleotides and [***]

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         Quantification Oligonucleotides per calendar year for ISIS over the
         term of this Agreement.

2.4      DEDICATED DATA MANAGEMENT SYSTEM. IDT will further utilize the
         Customer Deposit to design and implement the Dedicated Data Management
         System to accommodate the expected ordering parameters of Program
         Oligonucleotides and to specifically track the utilization of ISIS's
         Customer Deposit.

2.5      SALE OF PROGRAM OLIGONUCLEOTIDES. For the duration of the Assigned
         Supply Period, IDT will make and sell Program Oligonucleotides to ISIS
         in accordance with the pricing provisions contained in Article 3. IDT
         will invoice ISIS at the listed prices less [***] for each Program
         Oligonucleotide ordered by ISIS and shipped by IDT, and shall reduce
         ISIS's Customer Deposit by the corresponding [***] sum.

                                    ARTICLE 3
                PROGRAM OLIGONUCLEOTIDE SPECIFICATIONS COMMITTEE

3.1      COMMITTEE OBJECTIVE. In order to ensure the manufacture and supply to
         ISIS of optimized Program Oligonucleotides for the duration of this
         Agreement, IDT and ISIS will form a joint committee of their respective
         employees to develop, enforce and continuously refine specifications
         for the manufacture, supply, and receipt of MOE Oligonucleotides and/or
         Quantification Oligonucleotides (the "Program Oligonucleotide
         Specifications Committee").

3.2      COMMITTEE FORMATION AND MANAGEMENT. It is contemplated by the Parties
         that all decisions affecting or regarding Program Oligonucleotide
         specifications (Appendix A) will be the result of informed deliberation
         and mutual consent of the Program Oligonucleotide Specifications
         Committee (POSC). Each Party shall appoint a Committee Co-Chair, who
         will have the joint authority, independent of the POSC, to make any
         decision regarding modifications to the Program Oligonucleotide
         specifications. The Co-Chairs will appoint additional individuals to
         serve on the POSC. The POSC will meet at least once monthly to review
         the performance of each Party under the Agreement, to forecast future
         supply requirements, and to resolve any Program Oligonucleotide supply,
         quality and/or invoicing issues. The POSC will instruct staff members
         to direct all related issues or concerns through the POSC and will
         distribute minutes of its meetings to the relevant members of their
         organizations. IDT hereby appoints Trey Martin and ISIS hereby appoints
         Henry Sasmor as the acting Committee Co-Chairs for each respective
         Party.

3.3      INITIAL OLIGO SPECIFICATION DEVELOPMENT. The specifications listed on
         Appendix A will serve as the Program Oligonucleotide Specifications
         until amended by POSC. Within ten (10) days of the Effective Date, the
         POSC will meet to initiate the controlled development of refined
         manufacturing specifications (including yield, purity, quality control
         tests and criteria, shipping standards, remake policies, etc.) for both
         MOE Oligonucleotides and Quantification Oligonucleotides.

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3.4      SCOPE OF POSC AUTHORITY. The POSC (or the Co-Chairs acting jointly)
         has the authority to change the following with respect to Program
         Oligonucleotide specifications: synthesis scale; yield guarantees;
         chemical compositions; purity requirements; analytical or quality
         control tests and/or specifications; and all pricing changes directly
         related to such changes, provided that the resulting prices reflect,
         whenever possible, the fixed percentage discount rate of paragraph 4.3.
         All price changes require the signed written agreement of both
         Co-Chairs prior to their use in an invoice issued to ISIS pursuant to
         paragraph 4.8 hereunder. The POSC shall not have the authority to apply
         Customer Deposit to oligonucleotides or other products other than to
         Program Oligonucleotides.

                                    ARTICLE 4
                         ORDERING, PRICING AND INVOICING

4.1      PROGRAM OLIGONUCLEOTIDE ORDERING. ISIS shall place all orders for
         Program Oligonucleotides over the Dedicated Data Management System,
         using the customer order entry software developed by IDT for ISIS
         pursuant to paragraph 2.5.

4.2      MOE OLIGONUCLEOTIDE PRICING. Subject to the provisions contained in
         paragraphs 2.4, 4.4, and 4.5 hereunder, the invoice price for MOE
         Oligonucleotides prior to the application of Customer Deposit will be:

                  (i)      [***] for each MOE Oligonucleotide manufactured on
                           the [***] scale that meets the MOE specifications;

                  (ii)     [***] for each MOE Oligonucleotide manufactured on
                           the [***] scale that meets the MOE specifications.

4.3      QUANTIFICATION OLIGONUCLEOTIDE PRICING/FIXED PERCENTAGE DISCOUNT.
         Subject to the provisions contained in paragraphs in 2.4, 4.4 and 4.5
         hereunder, the invoice price for Quantification Oligonucleotides
         (and/or Antisense Oligonucleotide) prior to application of Customer
         Deposit shall be [***] of the IDT List Price for corresponding
         oligonucleotide Primers and/or Probes and the associated purification,
         analytical and/or set-up fees. This fixed percentage discount is also
         to be used by the POSC to guide its pricing decisions relevant to
         changes to MOE Oligonucleotide specifications, including specifically
         changes to purification, analytical, loading, shipping or handling
         specifications. Appendix B illustrates the application of this fixed
         percentage discount to Primer-Probe Sets and MOE Oligonucleotides using
         IDT List Prices.

4.4      EXTERNAL FACTORS & PRICE INCREASES. IDT warrants that it has performed
         adequate manufacturing cost-forecasting to ensure that IDT can supply
         Program Oligonucleotides in commercially viable fashion at the above
         quoted per base prices or at the established [***] discount. However,
         should unforeseeable events beyond the control of IDT cause the
         manufacturing costs of IDT to increase by [***] then IDT shall have the
         right to

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         increase the per [***] price to reflect the increased manufacturing
         cost. The term "unforeseeable events" as used in this paragraph
         includes, but is not limited to:

           (i)    new and substantial regulatory or legal restrictions imposed
                  on the manufacture of oligonucleotides or related
                  manufacturing processes;

           (ii)   substantial increase(s) in the cost of necessary
                  oligonucleotide manufacturing amidites, reagents, solvents, or
                  quality control components, necessary to manufacture Program
                  Oligonucleotides;

         Should IDT rely upon "unforeseeable events" beyond the control of IDT
         as a basis for a price increase, IDT shall immediately as is practical
         disclose in writing to ISIS through the POSC the cause of the price
         increase, and IDT's relevant manufacturing costs in sufficient detail
         to allow for confirmation of the costs by ISIS.

4.5      PRICE DECREASES/MOST FAVORED PRICING. If there are substantial
         decreases in the market cost of commercial amidites, reagents,
         solvents, or quality control components necessary to manufacture
         Program Oligonucleotides that result in [***] or greater reduction in
         the average cost [***] to IDT, then IDT shall reduce the [***] price
         charges to ISIS by the amount greater than the [***] cost per base
         threshold.

4.6      TURNAROUND. The specifications and requirements for delivery of
         manufacture of Program Oligonucleotides will be those specifications
         and turnaround requirements identified in Appendix A, as amended from
         time-to-time by the POSC.

4.7      SUPPLY FORECASTS/ISIS SUPPLIED REAGENT INVENTORY. On or before the
         [***] of each month during the Assigned Supply Period, ISIS will supply
         IDT with a forecast of its intended Program Oligonucleotide orders for
         the following month. IDT will advise ISIS within [***] Days of receipt
         of its ability to meet the forecast. IDT will specifically advise ISIS
         of its then current inventory of ISIS Supplied Reagents and of its need
         for additional ISIS Supplied Reagents to meet the forecast for the
         following month. It is the expectation of both Parties that IDT will:

                  (i)      maintain on-site, a constant minimum [***] inventory
                           of quality-controlled ISIS Supplied Reagents;

                  (ii)     maintain available manufacturing capacity to meet any
                           forecast that requires a monthly MOE Oligonucleotide
                           supply of [***] MOE Oligonucleotides or less, and a
                           monthly Quantification Oligonucleotide supply of
                           [***] Primer-Probe Sets or less;

                  (iii)    make reasonable efforts to meet forecasts that exceed
                           those limits in (ii) above. In the event that an ISIS
                           forecast is for volumes of Program Oligonucleotides,
                           which volumes are [***] greater than the prior month,
                           then IDT's ability to meet such a forecast may
                           require a scale-up period.

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4.8      INVOICING. During the Assigned Supply Period, IDT will invoice ISIS
         following the close of each month in accordance with 2.5 herein, for
         Program Oligonucleotides delivered that meet the specifications
         established by the POSC. Payment of the invoice by ISIS will be due
         within [***] Days from receipt of the invoice by ISIS, and payment will
         be made by electronic wire transfer into an account as designated by
         IDT. Should ISIS fail to pay the full invoice within [***] Days, IDT
         will have the right to suspend Program Oligonucleotide manufacturing
         until the invoice is paid in full.

4.9      MOST-FAVORED QUANTIFICATION OLIGONUCLEOTIDE PRICING. In addition to
         IDT's commitment to maintain a fixed [***] discount for Quantification
         Oligonucleotides and Antisense Oligonucleotides, IDT agrees not to
         extend more favorable pricing to third-parties with comparable orders
         for Antisense Oligonucleotides and/or Probes, whether ordered
         individually or as part of a Primer-Probe Set. For purposes of this
         provision, "comparable orders" shall mean orders for oligonucleotides
         in equal or lesser volumes, on the same or substantially similar scale,
         with the same or substantially similar modifications, purification or
         purity requirements, analytical specifications, and loading
         requirements. This provision shall not apply to more favorable prices
         extended to third-parties by IDT for Primers ordered without
         corresponding orders for Probes, nor shall it apply to Probes, Primers,
         or Antisense Oligonucleotides when sold or transferred in any of the
         following non-limiting circumstances: as part of a bona-fide research
         collaboration; as a component of a kit; as part of a defined promotion;
         as a test-order; or as a remake.

4.10     CUSTOMER DEPOSIT DEPLETION. Unless IDT and ISIS agree in writing to
         extend the Agreement and the Assigned Supply Period, any unused
         portions of the Customer Deposit at the end of the Assigned Supply
         Period will be forfeited by ISIS and will become the exclusive property
         of IDT.

                                    ARTICLE 5
                              INTELLECTUAL PROPERTY

5.1      INVENTIONS AND DISCOVERIES. The Parties do not anticipate but do
         acknowledge that Intellectual Property may be developed through the
         joint efforts of the Parties and their employees under this Agreement.
         If Intellectual Property is developed by an individual Party, or by or
         through the joint efforts of the Parties, the ownership of the
         Intellectual Property, whether joint or separate, will be determined by
         the relevant applicable United States patent laws. In the event that an
         invention or know-how is developed through the joint or collaborative
         efforts of the Parties and their employees, IDT and ISIS agree to
         instruct their respective employees to report the invention or the
         development in a thorough and prudent manner to the management of the
         respective Parties, and each Party and agrees to notify the other Party
         of the invention or the development as soon as commercially practical
         following internal reporting. The Parties thereafter agree to initiate
         good faith negotiations directed toward the completion of a separate
         written agreement directed to licensing and/or assignment of such
         Intellectual Property.

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5.2      TRADENAMES AND TRADEMARKS. IDT acknowledges that GeneTrove-TM- and
         ISIS, among others, are trademarks and tradenames of ISIS, and that
         nothing in this Agreement is intended as a grant to IDT, express,
         implied, or otherwise, to use any trademark, tradename or trade dress
         of ISIS unless expressly agreed to in writing by ISIS.

5.3      PROGRAM OLIGONUCLEOTIDES AND OLIGONUCLEOTIDE MANUFACTURING METHODS.
         Notwithstanding the provisions of paragraph 5.1, ISIS shall be the sole
         owner of the Program Oligonucleotides, which are or contain the
         Confidential Information of ISIS and subject to the provisions of
         Article 7. Except with respect to patents and patent applications
         exclusively licensed to IDT in the field of antisense technology, IDT
         hereby assigns its entire worldwide right, title, and interest, if any,
         in any Program Oligonucleotide to ISIS, and IDT agrees to take all
         necessary action to effect any such transfer, and to cooperate with and
         assist ISIS, at ISIS's expense, in the pursuit, enforcement, and
         defense of any Intellectual Property rights in any Program
         Oligonucleotide. IDT shall be the sole owner of the oligonucleotide
         manufacturing and tracking methods developed by IDT prior to and/or
         during the term of this Agreement, including, but not limited to, IDT's
         proprietary technology in the following fields: oligo reagent
         preparation methods; oligo synthesis methods; oligo processing and
         automation protocols; oligo mass order entry software; oligo tracking
         software; and oligo quality control systems; excluding, however, the
         aforementioned IDT manufacturing and tracking methods pertaining
         specifically and/or exclusively to ISIS Supplied Reagents.

                                    ARTICLE 6
                         REPRESENTATIONS AND WARRANTIES

6.1      REPRESENTATIONS AND WARRANTIES BY IDT:

         IDT represents and warrants as follows:

           (i)    IDT is a corporation duly organized, validly existing and in
                  corporate good standing under the laws of the State of Iowa;

           (ii)   IDT has the legal right, authority and power to enter into
                  this Agreement;

           (iii)  IDT has taken all necessary action to authorize the execution,
                  delivery and performance of this Agreement;

           (iv)   upon the execution and delivery of this Agreement, this
                  Agreement shall constitute valid and binding obligations
                  against IDT enforceable in accordance with its terms, except
                  as enforceability may be limited by applicable bankruptcy,
                  insolvency, reorganization, moratorium or similar laws
                  affecting creditors' and contracting parties' rights
                  generally;

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           (v)    the performance of its obligations under this Agreement will
                  not conflict with its charter documents or result in a breach
                  of any agreements, contracts or other arrangements to which it
                  is a Party;

           (vi)   IDT will not during the term of this Agreement enter into any
                  agreements, contracts or other arrangements that would be
                  inconsistent with its obligations under this Agreement;

           (vii)  IDT has obtained, or will obtain, all governmental permits,
                  licenses, agreements, contracts, and other enabling documents
                  to fully implement and fulfill its duties hereunder; and

           (viii) IDT represents and warrants that all employees or others
                  acting on its behalf pursuant to this Agreement are and shall
                  be obligated under a binding written agreement to assign to
                  IDT all inventions made or conceived by such employee or other
                  person.

6.2      REPRESENTATIONS AND WARRANTIES BY ISIS:

         ISIS represents and warrants as follows:

           (i)    ISIS is a corporation duly organized, validly existing and
                  in corporate good standing under the laws of the State of
                  Delaware;

           (ii)   ISIS has the legal right, authority and power to enter into
                  this Agreement;

           (iii)  ISIS has taken all necessary action to authorize the
                  execution, delivery and performance of this Agreement;

           (iv)   upon the execution and delivery of this Agreement, this
                  Agreement shall constitute valid and binding obligations
                  against ISIS enforceable in accordance with its terms, except
                  as enforceability may be limited by applicable bankruptcy,
                  insolvency, reorganization, moratorium or similar laws
                  affecting creditors' and contracting parties' rights
                  generally;

           (v)    the performance of its obligations under this Agreement will
                  not conflict with its charter documents or result in a breach
                  of any agreements, contracts or other arrangements to which it
                  is a Party;

           (vi)   to the best of ISIS's knowledge, IDT's manufacture of
                  Program Oligonucleotides for use by ISIS does not constitute
                  contributory infringement with respect to any issued patent of
                  any third party that has issued prior to the effective date of
                  this Agreement;

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           (vii)  ISIS will not during the term of this Agreement enter into any
                  agreements, contracts or other arrangements that would be
                  inconsistent with its obligations under this Agreement; and,

           (viii) ISIS represents and warrants that all employees or others
                  acting on its behalf pursuant to this Agreement are and shall
                  be obligated under a binding written agreement to assign to
                  ISIS all inventions made or conceived by such employee or
                  other person.

6.3      LIMITED WARRANTY FOR PROGRAM OLIGONUCLEOTIDES. IDT warrants that
         Program Oligonucleotides will meet the specifications as determined in
         Appendix A, and as later amended by the POSC if applicable. This
         limited warranty represents ISIS's sole and exclusive remedy with
         respect to Program Oligonucleotides manufactured for and sold to ISIS
         or its Affiliates. IDT does not warrant, guarantee or make any
         representations above and beyond the criteria set forth in Appendix A
         (as amended from time to time) regarding the use of Program
         Oligonucleotides in functional genomics, target validation, or any
         other application, or with respect to the correctness, accuracy,
         reliability or otherwise of the results of any such use. ISIS ASSUMES
         THE ENTIRE RISK AS TO THE RESULTS OBTAINED FROM THE USE OF PROGRAM
         OLIGONUCLEOTIDES. ISIS FURTHER ACKNOWLEDGES THAT ISIS, AND NOT IDT, IS
         SOLELY RESPONSIBLE FOR ANY WARRANTY OR GUARANTEE MADE TO COLLABORATORS
         OF ISIS OR GENETROVE WITH RESPECT TO THE USE OF PROGRAM
         OLIGONUCLEOTIDES. THE FOREGOING WARRANTY IS EXCLUSIVE AND IS MADE IN
         LIEU AND TO THE EXCLUSION OF ANY OTHER WARRANTIES, WHETHER ORAL OR
         WRITTEN, EXPRESS OR IMPLIED, DIRECT OR INDIRECT, BY ESTOPPEL, OR BY
         EFFECT OF THE UNIFORM COMMERCIAL CODE, USAGE IN THE INDUSTRY OR THROUGH
         COURSE OF DEALINGS OF THE PARTIES, INCLUDING BUT NOT LIMITED TO THOSE
         CONCERNING MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE.

6.4      NO CONSEQUENTIAL DAMAGES. NEITHER PARTY HERETO WILL BE LIABLE FOR
         SPECIAL, INCIDENTAL OR CONSEQUENTIAL DAMAGES ARISING OUT THE
         MANUFACTURE, SALE OR USE OF PROGRAM OLIGONUCLEOTIDES UNDER THIS
         AGREEMENT, OR ARISING OUT OF THE EXERCISE OF EITHER PARTY'S RIGHTS
         HEREUNDER, REGARDLESS OF ANY NOTICE OF SUCH DAMAGES.

                                    ARTICLE 7
                             CONFIDENTIAL INFORMATION

7.1      CONFIDENTIAL INFORMATION. For the purpose of this Agreement,
         Confidential Information means all information, data, and material,
         labeled or otherwise designated or identified as confidential by ISIS
         or by IDT.

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7.2      DESIGNATED CONFIDENTIAL INFORMATION OF ISIS. All information relating
         to Program Oligonucleotides including specifically target sequences
         (i.e., the sequence ordered and/or its complementary sequence or
         components thereof) ordered by ISIS during the course of this Agreement
         are hereby permanently designated as ISIS Confidential Information.
         ISIS agrees that it will, in writing, clearly identify as confidential,
         any and all additional information that it provides to IDT that it
         considers to be the Confidential Information of ISIS.

7.3      DESIGNATED CONFIDENTIAL INFORMATION OF IDT. Any and all data generated
         by IDT's validation or use of the Assigned Systems and/or the Dedicated
         Data Management System, except for the information described in 7.2
         herein, are hereby designated as IDT's Confidential Information. IDT
         agrees that it will, in writing, clearly identify as confidential, any
         and all such information that it provides to ISIS that it considers to
         be the Confidential Information of IDT.

7.4      USE OF CONFIDENTIAL INFORMATION. Each Party may use the other Party's
         Confidential Information only for the purpose of performing each
         Party's duties and obligations under this Agreement.

7.5      OBLIGATIONS OF CONFIDENTIALITY. Except as expressly provided herein,
         ISIS and IDT, and their officers, employees, agents, consultants, and
         authorized representatives (a) shall hold in strict confidence all
         Confidential Information from the other Party or any of its officers,
         employees, agents or representatives and (b) shall not distribute,
         disclose or disseminate such Confidential Information to any third
         party without the prior written approval of the other Party (that is,
         the original disclosing Party), provided, however, that such approval
         will not be unreasonably withheld where the receiving Party reasonably
         believes that disclosure of the other Party's Confidential Information
         is reasonably necessary to obtain patents, authorization to conduct
         clinical trials, or regulatory approval.

7.6      OTHER INFORMATION. For purposes of this section, information will not
         be considered to be Confidential Information of a Party if the
         information:

           (i)    was lawfully in the receiving Party's possession prior to
                  disclosure under this Agreement and was not acquired directly
                  or indirectly from the disclosing Party; or,

           (ii)   was, at the date of disclosure by the disclosing Party, public
                  knowledge; or subsequently becomes public knowledge other than
                  through the failure of the receiving Party to comply with its
                  obligations of confidentiality under the terms of this
                  Agreement; or,

           (iii)  was or is acquired by the receiving Party from any third party
                  lawfully having possession of such information and who is not
                  under an obligation of confidentiality to the disclosing
                  Party; or,

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           (iv)   was or becomes independently known by the receiving Party
                  without utilizing information provided by the disclosing Party
                  and wherein such independent knowledge is supported in
                  contemporaneously written and dated documentation of the
                  receiving Party; or,

           (v)    is required to be disclosed, retained, or maintained by either
                  Party, by applicable law or regulation or under the rules of
                  any regulatory or governmental authority, including
                  specifically federal district courts; provided however that
                  each Party shall immediately notify the other Party in writing
                  of such required disclosure and must provide such notice at
                  least thirty (30) days prior to the date when disclosure is
                  proposed to take place, and provided that the Party or third
                  party required to make disclosure shall use its best efforts
                  to secure confidential treatment of any such information
                  required to be disclosed.

7.7      ADDITIONAL REMEDIES. The Parties hereto understand and agree that
         remedies at law may be inadequate to protect against any breach of any
         of the provisions of this Article 7 by either Party or their employees,
         agents, officers or directors or any other person acting in concert
         with it or on its behalf. Accordingly, each Party shall be entitled to
         the granting of injunctive relief by a court of competent jurisdiction
         against any action that constitutes any such breach of this Article 7.

7.8      EXTENDED TERM. The provisions of this Article 7 shall survive any
         termination or expiration of this Agreement and continue in force for a
         period of [***] years.

                                    ARTICLE 8
                              TERM AND TERMINATION

8.1      TERM. The term of this Agreement will be from the Effective Date and
         will continue for a period of eight (8) years from the Effective Date,
         unless earlier terminated by a Party or the Parties under one of the
         provisions of this Article 8.

8.2      BANKRUPTCY. This Agreement shall terminate upon written notice subject
         to paragraph 10. 4, by one Party to the other Party in the event the
         other Party shall become insolvent, asks its creditors for a
         moratorium, files a bankruptcy petition, or suffers appointment of a
         temporary or permanent receiver, trustee, or custodian, for all or a
         substantial portion of its assets. In the event of any termination
         pursuant to this provision, any unused Customer Deposit shall be
         immediately forfeited by ISIS, and shall become the exclusive property
         of IDT.

8.3      TERMINATION. Either Party may terminate this Agreement for default by
         the other Party in performing any of its material obligations under
         this Agreement by notifying the other Party in writing of such default
         and allowing the other Party [***] Days within which to cure such
         default, unless the default is the failure to pay money, in which case
         the defaulting Party shall have only [***] Days to cure such default
         after receiving written

                                       13
<Page>

         notice of non-payment. If such default is not cured within [***] Days
         from receipt of such notice of default (or [***] Days in the case of
         non-payment of money owed), the non-defaulting Party may terminate
         this Agreement by written notice, subject to paragraph 10.4, to the
         defaulting Party.

8.4      ELECTIVE TERMINATION. ISIS may terminate this Agreement by providing
         IDT [***] days written notice if IDT materially fails to comply with
         any of the Program Oligonucleotide manufacturing or supply requirements
         set forth in Article 4 and in Appendix A, as amended from time to time.
         The Parties recognize and acknowledge that the production of Program
         Oligonucleotides conforming to the specifications is important to ISIS
         and is a material term of this Agreement, and further that time is of
         the essence with respect to ISIS's demand for Program Oligonucleotides.
         IDT's failure to materially produce and deliver Program
         Oligonucleotides to ISIS as set forth in Article 4 and in conformity
         with the specifications, is considered a material breach of this
         Agreement and must be cured to the satisfaction of ISIS within [***]
         Days of notice of the same to IDT by ISIS. Failure by IDT to cure such
         a breach within thirty [***] Days is grounds for ISIS's elective
         termination of this Agreement. In the event IDT refuses to supply
         Program Oligonucleotides to ISIS in accordance with Article 2 herein,
         and/or IDT refuses to cure a material breach of this Agreement, such
         acts shall constitute an elective termination by IDT, and in such
         events ISIS shall be entitled to a refund of its unused and outstanding
         Customer Deposit.

8.5      EFFECT OF EXPIRATION OR TERMINATION OF AGREEMENT. Within [***] days
         after expiration or termination (the date of termination will be the
         date upon which the [***] day notice period lapses) of this Agreement,
         each Party shall return to the other Party any and all Confidential
         Information (Article 7) provided by the other Party pursuant to this
         Agreement. ISIS shall have the right to obtain and use all Program
         Oligonucleotides for which ISIS has paid and that are in IDT's
         possession, or that are scheduled to be manufactured, at the time of
         termination. Except to the extent expressly provided to the contrary,
         the rights and obligations of the Parties pursuant to Articles 5,6,7 9,
         and 10, shall survive the expiration or termination of this Agreement.
         Any and all rights of IDT to payments accrued through expiration or
         termination as well as obligations of the Parties under firm orders for
         purchase and delivery of Program Oligonucleotides at the time of such
         expiration or termination shall remain in effect. IDT will have no
         obligation to sell and deliver Program Oligonucleotides to ISIS that
         have delivery dates more than thirty (30) Business Days after the date
         of termination, and in the case of termination under paragraphs 8.2 or
         8.3, the terminating Party has discretion in electing whether firm
         orders will remain in effect. Upon expiration of this Agreement, or
         termination of this Agreement for reasons other than an IDT elective
         termination as defined in 8.4 herein, any unused Customer Deposit shall
         be forfeited by ISIS and will default to IDT. Upon termination of this
         Agreement under paragraphs 8.2, 8.3, or 8.4, or upon expiration of this
         Agreement under 8.1, IDT shall immediately transfer to ISIS possession
         of ISIS Supplied Reagents upon notice from ISIS of the final
         post-termination receipt of Program Oligonucleotides, if any.

                                       14
<Page>

                                    ARTICLE 9
                                 INDEMNIFICATION

9.1      INDEMNIFICATION. Each Party (the "Indemnifying Party") agrees to defend
         the other Party and such other Party's Affiliates and their respective
         directors, officers, employees and agents (the "Indemnified Parties")
         at the Indemnifying Party's cost and expense, and shall hold the
         Indemnified Parties harmless from and against any losses, costs,
         damages, fees or expenses arising out of any third party claim relating
         to (i) any breach by the Indemnifying Party of any of its
         representations, warranties or obligations pursuant to this Agreement,
         or (ii) product liability or liability stemming from allegations of
         contributory infringement resulting from use of a product made, sold or
         imported by or for the Indemnifying Party.

9.2      NOTICE/REPRESENTATION. In the event of any claim against the
         Indemnified Parties by any third party for which indemnification may be
         sought pursuant to this Agreement, the Indemnified Party shall promptly
         notify the Indemnifying Party in writing of the claim; provided that
         the failure to promptly notify the Indemnifying Party of such claim
         shall not result in the loss of rights of indemnification hereunder
         except to the extent that the Indemnifying Party was materially
         prejudiced by such failure. The Indemnifying Party shall assume, at its
         sole expense, the defense of the claim and its settlement. The
         Indemnified Parties shall cooperate with the Indemnifying Party and
         may, at their option and expense, be represented in any such action or
         proceeding. The Indemnifying Party shall not be liable for any
         litigation costs or expenses incurred by the Indemnified Parties. In
         addition, the Indemnifying Party shall not be responsible for the
         indemnification of any Indemnified Party arising from any negligent or
         wrongful acts by such Indemnified Party, or as the result of any
         settlement or compromise by the Indemnified Parties without the
         Indemnifying Party's prior written consent. The Indemnifying Party may
         not settle or compromise any matter without the consent of the
         Indemnified Parties unless such settlement or compromise imposes no
         obligations on the Indemnified Parties and does not restrict the rights
         of the Indemnified Parties.

                                   ARTICLE 10
                                     GENERAL

10.1     GOVERNING LAW. This Agreement shall be construed and the respective
         rights of the Parties determined according to the laws of the State of
         New York (without regard to the conflict of law rules of any
         jurisdiction), except as regarding matters of intellectual property
         law, which shall be determined in accordance with the national
         intellectual property laws relevant of the intellectual property in
         question.

10.2     ASSIGNMENT. Neither IDT nor Isis may assign this Agreement in whole or
         in part without the consent of the other Party, except if such
         assignment occurs in connection with the sale or transfer of all or
         substantially all of the business or assets of the assigning Party to
         which the subject matters of this Agreement pertains.

                                       15
<Page>

10.3     ENTIRE AGREEMENT; AMENDMENTS. This Agreement, together with the
         Appendices incorporated herein, constitute the entire agreement between
         the Parties with respect to the subject matter hereof, and supersedes
         all previous arrangements with respect to the subject matter hereof,
         whether written or oral. Any amendment or modification to this
         Agreement shall be made in writing signed by both Parties.

10.4     NOTICES.  Notices with respect to IDT shall be sent to:

                 Joseph A. Walder, M.D., Ph.D.
                 Attn: Legal Department
                 Integrated DNA Technologies, Inc.
                 1710 Commercial Park
                 Coralville, IA
                 52241-9802;

                 With a duplicate sent to:

                 Mark Campbell, J.D., COO
                 Corporate Vice President
                 Integrated DNA Technologies, Inc.
                 8930 Gross Point Road, Suite 700
                 Skokie, Illinois,
                 60077;

         and with respect to ISIS:

                 B. Lynne Parshall, J.D.
                 Isis Pharmaceuticals, Inc.
                 Executive Vice President and CFO
                 2292 Faraday Avenue
                 Carlsbad, CA
                 92008

                 With a duplicate sent to:

                 President, GeneTrove Division
                 Isis Pharmaceuticals, Inc.
                 2292 Faraday Avenue
                 Carlsbad, CA
                 92008

         Any Party may change its address by giving notice to the other Party in
         the manner herein provided. Any notice required or provided for by the
         terms of this Agreement shall be in writing and shall be (a) delivered
         personally, (b) sent by registered or certified mail, return receipt
         requested, postage prepaid, (c) sent via a reputable overnight courier
         service, or (d)

                                       16
<Page>

         sent by facsimile transmission with an original to be followed the same
         day via a reputable overnight courier service, in each case properly
         addressed in accordance with the paragraph above. The effective date of
         notice shall be the actual date of receipt by the Party receiving the
         same.

10.6     FORCE MAJURE. No failure or omission by a Party in the performance of
         any of its obligations of this Agreement shall be deemed a breach of
         this Agreement or create any liability if the same shall arise from any
         cause or causes beyond the control of such Party, including, but not
         limited to, the following: acts of God; acts or omissions of any
         government; any rules, regulations or orders issued by any governmental
         authority or by any officer, department, agency or instrumentality
         thereof; fire; storm; flood; earthquake; accident; war; rebellion;
         insurrection; riot; terrorist activities; and invasion and provided
         that such failure or omission resulting from one of the above causes is
         cured as soon as is practicable after the occurrence of one or more of
         the above-mentioned causes.

10.7     DISCLOSURE OF PROVISIONS OF AGREEMENT.

         Each Party agrees to hold as confidential the terms of this Agreement,
         except that:

                  (i)      IDT may furnish a copy of this Agreement to the
                           University of Iowa Research Foundation; and,

                  (ii)     Each Party shall have the right to disclose the terms
                           of this Agreement to investors and other third
                           parties in connection with financing activities and
                           to potential collaborators, provided that any such
                           third party has entered into a written obligation
                           with the disclosing Party to treat such information
                           and materials as confidential and to not use the
                           information materials for any purposes other than the
                           evaluation of the potential investment or
                           collaboration and that the disclosing Party shall
                           enforce against the third party recipient of such
                           information and materials, for and on behalf of the
                           other Party, such written obligation; and,

                  (iii)    Each Party may furnish a copy of this Agreement or
                           disclose the terms of this if such is required to be
                           disclosed by the receiving Party to comply with
                           applicable laws, to defend, prosecute or preclude
                           litigation, or to comply with governmental
                           regulations, PROVIDED THAT the receiving Party
                           provides prior written notice of such disclosure to
                           the disclosing Party and takes reasonable and lawful
                           actions to avoid and/or minimize the degree of such
                           disclosure. At the request of the other Party, the
                           disclosing Party shall use commercially reasonable
                           efforts to enforce such obligations against such
                           third parties.

                  (iv)     Each Party may include this Agreement, in any report,
                           statement or other document filed by such Party with
                           the United States Securities and Exchange Commission
                           (the "SEC"). In such event, the disclosing Party
                           shall use reasonable efforts to obtain, to the extent
                           permitted by law,

                                       17
<Page>

                           confidential treatment from the SEC of any trade
                           secrets and commercial or financial information of
                           a privileged or confidential nature, including
                           without limitation all information on the Exhibits
                           hereto relating to patent applications of Isis or
                           IDT, and shall notify the other Party as to such
                           efforts and all related communications with the
                           SEC; provided that notwithstanding the foregoing
                           no Party shall submit a confidentiality request or
                           include this Agreement without the prior review
                           and approval of the confidentiality request by the
                           other Party, which review and approval shall not
                           be unreasonably withheld or delayed.

                  (v)      The Parties will cooperate in the development of any
                           public announcement announcements or similar
                           publicity with respect to the execution of this
                           Agreement. The content and timing of any such
                           announcement or publicity shall be agreed upon
                           between Parties in advance of such announcement.

10.8     INDEPENDENT CONTRACTORS. It is understood and agreed that the
         relationship between the Parties hereunder is that of independent
         contractors and that nothing in this Agreement shall be construed as
         authorization for either Party to act as agent for the other.

10.9     NO STRICT CONSTRUCTION. This Agreement has been prepared jointly and
         shall not be strictly construed against any Party.

10.10    HEADINGS. The captions or headings of the Sections or other
         subdivisions hereof are inserted only as a matter of convenience or for
         reference and shall have no effect on the meaning of the provisions
         hereof.

10.11    NO IMPLIED WAIVERS; RIGHTS CUMULATIVE. No failure on the part of either
         Party to exercise, and no delay in exercising, any right, power, remedy
         or privilege under this Agreement, or provided by statute or at law or
         in equity or otherwise, shall impair, prejudice or constitute a waiver
         of any such right, power, remedy or privilege or be construed as a
         waiver of any breach of this Agreement or as an acquiescence therein,
         nor shall any single or partial exercise of any such right, power,
         remedy or privilege preclude any other or further exercise thereof or
         the exercise of any other right, power, remedy or privilege.

10.12    SEVERABILITY. If any provision hereof should be held invalid, illegal
         or unenforceable in any respect in any jurisdiction, then, to the
         fullest extent permitted by law, (a) all other provisions hereof shall
         remain in full force and effect in such jurisdiction and shall be
         liberally construed in order to carry out the intentions of the Parties
         as nearly as may be possible and (b) such invalidity, illegality or
         unenforceability shall not affect the validity, legality or
         enforceability of such provision in any other jurisdiction.

10.13    CURRENCY.  All references to prices and/or monies owed in this
         Agreement are to United States dollars.

                                       18
<Page>

10.14    EXECUTION IN COUNTERPARTS. This Agreement may be executed in
         counterparts, each of which counterparts, when so executed and
         delivered, shall be deemed to be an original, and all of which
         counterparts, taken together, shall constitute one and the same
         instrument.

                 REMAINDER OF THIS PAGE LEFT INTENTIONALLY BLANK
                      SIGNATURE PAGE TO IMMEDIATELY FOLLOW

                                       19
<Page>

IN WITNESS WHEREOF, the Parties hereto have executed this Agreement by their
duly authorized representatives.

ISIS PHARMACEUTICALS, INC.                   INTEGRATED DNA TECHNOLOGIES, INC.

By:    Richard K. Brown                      By: Dr. Joseph A. Walder

Signature:  /s/ Richard K. Brown             Signature: /s/ Dr. Joseph A. Walder
          ----------------------                       -------------------------

Title: President, GeneTrove                  Title: President & CEO
       Vice President,
       ISIS Pharmaceuticals

Date: 12/04/01                               Date: 12/04/01
      --------                                     --------

                                       20
<Page>

                                   APPENDIX A

            PROGRAM OLIGONUCLEOTIDE SPECIFICATIONS AND OTHER CRITERIA

<Table>
<Caption>
PROGRAM OLIGONUCLEOTIDE TYPE     PURITY BY       MASS SPEC         ABSORBANCE       ADDITIONAL
                                 HPLC                              RATIO            ANALYSIS/HANDLING
<S>                              <C>             <C>               <C>              <C>
 MOE OLIGOS

      [***]                      To be            To be            To be
                                 determined*      determined       determined

      [***]                      To be            To be            To be
                                 determined       determined       determined

 QUANTIFICATION OLIGOS

      Probes                     To be            To be            To be
                                 determined       determined       determined

      Primers                    To be            To be            To be
                                 determined       determined       determined

     "Primer Probe Sets"         To be            To be            To be
                                 determined       determined       determined
</Table>

 *  POSC to determine test use and test specifications

                                       A-1
<Page>

                                   APPENDIX B
                      APPLICATION OF 4.3 PRICING PROVISION

PROGRAM OLIGONUCLEOTIDE TYPE                          SYNTHESIS SCALE
--------------------------------------------------------------------------------

[***]

* NON-CATALOG ITEM

                                    CONFIDENTIAL TREATMENT REQUESTED UNDER
                                    17 C.F.R. SECTIONS 200.80(b)4, AND 240.24b-2<Page>

                                               CONFIDENTIAL TREATMENT REQUESTED
                             UNDER 17 C.F.R. Sections 200.80(b)4, AND 240.24b-2

                           [ISIS PHARMACEUTICALS LOGO]
-------------------------------------------------------------------------------

                           AMENDED & RESTATED IDT-ISIS
                               LICENSING AGREEMENT

                                 By and between

                           ISIS PHARMACEUTICALS, INC.

                 2292 Faraday Avenue, Carlsbad, California 92008
                        Hereinafter referred to as "ISIS"

                                       and

                        INTEGRATED DNA TECHNOLOGIES, INC
                  1710 Commercial Park, Coralville, Iowa 52241
                       Hereinafter referred to as ("IDT")

                                   Dated as of

                                DECEMBER 4, 2001.

                          --------------------------

                                      1

<Page>

                                    RECITALS

WHEREAS, ISIS and IDT entered into a Licensing Agreement dated as of March
12, 1999, (the "Original Agreement") which contains certain limitations in
the licenses obtained by each Party; and,

WHEREAS, ISIS and IDT would mutually benefit from expanding and clarifying
the scope of licenses obtained in the Original Agreement to include more
broad sublicensing rights for ISIS, including rights in the fields of
functional genomics, target validation, and antisense drug development, and
to provide IDT with rights under ISIS's RNase H suite of patents for sales of
oligonucleotides;

NOW, THEREFORE the parties hereby agree to replace and irrevocably supercede
the Original Agreement with this Amended and Restated IDT-ISIS Licensing
Agreement (hereinafter the "Restated Agreement") as follows:

                                    ARTICLE I
                             INTERPRETATION & EFFECT

1.1      SUPERCEDING AGREEMENT. It is the intent of the Parties to
         irrevocably supercede the Original Agreement with this Restated
         Agreement. The rights and obligations of the parties are to be
         exclusively defined by the terms, conditions, rights, and
         obligations as expressed herein. All existing and future rights and
         obligations of the Parties, including specifically all
         post-termination rights and obligations, contained in the Original
         Agreement are hereby null and void. In the event any term of the
         Original Agreement is not specifically superceded, modified or
         replaced by a corresponding term of the Restated Agreement, it shall
         be construed as a deliberate omission by the Parties.

1.2      EFFECTIVE DATE; WAIVERS. In exchange for the good and valuable
         consideration received by each Party described herein, each Party
         hereby irrevocably waives all claims to royalties or related damages
         arising out of the performance or conduct of the other Party prior
         to the Restated Agreement Effective Date, as hereinunder defined.
         The execution of this Restated Agreement shall not be interpreted as
         requiring either the repayment of licensing fees paid by ISIS
         pursuant to the Original Agreement, nor shall it be interpreted as
         requiring refund of such payments by IDT.

                                    ARTICLE 2
                                   DEFINTIONS

The following terms when used in this Restated Agreement shall be given the
meanings contained herein:

                                      2

<Page>

2.1      "Academic Market" shall mean end-users employed by and located at or
         in academic, university, government, and other 501(c)(3) registered
         not-for-profit organizations; provided however that specifically
         excluded from this definition shall be those end-users at such
         institutions whose research is directly funded by a for-profit
         corporation for the purpose of drug discovery, drug development, or
         target validation/gene functionalization wherein the funding
         corporation has a specific legal interest or right to the data and
         information of the funded research.

2.2      "Affiliates" shall mean any corporation, company, partnership, joint
         venture or other entity, which controls, is controlled or under
         common control with Isis or IDT as the case may be, and in the case
         of Isis shall also mean and include Pantheco, APS. For the purposes
         of this definition, control shall mean the direct or indirect
         ownership of at least fifty percent (50%) or, if less than fifty
         percent (50%), the maximum percentage as allowed by applicable law
         of (a) the stock shares entitled to vote for the election of
         directors; or (b) ownership interest.

2.3      "Antisense Drug Development Sublicenses" shall mean
         licenses/sublicenses under the Walder Patents to third parties to
         pursue all Medical Applications, which are not based on ISIS
         Licensed Products. Antisense Drug Development Sublicense holders
         shall have the limited right to issue sublicenses as a Product
         Sublicense under the Walder Patents to third-parties.

2.4      "Antisense Oligonucleotide" 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.

2.5      "Competing Oligonucleotide Supplier" shall mean any entity having a
         license from ISIS or its Affiliates to manufacture and/or sell
         Antisense Oligonucleotides for use in Research Applications.

2.6      "Confidential Information" shall mean information disclosed pursuant
         to an obligation contained in this Restated Agreement, including,
         without limitation, proprietary information and materials (whether
         or not patentable) regarding a Party's technology, products,
         business information or objectives, which is designated as
         confidential in writing by the disclosing Party, whether by letter
         or by the use of an appropriate stamp or legend, prior to or at the
         time any such information is disclosed by the disclosing Party to
         the other Party.

2.7      "Fee for Service FGTV Licenses" shall mean sublicenses under the
         Walder Patents to commercial entities offering antisense functional
         genomics/target validation products or services, including but not
         limited to database subscriptions, to third-parties. Specifically

                                      3

<Page>

         excluded from this definition shall be licenses under the Walder
         Patents to Competing Oligonucleotide Suppliers and other entities
         that sell oligonucleotides as an independent product (i.e, sales of
         oligonucleotides that are not related to the provision of a
         complementary functional genomic or target validation service to the
         third-party purchasing the oligonucleotides).

2.8      "IDT Licensed Commercial Product" shall mean and include any
         diagnostic, therapeutic, or prophylactic material, composition of
         matter, or method that either (a) is covered by a Valid Claims of
         any patent within the definition of the Walder Patents; or (b) the
         manufacture, use or sale of which would constitute, but for the
         license granted pursuant to this Restated Agreement, an infringement
         of any Valid Claim within the definition of the Walder Patents.

2.9      "In-House FGTV Licenses" shall mean licenses under the Walder
         patents to end-users at any for-profit commercial entity using
         Antisense Oligonucleotides to use antisense-based functional
         genomic/target validation products and services for that licensee's
         internal research and development.

2.10     "ISIS Academic Patents". Those patents defined, described or listed
         on Exhibit 1, as it may be expanded from time to time at ISIS's
         discretion. {Specifically INCLUDED in the definition of the "ISIS
         Academic Patents" are U.S. Patents [***] and the two allowed patent
         applications listed on Exhibit 1 herein, and all existing and future
         patent applications or patents that specifically claim the RNase H
         Mechanism of Action, which patents or applications ISIS can license
         or sublicense to IDT that IDT may require to make, use or sell
         Antisense Oligonucleotides for the Academic Market. Specifically
         EXCLUDED from the definition of "ISIS Academic Patents" shall be all
         patents or relevant patent claims related to clinical formulations
         and administration of oligonucleotides (including, without
         limitation, methods and reagents for the clinical delivery of
         oligonucleotides); gene-related patents, including without
         limitation patents to specific gene structures, gene targets and
         methods of treatment; 2' MOE technology, and any other patents
         and/or claims regarding chemistries not listed on Exhibit 1.}

2.11     "ISIS Licensed Product" an ISIS oligonucleotide drug or drug
         candidate molecule licensed to a third party for further
         development, commercialization, manufacture or distribution of the
         oligonucleotide drug or drug candidate molecule.

2.12     "Licensed Purchaser of RNase H Oligonucleotides " shall mean a
         third-party for-profit commercial entity that has obtained from ISIS
         a license to use RNase H Oligonucleotides.

2.13     "Medical Applications" shall mean diagnostic products, therapeutic
         and prophylactic drugs or vaccines, intended for the diagnosis,
         prevention, or treatment of disease in humans, animals or plants and
         all discovery, research, development, and commercialization efforts
         to support those uses, including without limitation, elucidation of
         gene function and target validation.

                                      4

<Page>

2.14     "Net Sales" shall mean the gross receipts received by ISIS or its
         Affiliates or sublicensees, as appropriate, for the sale of IDT
         Licensed Commercial Products by ISIS and its Affiliates or its
         sublicensees, as appropriate, less the following deductions:

         (i)      Prompt payment or other trade or quantity discounts
                  actually allowed and taken in such amounts as are customary
                  in the trade;

         (ii)     Commissions paid or allowed to distributors and agents who
                  are independent third parties other than such parties who
                  are solely performing detailing functions;

         (iii)    Amounts paid or credited by reason of timely rejection or
                  returns;

         (iv)     Taxes (other than franchise or income taxes on the income
                  of Isis actually paid or withheld;

         (v)      Allowances including any allowances for bad debt. Provided
                  that upon the extinguishment of any such allowance, the
                  extinguishment will be determined to be a receipt;

         (vi)     Transportation and delivery charges, including insurance
                  premiums actually incurred;

         Notwithstanding the foregoing, amounts received by ISIS or its
         Affiliates or sublicensees for the sale of IDT Licensed Commercial
         Products among ISIS, its Affiliates or sublicensees whether for
         their internal use or for resale or other disposition will not be
         included in the computation of Net Sales hereunder. For purposes of
         this Restated Agreement a distributor will not be deemed a
         sublicensee and sales by ISIS, its Affiliates or sublicensees to a
         distributor will not be subject to royalties.

2.15     "Original Agreement" shall mean the Licensing Agreement executed by
         IDT and ISIS with an effective date of March 12, 1999 (attached
         hereto as Attachment 1).

2.16     "Product Sublicense" shall mean a sublicense under the Walder
         Patents to further develop, commercialize, manufacture or distribute
         an oligonucleotide drug or drug candidate molecule, which sublicense
         is granted by either: (a) ISIS under Article 3 of the Restated
         Agreement; or (b) an Antisense Drug Development Sublicense holder.

2.17     "Restated Agreement Effective Date" shall be the day of last dated
         signature of a signatory to this Restated Agreement.

2.18     "RNase H Mechanisms of Action" means methods of using RNase H
         enzymes to cleave a targeted RNA in cells.

2.19     RNase H Oligonucleotides" shall mean an Antisense Oligonucleotide
         that acts by the RNase H Mechanism of Action.

                                      5

<Page>

2.20     "Research Applications" shall mean all non-therapeutic uses of
         oligonucleotides including but not limited to all in vitro cell
         culture, tissue culture, laboratory animal, plant and microorganism
         studies.

2.21     "Walder Patents" shall mean and include [***] and all divisionals,
         reissues, and foreign counterparts derived from these patents and
         patent applications.

2.22     "Valid Claim" shall mean a claim of an issued patent that has not
         been ruled invalid or unenforceable by a court of competent
         jurisdiction in an unappealed or unappealable decision.

                                    ARTICLE 3
                          IDT GRANT OF LICENSES TO ISIS

3.1      MEDICAL APPLICATIONS. IDT grants to Isis, a non-exclusive,
         royalty-bearing, worldwide license to make, have made, use, offer to
         sell, import, and sell IDT Licensed Commercial Products for all
         Medical Applications (the "Medical Applications License"). Isis may
         at its option extend the licenses granted hereunder to an Affiliate,
         in which event a sublicensing fee will not be required.

         3.1.1    PRODUCT SUBLICENSES. ISIS may grant written sublicenses
                  under this Medical Applications License to third parties to
                  further develop, commercialize, manufacture or distribute
                  an oligonucleotide drug or drug candidate molecule (a
                  "Product Sublicense" and/or Product Sublicensee). Isis will
                  inform IDT of the identity of any such Product Sublicensee
                  and the nature of such sublicense within 60 days of
                  execution of such sublicense and warrant to IDT that the
                  grant of rights to any sublicensee will conform to the
                  grant of rights hereunder. Any agreement granting a
                  sublicense shall state that the sublicense is subject to
                  the terms of this Restated Agreement. Isis shall have the
                  same accounting and reporting responsibilities for the
                  activities of any sublicensee, as if the activities were
                  directly those of Isis.

3.2      FUNCTIONAL GENOMICS AND TARGET VALIDATION LICENSE. IDT grants to
         ISIS a fully paid-up, non-royalty bearing, worldwide, exclusive
         license (except with respect to IDT, and with respect to rights
         already granted to [***] (as described in section 3.2.1 hereunder)
         under the Walder Patents to make, have made, use, import, offer to
         sell, and sell all functional genomics and target validation
         products and services ("the FGTV License").

         3.2.1    FEE-FOR-SERVICE FGTV SUBLICENSES. IDT grants to ISIS the
                  exclusive right, even as to IDT, to issue Fee-for Service
                  FGTV Licenses under the Walder Patents to third parties.
                  ISIS will have no royalty or other contingent payment
                  obligations to IDT with respect to sublicenses granted
                  under this provision. ISIS acknowledges that prior to the
                  execution of this Restated Agreement, [***] has obtained a
                  Fee for Service FGTV license from IDT, the scope and
                  validity of which is not affected by the exclusive rights
                  granted ISIS in 3.2.1, herein. IDT agrees that it shall not

                                      6

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                  amend or expand the [***] attached hereto as Exhibit 3,
                  without the prior written approval of ISIS.

         3.2.2    IN-HOUSE FGTV SUBLICENSES. IDT grants to ISIS the exclusive
                  right even as to IDT to issue future In-House FGTV Licenses
                  under the Walder Patents to third parties. ISIS will have
                  no royalty or other contingent payment obligations to IDT
                  with respect to sublicenses granted under this provision.

         3.2.3    IDT RETAINED RIGHTS. IDT reserves all rights under the
                  Walder Patents to make, use and sell oligonucleotides and
                  other products and services.

3.3      ANTISENSE DRUG DEVELOPMENT SUBLICENSES. IDT grants to ISIS a
         term-limited exclusive license (even as to IDT) to issue Antisense
         Drug Development Sublicenses under the Walder patents to
         third-parties. ISIS's shall pay IDT a [***] initial license payment
         pursuant to Article 5 herein, within ten (10) days of the Restated
         Agreement Effective Date, to maintain the exclusivity of the license
         for a period of [***] years following the Restated Agreement
         Effective Date.

         3.3.1    OPTION TO EXTEND EXCLUSIVITY. ISIS will have the option to
                  extend the exclusivity of the license for the duration of
                  the last to expire of the Walder Patents for an additional
                  [***]payment, such payment to be made within thirty (30)
                  days of the expiration of the initial [***] period, stated
                  herein.

         3.3.2    EFFECT OF LOST EXCLUSIVITY. Should ISIS not exercise the
                  option in 3.3.1 ISIS's exclusive right to issue Antisense
                  Drug Development Sublicenses will revert to a non-exclusive
                  right, without further initial payment obligation to IDT.
                  In that event, IDT shall have the right to issue Antisense
                  Drug Development Sublicenses under the Walder Patents to
                  third-parties. In this instance, notwithstanding the
                  provisions of 3.2.2., IDT shall have the right to grant an
                  In-House FGTV Licenses under the Walder Patents as a part
                  of an Antisense Drug Development Sublicense.

        3.3.3     SUBLICENSING PAYMENTS. For each Antisense Drug Development
                  sublicense issued by ISIS under this provision, ISIS will
                  pay IDT or will obligate the Antisense Drug Development
                  Sublicense Holder to pay IDT, the initial sublicensing fees
                  and Royalties as established in Appendix A, attached, and
                  to comply with or fulfill all necessary reporting and
                  accounting obligations as defined in this Restated
                  Agreement. ISIS's initial license payments (specifically
                  the [***] payment and the optional [***] payment) made
                  under this provision will be creditable against initial
                  sublicensing fees and royalty payments owed to IDT pursuant
                  to the issuance of Antisense Drug Development Sublicenses.

         3.3.4    PRIOR LICENSES. ISIS acknowledges that prior to this First
                  Amendment, Hybridon Inc., and Epigenesis Pharmaceuticals,
                  Inc., have each obtained an Antisense Drug Development
                  Sublicense from IDT, the scope and validity of which is not
                  affected by the exclusive rights granted ISIS in paragraph
                  3.3 herein. IDT agrees that it shall not amend or expand
                  either of such licenses without ISIS's prior written
                  approval.

                                      7

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3.4      NOTICE OBLIGATIONS. To minimize confusion with respect to the
         sublicensing activities of ISIS, or its sublicensees, ISIS agrees to
         the following:

         3.4.1    NOTICES TO IDT OF SUBLICENSES. Isis shall provide IDT with
                  written notice of any sublicense granted pursuant to this
                  Restated Agreement within ten (10) days after the grant of
                  such sublicense, such written notice specifying the name of
                  the sublicensee, the date of the sublicense, and whether
                  such sublicense is a Product Sublicense, a Fee-for-Service
                  FGTV Sublicense, an In-House FGTV Sublicense, or an
                  Antisense Drug Development Sublicense. With respect to
                  Antisense Drug Development Sublicenses, ISIS will pay or
                  cause the Antisense Drug Development Sublicense Holder to
                  pay, the initial sublicensing fee to IDT within twenty (20)
                  days of the execution of such sublicense.

         3.4.2    NOTICE TO IDT OF LICENSED PURCHASERS. Along with notice of
                  an In-House FGTV Sublicense required in 3.4.1, Isis shall
                  provide to IDT, a complete list of Licensed Purchasers of
                  RNase H Oligonucleotides upon the written request of IDT,
                  such requests not to exceed two per calendar year.

         3.4.3    [***]

                                    ARTICLE 4
                                 LICENSES TO IDT

4.1      IDT SALES TO THE ACADEMIC MARKET. ISIS grants to IDT a worldwide,
         fully paid-up, non-royalty bearing, non-exclusive license under the
         ISIS Academic Patents to make, have made, use, import, offer to
         sell, sell, and have sold oligonucleotides and other related
         research products to the Academic Market.

4.2      RESTRICTIONS ON SALES. Within thirty (30) days of the Restated
         Agreement Effective Date, and consistent with the provisions of
         section 3.2.1 herein, IDT agrees to suspend sales of any RNase H
         Oligonucleotides to third-parties except as may be required by IDT's
         existing obligations, for incorporation into antisense-based
         functional genomics/target validation products or incorporation into
         a commercial service, unless IDT receives the prior written
         authorization from ISIS.

4.3      THIRD-PARTY OBLIGATIONS. IDT acknowledges that ISIS may have certain
         financial and reporting obligations under licenses it has obtained
         from third parties to certain patents included in the definition of
         ISIS Academic Patents. IDT agrees to either pay all associated
         financial obligations (except upfront licensing fees) and fulfill
         all associated legal/reporting obligations that may be required of
         ISIS to a third-party for sales of products by IDT under the
         sublicense, or IDT shall refuse the sublicense under such patent(s)
         and it shall be deleted from the Academic Patents. ISIS shall
         promptly notify IDT of the precise nature of all such obligations so
         that IDT can make the required election(s).

                                      8

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4.4      ISIS RETAINED RIGHTS. Notwithstanding the licenses granted to IDT
         herein, Isis shall retain all rights, however characterized under
         all ISIS Academic Patents and the RNase H Suite of Patents,
         including without limitation, rights to use, have used, make, have
         made, import, have imported, offer to sell, sell, and have sold
         oligonucleotides and related technologies for any and all
         applications.

4.5      [***]

                                    ARTICLE 5
                                  CONSIDERATION

5.1      GUARANTEED PAYMENTS. Within five (5) days of the Restated Agreement
         Effective Date, ISIS will pay to IDT the sum of $3,500,000
         structured as follows:

         (i)      $3 million in non-refundable licensing fees;
         (ii)     $500,000 for exclusive rights to issue Antisense Drug
                  Development sublicenses under section 3.3 herein,

         In addition, ISIS will pay IDT $350,000 in non-refundable licensing
         fees on or before each of the first four (4) anniversary dates of
         the Restated Agreement Effective Date (i.e. four anniversary
         payments totaling $1.4 million).

5.2      CONTINGENT ROYALTY PAYMENTS. In further consideration for the
         Medical Application License and the exclusive right to issue
         Antisense Drug Development Sublicenses granted herein, Isis agrees
         to pay IDT [***] of Net Sales from each IDT Licensed Commercial
         Product sold by Isis, or its Sublicensees, however characterized,
         beginning with the first sale to any unrelated third party,
         according to the terms and conditions of Article 6 herein.

5.3      CONTINGENT SUBLICENSING FEES. ISIS shall pay to IDT, or shall cause
         the sublicensee to pay to IDT, the initial licensing fees as defined
         in Appendix A for all Antisense Drug Development sublicenses issued
         by ISIS under this Restated Agreement.

                                    ARTICLE 6
                              ACCOUNTING /PAYMENTS

6.1      QUARTERLY ESTIMATES. For each calendar year in which there are Net
         Sales of IDT Licensed Commercial Products ISIS shall prepare, or
         cause its Affiliates or sublicensees to prepare, deliver and pay to
         IDT a quarterly estimate of the royalty payments due to IDT under
         Section 5.1 herein, within sixty (60) days following the last day of
         the first, second, and third quarters of each calendar year of ISIS.

6.2      ANNUAL REPORT. Within ninety (90) days following the last day of
         each calendar year, ISIS, its Affiliates, or licensees, whichever is
         applicable, shall prepare and deliver an annual report of the total
         royalty payments due to IDT for the calendar year expired. The
         reporting party shall tender payment of the balance owed for the
         year, including all payments owed for the fourth quarter of the year
         expired, and any necessary adjustments

                                      9

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         to the quarterly estimate payments previously paid. Each quarterly
         estimate or annual payment shall be accompanied by a statement of
         account which shall indicate the estimated or actual Net Sales, as
         the case may be, by the reporting party for the previous period and
         shall show the amount of royalties due IDT with sufficient detail to
         enable confirmation of the calculations by IDT.

6.3      PAYMENT CURRENCY. Except as otherwise directed, all amounts owing to
         IDT under this Restated Agreement shall be paid in U.S. dollars to
         IDT at the addresses provided or via wire transfer to a specified
         IDT account. All royalties owing with respect to Net Sales stated in
         currencies other than U.S. dollars shall be converted at the rate
         shown in the Wall Street Journal on the last day of the quarter for
         which the royalty is due, or shall be converted according to the
         terms governing conversion for an Isis sublicensee.

6.4      RECORDKEEPING. Isis, its Affiliates and its sublicensee(s) shall
         keep books and records sufficient to verify the accuracy and
         completeness of the accounting referred to above, including without
         limitation sales, accounts receivable, and invoice records relating
         to IDT Licensed Commercial Products. Such books and records shall be
         preserved for a period not less than five (5) years after they are
         created during and after the term of this Restated Agreement.

6.5      AUDITING/DEFICIENCIES. Isis, its Affiliates, and its sublicensee(s)
         shall take all steps necessary so that IDT may, within sixty days of
         its request, review and copy all the books and records at a single
         U.S. location to verify the accuracy of Isis and its
         sublicensee(s)'s accounting. Such review shall be made not more than
         once each calendar year, upon reasonable notice and during regular
         business hours, at the expense of IDT by a certified public
         accountant to whom there is no reasonable objection by either party.
         If a royalty payment deficiency for a calendar year is determined,
         the reporting party shall pay the royalty deficiency outstanding
         within thirty (30) days of receiving written notice thereof, and
         shall reimburse IDT for the cost of the inspection.

                                    ARTICLE 7
                          WARRANTIES/INDEMNIFICATIONS.

7.1      NO CONSEQUENTIAL DAMAGES. Neither Party shall be liable to the other
         Party, its Affiliates, sublicensees, successors, or assigns for any
         loss of profits, loss of business, interruption of business, nor for
         indirect, special or consequential damages of any kind under this
         Restated Agreement.

7.2      WARRANTY OF AUTHORITY. The parties warrant each has the right to
         grant the licenses granted to the other party in this Restated
         Agreement. IDT warrants that it does not own or control any patents
         or patent applications with claims to antisense compounds and/or
         methods not already disclosed in the definition of the "Walder
         Patents".

7.3      WARRANTY DISCLAIMERS. Except as expressly set forth herein, IDT and
         Isis make no representations, extend no warranties of any kind,
         either express or implied, and assume no responsibilities whatsoever
         with respect to use, sale, or other disposition by the other

                                      10

<Page>

         party, its Affiliates, sublicensees or their vendees or other
         transferees, of IDT Licensed Commercial Products. EXCEPT AS
         EXPRESSLY SET FORTH HEREIN, NOTHING IN THIS RESTATED AGREEMENT, NOR
         ANY PRIOR COMMUNICATION, SHALL BE CONSTRUED AS:

              (i)     A WARRANTY OR REPRESENTATION BY IDT OR ISIS AS TO THE
                      VALIDITY OR SCOPE OF ANY OF THE PATENTS CONTAINED
                      WITHIN THE DEFINITIONS OF THE WALDER PATENTS AND ISIS
                      ACADEMIC PATENTS, RESPECTIVELY;

              (ii)    A WARRANTY OR REPRESENTATION THAT ANYTHING MADE, USED,
                      SOLD OR OTHERWISE DISPOSED OF UNDER THE LICENSES
                      GRANTED IN THIS RESTATED AGREEMENT WILL OR WILL NOT
                      INFRINGE PATENTS OF THIRD PARTIES; OR

              (iii)   AN OBLIGATION TO FURNISH ANY KNOW-HOW NOT PROVIDED IN
                      THE WALDER PATENTS OR THE ISIS ACADEMIC PATENTS OR ANY
                      SERVICES OTHER THAN THOSE SPECIFIED IN THIS RESTATED
                      AGREEMENT OR RELATED AGREEMENTS.

7.4      INDEMNIFICATION. Isis and IDT shall at all times during the term of
         this Restated Agreement and thereafter, indemnify, defend and hold
         each other, the University of Iowa Research Foundation/University of
         Iowa, and the authors and inventors of the Walder Patents and the
         Isis Academic Patents harmless against all claims and expenses,
         including legal expenses and reasonable attorneys fees, arising out
         of the death of or injury to any person or persons or out of any
         damage to property and against any other claim, proceeding, demand,
         expense and liability of any kind whatsoever resulting from the
         production, manufacture, sale, use, lease, consumption or
         advertisement of products or processes arising from any right or
         obligation of IDT or Isis, or their Affiliates, or any of its
         sublicensee(s) granted herein. Notwithstanding the above, IDT and
         Isis at all times reserves the right to retain counsel of its own to
         defend IDT's or Isis's interest.

                                    ARTICLE 8
                            CONFIDENTIAL INFORMATION

8.1      CONFIDENTIALITY. Isis and IDT each agrees to treat as confidential
         and to use only in the conduct of its business, all Confidential
         Information disclosed to it by the other party.

8.2      NON-DISCLOSURE AND NON-USE. Isis and IDT each agrees not to disclose
         any of the Confidential Information received from the other party to
         any unauthorized third party and not to use any of the Confidential
         Information except to fulfill the terms of the Restated Agreement,
         for a period of five (5) years from the receipt of the Confidential
         Information.

8.3      RELEASE FROM RESTRICTIONS. All information which is characterized as
         Confidential Information shall cease to be confidential and the
         receiving party shall be released from their respective obligations
         under sections 8.1 and 8.2 herein, if such information (i) is
         legally known to or was in the possession of the receiving party at
         the time of the disclosure; (ii) legally is or has become part of
         the public domain through no act or omission of the receiving party;
         (iii) has been disclosed to the recipient by a third party

                                      11

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         without restriction as to the use or disclosure of the information:
         (iv) is available to the general public as a result of a
         governmentally required release or disclosure.

                                   ARTICLE 9.
                              TERM AND TERMINATION.

9.1      TERM. The term of this Restated Agreement shall extend until the
         last patent to expire included within the Walder Patents or Isis
         Academic Patents, whichever expires later.

9.2      TERMINATION FOR BREACH. In the event either party shall materially
         breach any of the terms, conditions and agreements contained in this
         Restated Agreement, then the alleging party may, at its election,
         notify the other party of the alleged breach giving the other party
         thirty (30) days written notice to cure the breach or begin good
         faith negotiations to resolve such alleged breach. If the alleged
         breach is not resolved to the satisfaction of the alleging party
         within thirty (30) days of the first giving of notice the alleging
         party may, at its option, bring arbitration proceedings under
         Article 12. In the event of a good faith dispute about monetary
         obligations, the notified party will pay any undisputed amounts to
         the alleging party and pay any disputed amounts into escrow pending
         resolution of such dispute, with payment to be made to the
         prevailing party. The licenses granted hereunder are not terminable
         except in the event of bankruptcy of a Licensee, subject to Sections
         9.3 9.4, and 9.5, and the continuing rights of sublicensees.

9.3      ELECTIVE TERMINATION FOR BANKRUPTCY. In the event either Party shall
         become insolvent, bankrupt or subject to the provisions of the
         United States Bankruptcy Code, or makes any assignment for the
         benefit of creditors, or ceases to carry on business as a going
         concern, then the other Party shall have the right but not the
         obligation to terminate the licenses granted by the termination
         party in this Restated Agreement; provided however, that Isis hall
         have the right to grant to its sublicensee(s), the power to assume
         Isis's rights and obligations under its licenses, and
         correspondingly Isis, and its successor in interest, however
         organized, shall, to the extent permitted by law, maintain the
         licenses granted to IDT pursuant to this Restated Agreement.

         9.3.1    BANKRUPTCY RIGHTS. In the event that this Restated
                  Agreement is terminated by a Party hereto or its receiver
                  or trustee under applicable bankruptcy laws due to such
                  Party's bankruptcy, then all rights and licenses granted
                  under or pursuant to this Restated Agreement by such Party
                  to the other Party are, and will otherwise be deemed to be,
                  for purposes of Section 365(n) of the Bankruptcy code and
                  any similar law or regulation in any other country,
                  licenses of rights to "intellectual property" as defined
                  under section 101(35A) of the Bankruptcy Code. The Parties
                  agree that all intellectual property rights licensed
                  hereunder, including without limitation any patents or
                  patent applications in any country of a Party covered by
                  the license grants under this Restated Agreement, are part
                  of the "intellectual property" as defined under Section
                  101(35A) of the Bankruptcy Code subject to the protections
                  afforded the non-terminating Party under Section 365(n) of
                  the Bankruptcy Code, and any similar law or regulation in
                  any other country.

                                      12

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9.4      POST TERMINATION RIGHTS/OBLIGATIONS. Notwithstanding the foregoing,
         the following rights and obligations shall survive termination of
         this Restated Agreement to the degree necessary to permit their
         complete fulfillment or discharge:

         9.4.1    IDT's right to receive or recover and ISIS's obligation to
                  pay licensing or sublicensing fees or royalties accrued or
                  accruable for payment at the time of any termination.

         9.4.2    Licensee's obligation to maintain records and Licensor's
                  right to receive final year accounting reports as provided
                  in Section 3E.

         9.4.3    Any cause of action or claim of Licensor, accrued or to
                  accrue because of any breach or default by the Licensee;

         9.4.4    The rights and obligations of both parties regarding
                  confidentiality as defined in section 7 herein;

         9.4.5    The warranty, indemnification and insurance provisions as
                  set forth in Section 6C, 6D, and 6E.

         9.4.6    The rights of ISIS, its Affiliates or sublicensees within
                  [***] months following such date of termination, to sell or
                  dispose of IDT Licensed Commercial Products completed or
                  substantially completed on the date of termination and to
                  complete orders, outstanding on such date of termination
                  for such products.

         9.4.7    The right of IDT or its Affiliates within [***] months
                  following such date of termination, to sell or dispose of
                  RNase H Oligonucleotides completed or substantially
                  completed on the date of termination and to complete
                  orders, outstanding on such date of termination for such
                  products.

9.5      SUCCESSOR IN INTEREST TO IDT. Should IDT, or its assigns, become
         insolvent, bankrupt or subject to the provisions of the United
         States Bankruptcy Code or any other similar legislation of any
         jurisdiction, the right of the University of Iowa Research
         Foundation to assume IDT's interest in the Walder Patents shall not
         be abrogated in any way by any term or provision of this Agreement.

9.6      SURVIAL OF SUBLICENSES. Notwithstanding the termination of this
         Restated Agreement or any of the licenses or sublicenses granted
         hereunder, any sublicenses to the Walder Patents granted by ISIS or
         its Affiliates pursuant to Article 3 hereof prior to the termination
         of the Restated Agreement shall survive such termination. In such
         event, ISIS shall have the right to exercise all of the rights of
         IDT as the sublicensor under such sublicense, subject to its
         compliance with continuing obligations regarding surviving
         sublicenses as defined in section 9.4 herein.

                                      13

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                                   ARTICLE 10
                               DISPUTE RESOLUTION

10.1     DISPUTES--ARBITRATION. The parties agree to attempt initially, to
         solve all claims, disputes, or controversies arising under, out of,
         or in connection with this Restated Agreement by conducting good
         faith negotiations. Except with respect to disputes as to the
         validity of patents, applications for injunctions, specific
         performance, or other equitable relief, any dispute arising out of
         or in connection with this Restated Agreement or any legal
         relationship associated therewith, that cannot be resolved amicably
         by the parties, shall be finally resolved by arbitration. The
         arbitration shall be conducted in accordance with the arbitration
         rules of the American Arbitration Association ("AAA") then in force,
         by one or more arbitrators appointed in accordance with said rules;
         provided, however, that arbitration proceedings may not be
         instituted until the party alleging breach of this Restated
         Agreement by the other party has given the other party not less than
         sixty (60) days notice to remedy any alleged breach and the other
         party has failed to do so. The place of arbitration shall be Cedar
         Rapids, Iowa, if Isis institutes the proceeding, and San Diego,
         California, if IDT institutes the proceeding. The award rendered
         shall be final and binding upon both parties. The judgment rendered
         shall include costs of arbitration, reasonable attorney's fees and
         reasonable costs for any expert and other witnesses. The arbitration
         may expressly consider the amounts paid pursuant to Sections 3B, 3C,
         and 3D, in considering any claims of any damages. Judgment upon the
         award may be entered in any court having jurisdiction, or
         application may be made to such court for judicial acceptance of the
         award and/or an order of enforcement. Disputes as to the validity
         and scope of patents shall be resolved by the courts of appropriate
         jurisdiction.

                                   ARTICLE 11
                                  MISCELLANEOUS

11.1     APPLICABLE LAW. This Restated Agreement shall be construed in
         accordance with the internal laws of the State of New York. If any
         provisions of this Agreement are or shall come into conflict with
         the laws or regulations of any jurisdiction or any governmental
         entity having jurisdiction over the parties or this Restated
         Agreement, those provisions shall be deemed automatically deleted,
         if such deletion is allowed by relevant law, and the remaining terms
         and conditions of this Restated Agreement shall remain in full force
         and effect. If such a deletion is not so allowed or if such a
         deletion leaves terms thereby made clearly illogical or
         inappropriate in effect, the parties agree to substitute new terms
         as similar in effect to the present terms of this Restated Agreement
         as may be allowed under the applicable laws and regulations. The
         parties hereto are independent contractors and not joint ventures or
         partners.

11.2     CONSTRUCTION/EFFECT. The parties acknowledge that this Restated
         Agreement has been the subject of full opportunity for negotiation
         and amendment and that the party who has taken the role of drafter
         shall not suffer any adverse construction of any terms or language
         of this Restated Agreement because of such role.

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11.3     FORCE MAJEURE. A party hereto shall not be deemed in default with
         respect to the performance of or compliance with the terms,
         covenants, agreements conditions or provisos of this Agreement if
         the failure to perform or comply shall be due to any event of force
         majeure. "Force majeure" shall include natural disasters, acts of
         God, or any other event or cause beyond the control of the party
         claiming the benefit of this paragraph and which that party could
         not reasonably have protected itself against, provided however that
         lack of funds or credit shall not constitute an event of force
         majeure.

11.4     ASSIGNABILITY. This Restated Agreement may not be transferred or
         assigned by either party without the prior written consent of the
         other party, except that either Party may freely assign this
         Restated Agreement to (i) an Affiliate, if the assigning Party
         guarantees the full performance of its Affiliates' obligations
         hereunder, or (ii) an entity acquiring substantially all of
         Licensee's business to which the License relates. Any purported
         assignment in contravention of this section shall, at the option of
         the non-assigning party, be null and void and of no effect.

11.5     NOTICES. Any notice required to be given pursuant to the provisions
         of this Restated Agreement shall be in writing and shall be deemed
         to have been given at the earlier of the time when actually received
         as a consequence of any effective method of delivery, including but
         not limited to hand delivery, transmission by facsimile, or delivery
         by a professional courier service, or the time when sent by
         certified or registered mail addressed to the party. Any notice of
         change of address shall be effective only upon actual receipt, by
         the persons listed below or other formally authorized person(s)
         acting in their behalf.

         With respect to IDT:

                 Joseph A. Walder, M.D., Ph.D.
                 Attn: Legal Department
                 Integrated DNA Technologies, Inc.
                 1710 Commercial Park
                 Coralville, IA 52241-9802;

                 With a duplicate sent to:

                 Mark Campbell, J.D., COO
                 Corporate Vice President
                 Integrated DNA Technologies, Inc.
                 8930 Gross Point Road, Suite 700
                 Skokie, Illinois, 60077

         With respect to ISIS:

                 B. Lynne Parshall, J.D.
                 Isis Pharmaceuticals, Inc.
                 Executive Vice President and CFO

                                      15

<Page>

                 2292 Faraday Avenue
                 Carlsbad, CA 92008

                 With a duplicate sent to:

                 President of GeneTrove
                 Isis Pharmaceuticals, Inc.
                 2292 Faraday Avenue
                 Carlsbad, CA 92008

11.6     INTEGRATION. This Restated Agreement constitutes the full
         understanding between the parties with reference to the subject
         matter hereof, and no statements or agreements by or between the
         parties, whether orally or in writing, made prior to or at the
         signing hereof, shall vary or modify the written terms of this
         Restated Agreement. Neither party shall claim any amendment,
         modification, or release from any provisions of this Restated
         Agreement by mutual agreement, acknowledgement, or otherwise, unless
         such mutual agreement is in writing, signed by the other party, and
         specifically states that it is an amendment to this Restated
         Agreement.

11.7     BENEFITS. All terms and provisions of this Restated Agreement shall
         bind and inure to the benefit of the parties hereto, and upon their
         respective successors and assigns as those are permitted under the
         terms of this Restated Agreement.

11.8     AUTHORITY. The persons signing on behalf of IDT and Isis hereby
         warrant and represent that they have authority to execute this
         Restated Agreement on behalf of the party for whom they have signed.

                 REMAINDER OF THIS PAGE LEFT INTENTIONALLY BLANK
                      SIGNATURE PAGE TO IMMEDIATELY FOLLOW

                                      16

<Page>

IN WITNESS WHEREOF, the Parties hereto have executed this Agreement by their
duly authorized representatives.

<Table>
<S>                                           <C>
ISIS PHARMACEUTICALS, INC.                    INTEGRATED DNA TECHNOLOGIES, INC.

By:    Richard. K. Brown                      By: Dr. Joseph A. Walder

Signature:  /s/ Richard. K. Brown             Signature: /s/ Dr. Joseph A. Walder
            --------------------------                   ------------------------

Title: President, GeneTrove
       Vice President, ISIS Pharmaceuticals   Title: President & CEO

Date:    12/04/01                             Date: 12/04/01
</Table>

                                      17

<Page>

                               Restated Agreement
                                   Appendix A

                      LICENSE FEE AND ROYALTY SCHEDULES FOR
                     ANTISENSE DRUG DEVELOPMENT SUBLICENSES

[***]

                                    EXHIBIT 1
                              ISIS ACADEMIC PATENTS

[***]

                                      18

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