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`APPLICATION
`NUMBER
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`FILING or
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`F
`
`13/471,820
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`05/15/2012
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`1636
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`FEE REC'D
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`1430
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`87501
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`McCarter & English, LLP / Abbott Laboratories Ltd.
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`ATTY.DOCKET.NO
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`117813-16605
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`TOT CLAHVIS IND CLAIMS
`23
`3
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`CONFIRMATION NO. 4195
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`FILING RECEIPT
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`llllllllllllllllllllllIIIIIIIIIIIIlllllllllllllllllllllllllllllllllllllllllllllllllllllll
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`Date Mailed: 05/25/2012
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`Receipt is acknowledged of this non-provisional patent application. The application will be taken up for examination
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`Applicant(s)
`
`Hans-Jeurgen Krause, Gruenstadt, GERMANY;
`Lisa Baust, Ludwigshafen, GERMANY;
`Michael Dickes, Rodersheim-Gronau, GERMANY;
`Assignment For Published Patent Application
`ABBOTT BIOTECHNOLOGY, LTD., HAMILTON, BERMUDA
`Power of Attorney: The patent practitioners associated with Customer Number 87501
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`page 1 of 3
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`AMGEN INC.
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`Exhibit 1056
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`Ex. 1056 - Page 1 of 44
`
`Ex. 1056 - Page 1 of 44
`
`AMGEN INC.
`Exhibit 1056
`
`

`

`Title
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`FORMULATION OF HUMAN ANTIBODIES FOR TREATING TNF-ALPHA ASSOCIATED
`DISORDERS
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`Preliminary Class
`
`435
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`page 2 of 3
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`Ex. 1056 - Page 2 of 44
`
`Ex. 1056 - Page 2 of 44
`
`

`

`the conditions for issuance of a license have been met, regardless of whether or not a license may be required as
`set forth in 37 CFR 5.15. The scope and limitations of this license are set forth in 37 CFR 5.15(a) unless an earlier
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`page 3 of 3
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`Ex. 1056 - Page 3 of 44
`
`Ex. 1056 - Page 3 of 44
`
`

`

`PTO/SB/05 (08-08)
`Approved for use through 01/31/2014. OMB 0651-0032
`US. Patent and Trademark Office; US. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number.
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`UTILITY
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`Express Mail Label No.
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`See MPEP chapter 600 concerning utility patent application contents.
`
`ADDRESS TO:
`
`Hans-Juergen Krause et al.
`FORMULATION OF HUMAN
`ANTIBODIES FOR TREATING TNF—
`ALPHA ASSOCIATED DISORDERS
`
`Commissioner for Patents
`P.o. Box 1450
`Alexandria VA 2231 3-1450
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`1. I:I Fee Transmittal Form (e.g., PTO/SB/17)
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`2- I:I Applicant claims small entity status.
`See 37 CFR 1.27.
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`(For information on the preferred arrangement, see MPEP 608.01(a))
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`I:I (300““LiaIIOII’In’Part (CIP)
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`OI PVIOr application N05 10/252‘292................................................
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`Ex. 1056 - Page 4 of 44
`
`Ex. 1056 - Page 4 of 44
`
`

`

`Application Data Sheet
`
`Application Information
`
`Application Type:
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`Subject Matter:
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`Suggested Group Art Unit:
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`CD-ROM or CD-R?:
`
`Sequence submission?:
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`Computer Readable Form (CRF)?:
`
`Title:
`
`Regular
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`Utility
`
`1647
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`None
`
`Yes
`
`Yes
`
`FORMULATION OF HUMAN ANTIBODIES
`FOR TREATING TNF-ALPHA
`ASSOCIATED DISORDERS
`
`Attorney Docket Number:
`
`117813-16605
`
`Request for Early Publication?:
`
`Request for Non-Publication?:
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`Total Drawing Sheets:
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`Small Entity?:
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`Petition included?:
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`No
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`Applicant Information
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`Country of mailing address:
`
`Postal or Zip Code of mailing address:
`
`ME1 13411433v.1
`
`Inventor
`
`DE
`
`Full Capacity
`
`Hans-Juergen
`
`Krause
`
`Gruenstadt
`
`Germany
`
`St. Killian-Strasse 14
`
`Gruenstadt
`
`Germany
`
`D-67269
`
`Initial 05/15/2012
`
`Ex. 1056 - Page 5 of 44
`
`Ex. 1056 - Page 5 of 44
`
`

`

`Applicant Authority Type:
`
`Primary Citizenship Country:
`
`Status:
`
`Given Name:
`
`Family Name:
`
`City of Residence:
`
`Country of Residence:
`
`Street of mailing address:
`
`Inventor
`
`DE
`
`Full Capacity
`
`Lisa
`
`Baust
`
`Ludwigshafen
`
`Germany
`
`Gothestr. 15 a
`
`City of mailing address:
`
`Ludwigshafen
`
`Country of mailing address:
`
`Postal or Zip Code of mailing address:
`
`Germany
`
`D-67063
`
`Applicant Authority Type:
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`Primary Citizenship Country:
`
`Status:
`
`Given Name:
`
`Family Name:
`
`Inventor
`
`DE
`
`Full Capacity
`
`Michael
`
`Dickes
`
`City of Residence:
`
`Rodersheim-Gronau
`
`Country of Residence:
`
`Germany
`
`Street of mailing address:
`
`Schafergasse 58
`
`City of mailing address:
`
`Country of mailing address:
`
`Postal or Zip Code of mailing address:
`
`Rodersheim-Gronau
`
`Germany
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`D-67127
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`Correspondence Information
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`Correspondence Customer Number:
`
`87501
`
`Representative Information
`
`Representative Customer Number:
`
`87501
`
`ME1 13411433v.1
`
`Initial 05/15/2012
`
`Ex. 1056 - Page 6 of 44
`
`Ex. 1056 - Page 6 of 44
`
`

`

`Domestic Priority Information
`
`Continuit T oe:
`
`Parent Ao olication: Parent Filino Date:
`
`05/15/03 PCT/lB2003/00502
`
`This Ao olication
`
`Continuation of
`
`10/525,292
`
`10/27/05
`
`10/525,292
`
`National Staoe Of
`
`PCT/IBZOO3/00502
`
`An application
`claiming the benefit
`of
`
`10/222,140
`
`08/16/02
`
`Foreign Priority Information
`
`Assignee Information
`
`Assignee name:
`
`Abbott Biotechnology, Ltd.
`
`Street of mailing address:
`
`Clarendon House
`
`2 Church Street
`
`City of mailing address:
`
`Country of mailing address:
`
`Hamilton
`
`Bermuda
`
`Postal or Zip Code of mailing address:
`
`HM 11
`
`ME1 13411433v.1
`
`Initial 05/15/2012
`
`Ex. 1056 - Page 7 of 44
`
`Ex. 1056 - Page 7 of 44
`
`

`

`Attorney Docket No. 117813-16605
`
`-1-
`
`FORMULATION OF HUMAN ANTIBODIES FOR TREATING TNF-oc
`ASSOCIATED DISORDERS
`
`Related Applications:
`
`5
`
`This application is a continuation of US. Patent Application No.10/525,292,
`
`filed on October 27, 2005, which is a 35 U.S.C. § 371 national stage filing of
`
`International Application No. PCT/IB2003,0502, filed on May 15, 2003, which claims
`
`the benefit of US. Patent Application No. 10/222,140, filed on August 16, 2002. The
`
`entire contents of each of the foregoing applications are incorporated herein by
`
`10
`
`reference.
`
`Background of the Invention
`
`Tumor necrosis factor 0t (TNFOt) is a cytokine produced by numerous cell types,
`
`15
`
`including monocytes and macrophages, that was originally identified based on its
`
`capacity to induce the necrosis of certain mouse tumors (see e. g., Old, L. (1985) Science
`
`@630-632). Subsequently, a factor termed cachectin, associated with cachexia, was
`
`shown to be the same molecule as TNFOt. TNFOt has been implicated in mediating
`
`shock (see e. g., Beutler, B. and Cerami, A. (1988) Annu. Rev. Biochem. 5_7:505-518;
`
`20 Beutler, B. and Cerami, A. (1989) Annu. Rev. Immunol. 7:625-655). Furthermore,
`
`TNFOt has been implicated in the pathophysiology of a variety of other human diseases
`
`and disorders, including sepsis, infections, autoimmune diseases, transplant rejection
`
`and graft-versus-host disease (see e. g., Moeller, A., et a1. (1990) Cytokine 2:162-169;
`
`US. Patent No. 5,231,024 to Moeller et (11.; European Patent Publication No. 260 610
`
`25
`
`B1 by Moeller, A., et al.Vasilli, P. (1992) Annu. Rev. Immunol. m:411-452; Tracey,
`
`K.J. and Cerami, A. (1994) Annu. Rev. Med. fli491-503).
`
`Because of the harmful role of human TNFOt (hTNFoc) in a variety of human
`
`disorders, therapeutic strategies have been designed to inhibit or counteract hTNFoc
`
`activity. In particular, antibodies that bind to, and neutralize, hTNFoc have been sought
`
`30
`
`as a means to inhibit hTNFoc activity. Some of the earliest of such antibodies were
`
`mouse monoclonal antibodies (mAbs), secreted by hybridomas prepared from
`
`lymphocytes of mice immunized with hTNFoc (see e. g., Hahn T; et al., (1985) Proc Natl
`
`Acad Sci USA g: 3814-3818; Liang, C—M., et al. (1986) Biochem. Biophys. Res.
`
`Commun. 13_7:847-854; Hirai, M., et a]. (1987) J. Immunol. Methods %:57-62; Fendly,
`
`35
`
`B.M., et al. (1987) Hybridoma 6:359-370; Moeller, A., et al. (1990) Cytokine 2:162-
`
`169; US. Patent No. 5,231,024 to Moeller et (11.; European Patent Publication No. 186
`
`MEI 13427587v.1
`
`Ex. 1056 - Page 8 of 44
`
`Ex. 1056 - Page 8 of 44
`
`

`

`Attorney Docket No. 117813-16605
`
`-2-
`
`833 B1 by Wallach, D.; European Patent Application Publication No. 218 868 A1 by
`
`Old et al.; European Patent Publication No. 260 610 B1 by Moeller, A., et al.). While
`
`these mouse anti-hTNFoc antibodies often displayed high affinity for hTNFoc (e. g., Kd S
`
`10'9M) and were able to neutralize hTNFoc activity, their use in vivo may be limited by
`
`problems associated with administration of mouse antibodies to humans, such as short
`
`serum half life, an inability to trigger certain human effector functions and elicitation of
`
`an unwanted immune response against the mouse antibody in a human (the "human anti-
`
`mouse antibody" (HAMA) reaction).
`
`In an attempt to overcome the problems associated with use of fully-murine
`
`antibodies in humans, murine anti-hTNFoc antibodies have been genetically engineered
`
`to be more "human-like." For example, chimeric antibodies, in which the variable
`
`regions of the antibody chains are murine-derived and the constant regions of the
`
`antibody chains are human-derived, have been prepared (Knight, D.M, et al. (1993)
`
`M01. Immunol. fl:1443-1453; PCT Publication No. W0 92/ 16553 by Daddona, P.E., et
`
`al.). Additionally, humanized antibodies, in which the hypervariable domains of the
`
`antibody variable regions are murine-derived but the remainder of the variable regions
`
`and the antibody constant regions are human-derived, have also been prepared (PCT
`
`Publication No. W0 92/ 1 1383 by Adair, J .R., et al.). However, because these chimeric
`
`and humanized antibodies still retain some murine sequences, they still may elicit an
`
`unwanted immune reaction, the human anti-chimeric antibody (HACA) reaction,
`
`especially when administered for prolonged periods, e. g., for chronic indications, such
`
`as rheumatoid arthritis (see e. g., Elliott, M.J., et al. (1994) Lancet fi:1125-1127; Elliot,
`
`M.J., et al. (1994) Lancet fileS-lllO).
`
`A preferred hTNFoc inhibitory agent to murine mAbs or derivatives thereof (e. g.,
`
`chimeric or humanized antibodies) would be an entirely human anti-hTNFoc antibody,
`
`since such an agent should not elicit the HAMA reaction, even if used for prolonged
`
`periods. Human monoclonal autoantibodies against hTNFoc have been prepared using
`
`human hybridoma techniques (Boyle, P., et al. (1993) Cell. Immunol. @556-568;
`
`Boyle, P., et al. (1993) Cell. Immunol. @569-581; European Patent Application
`
`Publication No. 614 984 A2 by Boyle, et al.). However, these hybridoma-derived
`
`monoclonal autoantibodies were reported to have an affinity for hTNFoc that was too
`
`low to calculate by conventional methods, were unable to bind soluble hTNFoc and were
`
`unable to neutralize hTNFoc-induced cytotoxicity (see Boyle, et al.; supra). Moreover,
`
`the success of the human hybridoma technique depends upon the natural presence in
`
`human peripheral blood of lymphocytes producing autoantibodies specific for hTNFoc.
`
`Certain studies have detected serum autoantibodies against hTNFoc in human subjects
`
`(Fomsgaard, A., et al. (1989) Scand. J. Immunol. $219223; Bendtzen, K., et al.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`MEI 13427587v.1
`
`Ex. 1056 - Page 9 of 44
`
`Ex. 1056 - Page 9 of 44
`
`

`

`Attorney Docket No. 117813-16605
`
`-3-
`
`(1990) Prog. Leukocyte Biol. 10_B:447-452), whereas others have not (Leusch, H-G., et
`
`a1. (1991) J. Immunol. Methods @145-147).
`
`Alternative to naturally-occurring human anti-hTNFoc antibodies would be a
`
`recombinant hTNFoc antibody. Recombinant human antibodies that bind hTNFoc with
`relatively low affinity (i.e., Kd ~10'7M) and a fast off rate (i.e., Koff ~ 10'2 sec'l) have
`
`been described (Griffiths, A.D., et a1. (1993) EMBO J. Q:725-734). However, because
`
`of their relatively fast dissociation kinetics, these antibodies may not be suitable for
`
`therapeutic use. Additionally, a recombinant human anti-hTNFoc has been described
`
`that does not neutralize hTNFoc activity, but rather enhances binding of hTNFoc to the
`
`surface of cells and enhances internalization of hTNFoc (Lidbury, A., et a1. (1994)
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`Biotechnol. Ther. 5:27-45; PCT Publication No. WO 92/03145 by Aston, R. et a1.)
`
`Recombinant human antibodies that bind soluble hTNFoc with high affinity and
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`slow dissociation kinetics and that have the capacity to neutralize hTNFoc activity,
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`including hTNFoc-induced cytotoxicity (in vitro and in vivo) and hTNFoc-induced cell
`
`activation, have also been described (see U.S. Patent No. 6,090,382).
`
`Summary of the Invention
`
`There is a need for a stable aqueous pharmaceutical formulation with an
`
`extended shelf life, comprising an antibody which is suitable for therapeutic use to
`
`inhibit or counteract detrimental hTNFoc activity. There is also a need for a stable
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`aqueous pharmaceutical formulation with an extended shelf life, comprising an antibody
`
`suitable for therapeutic use which is easily administered and contains a high protein
`concentration.
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`This invention provides a liquid aqueous pharmaceutical formulation consisting
`
`of a therapeutically effective amount of an antibody in a buffered solution forming a
`
`formulation having a pH between about 4 and about 8 and having a shelf life of at least
`
`18 months. The invention also includes an aqueous pharmaceutical formulation
`
`comprising a therapeutically effective amount of an antibody in a buffered solution
`
`forming a formulation having a pH between about 4 and 8 and having a shelf life of at
`
`least 18 months in the liquid state. In one embodiment, the pharmaceutical formulation
`
`has enhanced stability. In a further embodiment, the formulation of the invention is
`
`stable following at least 3 freeze/thaw cycles of the formulation. In another
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`embodiment, the antibody is directed to TNFOt. In yet another embodiment, the
`
`antibody is directed to human TNFOt. In still another embodiment, the antibody is
`D2E7.
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`Attorney Docket No. 117813-16605
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`-4-
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`This invention also provides a liquid aqueous pharmaceutical formulation
`
`comprising a therapeutically effective amount of an antibody in a buffered solution
`
`forming a formulation having a pH between 4 and 8 and having enhanced stability of at
`
`least 12 months at a temperature of 2 - 8°C. In one embodiment, the formulation has
`
`enhanced stability of at least 18 months. In another embodiment, the antibody is
`
`directed to TNFOt.
`
`In yet another embodiment, the antibody is directed to human
`
`TNFoc. In a further embodiment, the antibody is D2E7.
`
`The invention further provides a liquid aqueous pharmaceutical formulation
`
`comprising a therapeutically effective amount of an antibody in a buffered solution
`
`forming a formulation having a pH between about 4 and about 8 which is easily
`
`administratable. In one embodiment, the antibody is directed to TNFOt.
`
`In yet another
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`embodiment, the antibody is directed to human TNFOt. In a further embodiment, the
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`antibody is D2E7.
`
`In one embodiment of the invention, the liquid aqueous pharmaceutical
`
`formulation is suitable for injection. In a further embodiment, the formulation is
`
`suitable for single use sc injection. In another embodiment, the concentration of the
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`antibody in the liquid aqueous pharmaceutical formulation is about l-l50 mg/ml. In yet
`
`another embodiment, the concentration of the antibody in the formulation is about 50
`
`mg/ml. In still another embodiment, the formulation has a high protein concentration.
`
`In yet another embodiment of the invention, the formulation is not light sensitive.
`
`In one embodiment of the invention, the liquid aqueous pharmaceutical
`
`formulation contains an antibody, or an antigen-binding portion thereof, that dissociates
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`from human TNFOt with a Kd of l X 10'8 M or less and a Koff rate constant of l X 10'3 S"
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`1 or less, both determined by surface plasmon resonance, and neutralizes human TNFOt
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`cytot0Xicity in a standard in vitro L929 assay with an IC5O of l X 10'7 M or less.
`
`In
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`another embodiment, the formulation of the invention contains an antibody, or antigen-
`
`binding portion thereof, which dissociates from human TNFOt with a Koff rate constant
`
`of 5 X 10'4 s1 or less. In a further embodiment,
`
`the formulation contains an antibody,
`
`or antigen-binding portion thereof, which dissociates from human TNFOt with a Koff rate
`
`constant of l X 10'4 S'1 or less. In still a further embodiment, the formulation of the
`
`invention contains an antibody, or antigen-binding portion thereof, which neutralizes
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`human TNFOt cytot0Xicity in a standard in vitro L929 assay with an IC5O of l X 10'8 M
`
`or less. In yet another embodiment of the invention, the claimed formulation includes
`
`an antibody, or antigen-binding portion thereof, which neutralizes human TNFOt
`
`cytot0Xicity in a standard in vitro L929 assay with an IC5O of l X 10'9 M or less.
`
`Another embodiment of the invention, includes a formulation where the antibody, or
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`Attorney Docket No. ll78l3-l6605
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`-5-
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`antigen-binding portion thereof, neutralizes human TNFOt cytot0Xicity in a standard in
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`vitro L929 assay with an IC5O of l X 10'10 M or less.
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`In another embodiment of the invention, the liquid aqueous pharmaceutical
`
`formulation contains of an antibody, or antigen-binding portion thereof, which is a
`
`recombinant antibody, or antigen-binding portion thereof. In another embodiment, the
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`formulation contains an antibody, or antigen-binding portion thereof, which inhibits
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`human TNFOt-induced expression of ELAM-l on human umbilical vein endothelial
`
`cells. In still another embodiment, the claimed formulation includes the D2E7 antibody.
`
`In another embodiment of the invention, the liquid aqueous pharmaceutical
`
`formulation includes an antibody, or antigen-binding portion, thereof which dissociates
`
`from human TNFOt with a Koff rate constant of l X 10'3 s—1 or less, as determined by
`
`surface plasmon resonance;
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`b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ
`
`ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1,
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`4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6,
`
`7, 8 and/or 9;
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`c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ
`
`ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2,
`
`3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at
`
`positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12. In another embodiment, the formulation of
`
`the invention includes an antibody, or an antigen-binding portion thereof, which
`
`dissociates from human TNFOt with a Koff rate constant of 5 X 10'4 S'1 or less. In yet
`
`another embodiment of the invention, the formulation includes an antibody, or an
`
`antigen-binding portion thereof, which dissociates from human TNFOt with a Koff rate
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`constant of l X 10'4 s'1 or less.
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`In yet another embodiment of the invention, the liquid aqueous pharmaceutical
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`formulation, contains of an antibody, or antigen-binding portion thereof, which has a
`
`light chain variable region (LCVR) having a CDR3 domain comprising the amino acid
`
`sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine
`
`substitution at position 1, 4, 5, 7 or 8, and with a heavy chain variable region (HCVR)
`
`having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or
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`modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8,
`
`9, 10 or 11. In a further embodiment, the formulation of the invention contains an
`
`antibody, wherein the LCVR of the antibody, or an antigen-binding portion thereof,
`
`further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5 and
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`the HCVR of the antibody, or an antigen-binding portion thereof, further has a CDR2
`
`domain comprising the amino acid sequence of SEQ ID NO: 6. In yet another
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`Attorney Docket No. 117813-16605
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`-6-
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`embodiment, the formulation of the invention contains an antibody, wherein the LCVR
`
`of the antibody, or an antigen-binding portion thereof, further has CDRl domain
`
`comprising the amino acid sequence of SEQ ID NO: 7 and the HCVR has a CDRl
`
`domain comprising the amino acid sequence of SEQ ID NO: 8.
`
`In yet another embodiment of the invention, the antibody or antigen-binding
`
`portion thereof, contained in the liquid aqueous pharmaceutical formulation has a light
`
`chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1
`
`and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ
`
`ID NO: 2. In another embodiment, the antibody, or antigen-binding portion thereof, has
`
`an IgGl heavy chain constant region. In still another embodiment, the antibody, or
`
`antigen-binding portion thereof, has an IgG4 heavy chain constant region. In another
`
`embodiment, the antibody, or antigen-binding portion thereof, is a Fab fragment. In still
`
`a further embodiment, the antibody, or antigen-binding portion thereof, is a single chain
`
`Fv fragment.
`
`In one embodiment of the invention, the liquid aqueous pharmaceutical
`
`formulation, contains an antibody, or antigen-binding portion thereof, which has a light
`
`chain variable region (LCVR) having a CDR3 domain comprising an amino acid
`
`sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID
`
`NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID
`
`NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID
`
`NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or with a
`
`heavy chain variable region (HCVR) having a CDR3 domain comprising an amino acid
`
`sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID
`
`NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID
`
`NO: 33 and SEQ ID NO: 34. In still another embodiment, the antibody, or antigen-
`
`binding portion thereof, neutralizes the activity of human TNFOt, chimpanzee TNFOt and
`
`at least one additional primate TNFOt selected from the group consisting of baboon
`
`TNFOt, marmoset TNFOt, cynomolgus TNFOt and rhesus TNFOt. In a further
`
`embodiment, the formulation of the invention includes an antibody, or an antigen-
`
`binding portion thereof, which also neutralizes the activity of mouse TNFOt. The
`
`formulation of the invention also an antibody, or an antigen-binding portion thereof,
`
`which neutralizes the activity of pig TNFoc.
`
`In a further embodiment, the inventio