REPLIDYNE, INC. FOURTH AMENDED AND RESTATED STOCKHOLDERS AGREEMENT

Exhibit 4.5

REPLIDYNE, INC.

FOURTH AMENDED AND RESTATED
STOCKHOLDERS AGREEMENT

     THIS FOURTH AMENDED AND RESTATED STOCKHOLDERS AGREEMENT (this “ Agreement ”) is entered into as of August 17, 2005, by and among REPLIDYNE, INC., a Delaware corporation (the “ Corporation ”), those original stockholders of the Corporation listed on Schedule 1 hereto (hereinafter referred to collectively as the “ Original Stockholders ”), those stockholders of the Corporation listed on Schedule 2 hereto (hereinafter referred to collectively as the “ Investors ”), those certain stockholders of the Corporation that shall from time-to-time become party to this Agreement effective as of the date indicated on the counterpart signature page hereto (together with the Original Stockholders and Investors, the “Holders”) and the holders of the Warrants listed on Schedule 3 hereto (the “ Warrant Holders ”).

W I T N E S S E T H:

      Whereas , the Corporation has agreed to issue shares of its Series D Preferred Stock to certain investors pursuant to the Series D Preferred Stock Purchase Agreement (the “ Series D Stock Purchase Agreement ”) of even date herewith (the “ Financing ”);

      Whereas , the obligations in the Series D Stock Purchase Agreement are conditioned upon the execution and delivery of this Agreement;

      Whereas , the Corporation and the certain of the Investors entered into the Convertible Preferred Stock Purchase Agreement, dated February 20, 2002 (the “ Series A Stock Purchase Agreement ”), in connection with which the Corporation agreed to sell to such Investors shares of its Series A Preferred Stock and the Corporation desired to grant to such Investors certain registration and other rights with respect to such shares;

      Whereas , as a condition to entering into the Series A Stock Purchase Agreement, the Original Stockholders agreed to certain restrictions on their rights to dispose of their shares of Common Stock of the Corporation set forth in that certain Stockholders Agreement, dated February 20, 2002 (the “ Original Stockholders Agreement ”);

      Whereas , in connection with an equipment lease transaction between the Corporation and the Warrant Holders, the Original Stockholders Agreement was amended pursuant to that certain First Amendment to Stockholders’ Agreement, dated July 31, 2002;

      Whereas , the Original Stockholders Agreement was amended and restated pursuant to the Amended and Restated Stockholders Agreement, dated February 1, 2003 (the “Restated Stockholders Agreement”), pursuant to which the parties thereto accepted certain rights and covenants relating to the Offered Securities (as defined below) and the right to dispose of shares of Offered Securities acquired prior to or after the execution of this Agreement by the parties thereto;

      Whereas , in connection with the issuance by the Corporation of shares of its Series B Preferred Stock to GSK (as defined herein) pursuant to the Asset Sale and Purchase and

Licensing Agreement (the “ Asset Purchase Agreement ”) dated June 4, 2003 and the Series B Preferred Stock Purchase Agreement (the “ Series B Stock Purchase Agreement ”) dated June 4, 2003, the Restated Stockholders Agreement was amended and restated pursuant to the Second Amended and Restated Stockholders Agreement, dated June 4, 2003 (the “Second Restated Stockholders Agreement”);

      Whereas , in connection with the issuance by the Corporation of shares of its Series C Preferred Stock pursuant to the Series C Preferred Stock Purchase Agreement (the “ Series C Stock Purchase Agreement ”) dated April 28, 2004, the Second Restated Stockholders Agreement was amended and restated pursuant to the Third Amended and Restated Stockholders Agreement, dated April 28, 2004 (the “ Third Restated Stockholders Agreement ”);

      Whereas, the parties to the Third Restated Stockholders Agreement (the “ Prior Investors ”) desire to terminate the Third Restated Stockholders Agreement and accept the rights and covenants hereof in lieu of their rights and covenants under the Third Restated Stockholders Agreement; and

      Whereas , in connection with the consummation of the Financing, the parties desire to enter into this Agreement in order to grant registration, information rights and other rights to the Investors as set forth below.

      Now, Therefore, in consideration of the premises and for other good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the parties agree hereto as follows:

ARTICLE 1

DEFINITIONS

     As used herein, the following terms shall have the following respective meanings:

           (a) Agreement shall have the meaning set forth in the preamble hereto.

           (b) Approved Plan shall mean any written agreement, plan or arrangement, including the 2001 Long-Term Incentive Plan of the Corporation, as may be amended from time to time pursuant to the terms of this Agreement and in compliance with the terms of such plan or arrangement (the “ Current Incentive Plan ”), to purchase, or rights to subscribe for, stock options, Common Stock or any other equity securities of the Corporation, that has been approved in form and in substance by the holders of a majority of the combined voting power of the Series A Preferred Stock, Series C Preferred Stock and Series D Preferred Stock then outstanding, voting together as a single class, held by the Investors, calculated in accordance with Section A.5(a) of Article III of the Certificate (including, in such calculation, any outstanding Restricted Shares held by such holders), and which, as a condition precedent to the issuance of stock options, Common Stock, or any other equity security, provides for the vesting of stock options, Common Stock or any other equity security and/or subjects such stock options, shares or securities to restrictions on transfers and rights of first offer in favor of the Corporation; provided, however, that the maximum number of shares of Common Stock heretofore or hereafter issuable pursuant to the Current Incentive Plan and all such agreements, plans and

arrangements shall not exceed 12,910,000 shares, as such number may be increased only with the approval of the holders of a majority of the combined voting power of the Series A Preferred Stock, Series C Preferred Stock and Series D Preferred Stock then outstanding, voting together as a single class, held by the Investors, calculated in accordance with Section A.5(a) of Article III of the Certificate (including, in such calculation, any outstanding Restricted Shares held by such holders) and subject to adjustment as required to comply with any anti-dilution rights set forth in the Current Incentive Plan and any such agreement, plan or arrangement.

           (c) Asset Purchase Agreement shall mean the Asset Purchase Agreement, dated June 4, 2003, between the Corporation and GSK.

           (d) Board shall mean the Board of Directors of the Corporation.

           (e) Budget shall have the meaning set forth in Section 2.8 hereof.

           (f) Certificate shall mean the Restated Certificate of Incorporation of the Corporation, filed with the Secretary of State of Delaware on August 17, 2005, as may be amended from time to time.

           (g) Claim shall have the meaning set forth in Section 7.1 hereof.

           (h) Commission shall mean the U.S. Securities and Exchange Commission.

           (i) Common Stock shall mean the Common Stock, par value $.01 per share, of the Corporation.

           (j) Corporation shall have the meaning set forth in the preamble hereto.

           (k) Designating Party shall have the meaning set forth in Section 5.4 hereof.

           (l) Domestic Partner shall mean an adult of the same or opposite sex with whom another adult has an intimate relationship in which the adults (1) reside together or share the same permanent address for a period of at least 12 consecutive months, (2) each share responsibility and contribute, in equal or unequal amounts, to providing food, shelter, other expenses and other non-financial aspects of the relationship, (3) each have the current intent to remain in the relationship indefinitely, (4) are not married to any other person, (5) are not related by blood closer than law would prohibit in legal marriage in the state of residence, and (6) each do not have a different Domestic Partner.

           (m) Duquesne shall mean Juggernaut Fund, L.P., a Delaware limited partnership, Steeler Fund, Ltd., a corporation organized under the laws of the Cayman Islands, and Iron City Fund, Ltd., a corporation organized under the laws of the Cayman Islands, collectively, including any successor thereto or any permissible assignee of the interest, in whole or in part, of any of such entities under this Agreement.

           (n) Environmental Laws shall mean all applicable federal, state and local laws, ordinances, rules and regulations that regulate, fix liability for, or otherwise relate to, the handling, use (including use in industrial processes, in construction, as building materials, or

otherwise), storage and disposal of hazardous and toxic wastes and substances, and to the discharge, leakage, presence, migration, threatened release or release (whether by disposal, a discharge into any water source or system or into the air, or otherwise) of any pollutant or effluent. Without limiting the preceding sentence, the term “Environmental Laws” shall specifically include the following federal and state laws, as amended:

FEDERAL

     Comprehensive Environmental Response, Compensation and Liability Act of 1980, 42 U.S.C. 9601 et seq. ;

     Resource Conservation and Recovery Act of 1976, 42 U.S.C. 6901 et seq. ;

     Clean Water Act, 33 U.S.C. 1251 et seq. ; and

     Clean Air Act, 42 U.S.C. 7401 et seq.

STATE
COLORADO ENVIRONMENTAL STATUTES

     Colorado Hazardous Waste Sites Act, Colo. Rev. Stat. § 25-16-101 et seq. ;

     Colorado Hazardous Waste Act, Colo. Rev. Stat. § 25-15-101 et seq. ;

     Colorado Water Quality Control Act, Colo. Rev. Stat. § 25-8-101 et seq. ; and

     Colorado Air Pollution Prevention and Control Act, Colo. Rev. Stat. § 25-7-101 et seq.

           (o) Equity Percentage shall mean, as to any Investor, that percentage figure which expresses the ratio that (a) the number of shares of issued and outstanding Common Stock then owned by such Investor bears to (b) the aggregate number of shares of issued and outstanding Common Stock then owned by all Investors. For purposes solely of the computation set forth in clauses (a) and (b) above and the rights of oversubscription as set forth in Article 2 and Article 6, all issued and outstanding equity securities held by the Investors that are convertible into or exercisable or exchangeable for shares of Common Stock (including any issued and issuable shares of Preferred Stock) or for any such convertible, exercisable or exchangeable securities, shall be treated as having been so converted, exercised or exchanged at the rate or price at which such securities are convertible, exercisable or exchangeable for shares of Common Stock in effect at the time in question (which, for purposes of Section 2.3 of this Agreement, shall be at the time of delivery by the Corporation of the notice of the Offer contemplated by Section 2.3(b)), whether or not such securities are at such time immediately convertible, exercisable or exchangeable.

           (p) Exchange Act shall mean the Securities Exchange Act of 1934, as amended.

           (q) Exchange Act Registration Statement shall have the meaning set forth in Section 2.5 hereof.

           (r) Excess Securities shall have the meaning set forth in Section 2.3(d) hereof.

           (s) Excess Securities Notice shall have the meaning set forth in Section 2.3(d) hereof.

           (t) Excess Securities Period shall have the meaning set forth in Section 2.3(d) hereof.

           (u) Excluded Forms shall have the meaning given such term in Section 3.5 hereof.

           (v) Excluded Securities shall mean, collectively:

                (i)  the Reserved Shares;

                (ii)  stock options issued or issuable to officers, directors or employees of, or consultants or independent contractors to, the Corporation, pursuant to an Approved Plan;

                (iii)  Common Stock issued as a stock dividend payable in shares of Common Stock, or capital stock of any class issuable upon any subdivision, recombination, split-up or reverse stock split of all the outstanding shares of such class of capital stock of the Corporation;

                (iv)  Common Stock issued or issuable pursuant to the acquisition of another corporation or other entity (or its assets) by the Corporation by any merger, stock acquisition, reorganization, purchase of substantially all assets or otherwise in which the Corporation, or its stockholders of record immediately prior to the effective date of such transaction, directly or indirectly, own at least a majority of the voting power of the acquired entity or the resulting entity after such transaction, provided that such issuance is approved by the Board and the holders of shares representing a majority of the voting power of the Preferred Stock then outstanding (the “ Acquisition Stockholder Vote ”), provided, that , the Acquisition Stockholder Vote shall not be required if the aggregate of any such shares issued or issuable pursuant to this subsection (iv) does not exceed three percent (3%) of the Corporation’s shares, calculated on a fully-diluted basis after giving effect to such issuance;

                (v)  Common Stock issued or issuable to banks, lenders, landlords or equipment lessors, provided that each such issuance is approved by the Board and the aggregate of any such shares issued or issuable pursuant to this subsection (v) does not exceed one percent (1%) of the Corporation’s shares, calculated on a fully-diluted basis after giving effect to such issuance;

                (vi)  Common Stock issued or issuable to third parties in connection with strategic partnerships or alliances, joint ventures or other licensing transactions, provided that each such transaction and related issuance is approved by the Board and the holders of shares representing a majority of the voting power of the Preferred Stock then outstanding (the “ Strategic Stockholder Vote ”), provided, that , the Strategic Stockholder Vote shall not be required if the aggregate of any such shares issued or issuable pursuant to this subsection (vi) does not exceed three percent (3%) of the Corporation’s shares, calculated on a fully-diluted basis after giving effect to such issuance;

                (vii)  Securities issued to GSK pursuant to the Series B Stock Purchase Agreement or the Asset Purchase Agreement;

                (viii)  shares of Series D Preferred Stock (and the Common Stock issuable upon the conversion thereof) issued pursuant to the Series D Stock Purchase Agreement.

           (w) Family of an individual shall mean only that individual’s spouse, Domestic Partner and lineal descendants (including by adoption).

           (x) Founder shall have the meaning set forth in Section 5.1(c) hereof.

           (y) Fourth Restated Stockholders Agreement shall have the meaning set forth in the recitals hereto.

           (z) Group shall mean: (i) as to an Investor that is a corporation: any and all of the venture capital limited partnerships or corporations now existing or hereafter formed that are affiliated with or controlling, controlled by or under common control with one or more of the controlling stockholders of such Investor and any predecessor or successor thereto, (ii) as to an Investor that is a partnership, limited liability company or other entity, any current or former partner, member or manager, any current or former partner, member or manager of a partnership, limited liability company or other entity that serves as a general partner or manager of such entity, or any and all of the venture capital or private equity limited partnerships or corporations now existing or hereafter formed that are affiliated with or controlling, controlled by or under common control with such Investor and any predecessor or successor thereto, (iii) in the case of HCV, the HCV Group, (iv) in the case of any MDS Entity, any other MDS Entity, and (v) as to any Investor, any other Investor.

           (aa) GSK shall mean SmithKline Beecham plc, an English corporation whose registered office is at 980 Great West Road, Brentford, Middlesex, TW8 9GS, England, a wholly owned subsidiary of GlaxoSmithKline plc.

           (bb) Hazardous Materials shall include, without limitation, any flammable explosives, petroleum products, petroleum byproducts, radioactive materials, hazardous wastes, hazardous substances, toxic substances or other similar materials regulated by Environmental Laws.

           (cc) HCV Group shall mean (i) HCV VI; (ii) HCV VIII, (iii) any venture capital limited partnership now existing or hereafter formed which is affiliated with or under common control with one or more general partners of any general partner of HCV VI or HCV VIII (an “ HCV Fund ”); (iii) any limited partners or affiliates of HCV VI or HCV VIII or any other HCV Fund; and (iv) any successors or permissible assigns of any of the foregoing.

           (dd) HCV VI shall mean HealthCare Ventures VI, L.P., a Delaware limited partnership, including any successor thereto or any permissible assignee of the interest, in whole or in part, of HCV VI under this Agreement.

                HCV VIII shall mean HealthCare Ventures VIII, L.P., a Delaware limited partnership, including any successor thereto or any permissible assignee of the interest, in whole or in part, of HCV VIII under this Agreement.

                HCV shall mean HCV VI and HCV VIII collectively.

           (ee) HealthCare Investment Partners shall mean HealthCare Investment Partners, including any successor thereto or any permissible assignee of the interest, in who or in part, of HealthCare Investment Partners under this Agreement.

           (ff) Holders shall have the meaning set forth in the preamble hereto and, in the interest of clarity, shall not include the use of the term without capitalization.

           (gg) Indemnitees shall have the meaning set forth in Section 7.1 hereof.

           (hh) Investors shall have the meaning set forth in the preamble hereto, severally, but not jointly and severally.

           (ii) Major Investors shall have the meaning set forth in Section 2.6.

           (jj) MDS Entity shall mean any corporation, trust, partnership, limited liability corporation or partnership or other form of business entity which is an investment fund to which MDS Capital Corp., a corporation existing under the laws of the province of Ontario, or any of its affiliates provides services and also means MDS Capital Corp. and its affiliates and “ MDS Entities ” means all of them.

           (kk) Morgenthaler shall mean Morgenthaler Partners, VII, L.P., a Delaware limited partnership, including any successor thereto or any permissible assignee of the interest, in whole or in part, of Morgenthaler under this Agreement.

           (ll) Notice of Acceptance shall have the meaning set forth in Section 2.3(c) hereof.

           (mm) Och-Ziff shall mean Och-Ziff Capital Management, including any successor thereto or any permissible assignee of the interest, in whole or in part, of Och-Ziff under this Agreement.

           (nn) Offer shall have the meaning set forth in Section 2.3(b) hereof.

           (oo) Offered Securities shall mean, except for Excluded Securities, (i) any shares of Common Stock, Preferred Stock or any other equity security of the Corporation, in the interest of clarity, specifically including Option Shares or other securities issued upon the exercise or conversion of stock options or other derivative or convertible securities of the Corporation, (ii) any debt security or capitalized lease with any equity feature with respect to the Corporation, or (iii) any option, warrant or other right to subscribe for, purchase or otherwise acquire any such equity security, debt security or capitalized lease.

           (pp) Option Shares shall mean 12,910,000 shares of Common Stock which have been duly reserved for issuance upon the exercise of the options granted under an Approved Plan.

           (qq) Original Stockholders shall have the meaning set forth in the preamble hereto.

           (rr) Original Stockholders Agreement shall have the meaning set forth in the recitals hereto.

           (ss) Other Shares shall have the meaning set forth in Section 3.5(e) hereof.

           (tt) Outstanding Equity Securities shall mean the outstanding Common Stock, the Common Stock issued or issuable upon the conversion of the outstanding Preferred Stock, and any other outstanding securities of the Corporation which are convertible into or exercisable for shares of Common Stock (including, without limitation, warrants, options or other rights to purchase Common Stock or convertible debentures or other convertible debt securities).

           (uu) Preferred Stock shall mean all series of the Preferred Stock, par value $.01 per share, of the Corporation.

           (vv) Prior Stockholders Agreement shall have the meaning set forth in the preamble hereto.

           (ww) Prior Agreements shall have the meaning set forth in Article 11 hereof.

           (xx) Property shall include, without limitation, land, buildings and laboratory facilities owned or leased by the Corporation or as to which the Corporation now has any duties, responsibilities (for clean-up, remedy or otherwise) or liabilities under any Environmental Laws, or as to which the Corporation or any subsidiary of the Corporation may have such duties, responsibilities or liabilities because of past acts or omissions of the Corporation or any such subsidiary or their predecessors, or because the Corporation or any such subsidiary or their predecessors in the past was such an owner or operator of, or bore some other relationship with, such land, buildings and/or laboratory facilities.

           (yy) Proposed Sale shall have the meaning set forth in Section 6.3(a) hereof.

           (zz) Refused Securities shall have the meaning set forth in Section 2.3(f) hereof.

           (aaa) Reserved Shares shall mean the shares of Common Stock reserved by the Corporation for issuance upon the conversion of the Series A Preferred Stock, Series B Preferred Stock, Series C Preferred Stock and Series D Preferred Stock.

           (bbb) Restated Stockholders Agreement shall have the meaning set forth in the recitals hereto.

           (ccc) Restricted Securities shall mean (i) any of the Series A Preferred Stock, Series B Preferred Stock, Series C Preferred Stock, Series D Preferred Stock and the Common Stock issued or issuable upon the conversion of the Series A Preferred Stock, Series B Preferred Stock, Series C Preferred Stock and Series D Preferred Stock, (ii) all shares of Common Stock issued or issuable in respect thereof by way of stock splits, stock dividends, stock combinations, recapitalizations or like occurrences, and (iii) any other shares of Common Stock or other securities of the Corporation which may be issued hereafter to any of the Investors or any member of their Group which are convertible into or exercisable for shares of Common Stock (including, without limitation, other classes or series of Convertible Preferred Stock, warrants, options or other rights to purchase Common Stock or convertible debentures or other convertible debt securities) and the Common Stock issued or issuable upon such conversion or exercise of such other securities, which have not been sold (a) in connection with an effective registration statement filed pursuant to the Securities Act, or (b) pursuant to Rule 144 or Rule 144A promulgated by the Commission under the Securities Act.

           (ddd) Restricted Shares shall mean the shares of Common Stock issued or issuable upon the conversion or exchange of the Restricted Securities or otherwise constituting a portion of the Restricted Securities.

           (eee) Second Restated Stockholders Agreement shall have the meaning set forth in the recitals hereto.

           (fff) Securities Act shall mean the Securities Act of 1933, as amended.

           (ggg) Seller shall have the meaning set forth in Section 6.3(a) hereof.

           (hhh) Sequel shall mean Sequel Limited Partnership III, a Delaware limited partnership, and Sequel Entrepreneurs’ Fund III, L.P., a Delaware limited partnership, including any successor thereto or any permissible assignee of the interest, in whole or in part, of Sequel under this Agreement.

           (iii) Series A Investors shall mean the Investors who hold shares of Series A Preferred Stock.

           (jjj) Series A Preferred Shares shall mean shares of Series A Preferred Stock held by the Investors; provided, however, that for purposes of Sections 3.4 through 3.11, inclusive, only, Series A Preferred Shares shall include, in addition to shares of Series A Preferred Stock held by the Investors, shares of Series A Preferred Stock issued or issuable upon exercise of the Warrants.

           (kkk) Series A Preferred Stock shall mean Series A Convertible Preferred Stock, par value $.01 per share, of the Corporation.

           (lll) Series A Stock Purchase Agreement shall have the meaning set forth in the recitals hereto.

           (mmm) Series B Investors shall mean the Investor(s) who hold(s) shares of Series B Preferred Stock.

           (nnn) Series B Preferred Stock shall mean Series B Convertible Preferred Stock, par value $.01 per share, of the Corporation.

           (ooo) Series B Stock Purchase Agreement shall have the meaning set forth in the recitals hereto.

           (ppp) Series C Investors shall mean the Investors who hold shares of Series C Preferred Stock.

           (qqq) Series C Preferred Stock shall mean Series C Convertible Preferred Stock, par value $.01 per share, of the Corporation.

           (rrr) Series C Stock Purchase Agreement shall have the meaning set forth in the recitals hereto.

           (sss) Series D Investors shall mean the Investors who hold shares of Series D Preferred Stock.

           (ttt) Series D Preferred Stock shall mean Series D Convertible Preferred Stock, par value $.01 per share, of the Corporation.

           (uuu) Series D Stock Purchase Agreement shall have the meaning set forth in the recitals hereto.

           (vvv) Stock Restriction Agreement shall have the meaning set forth in Article 20 hereof.

           (www) Stockholders shall mean all holders of capital stock of the Corporation.

           (xxx) Target Month shall have the meaning set forth in Section 2.7(a) hereof.

           (yyy) Third Restated Stockholders Agreement shall have the meaning set forth in the recitals hereto.

           (zzz) 30-Day Period shall have the meaning set forth in Section 2.3(b) hereof.

           (aaaa) TPGV shall mean TPG Ventures, L.P., a Delaware limited partnership, and TPG Biotechnology Partners, L.P., a Delaware limited partnership, including any successor thereto or any permissible assignee of the interest, in whole or in part, of TPGV under this Agreement, acting jointly where applicable.

           (bbbb) Transfer shall mean any actual or proposed disposition of all or a portion of an interest (legal, equitable, record or beneficial) by any means, direct or indirect, absolute or conditional, voluntary or involuntary, including, but not limited to, by sale, assignment, put, transfer, conveyance, pledge, hypothecation, mortgage or other encumbrance, court order, operation of law (including, without limitation, the laws of bankruptcy, insolvency, marital dissolution, intestacy, descent and distribution and succession), distribution, settlement, exchange, waiver, abandonment, gift, alienation, bequest or disposal.

           (cccc) Transfer Notice shall have the meaning set forth in Section 6.3(a) hereof.

           (dddd) Transfer Stock shall have the meaning set forth in Section 6.3(a) hereof.

           (eeee) Warrant Holders shall have the meaning set forth in the preamble hereto.

           (ffff) Warrants shall mean those certain warrants to purchase Series A Preferred Stock held by GATX Ventures, Inc. and TBCC Funding Trust II, dated July 31, 2002, and their permitted successors and assigns.

ARTICLE 2

CERTAIN COVENANTS OF THE CORPORATION

     The following covenants of the Corporation are made by the Corporation to, and for the sole benefit of, the Investors.

      2.1 Meetings of the Board of Directors .

           (a) The Corporation shall call, and use commercially reasonable efforts to have, regular meetings of the Board not less often than quarterly. The Corporation shall pay all reasonable and appropriately documented travel expenses and other out-of-pocket expenses incurred by directors who are not employed by the Corporation in connection with attendance at meetings to transact the business of the Corporation or attendance at meetings of the Board or any committee thereof.

           (b) The TPGV Director and the HCV Director, in each case as defined in Section 5.1 hereof, shall be members of the Compensation Committee of the Board, and the Compensation Committee shall consist of not more than three (3) members.

           (c) The Corporation shall form a Pharmaceutical Development Committee and the TPGV Director and the HCV Director shall be members of the Pharmaceutical Development Committee.

           (d) The Company shall allow one representative designated by (i) TPGV (in addition to any designee of such party to the Board), (ii) MDS Entities who are holders of Preferred Stock, (iii) Och-Ziff, (iv) Duquesne, (v) HealthCare Investment Partners, and (vi) each of HCV, Sequel and Morgenthaler at such time as HCV, Sequel or Morgenthaler, respectively, ceases to have a designee on the Board, to attend all meetings of the Board in a nonvoting capacity, and in connection therewith, the Company shall give such representatives copies of all notices, minutes, consents and other materials, financial or otherwise, which the Company provides to its Board; provided, however, that the Company reserves the right to exclude any such representative from access to any material or meeting or portion thereof if the Company believes upon advice of counsel that such exclusion is reasonably necessary to preserve the attorney-client privilege, to protect highly confidential proprietary information or for other similar reasons.

      2.2 Reservation of Shares of Common Stock and Preferred Stock, Etc . The Corporation shall at all times have authorized and reserved out of its authorized but unissued shares of Common Stock, a sufficient number of shares of Common Stock to provide for the conversion of the Preferred Stock. The issuance of the Common Stock issuable upon the conversion of the Preferred Stock shall not be subject to a preemptive right of any other Stockholder.

      2.3 Pre-emptive Rights .

           (a) Except pursuant to an Approved Plan, the Corporation shall not issue, sell or exchange, agree to issue, sell or exchange, or reserve or set aside for issuance, sale or exchange, any Offered Securities unless in each case the Corporation shall have first offered to sell to the Major Investors (as defined in Section 2.6) all of such Offered Securities on the terms set forth herein. Each Major Investor shall be entitled to purchase up to its Equity Percentage of the Offered Securities. Each Major Investor may delegate its rights and obligations with respect to such Offer to one or more members of its Group, which members shall thereafter be deemed to be “ Investors ” for the purpose of applying this Section 2.3 to such Offer.

           (b) The Corporation shall deliver to each Major Investor written notice of the offer to sell the Offered Securities, specifying the price and terms and conditions of the offer (the “ Offer ”). The Offer by its terms shall remain open and irrevocable for a period of 15 days from the date of its delivery to such Investor (the “ 15-Day Period ”), subject to extension to include the Excess Securities Period (as such term is hereinafter defined).

           (c) Each Major Investor shall evidence its intention to accept the Offer by delivering a written notice signed by the Major Investor setting forth the number of shares that the Investor elects to purchase (the “ Notice of Acceptance ”). The Notice of Acceptance must be delivered to the Corporation prior to the end of the 15-Day Period. The failure by a Major Investor to exercise its rights hereunder shall not constitute a waiver of any other rights or of the right to receive notice of and participate in any subsequent Offer.

           (d) If any Major Investor fails to exercise its right hereunder to purchase its Equity Percentage of the Offered Securities, the Corporation shall so notify the other Investors in a written notice (the “ Excess Securities Notice ”). The Excess Securities Notice shall be given by the Corporation promptly after it learns of any Major Investor’s intention not to purchase all of its Equity Percentage of the Offered Securities, but in no event later than ten (10) days after the expiration of the 15-Day Period. The Major Investors who or which have agreed to purchase their Equity Percentage of the Offered Securities shall have the right to purchase the portion not purchased by such Investor (the “ Excess Securities ”), on a pro rata basis, by giving notice within ten (10) days after receipt of the Excess Securities Notice from the Corporation. The twenty (20) day period during which (i) the Corporation must give the Excess Securities Notice to the other Investors, and (ii) each of the other Major Investors must give the Corporation notice of its intention to purchase all or any portion of its pro rata share of the its Excess Securities, is hereinafter referred to as the “ Excess Securities Period .”

           (e) If the Major Investors tender their Notice of Acceptance prior to the end of the 15-Day Period indicating their intention to purchase all of the Offered Securities or, if prior to the termination of the Excess Securities Period, the Major Investors tender Excess Securities Notices to purchase all of the Excess Securities, the Corporation shall schedule a closing of the sale of all such Offered Securities. Upon the closing of the sale of the Offered Securities to be purchased by the Major Investors, each Major Investor shall (i) purchase from the Corporation that portion of the Offered Securities (including the Excess Securities) for which it tendered a Notice of Acceptance and an Excess Securities Notice, if applicable, upon the terms specified in the Offer, and (ii) execute and deliver an agreement further restricting transfer of such Offered Securities substantially as set forth in Sections 3.1, 3.2 and 3.3 of this Agreement. In addition, with respect to the Offered Securities being purchased by the Major Investors, the Corporation shall provide each such Major Investor with the rights and benefits set forth in this Agreement. The obligation of the Major Investors to purchase such Offered Securities is further conditioned upon the preparation of a purchase agreement embodying the terms of the Offer, which shall be reasonably satisfactory in form and substance to such Major Investor and the Major Investor’s counsel.

           (f) The Corporation shall have ninety (90) days from the expiration of the 15-Day Period, or the Excess Securities Period, if applicable, to sell the Offered Securities (including the Excess Securities) refused by the Investors (the “ Refused Securities ”) to any other person or persons, but only upon terms and conditions which are in all material respects (including, without limitation, price and interest rate) no more favorable to such other person or persons, and no less favorable to the Corporation, than those set forth in the Offer. Upon and subject to the closing of the sale of all of the Refused Securities (which shall include full payment to the Corporation), each Major Investor shall (i) purchase from the Corporation those Offered Securities (including the Excess Securities) for which it tendered a Notice of Acceptance and an Excess Securities Notice, if applicable, upon the terms specified in the Offer, and (ii) execute and deliver an agreement restricting transfer of such Offered Securities (including the Excess Securities) substantially as set forth in Sections 3.1, 3.2 and 3.3 of this Agreement. In addition, with respect to the Offered Securities being purchased by the Major Investors, the Corporation shall provide each such Major Investor with the rights and benefits set forth in this Agreement. The Corporation agrees, as a condition precedent to accepting payment for and making delivery of any Refused Securities to any executive officer, employee, consultant or independent contractor of or to the Corporation, or to any other person, to the extent such purchaser has not already executed this Agreement (or such agreement which amends and restates this Agreement in connection with the offer and sale of the Offered Securities), to have each and every such person execute and deliver a counterpart signature page to this Agreement (or such agreement which amends and restates this Agreement in connection with the offer and sale of the Offered Securities) whereby such purchaser shall become a Holder hereunder. The obligation of the Major Investor to purchase such Offered Securities (including the Excess Securities) is further conditioned upon the preparation of a purchase agreement embodying the terms of the Offer, which shall be reasonably satisfactory in form and substance to such Major Investor and the Major Investor’s counsel.

           (g) In each case, any Offered Securities not purchased either by the Major Investors or by any other person in accordance with this Section 2.3 may not be sold or otherwise disposed of until they are again offered to the Major Investors under the procedures specified in Paragraphs (a), (b), (c), (d), (e) and (f) hereof.

           (h) Each Major Investor may, by prior written consent, waive its rights under this Section 2.3. Such a waiver shall be deemed a limited waiver and shall only apply to the extent specifically set forth in the written consent of such Major Investor.

           (i) Each Major Investor may assign its rights under this Section 2.3 to any of the persons or entities within its Group.

      2.4 Negative Covenants .

           (a) Required Approvals of Preferred Stockholders or Board . The Corporation shall not, directly or indirectly, take any of the actions specified in Article III, Section A.5(c) of the Certificate without the prior written consent or vote of the holders of shares representing a majority of the Preferred Stock then outstanding voting together as a single class, each determined in accordance with Section A.5(a) of the Certificate. In addition, the Corporation shall not, directly or indirectly, take any of the actions specified in Article 5, Section A.2 of the Certificate without the written approval of the Board.

           (b) Stock and Option Agreements . Without the prior written consent or vote of the holders of shares representing a majority of the Series A Preferred Stock, Series C Preferred Stock and Series D Preferred Stock then outstanding voting together as a single class, each determined in accordance with Section A.5(a) of Article III of the Certificate, the Corporation shall not issue any shares of Common Stock or options, warrants or other rights to acquire Common Stock or other securities of the Corporation to any employee, officer, director, consultant, independent contractor or other person or entity except for (i) Excluded Securities or (ii) pursuant to an Approved Plan.

           (c) Registration Rights . The Corporation shall not hereafter grant to any persons any rights to register or qualify stock of the Corporation under federal or state securities laws, unless it shall have first obtained the written consent of (i) the holders of shares representing a majority of the Series D Preferred Stock, if such registration or qualification rights would adversely affect the registration or qualification rights of the holders of Series D Preferred Stock as set forth in this Agreement and (ii) the holders of shares representing a majority of the Series A Preferred Stock, Series C Preferred Stock and Series D Preferred Stock then outstanding voting together as a single class, each determined in accordance with Section A.5(a) of Article III of the Certificate.

           (d) Stock Vesting . Unless otherwise approved by the Board or the Compensation Committee of the Board, all stock options and other stock equivalents issued after the date of this Agreement to employees, directors, consultants and other service providers shall be subject to the Company’s standard vesting schedule, as may be approved by the Compensation Committee from time to time.

      2.5 Filing of Reports Under the Exchange Act .

           (a) The Corporation shall give prompt notice to the holders of Preferred Stock of (i) the filing of any registration statement (an “ Exchange Act Registration Statement ”) pursuant to the Exchange Act, relating to any class of equity securities of the Corporation, (ii) the effectiveness of such Exchange Act Registration Statement, and (iii) the number of shares of

such class of equity securities outstanding, as reported in such Exchange Act Registration Statement, in order to enable the Investors to comply with any reporting requirements under the Exchange Act or the Securities Act. Upon the written request of a majority in interest of the holders of Preferred Stock of the Corporation, the Corporation shall, at any time after the Corporation has registered any shares of Common Stock under the Securities Act, file an Exchange Act Registration Statement relating to any class of equity securities of the Corporation then held by the holders of Series A Preferred Shares, Series B Preferred Stock, Series C Preferred Stock or Series D Preferred Stock or issuable upon conversion or exercise of any class of debt or equity securities or warrants or options of the Corporation then held by the Investors, whether or not the class of equity securities with respect to which such request is made shall be held by the number of persons which would require the filing of a registration statement under Section 12(g)(1) of the Exchange Act.

           (b) If the Corporation shall have filed an Exchange Act Registration Statement or a registration statement (including an offering circular under Regulation A promulgated under the Securities Act) pursuant to the requirements of the Securities Act, which shall have become effective (and in any event, at all times following the initial public offering of any of the securities of the Corporation), then the Corporation shall comply with all of the reporting requirements of the Exchange Act (whether or not it shall be required to do so) and shall comply with all other public information reporting requirements of the Commission as a condition to the availability of an exemption from the Securities Act for the sale of any of the Restricted Securities by any holder of Restricted Securities (including any such exemption pursuant to Rule 144 or Rule 144A thereof, as amended from time to time, or any successor rule thereto or otherwise). The Corporation shall cooperate with each holder of Restricted Securities in supplying such information as may be necessary for such holder of Restricted Securities to complete and file any information reporting forms presently or hereafter required by the Commission as a condition to the availability of an exemption from the Securities Act (under Rule 144 or Rule 144A thereunder or otherwise) for the sale of any of the Restricted Securities by any holder of Restricted Securities.

      2.6 Access to Records . So long as a holder of Preferred Stock continues to hold at least ten percent (10%) of the shares of Preferred Stock that such holder originally acquired or Common Stock issued upon conversion of Preferred Stock, and this amount is greater than 500,000 shares ( as adjusted) (a “ Major Investor ” or, collectively, the “ Major Investors ”), the Corporation shall afford to each Major Investor and such Investor’s employees, counsel and other authorized representatives, free and full access, at all reasonable times and for reasonable periods of time, to all of the books, records and properties of the Corporation and to all officers and employees of the Corporation. All shares of capital stock held or acquired by affiliated entities or persons or persons or entities under common management or control shall be aggregated together for the purpose of determining the availability of any rights under this Agreement.

      2.7 Financial Reports . Until such time that the Corporation has a class of its equity securities registered under the Exchange Act and is required to file reports thereunder pursuant to Sections 13 or 15(d) of the Exchange Act, except with respect to the obligation set forth in Section 2.7(e)(i) hereunder which shall survive such time, the Corporation shall furnish each of the Major Investors with the financial information described below:

           (a) Within 30 days after the last day of each month (the “ Target Month ”) (or such other calendar period as is approved by the Board), financial statements, including a balance sheet as of the last date of such Target Month, a statement of income (or monthly operating expenses) for such month, together with a cumulative statement of income from the first day of the current year to the last day of such month, which statements shall be prepared from the books and records of the Corporation, a cash flow analysis, together with cumulative cash flow analyses from the first day of the current year to the last day of such month, and a comparison between the actual monthly operating expenses and the projected figures for such month and the comparable figures for the prior year, subject to the provisions of Section 2.9 hereof.

           (b) Upon receipt of a request from any of the Major Investors prior to the end of a quarterly accounting period, the Corporation shall deliver to each of the Major Investors, within 45 days after the end of such quarterly accounting period, unaudited financial statements for such quarterly accounting period, certified by the Chief Financial Officer or the Treasurer of the Corporation, as presenting fairly the financial condition and results of operations of the Corporation and as having been prepared on a basis consistent with the accounting principles reflected in the Corporation’s annual audited financial statements, accompanied by a report, signed by the Chief Financial Officer or the Treasurer of the Corporation, summarizing the operating and financial highlights of the Corporation for such quarterly accounting period, which report shall include (a) a comparison between the actual quarterly operating and financial results, the Budget (as defined in Section 2.8 hereof) and the results of the similar quarterly accounting period for the prior fiscal year of the Corporation, together with an explanation of material variances from the Budget and such similar quarterly accounting period, as the case may be, and (b) a narrative analysis of operations and trends in the business of the Corporation during such quarterly accounting period.

           (c) Within 90 days after the end of each fiscal year of the Corporation, audited financial statements of the Corporation, which shall include an income statement and a statement of cash flow for such fiscal year and a balance sheet as of the last day thereof, each prepared in accordance with generally accepted accounting principles consistently applied, and accompanied by the report of such independent certified public accountants as shall have been approved by the Board.

           (d) If for any period the Corporation shall have any subsidiary or subsidiaries whose accounts are consolidated with those of the Corporation, then the financial statements delivered for such period pursuant to paragraphs (a), (b) and (c) of this Section 2.7 shall be the consolidated and consolidating financial statements of the Corporation for all such consolidated subsidiaries.

           (e) Promptly upon becoming available:

                (i)  copies of all financial statements, reports, press releases, notices, proxy statements and other documents sent by the Corporation to its Stockholders or released to the public and copies of all regular and periodic reports, if any, filed by the Corporation with the Commission or any securities exchange or self-regulatory organization; and

                (ii)  any other financial or other information available to management of the Corporation that any of the Major Investors shall have reasonably requested on a timely basis.

      2.8 Budget and Operating Forecast . The Corporation shall prepare and submit to the Board and each of the Major Investors an operating plan with monthly and quarterly breakdowns (the “ Budget ”) for each fiscal year at least 45 days prior to the beginning of each fiscal year of the Corporation. The Budget shall be deemed accepted as the Budget for such fiscal year only when it has been approved by the Board. The Budget shall be reviewed by the Corporation periodically and all changes therein, and all material deviations therefrom, shall be reviewed by the Board on at least a quarterly basis.

      2.9 System of Accounting . The Corporation shall maintain, and cause each of its subsidiaries, when and if any shall exist, to maintain, its books of accounts, related records and system of accounting in accordance with good business practices and generally accepted accounting principles, and shall cause the matters contained therein to be appropriately and accurately reflected in the financial reports (which shall be prepared in accordance with generally accepted accounting principles) furnished pursuant to this Agreement.

      2.10 Restriction on Transfer Rights; Confidentiality . The rights granted to each of the Major Investors pursuant to Sections 2.6 through 2.8 hereof shall not be transferred or assigned by any Major Investor to, and shall not inure to the benefit of, any successor, transferee or assignee of any Major Investor, which is engaged in any business directly competitive with the Corporation. In addition to the foregoing obligations, the Corporation and GSK have entered into a separate letter agreement which imposes additional confidentiality obligations on the parties.

      2.11 Confidentiality Agreements for Key Employees . The Corporation shall cause each person who is presently an employee of or a consultant or independent contractor to the Corporation or who becomes an employee of or a consultant to the Corporation subsequent to the date hereof to execute a confidentiality agreement in a form approved by the Board prior to the commencement of such person’s employment by the Corporation in such capacity.

      2.12 Stockholders Agreement for Directors, Officers, Employees, Consultants and Others Who Are or Shall Become Stockholders . The Corporation shall cause each of its directors, officers, employees, consultants and independent contractors who are Stockholders, and any other Stockholders, to execute a counterpart signature page to this Agreement pursuant to which such holder shall become a Holder hereunder and the subject securities shall become subject to the terms and conditions of this Agreement, prior and as a condition precedent to the acquisition of any Offered Securities.

      2.13 Marketing and Promotional Material . Each of the Investors will have the right to review and approve, in advance of publication, distribution or dissemination, any reference to such Investor or any entity affiliated with such Investor (other than the Corporation), contained in any document, instrument, report or filing or in any advertising, marketing, promotional and similar materials. If not approved or rejected by each of the Investors so identified within ten (10) business days after delivery of such document, instrument, report or filing to such Investor, such document, instrument, report or filing shall be deemed approved.

      2.14 Environmental Matters . The Corporation shall promptly advise the Investors in writing of any pending or threatened claim, demand or action by any governmental authority or third party relating to any Hazardous Materials affecting the Property of which it has knowledge. The Corporation shall not discharge, place, release, spill or dispose of any Hazardous Materials or any other pollutants or effluents upon the Property or elsewhere (including, but not limited to, underground injection of such substances), and the Corporation shall not discharge into the air any emission which would require a permit under the Clean Air Act or its state counterparts or any other Environment