USOO8802100B2
`
`(12) Unlted States Patent
`(10) Patent No.:
`US 8,802,100 B2
`
`Krause et al.
`(45) Date of Patent:
`*Aug. 12, 2014
`
`(54) FORMULATION OF HUMAN ANTIBODIES
`FOR TREATING TNF-ALPHA ASSOCIATED
`DISORDERS
`
`(56)
`
`References Cited
`U S PATENT DOCUMENTS
`’
`’
`
`,
`_
`_
`,
`(71) Applicant: Abele Blotenchology Ltd., Hamilton
`(BM)
`
`(72)
`
`_
`.
`Inventors. Hans Juergen Krause, Gruenstadt
`(DE); Lisa Ballsts LudWIgshafen (DE);
`Michael Dickes, Rodersheim-Gronau
`(DE)
`
`(73) Assignee: Abeie Biotechnology Ltd., Hamilton
`(BM)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`atent is extended or ad'usted under 35
`J
`
`P
`USC 15403) by 0 days
`.
`.
`.
`.
`.
`This patent is subject to a terminal d1s-
`claimer.
`
`(21) Appl.N0.: 14/091 661
`3
`.
`Flledi
`
`(22)
`
`N0“ 27, 2013
`_
`_
`_
`Prlor Publlcatlon Data
`
`(65)
`
`US 2014/0086929 A1
`
`Mar. 27, 2014
`
`Related US. Application Data
`
`(63) Continuation of application No. 13/471,820, filed on
`May 15, 2012, which is a continuation of application
`No.
`10/525,292,
`filed
`as
`application No.
`PCT/1B03/04502 on Aug. 15, 2003, now Pat. No.
`8,216,583, which is a continuation of application No.
`10/222,140, filed on Aug. 16, 2002, now abandoned.
`
`<51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`888288
`(2006.01)
`(2006.01)
`(2006.01)
`
`A61K 39/395
`co 7K 16/24
`C07K 14/525
`A61K 47/12
`jig; 37/73
`A61K 47/18
`A61K 9/00
`A61K 47/22
`(52) US. Cl.
`CPC ................. A61K 4 7/26 (2013.01); A61K 4 7/12
`(2013.01); C07K16/241(2013.01);A61K
`39/39591 (2013.01); A61K 47/10 (2013.01);
`A61K47/183 (2013.01); A61K 39/3955
`(2013.01); A61K 9/0019 (2013.01); A61L 9/19
`(2013.01); C07K 2317/2] (2013.01);A61K
`47/22 (2013.01)
`USPC .................. 424/1581; 424/130.1; 424/141.1;
`424/145-1; 530/351; 530/3871; 530/3881;
`53038823; 53038824; 530/399
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`4,597,966 A
`4,897,465 A
`5,231,024 A
`5,237,054 A
`5,358,708 A
`5,608,038 A
`5,654,403 A
`5,792,838 A
`5,945,098 A
`6,015,557 A
`2:853:23; :
`6,165,467 A
`6,171,586 B1
`6,177,077 Bl
`6’235’281 B1
`6,258,562 B1
`6,267,958 B1
`6,379,666 B1
`6419 934 B1
`6,419,944 B2
`6,423,321 B2
`
`6,428,787 B1
`6,485,725 B1
`6,485,932 B1
`6,509,015 B1
`6,737,405 B2
`6,818,613 B2
`6,875,432 B2
`7,070,775 B2
`7,141,542 B2
`7,220,409 B2
`7,223,394 B2
`7,250,165 B2
`7,276,239 B2
`7318931 32
`7’541’031 B2
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`FOREIGN PATENT DOCUMENTS
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`51:
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`
`713::
`
`,
`(Commued)
`
`OTHER PUBLICATIONS
`Adalimumab entry from National Library of Medicine website:
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`(Continued)
`
`Primary Examiner 7 Bridget E Bunner
`
`(74) Attorney, Agent, or Firm 7 Ropes & Gray LLP; James
`F. Haley, Jr.; Z. Ying Li
`
`(57)
`
`ABSTRACT
`
`A liquid aqueous pharmaceutical formulation is described
`which has a high protein concentration, a pH of between
`about 4 and about 8, and enhanced stability.
`
`29 Claims, No Drawings
`
`AMG EN INC.
`
`Exhibit 1051
`
`Ex. 1051 - Page 1 of 25
`
`Ex. 1051 - Page 1 of 25
`
`AMGEN INC.
`Exhibit 1051
`
`

`

`US 8,802,100 B2
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`factor (TNF) activity in severely burned patients,” Burns, 20(1):40-
`44 (1994).
`VIacDonald et al., “Tumour necrosis factor-alpha and interferon-
`gamma production measured at the single cell level in normal and
`inflamed human intestine,” Clinical and Experimental Immunology,
`81(2):301-305 (1990).
`VIcCauley et al., “Altered cytokine production in black patients with
`keloids,” Journal of Clinical Immunology, 12(4):300-308 (1992).
`VIcClain et al., “Increased tumor necrosis factor production by
`monocytes in alcoholic hepatitis,” Hepatology, 9(3):349-351 (1989).
`VIoeller et al., “Monoclonal antibodies to human tumor necrosis
`factor alpha: in vitro and in vivo application,” Cytokine, 2(3): 162-169
`(1990).
`\Iotice of opposition of European Patent EP1528933, submitted by
`Alfred E. Tiefenbacher, Feb. 1, 2013 (with English Translation).
`\Iotice of opposition of European Patent EP1528933, submitted by
`Dr. Ulrich Storz, Feb. 1, 2013.
`\Iotice of opposition of European Patent EP1528933, submitted by
`Teva Pharmaceutical Industries Ltd., Feb. 4, 2013.
`\Iotice of opposition of European Patent EP1528933, submitted by
`William Edward Bird, Jan. 31, 2013.
`Old, “Tumor necrosis factor (TNF),” Science, 230(4726):630-632
`(1985).
`Patentee’s Compilation Record submitted during Opposition of
`EP1528933 (Jan. 10, 2014).
`Patentee’s Recordation of Name Change in PCT/IB2003/004502
`submitted by Patentee during Opposition of EP1528933 (Jan. 18,
`2005).
`Patentee’ 3 Request for Name Change submitted during Opposition of
`EP1528933 (Dec. 1,2005).
`Patentee’s Response on 71(3 ) Communication submitted during
`Opposition of EP1528933, plus Request to Correct the Sequence
`Listing (Feb. 15, 2012).
`Patentee’s Response submitted during Oppositions of EP1528933
`(Jan. 17,2014).
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`loaded Dec. 19, 2012).
`Pearlman et al., “Analysis of Protein Drugs,” Peptide and Protein
`Drug Delivery, Marcel Dekker, Inc., pp. 247-301 (1991).
`Pennica et al., “Human tumour necrosis factor: precursor structure,
`expression and homology to lymphotoxin,” Nature, 312(5996):724-
`729 (1984).
`Polj ak,
`“Production and structure of diabodies,” Structure,
`2(12):1121-1123 (1994).
`in US. Appl. No.
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`2002).
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`(EMA) with Respect
`to adalimumab/Humira®7EMENH/C/
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`tumour necrosis factor alpha antibody (CDP571) in rheumatoid
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`Rau, “Adalimumab (a fully human anti -tumour necrosis factor alpha
`monoclonal antibody) in the treatment of active rheumatoid arthritis:
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`
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`

`

`US 8,802,100 B2
`Page 5
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`(56)
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`References Cited
`OTHER PUBLICATIONS
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`
`Ex. 1051 - Page 5 of 25
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`US 8,802,100 B2
`
`1
`FORMULATION OF HUMAN ANTIBODIES
`FOR TREATING TNF-ALPHA ASSOCIATED
`DISORDERS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of US. patent applica-
`tion Ser. No. 13/471,820, filed May 15, 2012 (now pending),
`which is a continuation of US. patent application Ser. No.
`10/525,292 filed Oct. 27, 2005, now US. Pat. No. 8,216,583,
`issued Jul. 10, 2012, which is a United States National Stage
`Application under 35 U.S.C. §371 of PCT/IB2003/004502,
`filed Aug. 15, 2003 (now expired), which is a continuation of
`US. patent application Ser. No. 10/222,140, filed Aug. 16,
`2002 (now abandoned). Each of these applications is herein
`incorporated by reference in its entirety.
`
`SEQUENCE LISTING
`
`The Sequence Listing associated with this application is
`provided in text format in lieu of a paper copy, and is hereby
`incorporated by reference into the specification. The name of
`the text file containing the Sequence Listing is 1 10222-0005-
`303-Sequence-Listing.txt. The text file is 1 1,274 bytes in size,
`was created on Nov. 26, 2013, and is being submitted elec-
`tronically Via EFS Web.
`
`BACKGROUND OF THE INVENTION
`
`Tumor necrosis factor (X (TNFot) is a cytokine produced by
`numerous cell types, 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 230: 630-632). Subsequently, a factor termed cachec-
`tin, 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. 57:505-518; 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 al. (1990) Cytokine
`2:162-169; US. Pat. No. 5,231,024 to Moeller et al.; Euro-
`pean Patent Publication No. 260 610 B1 by Moeller, A., et al.
`Vasilli, P. (1992)Annu. Rev. Immunol. 10:41 1-452; Tracey, K.
`J. and Cerami, A. (1994) Annu. Rev. Med. 45:491-503).
`Because of the harmful role ofhuman TNFot (hTNFot) in a
`variety of human disorders, therapeutic strategies have been
`designed to inhibit or counteract hTNFot activity. In particu-
`lar, antibodies that bind to, and neutralize, hTNFot have been
`sought as a means to inhibit hTNFot activity. Some of the
`earliest of such antibodies were mouse monoclonal antibod-
`
`ies (mAbs), secreted by hybridomas prepared from lympho-
`cytes ofmice immunized with hTNFot (see e.g., Hahn T; et al.,
`(1985) Proc NatlAcadSci USA 82: 3814-3818; Liang, C-M.,
`et al. (1986) Biochem. Biophys. Res. Commun. 137:847-854;
`Hirai, M., et al. (1987) J. Immunol. Methods 96:57-62;
`Fendly, B. M., et al. (1987) Hybridoma 6:359-370; Moeller,
`A., et al. (1990) Cytokine 2: 162-169; US. Pat. No. 5,231,024
`to Moeller et al.; European Patent Publication No. 186 833 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-
`hTNFot antibodies often displayed high affinity for hTNFot
`(e. g., de 1 0'9M) and were able to neutralize hTNFot activity,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`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-hTNFot
`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)Mol.
`Immunol. 30: 1443-1453; PCT Publication No. WO 92/16553
`by Daddona, P. E., et al.). Additionally, humanized antibod-
`ies, in which the hypervariable domains of the antibody vari-
`able 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. WO 92/11383 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) reac-
`tion, especially when administered for prolonged periods,
`e.g., for chronic indications, such as rheumatoid arthritis (see
`e.g., Elliott, M. J., etal. (1994)Lancet344:1 125-1127; Elliot,
`M. J., et al. (1994) Lancet 344:1105-1110).
`A preferred hTNFot inhibitory agent to murine mAbs or
`derivatives thereof (e.g., chimeric or humanized antibodies)
`would be an entirely human anti-hTNFot antibody, since such
`an agent should not elicit the HAMA reaction, even ifused for
`prolonged periods. Human monoclonal
`autoantibodies
`against hTNFot have been prepared using human hybridoma
`techniques (Boyle, P., et al. (1993) Cell. Immunol. 152:556-
`568; Boyle, P., et al. (1993) Cell. Immunol. 152:569-581;
`European Patent Application Publication No. 614 984 A2 by
`Boyle, et al.). However,
`these hybridoma-derived mono-
`clonal autoantibodies were reported to have an affinity for
`hTNFot that was too low to calculate by conventional meth-
`ods, were unable to bind soluble hTNFot and were unable to
`neutralize hTNFot-induced cytotoxicity (see Boyle, et al.;
`supra). Moreover, the success of the human hybridoma tech-
`nique depends upon the natural presence in human peripheral
`blood of lymphocytes producing autoantibodies specific for
`hTNFot. Certain studies have detected serum autoantibodies
`
`against hTNFot in human subjects (Fomsgaard, A., et al.
`(1989) Scand. J. Immunol. 30:219-223; Bendtzen, K., et al.
`(1990) Frog. Leukocyte Biol. 10B:447-452), whereas others
`have not (Leusch, H-G., et al. (1991) J. Immunol. Methods
`139:145-147).
`Alternative to naturally-occurring human anti-hTNFot
`antibodies would be a recombinant hTNFot antibody. Recom-
`binant human antibodies that bind hTNFot with relatively low
`affinity (i.e., Kd~10'7M) and a fast off rate (i.e., Kofl~10'2
`sec—1) have been described (Griffiths, A. D., et al. (1993)
`EMBO J. 12:725-734). However, because of their relatively
`fast dissociation kinetics, these antibodies may not be suitable
`for therapeutic use. Additionally, a recombinant human anti-
`hTNFot has been described that does not neutralize hTNFot
`
`activity, but rather enhances binding of hTNFot to the surface
`of cells and enhances internalization of hTNFot (Lidbury, A.,
`et al. (1994) Biotechnol. Ther. 5:27-45; PCT Publication No.
`WO 92/03145 by Aston, R. et al.)
`Recombinant human antibodies that bind soluble hTNFot
`
`with high affinity and slow dissociation kinetics and that have
`the capacity to neutralize hTNFot activity, including hTNFot-
`
`Ex. 1051 - Page 6 of 25
`
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`

`US 8,802,100 B2
`
`3
`induced cytotoxicity (in vitro and in vivo) and hTNFot-in-
`duced cell activation, have also been described (see US. Pat.
`No. 6,090,382).
`
`SUMMARY OF THE INVENTION
`
`There is a need for a stable aqueous pharmaceutical for-
`mulation with an extended shelf life, comprising an antibody
`which is suitable for therapeutic use to inhib