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FIRST SUPPLEMENTAL INDENTURE
 dated as of September 21, 2007
 by and between
 ARGATROBAN ROYALTY SUB LLC,
a Delaware limited liability company,
as issuer of the New Class A Notes described herein,
 and
 U.S. BANK NATIONAL ASSOCIATION,
as initial trustee of the New Class A Notes described herein




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PageARTICLE IRULES OF CONSTRUCTION AND DEFINED TERMSSection 1.1
    
    Rules of Construction and Defined Terms
    
    
    2Section 1.2
    
    Certain Defined Terms
    
    
    2ARTICLE IINEW CLASS A NOTESSection 2.1
    
    Amount, Form and Other Terms of New Class A Notes
    
    
    3Section 2.2
    
    Form of Resale Confidentiality Agreement
    
    
    5Section 2.3
    
    Coverage of Distribution Report
    
    
    5Section 2.4
    
    Other Exhibits
    
    
    5Section 2.5
    
    Payments on Date of Issuance of the New Class A Notes
    
    
    6Section 2.6
    
    Redemption of the Original Class A Notes
    
    
    6ARTICLE IIIAMENDMENTS OF ORIGINAL INDENTURESection 3.1
    
    Issuance of New Class A Notes and Redemption of OriginalClass A Notes
    
    
    6Section 3.2
    
    Limitation on Number of Holders of New Class A Notes
    
    
    7Section 3.3
    
    Release of Funds from Holdback Account
    
    
    7Section 3.4
    
    Reports and Other Deliverables by the Issuer
    
    
    7Section 3.5
    
    Method of Payment
    
    
    8ARTICLE IVMISCELLANEOUSSection 4.1
    
    GOVERNING LAW
    
    
    8Section 4.2
    
    Counterparts
    
    
    8Section 4.3
    
    Table of Contents and Headings
    
    
    8Section 4.4
    
    Supplement to Original Indenture
    
    
    8
 Schedule A
    
    Base Case Amortization ScheduleExhibit A
    
    Form of New Class A NotesExhibit B
    
    Form of Resale Confidentiality AgreementExhibit C
    
    Intentionally OmittedExhibit D
    
    Coverage of Distribution ReportExhibit E
    
    Intentionally OmittedExhibit F
    
    Form of Certificate of Euroclear or Clearstream for Permanent Regulation S Global NoteExhibit G
    
    Form of Certification of Beneficial Owner of Temporary Regulation S Global Note
 i




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Exhibit H
    
    Form of Certification of Euroclear or Clearstream for PaymentsExhibit I
    
    Form of Certificate of Proposed TransferorExhibit J
    
    Form of Certificate of Certain Proposed Institutional Accredited Investor Transferees
 ii




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FIRST SUPPLEMENTAL INDENTURE
 First Supplemental
Indenture
 WITNESSETH:
 Original Indenture
     Note Purchase
Agreement Note Purchase Agreements
 SM New Class A
Notes
 1




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New Class A Notes Manager Resolution
   RULES OF CONSTRUCTION AND DEFINED TERMS
 Rules of Construction and Defined Terms Annex A Annex A Annex A Annex A
 Certain Defined Terms
 Term
    
    SectionApplicable Treasury Rate
    
    2.1(i)Average Life Date
    
    2.1(i)Base Case Amortization Schedule
    
    2.1(h)First Supplemental Indenture
    
    PreambleNew Class A Notes
    
    RecitalsNew Class A Notes Manager Resolution
    
    RecitalsNote Purchase Agreement
    
    RecitalsNote Purchase Agreements
    
    RecitalsOptional Redemption
    
    2.1(i)Original Indenture
    
    RecitalsPayment Dates
    
    2.1(d)Redemption Price
    
    2.1(i)Remaining Weighted Average Life
    
    2.1(i)
 2




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NEW CLASS A NOTES
 Amount, Form and Other Terms of New Class A Notes
 SM provided
 Exhibit A
  Payment Dates provided provided further
  3




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Base Case Amortization Schedule Schedule A
 Optional Redemption
 Redemption Price
 4




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New Class A NotesPayment Dates Between Indicated Payment Dates
    
    Redemption PercentageFrom September 30, 2008 to and
including June 30, 2009
    
    
    109.250
    %From September 30, 2009 to and
including June 30, 2010
    
    
    104.625
    %From September 30, 2010 and thereafter
    
    
    100.000
    %
 Applicable Treasury Rate
 Average Life Date
 Remaining Weighted Average Life
 Form of Resale Confidentiality Agreement Exhibit B Exhibit B
 Coverage of Distribution Report Exhibit D Exhibit D
 Other Exhibits Exhibit F Exhibit G Exhibit H Exhibit I Exhibit J
 5




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Exhibit F Exhibit G Exhibit
H Exhibit I Exhibit J
 Payments on Date of Issuance of the New Class A Notes
    Redemption of the Original Class A Notes
 AMENDMENTS OF ORIGINAL INDENTURE
 Issuance of New Class A Notes and Redemption of Original Class A Notes
 Issuance of New Class A Notes and Redemption of Original Class
A Notes
 6




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Limitation on Number of Holders of New Class A Notes
  Limitation on Number of Holders of New Class A Notes
    Release of Funds from Holdback Account
 Reports and Other Deliverables by the Issuer
 7




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Method of Payment
    MISCELLANEOUS
 GOVERNING LAW
 Counterparts
 Table of Contents and Headings
 Supplement to Original Indenture
  8




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ARGATROBAN ROYALTY SUB LLC,
   as IssuerBy:
    Encysive Pharmaceuticals Inc., its ManagerBy:
    /s/ George W. ColeName:
    George W. ColeTitle:
    President and Chief Executive OfficerU.S. BANK NATIONAL ASSOCIATION,
   as TrusteeBy:
    /s/ Alison D.B. NadeauName: Alison D.B. NadeauTitle:
    Vice President




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SCHEDULE A
 BASE CASE AMORTIZATION SCHEDULE
 Payment Date
    
    Principal Payment
    
    Remaining Balance of the Notes$
    68,000,000September 30, 2007
    
    $
    6,099,209
    
    
    $
    61,900,791December 30, 2007
    
    $
    2,604,298
    
    
    $
    59,296,493March 30, 2008
    
    $
    2,561,874
    
    
    $
    56,734,619June 30, 2008
    
    $
    1,637,183
    
    
    $
    55,097,436September 30, 2008
    
    $
    4,547,087
    
    
    $
    50,550,350December 30, 2008
    
    $
    3,616,362
    
    
    $
    46,933,988March 30, 2009
    
    $
    3,974,328
    
    
    $
    42,959,660June 30, 2009
    
    $
    2,490,352
    
    
    $
    40,469,307September 30, 2009
    
    $
    5,155,820
    
    
    $
    35,313,487December 30, 2009
    
    $
    3,876,750
    
    
    $
    31,436,737March 30, 2010
    
    $
    3,901,129
    
    
    $
    27,535,608June 30, 2010
    
    $
    2,505,603
    
    
    $
    25,030,005September 30, 2010
    
    $
    3,007,749
    
    
    $
    22,022,256December 30, 2010
    
    $
    5,316,428
    
    
    $
    16,705,828March 30, 2011
    
    $
    3,442,825
    
    
    $
    13,263,004June 30, 2011
    
    $
    2,364,603
    
    
    $
    10,898,401September 30, 2011
    
    $
    2,643,968
    
    
    $
    8,254,433December 30, 2011
    
    $
    4,721,825
    
    
    $
    3,532,608March 30, 2012
    
    $
    3,125,534
    
    
    $
    407,073June 30, 2012
    
    $
    407,073
    
    
    $
    0
 A-1




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EXHIBIT A
 FORM OF NEW CLASS A NOTE
 
 ARGATROBAN ROYALTY SUB LLC
 Argatroban PhaRMA SM Secured 18.5% Notes Due 2014
 New Class A
 No.
    
    CUSIP:
  Issuer Schedule I Final Legal Maturity Date Stated Rate of Interest provided
 SM Indenture Trustee
 A-1




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Additional Interest
    A-2




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A-3




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A-4




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Date: September 21, 2007
    ARGATROBAN ROYALTY SUB LLCBy:
    Encysive Pharmaceuticals Inc., its ManagerBy:Name:Title:  SM
 Date: September 21, 2007
    U.S. BANK NATIONAL ASSOCIATION,
   as TrusteeBy:Authorized Signatory A-5




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FORM OF TRANSFER NOTICE
  
 
  
  Date
    
    Signature of Transferor
     o
 o
   Date
    
    NOTICE: The signature to this assignment must correspond with the name as written upon the
face of the within-mentioned instrument in every particular, without alteration or any change
whatsoever.
 A-6




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Executive Officer A-7




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SM
 
 Notation Explaining
    
    Authorized SignaturePrincipal Amount
    
    of Trustee orDate
    
    Principal Amount
    
    Recorded
    
    Custodian
 A-8




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EXHIBIT B
 FORM OF RESALE CONFIDENTIALITY AGREEMENT
  
  RESALE CONFIDENTIALITY AGREEMENT
 SM Notes Company Transaction Private Placement Memorandum Your Representatives Our Representatives Information
   B-1




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provided however provided provided further
    B-2




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B-3




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17. Attached hereto is an expanded Internal Revenue Service Form W-9 in the form attached as Exhibit A hereto that has been executed by us.
 B-4




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In accordance with
Section 2. 11(j) of the Indenture dated as of February 6, 2007 (as amended and supplemented, the
Indenture), made by and between you and U.S. Bank National Association, as trustee, we will
provide a fully executed copy of this Resale Confidentiality Agreement to the Registrar (as defined
in the Indenture) promptly after receipt thereof from you.
 Very truly yours,[Please insert prospective purchasers name]By:Name:Title:Address:    By:Name:Title: B-5




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EXHIBIT A
   B-A-1




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EXHIBIT C
 INTENTIONALLY OMITTED
 C-1




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EXHIBIT D
 COVERAGE OF DISTRIBUTION REPORT
 (i)
    
    With respect to the current Payment Date, (A) the balances on deposit in the Collection
Account and any other Account established under the Indenture on the Calculation Date
immediately preceding the prior Payment Date (or, with respect to the first Payment Date, on
the date of issuance of the New Class A Notes) (the Preceding Calculation Date), (B)
the aggregate amounts of deposits into and withdrawals from the Collection Account and any
other Account established under the Indenture from but excluding the Preceding Calculation
Date to and including the Calculation Date immediately preceding the Payment Date (the
Current Calculation Date) and (C) the balances on deposit in the Collection Account
and any other Account established under the Indenture on the Current Calculation Date.(ii)
    
    Analysis of Collection Account activity from the Preceding Calculation Date to the Current
Calculation DateBalance on the Preceding Calculation DateCollections from but excluding the Preceding Calculation Date to and including the
Current Calculation Date (Current Collections)Aggregate Note payments from but excluding the Preceding Calculation Date to and
including the Current Calculation Date, including pursuant to Section 2.5(e) of the
Original IndentureExpense payments payable on the Current Calculation Date (Current Expenses)
Balance on the Current Calculation Date(iii)
    
    Payments on the current Payment DateCurrent Expenses
Servicing Fee
Interest Amount
Additional Interest, if any
Principal payments, if any(iv)
    
    Outstanding Principal Balance
Opening Outstanding Principal Balance
Principal payments, if any, made on the current Payment Date
Closing Outstanding Principal Balance(v)
    
    Amount distributed to the Issuer from the Collection Account, if any, with respect to the
current Payment Date(vi)
    
    A withholding obligation may be included(vii)
    
    Appropriate modifications will be made to contemplate any Refinancing Notes and/or
Class B Notes
 D-1




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EXHIBIT E
 INTENTIONALLY OMITTED
 E-1




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EXHIBIT F
 FORM OF CERTIFICATE OF EUROCLEAR OR CLEARSTREAM FOR
PERMANENT REGULATION S GLOBAL NOTE
  
 
 Re:
    
    Argatroban Royalty Sub LLC (the Issuer)
  SM Notes Legended Note Indenture Regulation S
 F-1




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Very truly yours,
[Euroclear Bank S.A./N.V.][Clearstream Banking]By:Authorized Signatory F-2




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EXHIBIT G
 FORM OF CERTIFICATE OF BENEFICIAL OWNER OF TEMPORARY
REGULATION S GLOBAL NOTE
 
  
 Re:
    
    Argatroban Royalty Sub LLC (the Issuer)
 Indenture Trustee
 SM  Holder
   [Name of Holder]By:Name:Title: G-1




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EXHIBIT H
 FORM OF CERTIFICATE OF EUROCLEAR OR CLEARSTREAM FOR PAYMENTS
 
 Re:
    
    Argatroban Royalty Sub LLC (the Issuer)
 Indenture Trustee
 SM  Holder
  
 [Clearstream Banking][Euroclear Bank S.A./N.V.]By:Name:Title: H-1




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EXHIBIT I
 FORM OF CERTIFICATE OF PROPOSED TRANSFEROR
  
 
 Re:

    Argatroban Royalty Sub LLC (the Issuer)
  SM Notes Regulation S
       I-1




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Very truly yours,
[Name of Transferor]By:Authorized Signatory I-2




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EXHIBIT J
 FORM OF CERTIFICATE OF CERTAIN PROPOSED INSTITUTIONAL
ACCREDITED INVESTOR TRANSFEREES
  
 
  Notes Issuer
 Indenture Private Placement
Memorandum
 Securities Act
  J-1




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Institutional Accredited Investor
     J-2




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Very truly yours,By:Name:Title J-3