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                                                                     EXHIBIT 4.2

                  AMENDMENT, REDEMPTION AND EXCHANGE AGREEMENT

        This AMENDMENT, REDEMPTION AND EXCHANGE AGREEMENT ("Agreement") is made
as of this 4th day of June, 2003 by and between GENOME THERAPEUTICS CORP., a
Massachusetts corporation (the "Company"), and The Tail Wind Fund, Ltd. (the
"Investor").

                              W I T N E S S E T H:

                WHEREAS, pursuant to that certain Purchase Agreement, dated as
of March 5, 2002 (the "Purchase Agreement"), by and among the Company, the
Investor and Smithfield Fiduciary LLC (the "Other Investor," and collectively
with the Investor, the "Investors"), the Company sold and issued to the
Investor, and the Investor purchased from the Company, (i) $3 million in
principal amount of the Company's 6% Convertible Notes (the "Note"), which Note
is convertible into shares of common stock of the Company, $0.10 par value per
share (the "Common Stock"), in accordance with the terms of the Note and (ii)
warrants ("Initial Warrants") to purchase up to 97,500 shares of Common Stock;
capitalized terms used herein and not otherwise defined shall have the meanings
ascribed thereto in the Purchase Agreement;

                WHEREAS, a registration statement (file no. 333-85500) (the
"Current Registration Statement") was originally filed by the Company with the
SEC under the Securities Act of 1933, as amended, and the rules and regulations
promulgated thereunder (the "1933 Act"), on April 4, 2002, and was declared
effective April 18, 2002;

                WHEREAS, the Investor has not converted or sold any of the Note;

                WHEREAS, the Investor wishes to sell to the Company, and the
Company wishes to redeem and purchase from the Investor, two-thirds (2/3) of the
outstanding principal amount of Notes held by the Investor at a redemption price
equal to the portion of the outstanding principal amount of such Note so
redeemed plus accrued and unpaid interest thereon through the Closing Date (as
defined below); and

                WHEREAS, in order to induce the Investor to convert the
remaining Note not redeemed hereunder, the Company has agreed to reduce the
Conversion Price under the Note and to exchange the Initial Warrants for
warrants in the form of Exhibit A attached hereto (the "Exchange Warrants") as
more fully described herein;

                NOW, THEREFORE, in consideration of the foregoing premises and
the mutual covenants set forth in this Agreement, and for other good and
valuable consideration, the receipt and sufficiency of which are hereby
acknowledged, the parties hereto agree as follows:

        1. Redemption. The Investor hereby sells, assigns, transfers and conveys
to the Company, and the Company hereby redeems and purchases from the Investor,
$2,000,000 of the outstanding principal amount of the Note held by the Investor
at a redemption price (the "Redemption Price") equal to $2,050,959, which
represents the

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outstanding principal amount of the Note plus accrued and unpaid interest
thereon through and including the date hereof. Simultaneous with the execution
hereof, the Company shall pay the Redemption Price by wire transfer to the
account designated in writing by the Investor.

        2. Amendment. Notwithstanding anything contained in the Note, effective
upon execution hereof and receipt of the Redemption Price, the Conversion Price
(as defined in the Note) of the Note is hereby amended to equal $2.5686 (the
"New Conversion Price").

        3. Conversion. Simultaneously with the Investor's receipt of the
Redemption Price, the remaining $1,000,000 outstanding principal amount of the
Note plus accrued and unpaid interest thereon held by the Investor after the
redemption pursuant to Section 1 above at the Redemption Price shall be
converted at the New Conversion Price as if the Investor delivered the
Conversion Notice (as defined in the Notes) attached to the Note. As a result,
the Investor is converting a total of $1,025,479.50 principal amount of Notes
plus accrued and unpaid interest thereon into 399,237 shares of Common Stock
(the "Conversion Shares"). The Company and the Investor acknowledge that, upon
the Investor's receipt of the Redemption Price, the foregoing constitutes valid
delivery of the applicable Conversion Notice to the Company as of the date
hereof. By execution hereof, the Company hereby waives the requirements under
Section 3(a) of the Note and Section 9.4 of the Purchase Agreement that the
Investor email three designees of the Company confirming delivery of such
Conversion Notice. Simultaneously with the delivery by the Company of the
Redemption Price, the Company shall cause its transfer agent to electronically
transmit the Conversion Shares to the Investor, by crediting the account of the
Investor's prime broker with DTC through its Deposit Withdrawal Agent Commission
system designated in writing by the Investor to the Company concurrently
herewith. Upon the receipt by the Investor of the Redemption Price and the
Conversion Shares, the Purchase Agreement and the Note shall be deemed
terminated and of no further force or effect.

        4. Warrant Exchange. As of the date hereof, the Company will issue to
the Investor the Exchange Warrants to subscribe for 97,329 shares of Common
Stock ("Warrant Shares") at an initial exercise price of $3.71 per share, in
exchange for the surrender of the Initial Warrants currently held by such
Investor.

        5. Simultaneous Signing and Closing. The transactions contemplated by
this Agreement shall be consummated on the date hereof (such event referred to
as the "Closing" and the date of such Closing, the "Closing Date"). At the
Closing, the Investor shall surrender to the New York office of Ropes & Gray
LLP, counsel to the Company, at 885 Third Avenue, Suite 3200, New York, New York
10022, the Note and Initial Warrants held by the Investor or in lieu of the
foregoing an indemnification undertaking reasonably satisfactory to the Company.
On the Closing Date and as a condition to the Closing, the Company shall have
entered into a separate but substantially identical redemption, amendment and
exchange agreement with the Other Investor (the "Other Investor Agreement") and
shall consummate the transactions contemplated by

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the Other Investor Agreement concurrently with the consummation of the
transactions contemplated by this Agreement.

        6. Registration Rights.

                (a) Prospectus Supplement. On or before the date which is one
        (1) day following the Closing Date, the Company shall, to the extent
        required or advisable by law, at its sole cost and expense and in
        accordance with the 1933 Act, file a prospectus supplement to the
        Current Registration Statement with the SEC describing the change of the
        conversion price to the Notes to the New Conversion Price and the
        exchange of the Initial Warrants with the Exchange Warrants as described
        herein.

                (b) New Warrant Shares. Promptly following the Closing Date,
        (but by no later than 30 calendar days following the Closing Date), the
        Company shall, at its sole cost and expense and in accordance with the
        1933 Act, use its best efforts to prepare and file a registration
        statement (the "Exchange Warrants Registration Statement") on Form S-3
        (or other appropriate form acceptable to the Investor) under the 1933
        Act with the SEC covering all the shares of Common Stock issued or
        issuable upon exercise of the Exchange Warrants. The Company shall use
        its best efforts to have such Exchange Warrants Registration Statement
        declared effective as soon thereafter as possible (but by no later than
        120 calendar days following the Closing Date). All the terms and
        conditions of the Registration Rights Agreement, dated as of March 5,
        2002 (the "Registration Rights Agreement"), by and among the Company and
        the Investors shall apply mutatis mutandis to the registration of such
        shares issued or issuable upon exercise of the Exchange Warrants,
        including without limitation the indemnification and contribution
        provisions contained therein, and all such terms are incorporated by
        reference herein. Therefore, the Warrant Shares underlying the Exchange
        Warrants shall be deemed to be Warrant Shares constituting Registrable
        Securities for all purposes of the Registration Rights Agreement and the
        Exchange Warrants Registration Statement shall be deemed to be a
        Registration Statement for all purposes of the Registration Rights
        Agreement. Notwithstanding the foregoing and in lieu of the amount set
        forth as liquidated damages under Section 3(c) of the Registration
        Rights Agreement, the amount which shall be paid to the Investor, if the
        Company breaches the provisions of this Section 6(b), subject to the
        provisions of Section 2(c)(ii) of the Registration Rights Agreement, and
        the applicable provisions of Section 3(c) of the Registration Rights
        Agreement, for each month (or portion thereof) following any such
        breach, shall equal 2% of the product of (x) the number of Warrant
        Shares issued and issuable upon exercise of the Exchange Warrants and
        not available for resale under the Exchange Warrants Registration
        Statement multiplied by (y) the greater of (I) the Warrant Price (as
        defined in the Exchange Warrant) and (II) the closing price of the
        Common Stock as reported by the NASDAQ National Market (or other
        exchange or market on which the Common Stock is principally traded) on
        the date of determination.

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        7. Representations and Warranties of the Company. The Company hereby
represents and warrants to the Investor that:

                (a) Organization, Good Standing and Qualification. The Company
        is a corporation duly incorporated, validly existing and in good
        standing under the laws of the jurisdiction of its incorporation and has
        all requisite corporate power and authority to carry on its business as
        now conducted and own its properties. The Company is duly qualified to
        do business as a foreign corporation and is in good standing in each
        jurisdiction in which the conduct of its business or its ownership or
        leasing of property makes such qualification or licensing necessary
        unless the failure to so qualify would not be reasonably likely to
        result in a Material Adverse Effect. All of the Company's subsidiaries
        are listed by name and jurisdiction on Schedule 4.1 attached to the
        Purchase Agreement.

                (b) Authorization. The Company has full corporate power and
        authority and has taken all requisite action on the part of the Company,
        its officers, directors and stockholders necessary for (i) the
        authorization, execution and delivery of this Agreement and the Exchange
        Warrants, (ii) authorization of the performance of all obligations of
        the Company hereunder and thereunder, and (iii) the authorization,
        issuance (or reservation for issuance) and delivery of the Conversion
        Shares and Warrant Shares. Each of this Agreement and the Exchange
        Warrant constitutes the legal, valid and binding obligations of the
        Company, enforceable against the Company in accordance with their
        respective terms, subject to bankruptcy, insolvency, fraudulent
        transfer, reorganization, moratorium and similar laws of general
        applicability, relating to or affecting creditors' rights generally.

                (c) Capitalization. Set forth on Schedule 7(c) hereto is (a) the
        authorized capital stock of the Company on the date hereof; (b) the
        number of shares of capital stock issued and outstanding on the date
        hereof; (c) the number of shares of capital stock issuable pursuant to
        the Company's stock plans; and (d) the number of shares of capital stock
        issuable and reserved for issuance pursuant to securities (other than
        the Exchange Warrants) exercisable for, or convertible into or
        exchangeable for any shares of capital stock. All of the issued and
        outstanding shares of the Company's capital stock have been duly
        authorized and validly issued and are fully paid, nonassessable and free
        of preemptive rights. Except as set forth on Schedule 7(c), no Person is
        entitled to preemptive or similar statutory or contractual rights with
        respect to any securities of the Company. Except as set forth on
        Schedule 7(c), there are no outstanding warrants, options, convertible
        securities or other rights, agreements or arrangements of any character
        under which the Company is or may be obligated to issue any equity
        securities of any kind and except as contemplated by this Agreement, the
        Other Investor Agreement or set forth on Schedule 7(c), the Company is
        not currently in negotiations for the issuance of any equity securities
        of any kind. Except as set forth on Schedule 7(c), the Company has no
        knowledge of any voting agreements, buy-sell agreements, option or right
        of first purchase agreements or other agreements of any kind among any
        of the securityholders of the Company relating

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        to the securities of the Company held by them. Except pursuant to the
        Registration Rights Agreement, this Agreement, the Other Investor
        Agreement and as set forth on Schedule 7(c), the Company has not granted
        any Person the right to require the Company to register any securities
        of the Company under the 1933 Act, whether on a demand basis or in
        connection with the registration of securities of the Company for its
        own account or for the account of any other Person.

                (d) Valid Issuance. As of the Closing, the Company has reserved
        a sufficient number of shares of Common Stock for the issuance upon
        exercise of the Exchange Warrants. The Exchange Warrants are duly
        authorized, and the Conversion Shares, the Exchange Warrants and the
        Warrant Shares (collectively, the "Securities"), respectively, when
        issued in accordance herewith and with the terms of the Note, the
        Exchange Warrants and this Agreement, will be duly authorized, validly
        issued, fully paid, non-assessable and free and clear of all
        encumbrances and restrictions, except for restrictions on transfer
        imposed by applicable securities laws. The number of shares to be
        reserved hereunder shall be determined without regard to any
        restrictions on beneficial ownership contained in this Agreement or in
        the Exchange Warrants.

                (e) Consents. The execution, delivery and performance by the
        Company of this Agreement and the Exchange Warrants and the offer,
        issuance and sale of the Securities, require no consent of, action by or
        in respect of, or filing with, any Person, governmental body, agency, or
        official other than filings that will have been made pursuant to
        applicable state securities laws and post-sale filings pursuant to
        applicable state and federal securities laws and the additional listing
        application requirements of the NASDAQ National Market, which the
        Company undertakes to file within the applicable time periods.

                (f) Delivery of SEC Filings; Business. The SEC Filings represent
        all filings required of the Company pursuant to the 1934 Act since
        August 31, 2000. The SEC Filings complied as to form in all material
        respects with the requirements of the 1934 Act and did not contain any
        untrue statement of a material fact or omit to state any material fact
        necessary in order to make the statements made therein, in the light of
        the circumstances under which they were made, not misleading. The
        Company is engaged only in the business described in the SEC Filings and
        the SEC Filings contain a complete and accurate description of the
        business of the Company in all material respects. The Company has not
        provided to the Investor (i) any information required to be filed under
        the 1934 Act that has not been so filed or (ii) any non-public
        information.

                (g) No Material Adverse Change. Since the filing of the
        Company's Annual Report on Form 10-K for the fiscal year ended December
        31, 2002, no event, transaction or condition has occurred that,
        individually or in the aggregate, has had or could reasonably be
        expected to have a Material Adverse Effect.

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                (h) Registration Statements; Material Contracts.

                                (1) During the preceding two years, each
                registration statement and any amendment thereto filed by the
                Company pursuant to the 1933 Act, as of the date such statement
                or amendment became effective, complied as to form in all
                material respects with the 1933 Act and did not contain any
                untrue statement of a material fact or omit to state any
                material fact required to be stated therein or necessary in
                order to make the statements made therein, in the light of the
                circumstances under which they were made, not misleading; and
                each prospectus filed pursuant to Rule 424(b) under the 1933
                Act, as of its issue date and as of the closing of any sale of
                securities pursuant thereto did not contain any untrue statement
                of a material fact or omit to state any material fact required
                to be stated therein or necessary in order to make the
                statements made therein, in the light of the circumstances under
                which they were made, not misleading.

                                (2) Except as set forth on Schedule 4.3 to the
                Purchase Agreement, there are no agreements or instruments
                currently in force and effect that constitute a warrant, option,
                convertible security or other right, agreement or arrangement of
                any character under which the Company is or may be obligated to
                issue any material amounts of any equity security of any kind,
                or to transfer any material amounts of any equity security of
                any kind.

                (i) Form S-3 Eligibility. The Company is currently eligible to
        register the resale of its Common Stock on a registration statement on
        Form S-3 under the 1933 Act. The Current Registration Statement is
        effective and available for the sale of at least all of the Registrable
        Securities required to be included in such Current Registration
        Statement.

                (j) No Conflict, Breach, Violation or Default.

                                (1) The execution, delivery and performance of
                this Agreement and the Exchange Warrants by the Company and the
                issuance and sale of the Securities will not conflict with or
                result in a breach or violation of any of the terms and
                provisions of, or constitute a default under (i) the Company's
                Restated Articles of Organization (including any certificates of
                designation) or the Company's Bylaws, both as in effect on the
                date hereof (copies of which have been provided to the Investor
                before the date hereof to the extent there have been any changes
                since execution of the Purchase Agreement) and the date of
                issuance of such securities, or (ii) except where it would not
                have a Material Adverse Effect, (A) any statute, rule,
                regulation or order of any governmental agency or body or any
                court, domestic or foreign, having jurisdiction over the Company
                or any of its properties, or (B) any agreement or instrument to
                which the

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                Company is a party or by which the Company is bound or to which
                any of the properties of the Company is subject.

                                (2) Except where it would not have a Material
                Adverse Effect, the Company (i) is not in violation of any
                statute, rule or regulation applicable to the Company or its
                assets, (ii) is not in violation of any judgment, order or
                decree applicable to the Company or its assets, and (iii) is not
                in breach or violation of any agreement, note or instrument to
                which it or its assets are a party or are bound or subject. The
                Company has not received notice from any Person of any claim or
                investigation that, if adversely determined, would render the
                preceding sentence untrue or incomplete.

                (k) Tax Matters. The Company has timely prepared and filed all
        tax returns required to have been filed by the Company with all
        appropriate governmental agencies and timely paid all taxes owed by it.
        The charges, accruals and reserves on the books of the Company in
        respect of taxes for all fiscal periods are adequate in all material
        respects, and there are no material unpaid assessments against the
        Company nor, to the knowledge of the Company, any basis for the
        assessment of any additional taxes, penalties or interest for any fiscal
        period or audits by any federal, state or local taxing authority except
        such as which are not material and except as set forth on Schedule 4.12
        to the Purchase Agreement. All material taxes and other assessments and
        levies that the Company is required to withhold or to collect for
        payment have been duly withheld and collected and paid to the proper
        governmental entity or third party when due. There are no material tax
        liens or claims pending or, to the Company's knowledge, threatened
        against the Company or any of its respective assets or property. There
        are no outstanding tax sharing agreements or other such arrangements
        between the Company and any other corporation or entity.

                (l) Title to Properties. Except as disclosed in the SEC Filings,
        the Company has good and marketable title to all real properties and all
        other properties and assets owned by it, in each case free from liens,
        encumbrances and defects, except for such liens, encumbrances and
        defects which could not reasonably be expected to have a Material
        Adverse Effect; and except as disclosed in the SEC Filings, the Company
        holds any leased real or personal property under valid and enforceable
        leases with no exceptions that would materially interfere with the use
        made or currently planned to be made thereof by them.

                (m) Certificates, Authorities and Permits. The Company possesses
        adequate certificates, authorities or permits issued by appropriate
        governmental agencies or bodies necessary to conduct the business now
        operated by it and has not received any notice of proceedings relating
        to the revocation or modification of any such certificate, authority or
        permit that, if determined adversely to the Company, would individually
        or in the aggregate have a Material Adverse Effect.

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                (n) No Labor Disputes. No material labor dispute with the
        employees of the Company exists or, to the knowledge of the Company, is
        imminent.

                (o) Intellectual Property. The Company owns or possesses
        adequate rights or licenses to the inventions, know-how, patents, patent
        rights, copyrights, trademarks, trade names, licenses, approvals,
        governmental authorizations, trade secrets confidential information and
        other intellectual property rights (collectively, "Intellectual Property
        Rights"), free and clear of all liens, security interests, charges,
        encumbrances, equities and other adverse claims, necessary to conduct
        the business now operated by it, or presently employed by it and
        presently contemplated to be operated by it as described in the SEC
        Filings, and the Company has not received any notice of infringement of
        or conflict with asserted rights of others with respect to any
        Intellectual Property Rights except as disclosed in the SEC Filings.
        None of the Company's Intellectual Property Rights have expired or
        terminated, or are expected to expire or terminate within three years
        from the date of this Agreement, except where such expirations or
        termination would not result, either individually or in the aggregate,
        in a Material Adverse Effect. To the knowledge of the Company, the
        Company's patents and other Intellectual Property Rights and the present
        activities of the Company do not infringe any patent, copyright,
        trademark, trade name or other proprietary rights of any third party
        where such infringement may cause a Material Adverse Effect on the
        Company, and there is no claim, action or proceeding being made or
        brought against, or to the Company's knowledge, being threatened
        against, the Company or its subsidiaries regarding its Intellectual
        Property Rights (other than as set forth in the SEC Filings filed at
        least ten (10) day prior to the date hereof), and the Company and its
        subsidiaries are unaware of any facts or circumstances which could
        reasonably be expected to give rise to any of the foregoing. The Company
        has no knowledge of the material infringement of its Intellectual
        Property Rights by third parties and has no reason to believe that any
        of its Intellectual Property Rights is unenforceable, and the Company
        and its subsidiaries are unaware of any facts or circumstances which
        might give rise to any of the foregoing. The Company and its
        subsidiaries have taken reasonable security measures to protect the
        secrecy, confidentiality and value of all of their intellectual
        properties.

                (p) Environmental Matters. The Company is not in violation of
        any statute, rule, regulation, decision or order of any governmental
        agency or body or any court, domestic or foreign, relating to the use,
        disposal or release of hazardous or toxic substances or relating to the
        protection or restoration of the environment or human exposure to
        hazardous or toxic substances (collectively, "Environmental Laws"), does
        not own or operate any real property contaminated with any substance
        that is subject to any Environmental Laws, is not liable for any
        off-site disposal or contamination pursuant to any Environmental Laws,
        and is not subject to any claim relating to any Environmental Laws,
        which violation, contamination, liability or claim would individually or
        in the aggregate have a Material Adverse Effect; and the Company is not
        aware of any pending investigation that might lead to such a claim.

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                (q) Litigation. Except as disclosed in the SEC Filings, there
        are no pending actions, suits or proceedings against or affecting the
        Company or any of its properties that, if determined adversely to the
        Company, would individually or in the aggregate have a Material Adverse
        Effect; and to the Company's knowledge, no such actions, suits or
        proceedings are threatened or contemplated.

                (r) Financial Statements. The financial statements included in
        each SEC Filing present fairly and accurately in all material respects
        the consolidated financial position of the Company as of the dates shown
        and its consolidated results of operations and cash flows for the
        periods shown, and such financial statements have been prepared in
        conformity with generally accepted accounting principles applied on a
        consistent basis. Since December 31, 2002, no event has occurred that
        would cause a Material Adverse Effect on the financial condition of the
        Company except as otherwise reflected in the SEC Filings since such
        date, and there has not been any material adverse change in the
        consolidated assets, liabilities, financial condition or operating
        results of the Company from that reflected in the financial statements
        included in the Company's most recent Quarterly Report on Form 10-Q,
        except changes in the ordinary course of business which have not had, in
        the aggregate, a Material Adverse Effect.

                (s) Insurance Coverage. The Company maintains in full force and
        effect insurance coverage that the Company reasonably believes to be
        adequate against all liabilities, claims and risks against which it is
        customary for comparably situated companies to insure.

                (t) Compliance with NASDAQ Continued Listing Requirements. The
        Company is in material compliance with all applicable NASDAQ National
        Market continued listing requirements and is in good standing on such
        exchange. There are no proceedings pending or, to the Company's
        knowledge, threatened against the Company relating to the continued
        listing of the Common Stock on the NASDAQ National Market and the
        Company has not received any notice of, nor to the knowledge of the
        Company is there any basis for, the delisting of the Common Stock from
        the NASDAQ National Market.

                (u) Brokers and Finders. The Investor shall have no liability or
        responsibility for the payment of any commission or finder's fee to any
        third party in connection with or resulting from this Agreement or the
        transactions contemplated by this Agreement by reason of any agreement
        of or action taken by the Company.

                (v) No General Solicitation; 1933 Act Exemption. Neither the
        Company nor any Person acting on its behalf has conducted any general
        solicitation or general advertising (as those terms are used in
        Regulation D) in connection with the offer or sale of any of the
        Exchange Warrants or any of the Securities. The issuance of the
        Conversion Shares and the exchange of the Initial Warrants for the
        Exchange Warrants are exempt from registration under the 1933 Act
        pursuant to Section 3(a)(9) of the 1933 Act.

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                (w) No Integrated Offering. Neither the Company nor any of its
        Affiliates, nor any Person acting on its or their behalf has, directly
        or indirectly, made any offers or sales of any security or solicited any
        offers to buy any security, under circumstances that would require
        registration of the Exchange Warrants or the Securities under the 1933
        Act; or would require the integration of this offering with any other
        offering of securities for purposes of determining the need to obtain
        stockholder approval of the transactions contemplated hereby under the
        rules of the NASDAQ National Market.

                (x) Disclosures. For purposes of this Agreement and the
        transactions contemplated hereby, none of the representations or
        warranties made by the Company in this Agreement or in the Exchange
        Warrants and no information furnished by the Company pursuant hereto or
        thereto, or in any other document, certificate or statement furnished by
        the Company to the Investor or any authorized representative of the
        Investor, pursuant hereto or thereto or in connection therewith, contain
        any untrue statement of a material fact or omit to state a material fact
        necessary in order to make the statements contained herein and therein,
        in the light of the circumstances under which they were made, not
        misleading.

                (y) Rights Plan. None of the acquisition of the Exchange
        Warrants or any of the Securities nor the deemed beneficial ownership of
        shares of Common Stock issuable upon, or the acquisition of such shares
        pursuant to the exercise of the Exchange Warrants will in any event
        under any circumstances in and of itself trigger the poison pill
        provisions of any stockholder rights or similar agreements, or plan
        having a similar effect, to which the Company is a party.

        8. Representations and Warranties of the Investor. The Investor hereby
represents and warrants on the date hereof to that Company that:

                (a) Organization and Existence. The Investor is a validly
        existing entity and has all requisite power and authority to enter into
        this Agreement.

                (b) Authorization. The execution, delivery and performance by
        the Investor of this Agreement has been duly authorized and this
        Agreement will constitute the valid and legally binding obligation of
        the Investor, enforceable against the Investor in accordance with its
        terms, subject to bankruptcy, insolvency, fraudulent transfer,
        reorganization, moratorium and similar laws of general applicability,
        relating to or affecting creditors' rights generally.

                (c) Legends. It is understood that, until registration for
        resale pursuant to the Registration Rights Agreement or until sales
        under Rule 144 are permitted, certificates evidencing the Exchange
        Warrants and the Warrant Shares may bear one or all of the following
        legends or legends substantially similar thereto:

                                (1) "THE SHARES REPRESENTED BY THIS CERTIFICATE
MAY NOT BE TRANSFERRED WITHOUT (I) THE OPINION OF

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COUNSEL REASONABLY SATISFACTORY TO THE CORPORATION (IF REQUESTED) THAT SUCH
TRANSFER MAY LAWFULLY BE MADE WITHOUT REGISTRATION UNDER THE SECURITIES ACT OF
1933; OR (II) SUCH REGISTRATION OR QUALIFICATION."

                                (2) If required by the authorities of any state
in connection with the issuance of sale of the Securities, the legend required
by such state authority.

                Upon registration for resale pursuant hereto and the
Registration Rights Agreement or upon Rule 144(k) under the 1933 Act becoming
available, the Company shall promptly cause certificates evidencing the Warrant
Shares previously issued to be replaced with certificates which do not bear such
restrictive legends, and all Warrant Shares subsequently issued shall not bear
such restrictive legends. Certificates evidencing the Warrant Shares issued
following the registration for resale of such shares pursuant hereto and the
Registration Rights Agreement or Rule 144(k) under the 1933 Act becoming
available for the sale of such shares shall be issued without any restrictive
legends.

                (d) Title to Note and Initial Warrants. The Investor has good
        and valid title to the Note and the Initial Warrants, free of any
        encumbrances, has not transferred the Note or the Initial Warrants, and
        has not converted the Note into shares of Common Stock or exercised the
        Initial Warrants for shares of Common Stock.

        9. Covenants and Agreements of the Company.

                (a) Additional Financings. From the date hereof until the second
        anniversary of the Closing Date, the Investor will have a right of
        participation with respect to any sales of any of the Company's
        securities in a non-registered or "shelf" offering (subject to the
        exclusions set forth in the definition of "Excluded Transaction" in the
        Purchase Agreement) capital raising transaction on and subject to the
        terms and conditions set forth in this Section 9(a). During such period,
        the Company shall give written notice (a "Financing Notice") to the
        Investor within five (5) business days following any non-registered or
        "shelf" sale (subject to the exclusions set forth in the definition of
        "Excluded Transaction") of any of the Company's equity securities or any
        securities convertible into or exchangeable or exercisable for such
        securities in a capital raising transaction (including, without
        limitation, any Variable Rate Transaction or MFN Transaction) (a
        "Participation Transaction"); provided, however, that if the approval of
        the Company's shareholders is required by the rules and regulations of
        NASDAQ or any other applicable market, exchange, regulatory authority,
        agency or commission in order to enter into such Participation
        Transaction, then the Company shall provide the Financing Notice to the
        Investor at least 10 business days prior to the filing of any proxy or
        information statement with the SEC seeking shareholder approval of such
        Participation Transaction in order to provide the Investor a reasonable
        period of time to exercise its rights hereunder and to have the
        securities the Investor elects to purchase included in such proxy or

                                       11

<PAGE>

        information statement. Such Financing Notice shall describe the
        significant business terms of such transaction and be accompanied by a
        copy of all transaction documents pertaining to such transaction. The
        Investor shall have the right (pro rata with the Other Investor (based
        on a 4:1 ratio for the Other Investor and the Investor) respectively, or
        together with other investors selected by the Investor and reasonably
        acceptable to the Company) to purchase, in accordance with the
        procedures set forth below, an amount of identical securities issued in
        such transaction equal to the Investor's pro rata portion of 33 1/3% of
        the amount purchased by such other investors (i.e., 25% of the aggregate
        amount of such securities issuable to the Investors and such other
        investors together) for the same consideration and on the same terms and
        conditions as such third party sale, provided that if the aggregate
        amount of net proceeds raised by the Company in any such transaction
        exceeds $15 million, then for such portion of such transaction which
        exceeds $15 million the Investor shall have the right to purchase only
        its pro rata portion of 20% of such excess amount purchased by such
        other investors (i.e., 16 2/3% of the aggregate amount of such excess
        securities issuable to the Investors and such other investors together),
        and provided further that, notwithstanding the foregoing, the Investor
        shall be accorded the right to purchase not less than $1 million of
        securities of the Company on the same terms as the securities issued in
        such Participation Transaction. The Company shall not consummate any
        such third party transaction unless following such consummation the
        Investor is permitted to purchase such percentage under the terms of all
        transaction documents for such other transaction and under all
        applicable laws and regulations. Without limiting the foregoing (a) the
        Company shall authorize and reserve a sufficient number and amount of
        such securities, or class or series thereof, in order to enable full
        participation by the Investor in such securities, class or series that
        is purchased by such third party, and (b) the Company shall not issue in
        excess of such number of shares of Common Stock (or securities which are
        convertible, exchangeable or exercisable into such number of shares of
        Common Stock) which, together with the maximum amount of securities
        otherwise permitted to be purchased by the Investor and the other
        Investor hereunder, would cause the Company to violate any shareholder
        approval or other requirements of NASDAQ or any other applicable market,
        exchange, regulatory authority, agency or commission. The Investor may
        elect to participate in such transaction by delivering written notice of
        such election to the Company within ten (10) business days following
        receipt of the Financing Notice. If, subsequent to the Company giving
        any Financing Notice to the Investor hereunder, any material term or
        condition of such third-party sale is changed from that disclosed in the
        Financing Notice and the accompanying transaction documents, the Company
        shall be required to provide a new Financing Notice to the Investor
        hereunder and the Investor shall again have the right to exercise its
        rights to purchase a percentage of the securities in such transaction on
        such changed terms and conditions as provided hereunder. The rights and
        obligations of this Section 9(a) shall in no way diminish the other
        rights of the Investor pursuant to this Section 9. Notwithstanding
        anything to the contrary contained herein, the number of shares of
        Common Stock that may be acquired by the

                                       12

<PAGE>

        Investor pursuant to any Participation Transaction shall not exceed a
        number that, when added to the total number of shares of Common Stock
        deemed beneficially owned by the Investor (other than by virtue of the
        ownership of securities or rights to acquire securities that have
        limitations on the Investor's right to convert, exercise or purchase
        similar to the limitation set forth herein), together with all shares of
        Common Stock deemed beneficially owned by the Investor's "affiliates"
        (as defined in Rule 144 of the 1933 Act) that would be aggregated for
        purposes of determining whether a group under Section 13(d) of the 1934
        Act, exists, would exceed 4.99% of the total issued and outstanding
        shares of the Common Stock; provided, that the limitation set forth in
        this sentence shall not limit the ability of the Company to engage in a
        Participation Transaction. The rights of participation of the Investor
        set forth in this Section 9(a) will not apply to any Excluded
        Transaction. All rights of the Investor under this Section 9(a) shall
        cease and be of no further effect upon the consummation of a Change in
        Control Transaction (as defined in the Notes).

                (b) Reservation of Common Stock issuable upon Exercise of the
        Exchange Warrants. The Company hereby agrees at all times to reserve and
        keep available out of its authorized but unissued shares of Common
        Stock, solely for the purpose of providing for the full exercise of the
        Exchange Warrants, such number of shares of Common Stock as shall from
        time to time equal 100% of the number of shares sufficient to permit the
        full exercise of the Exchange Warrants in accordance with the terms of
        the Exchange Warrants. All calculations pursuant to this paragraph shall
        be made without regard to restrictions on beneficial ownership.

                (c) Press Releases; Form 8-K.

                                        (1) Other than the press release
                described in the next sentence, any press release or other
                publicity concerning this Agreement, the Other Investor
                Agreement or the transactions contemplated by this Agreement
                shall be submitted to the Investor for comment at least two (2)
                business days prior to issuance, unless the release is required
                to be issued within a shorter period of time by law or pursuant
                to the rules of the NASDAQ National Market or a national
                securities exchange. The Company shall issue a press release
                concerning the fact and material terms of this Agreement
                promptly upon execution hereof but in any event within one
                business day hereof in the form attached hereto as Exhibit B.

                                        (2) On or before 8:30 a.m. (New York
                City time), on the first business day following the date hereof,
                the Company shall file a Current Report on Form 8-K describing
                the terms of the transactions contemplated by (i) this Agreement
                and the Exchange Warrants and (ii) the Other Investor Agreement
                and the warrants issuable pursuant thereto on the Closing Date
                (collectively, the "Other Investor Documents"), in each case, in
                the form required by the 1934 Act, and

                                       13

<PAGE>

                attaching the material transaction documents (including, without
                limitation, this Agreement and the Other Investor Documents) as
                exhibits to such filing (including all attachments, the "8-K
                Filing", and the description and attachments, the "8-K
                Materials"). The 8-K Materials shall be subject to the
                Investor's prior approval, not to be unreasonably withheld or
                delayed. From and after the filing of the 8-K Filing with the
                SEC, the Investor shall not be in possession of any material,
                nonpublic information received from the Company, any of its
                Subsidiaries or any of its respective officers, directors,
                employees or agents, that is not disclosed in the 8-K Filing.
                The Company shall not, and shall cause each of its officers,
                directors, employees and agents, not to, provide the Investor
                with any material, nonpublic information regarding the Company
                from and after the filing of the 8-K Filing with the SEC without
                the express written consent of the Investor.

                (d) No Conflicting Agreements. The Company will not take any
        action, enter into any agreement or make any commitment that would
        conflict or interfere in any material respect with the obligations to
        the Investor under this Agreement or the Exchange Warrants.

                (e) Listing of Conversion Shares, Warrant Shares and Related
        Matters. The Company hereby agrees, promptly following the Closing of
        the transactions contemplated by this Agreement, to take such action to
        cause the Conversion Shares (if necessary) and the Warrant Shares to be
        listed on the NASDAQ National Market as promptly as possible but no
        later than the effective date of the registration contemplated by this
        Agreement. The Company further agrees that if the Company applies to
        have its Common Stock or other securities traded on any other principal
        stock exchange or market, it will include in such application the
        Conversion Shares and the Warrant Shares and will take such other action
        as is necessary to cause such Common Stock to be so listed. Neither the
        Company nor any of its Affiliates, nor any Person acting on its or their
        behalf, shall directly or indirectly make any offers or sales of any
        security or solicit any offers to buy any security which may cause the
        integration of the offering hereunder with any other offering of
        securities for purposes of determining the need to obtain stockholder
        approval of the transactions contemplated hereby under the rules of the
        NASDAQ National Market.

                (f) Corporate Existence. So long as any Exchange Warrants remain
        outstanding, the Company shall maintain its corporate existence, except
        in the event of a merger, consolidation or sale of all or substantially
        all of the Company's assets, as long as the surviving or successor
        entity in such transaction (a) assumes the Company's obligations
        hereunder and under the agreements and instruments entered into in
        connection herewith, regardless of whether or not the Company would have
        had a sufficient number of shares of Common Stock authorized and
        available for issuance in order to fulfill its obligations hereunder and
        effect the exercise in full of all Exchange Warrants outstanding as of
        the date of such transaction; (b) has no legal, contractual or other
        restrictions on its ability

                                       14

<PAGE>

        to perform the obligations of the Company hereunder and under the
        agreements and instruments entered into in connection herewith; and (c)
        is a publicly traded corporation whose common stock and the shares of
        capital stock issuable upon exercise of the Exchange Warrants are (or
        would be upon issuance thereof) listed for trading on an Approved
        Market, provided that this clause (c) shall not apply in the event of a
        merger, consolidation or sale of all or substantially all of the
        Company's assets with or to an unaffiliated third party in an arm's
        length transaction pursuant to which all holders, other than the
        acquiring entity, of outstanding shares of Common Stock receive
        consideration consisting solely of cash.

        10. Miscellaneous.

                (a) Full Force and Effect. Except as otherwise expressly
        provided herein, the Registration Rights Agreement shall remain in full
        force and effect.

                (b) Survival. All representations, warranties, covenants and
        agreements contained in this Agreement shall be deemed to be
        representations, warranties, covenants and agreements as of the date
        hereof and shall survive the execution and delivery of this Agreement.

                (c) Successors and Assigns; Amendment. This Agreement may not be
        assigned by a party hereto without the prior written consent of the
        other party hereto which consent may not be unreasonably withheld or
        delayed, except that without the prior written consent of the Company,
        but after notice duly given, the Investor may assign its rights and
        delegate its duties hereunder in whole or in part to an affiliate of the
        Investor or to the Other Investor. The terms and conditions of this
        Agreement shall inure to the benefit of and be binding upon the
        respective permitted successors and assigns of the parties. Nothing in
        this Agreement, express or implied, is intended to confer upon any party
        other than the parties hereto or their respective successors and assigns
        any rights, remedies, obligations, or liabilities under or by reason of
        this Agreement, except as expressly provided in this Agreement. No
        provision of this Agreement or the Exchange Warrant may be amended other
        than by an instrument in writing signed by the Company and the Investor
        and no amendment may be made to the Other Investor Documents without the
        written consent of the Investor if such amendment would be adverse to
        the rights of the Investor relative to the Other Investor or
        preferential to the Other Investor relative to the Investor. No
        consideration shall be offered or paid to any Person to amend or consent
        to a waiver or modification of any provision of this Agreement, the
        Purchase Agreement, the Registration Rights Agreement or the Exchange
        Warrants unless the same consideration also is offered to all of the
        parties to such agreements or holders of the Exchange Warrants, as the
        case may be. The Company has not entered into and does not currently
        contemplate entering into, directly or indirectly, any transaction with
        the Other Investor except as set forth in the Other Investor Documents.

                                       15

<PAGE>

                (d) Counterparts. This Agreement may be executed in two or more
        counterparts, each of which shall be deemed an original, but all of
        which together shall constitute one and the same instrument. This
        Agreement shall not become effective unless and until it is executed and
        delivered by each of the Company and the Investor.

                (e) Titles and Subtitles. The titles and subtitles used in this
        Agreement are used for convenience only and are not to be considered in
        construing or interpreting this Agreement.

                (f) Notices. Unless otherwise provided, any notice required or
        permitted under this Agreement shall be given in writing and shall be
        deemed effectively given only upon delivery to each party to be notified
        by (i) personal delivery, (ii) telecopier, upon receipt of confirmation
        of complete transmittal, or (iii) an internationally recognized
        overnight air courier, addressed to the party to be notified at the
        address as follows, or at such other address as such party may designate
        by ten days' advance written notice to the other party:

                         If to the Company:

                         Genome Therapeutics Corp.
                         100 Beaver Street
                         Waltham, Massachusetts 02453
                         Telephone: (781) 398-2300
                         Fax: (781) 893-9535
                         Attention: Stephen Cohen, CFO

                         with a copy to:

                         Ropes & Gray LLP
                         One International Place
                         Boston, Massachusetts 02110-2624
                         Telephone: (617) 951-7000
                         Fax: (617)951-7050
                         Attention: Patrick O'Brien, Esquire

                         If to the Investor, to the address set forth on the
                         signature page hereto.

                (g) Expenses. Promptly following the Closing Date, the Company
        shall pay for reasonable legal fees and expenses incurred by the
        Investor in connection with the transactions contemplated by this
        Agreement and the preparation and negotiation of this Agreement and the
        Exchange Warrants in an amount up to $12,500.

                (h) Severability. If one or more provisions of this Agreement
        are held to be unenforceable under applicable law, such provision shall
        be excluded from this

                                       16

<PAGE>

        Agreement and the balance of this Agreement shall be interpreted as if
        such provision were so excluded and shall be enforceable in accordance
        with its terms.

                (i) Entire Agreement. This Agreement, including the Exhibits and
        Schedules hereto, the Registration Rights Agreement, the Purchase
        Agreement, the Notes and the Exchange Warrants and other documents
        contemplated hereby constitute the entire agreement among the parties
        hereof with respect to the subject matter hereof and thereof and
        supersede all prior agreements and understandings, both oral and
        written, between the parties with respect to the subject matter hereof
        and thereof.

                (j) Further Assurances. The parties shall execute and deliver
        all such further instruments and documents and take all such other
        actions as may reasonably be required to carry out the transactions
        contemplated hereby and to evidence the fulfillment of the agreements
        herein contained.

                (k) APPLICABLE LAW. THIS AGREEMENT SHALL BE GOVERNED BY, AND
        CONSTRUED IN ACCORDANCE WITH, THE LAWS OF THE STATE OF NEW YORK WITHOUT
        REGARD TO PRINCIPLES OF CONFLICTS OF LAWS.

                (l) Remedies.

                                (1) The Investor shall be entitled to specific
                performance of the Company's obligations under the Agreements.

                                (2) The Company on the one hand, and the
                Investor on the other hand, shall indemnify the other and hold
                it harmless from any loss, cost, expense or fees (including
                attorneys' fees and expenses) arising out of any breach of any
                representation, warranty, covenant or agreement in this
                Agreement or the Exchange Warrants, or arising out of the
                enforcement of this Section.

                (m) JURISDICTION. THE PARTIES HEREBY AGREE THAT ALL ACTIONS OR
        PROCEEDINGS ARISING DIRECTLY OR INDIRECTLY FROM OR IN CONNECTION WITH
        THIS AGREEMENT OR THE OTHER AGREEMENTS SHALL BE LITIGATED ONLY IN THE
        SUPREME COURT OF THE STATE OF NEW YORK OR THE UNITED STATES DISTRICT
        COURT FOR THE SOUTHERN DISTRICT OF NEW YORK LOCATED IN NEW YORK COUNTY,
        NEW YORK. THE PARTIES CONSENT TO THE JURISDICTION AND VENUE OF THE
        FOREGOING COURTS AND CONSENT THAT ANY PROCESS OR NOTICE OF MOTION OR
        OTHER APPLICATION TO EITHER OF SAID COURTS OR A JUDGE THEREOF MAY BE
        SERVED INSIDE OR OUTSIDE THE STATE OF NEW YORK OR THE SOUTHERN DISTRICT
        OF NEW YORK BY REGISTERED MAIL, RETURN RECEIPT REQUESTED, DIRECTED TO
        THE PARTY BEING SERVED AT ITS ADDRESS SET FORTH IN THIS AGREEMENT (AND

                                       17

<PAGE>

        SERVICE SO MADE SHALL BE DEEMED COMPLETE THREE (3) DAYS AFTER THE SAME
        HAS BEEN POSTED AS AFORESAID) OR BY PERSONAL SERVICE OR IN SUCH OTHER
        MANNER AS MAY BE PERMISSIBLE UNDER THE RULES OF SAID COURTS. THE PARTIES
        HEREBY WAIVE ANY RIGHT TO A JURY TRIAL IN CONNECTION WITH ANY LITIGATION
        PURSUANT TO THIS AGREEMENT OR THE OTHER AGREEMENTS.

                (n) Payment Set Aside. To the extent that the Company makes a
        payment or payments to any Investor hereunder or pursuant to the
        Registration Rights Agreement or the Exchange Warrants or the Investor
        enforces or exercises its rights hereunder or thereunder, and such
        payment or payments or the proceeds of such enforcement or exercise or
        any part thereof are subsequently invalidated, declared to be fraudulent
        or preferential, set aside, recovered from, disgorged by or are required
        to be refunded, repaid or otherwise restored to the Company, a trustee,
        receiver or any other person or entity under any law (including, without
        limitation, any bankruptcy law, state or federal law, common law or
        equitable cause of action), then to the extent of any such restoration
        the obligation or part thereof originally intended to be satisfied shall
        be revived and continued in full force and effect as if such payment had
        not been made or such enforcement or setoff had not occurred.

                (o) Like Treatment of Investors and Holders. For so long as any
        Exchange Warrants remain outstanding, neither the Company nor any of its
        affiliates shall, directly or indirectly, pay or cause to be paid any
        consideration (immediate or contingent), whether by way of interest,
        fee, payment for the redemption, exchange or exercise of the Securities,
        or otherwise, to any Investor, Other Investor or holder of Securities,
        for or as an inducement to, or in connection with the solicitation of,
        any consent, waiver or amendment of any terms or provisions of the
        Agreement or the Exchange Warrants, unless such consideration is
        required to be paid to all Investors or holders of Securities bound by
        such consent, waiver or amendment. The Company shall not, directly or
        indirectly, redeem or exchange any Securities unless such offer of
        redemption or exchange is made pro rata to all Investors or holders of
        Securities, as the case may be, on identical terms.

                (p) Independent Nature of Investor's Obligations and Rights. The
        obligations of the Investor hereunder and under the documents
        contemplated hereby are several and not joint with the obligations of
        the Other Investor, and the Investor shall not be responsible in any way
        for the performance of the obligations of the Other Investor under any
        such document. Nothing contained herein or in any other document
        contemplated hereby, and no action taken by the Investor pursuant hereto
        or thereto, shall be deemed to constitute any of the Investors as a
        partnership, an association, a joint venture or any other kind of
        entity, or create a presumption that the Investors are in any way acting
        in concert or as a group with respect to such obligations or the
        transactions contemplated hereby or thereby. The Investor confirms that
        it has independently participated in

                                       18

<PAGE>

        the negotiation of the transaction contemplated hereby with the advice
        of its own counsel and advisors. The Investor shall be entitled to
        independently protect and enforce its rights, including, without
        limitation, the rights arising out of this Agreement or out of any other
        document contemplated hereby, and it shall not be necessary for any
        other Investor to be joined as an additional party in any proceeding for
        such purpose.

                          *** Signature Pages Follow***

                                       19

<PAGE>

        IN WITNESS WHEREOF, the parties have executed this Agreement as of the
date first above written.

The Company:                           GENOME THERAPEUTICS CORP.

                                       By: /s/ Steven M. Rauscher
                                           -------------------------------
                                       Name:   Steven M. Rauscher
                                       Title:  Chairman, President and CEO

                                       20

<PAGE>

                                      THE INVESTOR

                                      THE TAIL WIND FUND, LTD.
                                      By: TAIL WIND ADVISORY AND
                                          MANAGEMENT LTD.,
                                          as investment manager

                                          By: /s/ David Crook
                                              ---------------------------
                                          Name:   David Crook
                                          Title:  CEO

Address for Notices:                  The Tail Wind Fund Ltd.
                                      c/o Tail Wind Advisory and Management Ltd.
                                      1 Regent Street, 1st Floor
                                      London, SW1Y 4NS UK
                                      Attn: David Crook
                                      Telephone: 44-207-468-7660
                                      Facsimile: 44-207-468-7657

                                      with a copy to:

                                      Peter J. Weisman, P.C.
                                      110 East 59th Street, 18th Fl.
                                      New York, New York  10022
                                      Attn: Peter J. Weisman, Esq.
                                      Telephone: (212) 418-4792
                                      Facsimile: (212) 317-8855]

<PAGE>

Exhibits:

Exhibit A       Form of Exchange Warrants
Exhibit B       Press Release

Schedules:

Schedule 7(c)   Capitalization<PAGE>

                                                                     Exhibit 4.3

THIS SECURITY HAS NOT BEEN REGISTERED UNDER THE SECURITIES ACT OF 1933, AS
AMENDED (THE "SECURITIES ACT"), OR UNDER ANY STATE SECURITIES LAWS, IN RELIANCE
UPON EXEMPTIONS FROM REGISTRATION FOR NON-PUBLIC OFFERINGS. THIS SECURITY MAY
NOT BE SOLD OR TRANSFERRED UNLESS IT IS REGISTERED UNDER THE SECURITIES ACT AND
UNDER APPLICABLE STATE SECURITIES LAWS OR UNLESS THE ISSUER RECEIVES AN OPINION
OF COUNSEL REASONABLY SATISFACTORY TO IT THAT AN EXEMPTION FROM REGISTRATION IS
AVAILABLE (UNLESS WAIVED).

                            GENOME THERAPEUTICS CORP.

                                PURCHASE WARRANT

                    WARRANT ("WARRANT") TO PURCHASE SHARES OF
                     COMMON STOCK, $0.10 PAR VALUE PER SHARE

        This is to certify that, FOR VALUE RECEIVED, SMITHFIELD FIDUCIARY LLC
("Warrantholder"), is entitled to purchase, subject to the provisions of this
Warrant, from Genome Therapeutics Corp., a corporation organized under the laws
of The Commonwealth of Massachusetts ("Company"), at any time and from time to
time during an exercise period commencing on June 4 2003 and ending on June 4,
2008 ("Expiration Date"), all or a portion of up to 389,317 shares ("Warrant
Shares") of Common Stock, $0.10 par value ("Common Stock"), of the Company, at
an exercise price per share equal to $3.71, subject to adjustment as provided
herein (the exercise price in effect from time to time hereafter being herein
called the "Warrant Price").

        This Warrant has been issued pursuant to the terms of the Amendment,
Redemption and Exchange Agreement, dated as of June 4, 2003 (the "Agreement"),
by and between the Company and the Warrantholder. Capitalized terms used herein
and not defined herein shall have the meaning specified in the Agreement or the
Purchase Agreement dated March 5, 2002 (the "Purchase Agreement") among the
Company and certain purchasers of securities of the Company.

                Section 1.   Registration. The Company shall maintain books for
the transfer and registration of the Warrant. Upon the initial issuance of the
Warrant, the Company shall issue and register the Warrant in the name of the
Warrantholder.

                Section 2.   Transfers. As provided herein, this Warrant may be
transferred only pursuant to a registration statement filed under the Securities
Act of 1933, as amended (the "Securities Act") or an exemption from registration
thereunder. Subject to such restrictions, the Company shall transfer this
Warrant from time to time, upon the books to be maintained by the Company for
that purpose, upon surrender thereof for transfer properly endorsed or
accompanied by appropriate instructions for transfer upon any such transfer, and
a new Warrant shall be issued to the transferee and the surrendered Warrant
shall be canceled by the Company.

<PAGE>

                Section 3.   Exercise of Warrant

                (a) Exercise Procedure. Subject to the foregoing and the other
provisions hereof, the Warrantholder may exercise this Warrant from time to time
by (i) delivering (which may be by fax) a duly executed Warrant Exercise Form in
the form attached hereto (the "Exercise Agreement") to the Company on any
business day at the Company's principal executive offices (or such other office
or agency of the Company as it may designate by notice to the holder hereof),
and (ii) making payment to the Company either (A) in cash, by certified or
official bank check or by wire transfer of immediately available funds for the
account of the Company, of the Warrant Price for the Warrant Shares specified in
the Exercise Agreement or (B) by delivery to the Company of a written notice of
an election to effect a "Cashless Exercise" (as defined below) for the Warrant
Shares specified in the Exercise Agreement. The Warrant Shares so purchased
shall be deemed to be issued to the Warrantholder or such holder's designee, as
the record owner of such shares, as of the close of business on the date on
which the completed Exercise Agreement shall have been delivered to the Company
(or such later date as may be specified in the Exercise Agreement). Certificates
for the Warrant Shares so purchased, representing the aggregate number of shares
specified in the Exercise Agreement, shall be promptly delivered to the
Warrantholder within a reasonable time, not exceeding three (3) business days
after this Warrant shall have been so exercised. The certificates so delivered
shall be in such denominations as may be requested by the Warrantholder and
shall be registered in the name of such holder or such other name as shall be
designated by such holder. If this Warrant shall have been exercised only in
part, then, unless this Warrant has expired, the Company shall (subject to
Section 3(d) below), at its expense, at the time of delivery of such
certificates, deliver to the Warrantholder a new Warrant representing the number
of shares with respect to which this Warrant shall not then have been exercised.
As used herein, "business day" shall mean any day other than a Saturday, Sunday
or a day on which commercial banks in the city of New York, New York are
authorized or required by law or executive order to remain closed.

                (b) Cashless Exercise. Notwithstanding anything contained herein
to the contrary, a Cashless Exercise may only be effected if at any time during
the period commencing ten (10) Business Days prior to the holder's delivery of
an Exercise Agreement and ending on the day of delivery of the Exercise
Agreement, a Registration Statement (as defined in the Registration Rights
Agreement) covering the Warrant Shares that are the subject of the Exercise
Agreement is not available for the resale of such Warrant Shares. To effect a
"Cashless Exercise", the Warrantholder shall indicate on the Exercise Agreement
notice of the holder's intention to do so, including a calculation of the number
of shares of Common Stock to be issued upon such exercise in accordance with the
terms hereof. In the event of a Cashless Exercise, in lieu of paying the Warrant
Price in cash, the holder shall surrender this Warrant or the portion hereof
being exercised for that number of shares of Common Stock determined by
multiplying the number of Warrant Shares to which it would otherwise be entitled
by a fraction, the numerator of which shall be the difference between the then
current Fair Market Price per share of the Common Stock and the Warrant Price,
and the denominator of which shall be the then current Fair Market Price per
share of the Common Stock. For this purpose, the "Fair Market Price" of the
Common Stock shall be the closing price of the Common Stock as reported by the
NASDAQ National Market (or other exchange or market on which the Common Stock is
principally traded) on the trading day immediately preceding the date of the
Exercise Agreement.

                                        2

<PAGE>

                (c) Book-Entry. Notwithstanding anything to the contrary set
forth herein, upon exercise of any portion of this Warrant in accordance with
the terms hereof, the Warrantholder shall not be required to physically
surrender this Warrant to the Company unless such holder is purchasing the full
amount of Warrant Shares represented by this Warrant. The Warrantholder and the
Company shall maintain records showing the number of Warrant Shares so purchased
hereunder and the dates of such purchases or shall use such other method,
reasonably satisfactory to the Warrantholder and the Company, so as not to
require physical surrender of this Warrant upon each such exercise. The
Warrantholder and any assignee, by acceptance of this Warrant or a new Warrant,
acknowledge and agree that, by reason of the provisions of this paragraph,
following exercise of any portion of this Warrant, the number of Warrant Shares
which may be purchased upon exercise of this Warrant may be less than the number
of Warrant Shares set forth on the face hereof.

                Section 4.   Compliance with the Securities Act. Neither this
Warrant nor the Common Stock issued upon exercise hereof nor any other security
issued or issuable upon exercise of this Warrant may be offered or sold except
as provided in this agreement and in conformity with the Securities Act. The
Company may cause the legend set forth on the first page of this Warrant to be
set forth on each Warrant or similar legend on any security issued or issuable
upon exercise of this Warrant until the Warrant Shares have been registered for
resale pursuant to the Agreement and Registration Rights Agreement or until Rule
144(k) under the Securities Act is available, unless counsel for the Company is
of the opinion as to any such security that such legend is unnecessary.

                Section 5.   Payment of Taxes. The Company will pay any
documentary stamp taxes attributable to the initial issuance of Warrant Shares
issuable upon the exercise of the Warrant; provided, however, that the Company
shall not be required to pay any tax or taxes which may be payable in respect of
any transfer involved in the issuance or delivery of any certificates for
Warrant Shares in a name other than that of the registered holder of this
Warrant in respect of which such shares are issued, and in such case, the
Company shall not be required to issue or deliver any certificate for Warrant
Shares or any Warrant until the person requesting the same has paid to the
Company the amount of such tax or has established to the Company's satisfaction
that such tax has been paid. The holder shall be responsible for income taxes
due under federal or state law, if any such tax is due.

                Section 6.   Mutilated or Missing Warrants. In case this Warrant
shall be mutilated, lost, stolen, or destroyed, the Company shall issue in
exchange and substitution of and upon cancellation of the mutilated Warrant, or
in lieu of and substitution for the Warrant lost, stolen or destroyed, a new
Warrant of like tenor and for the purchase of a like number of Warrant Shares,
but only upon receipt of evidence reasonably satisfactory to the Company of such
loss, theft or destruction of the Warrant, and with respect to a lost, stolen or
destroyed Warrant, reasonable indemnity or bond with respect thereto, if
requested by the Company.

                Section 7.   Reservation of Common Stock. The Company hereby
represents and warrants that there have been reserved, and the Company shall at
all applicable times keep reserved, out of the authorized and unissued Common
Stock, a number of shares sufficient to provide for the maximum potential
exercise of the rights of purchase represented by the Warrant

                                        3

<PAGE>

(without regard to the limitations on exercise set forth herein), and the
transfer agent for the Common Stock ("Transfer Agent"), and every subsequent
transfer agent for the Common Stock or other shares of the Company's capital
stock issuable upon the exercise of any of the right of purchase aforesaid,
shall be irrevocably authorized and directed at all times to reserve such number
of authorized and unissued shares of Common Stock as shall be requisite for such
purpose. The Company agrees that all Warrant Shares issued upon exercise of the
Warrant shall be, at the time of delivery of the certificates for such Warrant
Shares, duly authorized, validly issued, fully paid and non-assessable shares of
Common Stock of the Company. The Company will keep a conformed copy of this
Warrant on file with the Transfer Agent and with every subsequent transfer agent
for the Common Stock or other shares of the Company's capital stock issuable
upon the exercise of the rights of purchase represented by the Warrant. The
Company will supply from time to time the Transfer Agent with duly executed
stock certificates required to honor the outstanding Warrant.

                Section 8.   Warrant Price. The Warrant Price, subject to
adjustment as provided in Section 9, shall, if payment is made in cash or by
certified check, be payable in lawful money of the United States of America.

                Section 9.   Adjustments. Subject and pursuant to the provisions
of this Section 9, the Warrant Price and number of Warrant Shares subject to
this Warrant shall be subject to adjustment from time to time as set forth
hereinafter.

                (a) If the Company shall at any time or from time to time while
the Warrant is outstanding, pay a dividend or make a distribution on its Common
Stock in shares of Common Stock, subdivide its outstanding shares of Common
Stock into a greater number of shares or combine its outstanding shares into a
smaller number of shares or issue by reclassification of its outstanding shares
of Common Stock any shares of its capital stock (including any such
reclassification in connection with a consolidation or merger in which the
Company is the continuing corporation), then the number of Warrant Shares
purchasable upon exercise of the Warrant and the Warrant Price in effect
immediately prior to the date upon which such change shall become effective,
shall be adjusted by the Company so that the Warrantholder thereafter exercising
the Warrant shall be entitled to receive the number of shares of Common Stock or
other capital stock which the Warrantholder would have received if the Warrant
had been exercised immediately prior to such event. Such adjustment shall be
made successively whenever any event listed above shall occur.

                (b) If any capital reorganization, reclassification of the
capital stock of the Company, consolidation or merger of the Company with
another corporation, or sale, transfer or other disposition of all or
substantially all of the Company's assets to another corporation shall be
effected, then, as a condition of such reorganization, reclassification,
consolidation, merger, sale, transfer or other disposition, lawful and adequate
provision shall be made whereby each Warrantholder shall thereafter have the
right to purchase and receive upon the basis and upon the terms and conditions
herein specified and in lieu of the Warrant Shares immediately theretofore

                                        4

<PAGE>

issuable upon exercise of the Warrant (whether or not then exercisable), such
shares of stock, securities or assets as would have been issuable or payable
with respect to or in exchange for a number of Warrant Shares equal to the
number of Warrant Shares immediately theretofore issuable upon exercise of the
Warrant (whether or not then exercisable), had such reorganization,
reclassification, consolidation, merger, sale, transfer or other disposition not
taken place, and in any such case appropriate provision shall be made with
respect to the rights and interests of each Warrantholder to the end that the
provisions hereof (including, without limitations, provision for adjustment of
the Warrant Price) shall thereafter be applicable, as nearly equivalent as may
be practicable in relation to any shares of stock, securities or properties
thereafter deliverable upon the exercise hereof. The Company shall not effect
any such consolidation, merger, sale, transfer or other disposition unless prior
to or simultaneously with the consummation thereof the successor corporation (if
other than the Company) resulting from such consolidation or merger, or the
corporation purchasing or otherwise acquiring such assets or other appropriate
corporation or entity shall assume, by written instrument executed and delivered
to the Company, the obligation to deliver to the holder of the Warrant such
shares of stock, securities or assets as, in accordance with the foregoing
provisions, such holder may be entitled to purchase and the other obligations
under this Warrant. The provisions of this paragraph (b) shall similarly apply
to successive reorganizations, reclassifications, consolidations, mergers,
sales, transfers or other dispositions.

                (c) In case the Company shall fix a record date for the making
of a distribution to all holders of Common Stock (including any such
distribution made in connection with a consolidation or merger in which the
Company is the continuing corporation) of evidences of indebtedness or assets
(other than cash dividends or cash distributions payable out of consolidated
earnings or earned surplus or dividends or distributions referred to in Section
9(a)), or subscription rights or warrants, the Warrant Price to be in effect
after such record date shall be determined by multiplying the Warrant Price in
effect immediately prior to such record date by a fraction, the numerator of
which shall be the total number of shares of Common Stock outstanding multiplied
by the Fair Market Value per share of Common Stock (as defined below), less the
fair market value (as determined by the Company's Board of Directors in good
faith) of said assets or evidences of indebtedness so distributed, or of such
subscription rights or warrants, and the denominator of which shall be the total
number of shares of Common Stock outstanding multiplied by such current Fair
Market Value per share of Common Stock. Such adjustment shall be made
successively whenever such a record date is fixed. For this purpose, the "Fair
Market Value" of the Common Stock shall be the closing price of the Common Stock
as reported by the NASDAQ National Market (or other Principal Market) on the
Trading Day immediately preceding such event.

                (d) In the event that the Company or any of its subsidiaries (A)
issues or sells any Common Stock or Convertible Securities or (B) directly or
indirectly effectively reduces the conversion, exercise or exchange price for
any Convertible Securities which are currently outstanding, at or to an
effective Per Share Selling Price which is less than the greater of (I) the
closing sale price per share of the Common Stock on the Principal Market on the
Trading Day next preceding such issue or sale or, in the case of issuances to
holders of its Common Stock, the date fixed for the determination of
stockholders entitled to receive such warrants, rights, or options ("Closing
Price"), or (II) the Warrant Price, then in each such case the Warrant Price in
effect immediately prior to such issue or sale or record date, as applicable,
shall be automatically reduced effective concurrently with such issue or sale to
an amount determined by multiplying the Warrant Price then in effect by a
fraction, (x) the numerator of which shall be the sum of (1)

                                        5

<PAGE>

the number of shares of Common Stock outstanding immediately prior to such issue
or sale, plus (2) the number of shares of Common Stock which the aggregate
consideration received by the Company from Persons other than the holders of
Warrants for such additional shares would purchase at such Closing Price or
Warrant Price, as the case may be, and (y) the denominator of which shall be the
number of shares of Common Stock of the Company outstanding immediately after
such issue or sale (excluding any shares outstanding or deemed outstanding which
were issued or deemed issued to the holders of Warrants as part of such issue or
sale). Upon consummation of a Change in Control Transaction (as defined in the
Notes issued pursuant to the Purchase Agreement), the provisions of clause (I)
in the first sentence of this Section 9(d) shall cease to have any further force
or effect.

        The foregoing provision shall not apply to any issuances or sales of
Common Stock or Convertible Securities in any transaction described in clauses
(i) through (viii) of the definition of Excluded Transaction (as defined in the
Notes issued pursuant to the Purchase Agreement) or in any transaction described
in clause (ix) of the definition of Excluded Transaction where the Per Share
Selling Price is greater than the then applicable Warrant Price.

        For the purposes of the foregoing adjustments, in the case of the
issuance of any Convertible Securities, the maximum number of shares of Common
Stock issuable upon exercise, exchange or conversion of such Convertible
Securities shall be deemed to be outstanding, provided that no further
adjustment shall be made upon the actual issuance of Common Stock upon exercise,
exchange or conversion of such Convertible Securities.

        For purposes of this Section 9(d), if an event occurs that triggers more
than one of the above adjustment provisions, then only one adjustment shall be
made and the calculation method which yields the greatest downward adjustment in
the Warrant Price shall be used.

                (e) An adjustment shall become effective immediately after the
record date in the case of each dividend or distribution and immediately after
the effective date of each other event which requires an adjustment.

                (f) In the event that, as a result of an adjustment made
pursuant to Section 9, the holder of this Warrant shall become entitled to
receive any shares of capital stock of the Company other than shares of Common
Stock, the number of such other shares so receivable upon exercise of this
Warrant shall be subject thereafter to adjustment from time to time in a manner
and on terms as nearly equivalent as practicable to the provisions with respect
to the Warrant Shares contained in this Warrant.

                (g) In the event of any adjustment in the number of Warrant
Shares issuable hereunder upon exercise, the Warrant Price shall be inversely
proportionately increased or decreased, as the case may be, such that the
aggregate purchase price for Warrant Shares upon full exercise of this Warrant
shall remain the same. Similarly, in the event of any adjustment in the Warrant
Price, the number of Warrant Shares issuable hereunder upon exercise shall be
inversely proportionately increased or decreased, as the case may be, such that
the aggregate purchase price for Warrant Shares upon full exercise of this
Warrant shall remain the same.

                                        6

<PAGE>

                Section 10.  Fractional Interest. The Company shall not be
required to issue fractions of Warrant Shares upon the exercise of the Warrant.
If any fraction of a Warrant Share would, except for the provisions of this
Section, be issuable upon the exercise of the Warrant (or specified portions
thereof), the Company shall round such calculation to the nearest whole number
and disregard the fraction.

                Section 11.  Benefits. Nothing in this Warrant shall be
construed to give any person, firm or corporation (other than the Company and
the Warrantholder) any legal or equitable right, remedy or claim, it being
agreed that this Warrant shall be for the sole and exclusive benefit of the
Company and the Warrantholder.

                Section 12.  Notices to Warrantholder. Upon the happening of any
event requiring an adjustment of the Warrant Price, the Company shall forthwith
give written notice thereof to the Warrantholder at the address appearing in the
records of the Company, stating the adjusted Warrant Price and the adjusted
number of Warrant Shares resulting from such event and setting forth in
reasonable detail the method of calculation and the facts upon which such
calculation is based. In the event of a dispute with respect to any such
calculation, the certificate of the Company's independent certified public
accountants shall be conclusive evidence of the correctness of any computation
made, absent manifest error. Failure to give such notice to the Warrantholder or
any defect therein shall not affect the legality or validity of the subject
adjustment. At the Warrantholder's request, the Company shall deliver to the
Warrantholder as of a requested date a notice specifying the Warrant Price and
the number of Warrant Shares into which this Warrant is exercisable as of such
date.

                Section 13.  Identity of Transfer Agent. The Transfer Agent for
the Common Stock is:

                EquiServe Trust Company, N.A.
                150 Royall Street
                Canton, MA  02021
                Telephone: 781-575-2000
                Fax: 781-575-2420

                Forthwith upon the appointment of any subsequent transfer agent
for the Common Stock or other shares of the Company's capital stock issuable
upon the exercise of the rights of purchase represented by the Warrant, the
Company will fax to the Warrantholder a statement setting forth the name and
address of such transfer agent.

                Section 14.  Notices. Any notice pursuant hereto to be given or
made by the Warrantholder to or on the Company shall be sufficiently given or
made personally or if sent by an internationally recognized courier by next day
or two day delivery service, addressed as follows:

                                        7

<PAGE>

                Genome Therapeutics Corp.
                100 Beaver Street
                Waltham, Massachusetts  02453
                Telephone:   (781) 398-2300
                Fax:         (781) 893-8277
                Attention:   Stephen Cohen, CFO

or such other address as the Company may specify in writing by notice to the
Warrantholder complying as to delivery with the terms of this Section 14.

                Any notice pursuant hereto to be given or made by the Company to
or on the Warrantholder shall be sufficiently given or made if personally
delivered or if sent by an internationally recognized courier service by
overnight or two-day service, to the address set forth on the books of the
Company or, as to each of the Company and the Warrantholder, at such other
address as shall be designated by such party by written notice to the other
party complying as to delivery with the terms of this Section 14.

                All such notices, requests, demands, directions and other
communications shall, when sent by courier, be effective two (2) days after
delivery to such courier as provided and addressed as aforesaid.

                Section 15.  Registration Rights. The initial holder of this
Warrant is entitled to the benefit of certain registration rights in respect of
the Warrant Shares as provided in the Agreement and the Registration Rights
Agreement incorporated by reference therein.

                Section 16.  Successors. All the covenants and provisions hereof
by or for the benefit of the Warrantholder shall bind and inure to the benefit
of its respective successors and assigns hereunder.

                Section 17.  Governing Law. This Warrant shall be deemed to be a
contract made under the laws of the State of New York, without giving effect to
its conflict of law principles, and for all purposes shall be construed in
accordance with the laws of said State.

                Section 18.  Limitations on Exercise. Notwithstanding anything
to the contrary contained herein, the number of shares of Common Stock that may
be acquired by the holder upon exercise pursuant to the terms hereof shall not
exceed a number that, when added to the total number of shares of Common Stock
deemed beneficially owned by such holder (other than by virtue of the ownership
of securities or rights to acquire securities (including the Warrant Shares)
that have limitations on the holder's right to convert, exercise or purchase
similar to the limitation set forth herein), together with all shares of Common
Stock deemed beneficially owned (other than by virtue of the ownership of
securities or rights to acquire securities that have limitations on the right to
convert, exercise or purchase similar to the limitation set forth herein) by the
holder's "affiliates" (as defined in Rule 144 of the Securities Act)
("Aggregation Parties") that would be aggregated for purposes of determining
whether a group under Section 13(d) of the Securities Exchange Act of 1934, as
amended, exists, would exceed 4.99% of the total issued and outstanding shares
of the Common Stock (the "Restricted Ownership

                                        8

<PAGE>

Percentage"). Each holder shall have the right at any time and from time to time
to reduce its Restricted Ownership Percentage immediately upon notice to the
Corporation.

                Section 19.  Replacement Warrants. The Company agrees that
within ten (10) business days after any request from time to time of the
Warrantholder, it shall deliver to such holder a new Warrant in substitution of
this Warrant which is identical in all respects except that the then Warrant
Price shall be appropriately specified in the Warrant and the number of Warrant
Shares into which this Warrant is or may become exercisable shall be
appropriately specified in the Warrant. Such changes are intended not as
amendments to the Warrant but only as clarification of the foregoing numbers for
convenience purposes, and such changes shall not affect any provisions
concerning adjustments to the Warrant Price or number of Warrant Shares
contained herein.

                Section 20.  Absolute Obligation to Issue Warrant Shares. The
Company's obligations to issue and deliver Warrant Shares in accordance with the
terms hereof are absolute and unconditional, irrespective of any action or
inaction by the holder hereof to enforce the same, any waiver or consent with
respect to any provision hereof (other than a waiver of the issuance or delivery
of shares), the recovery of any judgment against any Person or any action to
enforce the same, or any setoff, counterclaim or recoupment, or any breach or
alleged breach by the holder hereof or any other Person of any obligation to the
Company or any violation or alleged violation of law by the holder or any other
Person, and irrespective of any other circumstance which might otherwise limit
such obligation of the Company to the holder hereof in connection with the
issuance of Warrant Shares. The Company will at no time close its shareholder
books or records in any manner which interferes with the timely exercise of this
Warrant.

                            [Signature Page Follows]

                                        9

<PAGE>

        IN WITNESS WHEREOF, the Company has caused this Warrant to be duly
executed as of June 4, 2003.

                                          GENOME THERAPEUTICS CORP.

                                          By:
                                             ----------------------------
                                          Name:
                                          Title:

                                       10

<PAGE>

                            GENOME THERAPEUTICS CORP.
                              WARRANT EXERCISE FORM

Genome Therapeutics Corp.
100 Beaver Street
Waltham, Massachusetts 02453
Telephone:   (718) 398-2300
Fax:         (718) 893-8277
Attention:   Stephen Cohen, CFO

        The undersigned hereby irrevocably elects to exercise the right of
purchase represented by the within Warrant ("Warrant") for, and to purchase
thereunder by (CHECK AS APPLICABLE):

        [ ] payment by cash, wire transfer or certified check,

        [ ] Cashless Exercise of the within Warrant pursuant to Section 3(c) of
the Warrant,

_______________ shares of Common Stock* ("Warrant Shares") provided for therein,
and requests that certificates for the Warrant Shares be issued as follows:

                        Name:     _______________________________
                        Address:  _______________________________
                                  _______________________________
                                  _______________________________

and, if the number of Warrant Shares shall not be all the Warrant Shares
purchasable upon exercise of the Warrant, that a new Warrant for the balance of
the Warrant Shares (subject to book-entry) be delivered to the undersigned.

        In lieu of delivering physical certificates representing the Warrant
Shares purchasable upon exercise of this Warrant, provided the Company's
transfer agent is participating in the Depository Trust Company ("DTC") Fast
Automated Securities Transfer ("FAST") program, upon request of the Holder, the
Company shall use its best efforts to cause its transfer agent to electronically
transmit the Warrant Shares issuable upon conversion or exercise to the
undersigned, by crediting the account of the undersigned's prime broker with DTC
through its Deposit Withdrawal Agent Commission ("DWAC") system.

Dated:                                    Signature:
      ---------------------                         -------------------------
                                                    -------------------------
                                                    Name (please print)

                                                    -------------------------
                                                    Address

--------
*  NOTE: If exercise of the Warrant is made by surrender of the Warrant and the
   number of shares indicated exceeds the maximum number of shares to which a
   holder is entitled, the Company will issue such maximum number of shares
   purchasable upon exercise of the Warrant registered in the name of the
   undersigned Warrantholder or the undersigned's Assignee as below indicated
   and deliver same to the address stated below.

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