UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`FRESENIUS KABI USA, LLC and FRESENIUS KABI SWISSBIOSIM GmbH
`Petitioners,
`v.
`COHERUS BIOSCIENCES, INC.
`Patent Owner.
`
`
`PGR2019-00064
`Patent No. 10,155,039 B2
`Title: STABLE AQUEOUS FORMULATIONS OF ADALIMUMAB
`
`
`PETITION FOR POST-GRANT REVIEW
`OF U.S. PATENT NO. 10,155,039 B2
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`

`

`
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`SUMMARY OF GROUNDS FOR INSTITUTION AND
`CANCELLATION .......................................................................................... 1
`II. GROUNDS FOR STANDING ........................................................................ 2
`III. MANDATORY NOTICES ............................................................................. 2
`
`Real Parties In Interest (37 C.F.R. § 42.8(b)(1)) ................................... 2
`
`Related Matters (37 C.F.R. § 42.8(b)(2)) .............................................. 2
`
`Identification of Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4)) .................................................... 3
`IV. THE ’039 PATENT DISCLOSURE ............................................................... 3
`
`The Alleged Invention of the ’039 Patent ............................................. 3
`
`The Claims of the ’039 Patent ............................................................... 4
`
`Relevant Prosecution History ................................................................ 5
`
`Construction of Claim Terms ................................................................ 9
`
`“Stable aqueous pharmaceutical composition” ....................... 10
`
`“Buffer” .................................................................................... 13
`
`“Citrate and phosphate buffers” .............................................. 14
`
`“About” ..................................................................................... 14
`
`“Sugar” ..................................................................................... 14
`
`“Single dose” ............................................................................ 15
`The Disclosure In the Specification of the ’039 Patent ...................... 16
`
`THE ’039 PATENT IS ELIGIBLE FOR PGR BECAUSE NONE OF
`THE CLAIMS HAVE AN EFFECTIVE FILING DATE EARLIER
`THAN SEPTEMBER 6, 2013 ....................................................................... 20
`
`Chain of Priority For the ’039 Patent .................................................. 20
`
`The Provisional Applications Do Not Adequately Describe The
`Compositions of Claims 9-12, Which Require Acetate Buffer
`And A pH of About 5 To About 6 ...................................................... 21
`
`V.
`
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`- i -
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`
`E.
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`
`
`TABLE OF CONTENTS
`(Continued)
`
`Page
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`
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`
`The ’138 Provisional Application Does Not Describe
`Formulations Containing Acetate Buffer .................................. 23
`The ’421 Provisional Application Also Does Not
`Describe Formulations Containing Acetate Buffer .................. 24
`The ’581 Provisional Application Does Not Describe
`Stable Formulations Containing Acetate Buffer and
`Having a pH of About 5 to About 6 .......................................... 25
`The Provisional Applications Do Not Describe With Specificity
`The Compositions of Claims 5-12, Which Require Sucrose .............. 27
`
`The ’138 Provisional Application Does Not Describe the
`Sucrose Formulations of Claims 5-12 ...................................... 28
`The ’421 Provisional Application Does Not Describe The
`Sucrose Formulations of Claims 5-12 ...................................... 29
`The ’581 Provisional Application Does Not Disclose the
`Sucrose Formulations of Claims 5-12 ...................................... 30
`The Provisional Applications Do Not Disclose the “Stable”
`Formulations of Claims 1-12 ............................................................... 31
`
`The ’138 and ’421 Provisional Applications Do Not
`Contain Any Data Demonstrating Stability .............................. 33
`The Data in the ’581 Provisional Application Do Not
`Demonstrate the Claimed Stability ........................................... 35
`The Provisional Applications Do Not Demonstrate
`Possession of the Broad Genus of “Stable” Formulations
`of Claims 1-4 ............................................................................. 36
`The Provisional Applications Do Not Enable Claims 1-12 of the
`’039 Patent ........................................................................................... 39
`
`Claims 1-12 Are Extremely Broad ............................................ 40
`
`Antibody Stability is Unpredictable .......................................... 41
`
`The Specification of the Provisional Applications
`Provides No Working Examples ............................................... 43
`The Description of the Provisional Applications Provides
`No Written Examples ................................................................ 43
`
`
`
`ii
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`
`
`TABLE OF CONTENTS
`(Continued)
`
`Page
`
`
`
`
`
`
`
`
`
`The Amount of Guidance in the Provisional Applications
`Is Limited ................................................................................... 43
`Taken Together, the Wands Factors Show the
`Provisional Applications Do Not Enable Claims 1-12 ............. 44
`VI. THE PRECISE RELIEF REQUESTED FOR EACH CHALLENGED
`CLAIM AND THE REASONS THEREFOR ............................................... 44
` Ground 1: The Specification Of the ’039 Patent Does Not
`Provide Adequate Written Description Support For Claims 1-12 ...... 44
`
`The Specification Fails the Representative Species Test
`for Claim 1 ................................................................................ 45
`The Specification Fails the Common Structural Features
`Test for Claim 1 ......................................................................... 47
`The Additional Stability Data in the ’039 Patent
`Specification Do Not Describe Possession of the Claimed
`Stability Range .......................................................................... 50
`a) The SEC Results Do Not Prove Formulation D-12 Has
`the Claimed Long-Term Stability ......................................... 50
`b) The RP-HPLC Results Do Not Prove Formulation D-12
`Has The Claimed Long-Term Stability ................................ 52
`c) The cIEF and CE-SDS Results Do Not Prove
`Formulation D-12 Has the Claimed Long-Term Stability .. 52
`The Specification of the ’039 Patent Also Does Not
`Satisfy §112(a) Written Description Requirement For
`Claims 2-12 ............................................................................... 53
` Ground 2: The Specification Does Not Enable the Full Scope
`of Claims 1-12 Given The Extreme Breadth of the Claims,
`Unpredictability In The Art and Limited Guidance Provided ............ 56
`
`The Claims Are Very Broad and Include Difficult-to-
`Stabilize Embodiments .............................................................. 56
`Extensive Experimentation Is Required To Verify
`Stability; Indeed, the Alleged Act Of Invention Was
`Empirical Testing ...................................................................... 56
`
`
`
`
`
`
`
`iii
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`
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`
`
`TABLE OF CONTENTS
`(Continued)
`
`Page
`
`
`
`
`
`The Specification Provides Little Guidance As To Which
`Compositions Would Meet the Claimed Stability Limits
`And No Working Examples ....................................................... 58
`In Light Of the Above Factors, Making and Using
`Compounds Covered by the Claims Would Require
`Undue Experimentation ............................................................ 60
` Ground 3: Claims 1-12 Are Indefinite ............................................... 61
`
`CONCLUSION ................................................................................... 64
`
`iv
`
`

`

`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc.,
`759 F.3d 1285 (Fed. Cir. 2014) .................................................................... 32, 37
`Amgen, Inc. v. Sanofi,
`872 F.3d 1367 (Fed. Cir. 2017), cert. denied, 139 S. Ct. 787 (2019) .... 21, 33, 49
`Ariad Pharm., Inc. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) (en banc) .............................................. 37, 38, 39
`Coherus BioSciences, Inc, v. Amgen Inc.,
`C.A. No. 19-139 (RGA) (D. Del. 2019) ......................................................... 2, 36
`Enzo Life Sciences, Inc. v. Roche Molecular Sys., Inc.,
`928 F.3d 1340 (Fed. Cir. 2019) .......................................................................... 42
`Fujikawa v. Wattanasin,
`93 F.3d 1559 (Fed. Cir. 1996) ............................................................................ 24
`Hoffer v. Microsoft Corp.,
`405 F.3d 1326 (Fed. Cir. 2005) .......................................................................... 12
`Interval Licensing LLC v. AOL, Inc.,
`766 F.3d 1364 (Fed. Cir. 2014) .......................................................................... 62
`Lockwood v. Am. Airlines, Inc.,
`107 F.3d 1565 (Fed. Cir. 1997) .......................................................................... 33
`Magsil Corp. v. Hitachi Global Storage Techs.,
`687 F.3d 1377 (Fed. Cir. 2012) .......................................................................... 59
`MessagePhone Inc. v. SVI Sys., Inc.,
`243 F.3d 556 (Fed. Cir. 2000) ............................................................................ 23
`MorphoSys AG. v. Janssen Biotech, Inc.,
`358 F. Supp. 3d 354 (D. Del. 2019) .............................................................. 55, 60
`Nautilus, Inc. v. Biosig Instruments, Inc.,
`134 S. Ct. 2120 (2014) ........................................................................................ 62
`
`
`
`- v -
`
`

`

`
`
`Novozymes A/S v. DuPont Nutrition Biosciences APS,
`723 F.3d 1336 (Fed. Cir. 2013) .......................................................................... 31
`Nuvo Pharms. v. Dr. Reddy’s Labs.,
`923 F.3d 1368 (Fed. Cir. 2019) ........................................................ 21, 23, 31, 49
`Pernix Ireland Pain DAC v. Alvogen Malta Operations Ltd.,
`323 F. Supp. 3d 566 (D. Del. 2018) .............................................................. 31, 49
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) ............................................................ 9
`Poly-America, L.P. v. GSE Lining Tech., Inc.,
`383 F.3d 1303 (Fed. Cir. 2004) .......................................................................... 12
`Proveris Sci. Corp. v. Innovasystems Inc.,
`739 F.3d 1367 (Fed. Cir. 2014) .......................................................................... 12
`Vasudevan Software, Inc. v. MicroStrategy, Inc.,
`782 F.3d 671 (Fed. Cir. 2015) ............................................................................ 39
`In re Wands,
`858 F.2d 731 (Fed. Cir 1988) ................................................................. 39, 40, 55
`PTAB Decisions
`Adello Biologics LLC et al. v. Amgen Inc., et al.,
`Case PGR2019-00001, Paper No. 13 (PTAB April 19, 2019) ..................... 32, 46
`Statutes
`35 U.S.C. §112(a) .............................................................................................passim
`35 U.S.C. §112(b) .......................................................................................... 1, 62, 63
`35 U.S.C. § 119(e) ....................................................................................... 20, 21, 44
`35 U.S.C. § 282(b)(3)(A) ......................................................................................... 44
`35 U.S.C. §§ 314(a), (d) ............................................................................................. 1
`35 U.S.C. § 321 .......................................................................................................... 2
`
`
`
`vi
`
`

`

`
`
`Regulations
`Regulations
`37 C.F.R. § 42.6(e) ................................................................................................... 64
`37 C.F.R. § 42.6(e) ................................................................................................... 64
`37 C.F.R. §42.105 .................................................................................................... 64
`37 C.F.R. §42.105 .................................................................................................... 64
` (37 C.F.R. § 42.8 ................................................................................................... 2, 3
`(37 C.F.R. § 42.8 ................................................................................................... 2, 3
`37 C.F.R. § 42.100(b) ................................................................................................ 9
`37 C.F.R. § 42.100(b) ................................................................................................ 9
`37 C.F.R. § 42.103 ..................................................................................................... 2
`37 C.F.R. § 42.103 ..................................................................................................... 2
`37 C.F.R. § 42.204(a) ................................................................................................. 2
`37 C.F.R. § 42.204(a) ................................................................................................. 2
`MPEP § 2173.02 ...................................................................................................... 63
`MPEP § 2173.02 ...................................................................................................... 63
`
`
`
`vii
`Vii
`
`

`

`
`
`LIST OF EXHIBITS
`
`EXHIBIT NO.
`
`DESCRIPTION
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`United States Patent No. 10,155,039 B2
`
`Declaration of Christian Schӧneich, Ph.D.
`
`United States Patent No. 6,090,382
`
`United States Patent No. 6,171,586
`
`Excerpts of United States Patent No. 10,155,039 B2 File History
`
`United States Patent No. 8,420,081 (“Fraunhofer”)
`
`United States Provisional Application No. 61/698,138
`
`United States Provisional Application No. 61/769,581
`
`United States Provisional Application No. 61/770,421
`
`United States Patent Application No. 14/020,733
`
`United States Patent Application No. 15/360,678 (issued as a
`U.S. patent No. 9,861,695)
`
`Application Number: 761024Orig1s000, Labeling, Center for
`Drug Evaluation and Research (September 2016) (“Amjevita
`label”)
`
`Curriculum Vitae of Christian Schӧneich, Ph.D.
`
`Wang, W., “Instability, stabilization, and formulation of liquid
`protein pharmaceuticals,” Int J Pharaceutics 185:129-188 (1999)
`(“Wang 1999”)
`Manning, M. et al., “Stability of Protein Pharmaceuticals: An
`Update,” Pharm Res. 27(4):544-75 (April 2010) (“Manning
`2010”)
`
`
`
`- viii -
`
`

`

`
`
`EXHIBIT NO.
`
`DESCRIPTION
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`
`
`Wang, W. et al., “Antibody Structure, Instability, and
`Formulation,” J Pharm Sci. 96(1):1-26 (January 2007) (“Wang
`2007”)
`
`Drugbank, “Adalimumab,” available at
`https://www.drugbank.ca/drugs/DB00051 (“Drugbank”)
`
`Handbook of Therapeutic Antibodies, ed. by S. Dübel (WILEY-
`VCH Verlag GmbH & Co.KGaA, Vol. 1, 2007) (“Dübel 2007”)
`
`Compendium of Chemical Terminology, IUPAC
`Recommendations, compiled by A. McNaught and A. Wilkinson
`(Blackwell Science Ltd., 2nd ed, 1997) (“IUPAC 1997”)
`
`Immunobiology 5, ed. by C. Janeway et al. (Garland Publishing,
`2001) (“Janeway 2001”)
`Protein Formulation and Delivery, ed. by E. McNally and J.
`Hastedt (Informa Healthcare USA, Inc., Vol. 175, 2nd ed, 2008)
`(“McNally 2008”)
`Jefferis, R., “Glycosylation as a strategy to improve antibody-
`based therapeutics,” Nature 8:226-34 (March 2009) (“Jefferis
`2009”)
`
`Baker, M. et al., “Immunogenicity of protein therapeutics The
`key causes, consequences and challenges,” Self/Nonself
`1(4):314-322 (2010) (“Baker 2010”)
`
`Brummit, R. et al., “Nonnative Aggregation of an IgG1
`Antibody in Acidic Conditions, Part 2: Nucleation and Growth
`Kinetics with Competing Growth Mechanisms,” J Pharm Sci.
`100(6):2014-2119 (May 2011) (“Brummit 2011”)
`
`Kayser, V. et al., “Evaluation of a Non-Arrhenius Model for
`Therapeutic Monoclonal Antibody Aggregation,” J Pharm Sci
`100(7):2526-2542 (July 2011) (“Kayser I 2011”)
`Mason, B. et al., “Effect of pH and Light on Aggregation and
`Conformation of an IgG1 mAb,” Mol Pharmaceutics 9:774-790
`(2012) (“Mason 2012”)
`
`ix
`
`

`

`
`
`EXHIBIT NO.
`
`DESCRIPTION
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`Kayser, V. et al., “Glycosylation influences on the aggregation
`propensity of therapeutic monoclonal antibodies,” Biotechnol. J.
`6:34-44 (2011) (“Kayser II 2011”)
`USP 30/NF 25, “<788> Particulate Matter in Injections,” (The
`U.S. Pharmacopeial Convention, 2007) (“USP 2007, “<788>
`Particulate Matter in Injections””)
`FDA Guidance, Q4B Evaluation and Recommendation of
`Pharmacopoeial Texts for Use in the ICH Regions, Annex 3(R1)
`Test for Particulate Contamination: Subvisible Particles General
`Chapter Guidance for Industry, ICH (FDA, September 2017)
`(“FDA Guidance 2017”)
`
`Daugherty, A and Mrsny, R. “Formulation and delivery issues
`for monoclonal antibody therapeutics,” Adv Drug Delivery
`Reviews 58:686-706 (2006) (“Daugherty 2006”)
`McGraw-Hill Dictionary of Scientific and Technical Terms,
`(McGraw-Hill, 6th ed, 2003)
`Hawe, A. et al., “Forced degradation of therapeutic proteins,” J.
`Pharm. Sci. 101:895-913 (2012) (“Hawe 2011”)
`Parkins, D. and Lashmar, U., “The formulation of
`biopharmaceutical products,” PSIT 3(4) 129-137 (April 2000)
`(“Parkins 2000”)
`Kerwin, B., “Polysorbates 20 and 80 Used in the Formulation of
`Protein Biotherapeutics: Structure and Degradation Pathways,” J
`Pharm Sci. 97(8):2924-2935) (August 2008) (“Kerwin 2008”)
`Ha, E. et al., “Peroxide Formation in Polysorbate 80 and Protein
`Stability,” J Pharm Sci. 91(10):2252-2264 (May 2002) (“Ha
`2002”)
`
`Formulating Poorly Water Soluble Drugs, ed. by R. Williams et
`al. (Springer, 2012) (“Williams 2012”)
`Li, S. et al., “Effects of Reducing Sugars on the Chemical
`Stability of Human Relaxin in the Lyophilized State,” J Pharm
`Sci. 85(8):873-877 (August 1996) (“Li 1996”)
`
`
`
`x
`
`

`

`
`
`EXHIBIT NO.
`
`DESCRIPTION
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`Banks, D. et al., “The Effect of Sucrose Hydrolysis on the
`Stability of Protein Therapeutics during Accelerated Formulation
`Studies,” J Pharm Sci. 98(12):4501-4510 (December 2009)
`(“Banks 2009”)
`
`Gadgil, H. et al., “The LC/MS Analysis of Glycation of IgG
`Molecules in Sucrose Containing Formulations,” J Pharm Sci.
`96(10):2607-2621 (October 2007) (“Gadgil 2007”)
`
`Gekko, K. and Timasheff, S., “Mechanism of Protein
`Stabilization by Glycerol: Preferential Hydration in Glycerol-
`Water Mixtures,” Biochemistry 20:4667-4676 (1981) (“Gekko
`1981”)
`
`Wang, W., “Tolerability of hypertonic injectables,” Int J Pharm.
`490(1-2):308-15 (July 2015) (“Wang 2015”)
`
`Saunders Nursing Drug Handbook 2011, ed. by B. Hodgson and
`R. Kizior (Elsevier Saunders, 2011) (“Saunders 2011”)
`Zhou, S. et al., “Biologics Formulation Factors Affecting Metal
`Leachables from Stainless Steel,” AAPS PharmSciTech
`12(1):411-421 (March 2011) (“Zhou 2011”)
`Zhou, S. et al., “’ Biotherapeutic Formulation Factors Affecting
`Metal Leachables from Stainless Steel Studied by Design of
`Experiments AAPS PharmSciTech 13(1):284-294 (March 2012)
`(“Zhou 2012”)
`
`Carpenter, J. et al., “Rational Design of Stable Lyophilized
`Protein Formulations: Some Practical Advice,” Pharm Res.
`14(8):969-975 (1997) (“Carpenter 1997”)
`
`Guideline for Industry, Quality of Biotechnological Products:
`Stability Testing of Biotechnological/Biological Products, ICH
`Q5C Harmonized Tripartite Guideline (FDA, 1996) (“ICH Q5C
`1996”)
`
`
`
`xi
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`

`

`
`
`EXHIBIT NO.
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`
`
`
`
`DESCRIPTION
`USP 35/NF 30, “<1049> Quality of Biotechnological Products:
`Stability Testing of Biotechnological/Biological Products,” (The
`U.S. Pharmacopeial Convention, 2011) (“USP 2011”)
`Wang, W. and Roberts, C., “Non-Arrhenius Protein
`Aggregation,” AAPS J. 15(3) 840-851 (July 2013) (“Wang
`2013”)
`Guidance for Industry, Q1A(R2) Stability Testing of New Drug
`Substances and Products, ICH (FDA, November 2003) (“FDA
`Q1A(R2) Stability Testing Guidance”)
`Stability testing of active pharmaceutical ingredients and
`finished pharmaceutical products, Annex 2, WHO Technical
`Report Series, No. 953 (2009) (“WHO Technical Report Series,
`No. 953, 2009”)
`Hong, P. et al., “Size-exclusion Chomatography for the Analysis
`of Protein Biotherapeutics and their Aggregates,” J Liquid
`Chromatography & Related Techs. 34:2923-2950 (2012) (“Hong
`2012”)
`
`Chennamsetty, N. et al., “Design of therapeutic proteins with
`enhanced stability,” PNAS 106(29):11937-11942 (July 21, 2009)
`(“Chennamsetty 2009”)
`
`Stedman’s Medical Dictionary, (Lippincott Williams & Wilkins,
`28th ed, 2006)
`
`xii
`
`

`

`
`
`I.
`
`SUMMARY OF GROUNDS FOR INSTITUTION AND
`CANCELLATION
`Fresenius Kabi USA, LLC and Fresenius Kabi SwissBioSim GmbH
`
`(“Petitioners”) request Post-Grant Review (“PGR”) of claims 1-12 of U.S. Patent
`
`No. 10,155,039 B2 (“the ’039 patent”) (Ex. 1001).
`
`As shown in this Petition, and supported by the Expert Declaration of
`
`Christian Schӧneich, Ph.D. (Ex. 1002) and the other exhibits, the challenged claims
`
`have an effective filing date no earlier than September 6, 2013 because the earlier-
`
`filed priority provisional applications do not adequately disclose or enable them
`
`under 35 U.S.C. §112(a), and are thus eligible for PGR.
`
`Petitioner respectfully requests cancellation of the challenged claims on the
`
`grounds that the specification of the ’039 patent does not adequately describe the
`
`claimed stable compositions of adalimumab, or enable a person of ordinary skill in
`
`the art to practice their full scope without undue experimentation. The claims are
`
`also indefinite under 35 U.S.C. §112(b).
`
`The Board should institute review because there is a reasonable likelihood that
`
`Petitioners will prevail with respect to at least one challenged claim. 35 U.S.C.
`
`§ 314(a). There is no basis to deny institution under § 314(a) or § 325(d) since this
`
`is the first petition by the petitioner challenging a claim of the ’039 patent.
`
`A more detailed explanation of the reasons for the relief requested is set forth
`
`in section VI below.
`
`
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`- 1 -
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`

`

`
`
`II. GROUNDS FOR STANDING
`In accord with 37 C.F.R. § 42.204(a) and 35 U.S.C. § 321, Petitioners certify
`
`that less than 9 months have passed since the December 18, 2018 issue date of the
`
`’039 patent and that the ’039 patent is available for PGR. As explained in section V
`
`below, at least one claim of the ’039 patent has an effective filing date later than
`
`March 16, 2013. Petitioners also certify that they are not barred or estopped from
`
`requesting PGR on the grounds raised in this petition. The required fee set forth in
`
`§ 42.15(a) has been paid in accord with 37 C.F.R. § 42.103 and the Commissioner
`
`is hereby authorized to charge all fees due in connection with this matter to Attorney
`
`Deposit Account 506989.
`
`III. MANDATORY NOTICES
` Real Parties In Interest (37 C.F.R. § 42.8(b)(1))
`The real parties in interest are Fresenius Kabi USA, LLC, Fresenius Kabi
`
`LLC, Fresenius Kabi SwissBioSim GmbH, Fresenius Kabi AG, Fresenius Kabi
`
`Pharmaceuticals Holding, Inc., Fresenius Kabi Deutschland GmbH and Fresenius
`
`SE & Co. KGaA.
`
` Related Matters (37 C.F.R. § 42.8(b)(2))
`The ’039 patent is currently the subject of the following litigation: Coherus
`
`BioSciences, Inc, v. Amgen Inc., C.A. No. 19-139 (RGA) (D. Del. 2019).
`
`
`
`- 2 -
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`

`

`
`
`
`
`
`
`Identification of Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4))
`
`Lead Counsel
`Linnea P. Cipriano
`(Reg. No. 67,729)
`Goodwin Procter LLP
`620 Eighth Avenue
`New York, NY 10018
`Phone: (212) 459-7258
`Fax: (212) 937-2204
`lcipriano@goodwinlaw.com
`
`First Back-Up Counsel
`Huiya Wu
`(Reg. No. 44,411)
`Goodwin Procter LLP
`620 Eighth Avenue
`New York, NY 10018
`T: (212) 459-7270
`Fax: (212) 656-1477
`hwu@goodwinlaw.com
`
`Please direct all correspondence to lead counsel and back-up counsel at the
`
`contact information above. Petitioner consents to electronic mail service at the
`
`following addresses: lcipriano@goodwinlaw.com, hwu@goodwinlaw.com,
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`rcerwinski@goodwinlaw.com, bashbridge@goodwinlaw.com,
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`carmellino@goodwinlaw.com, alix.dubes@fresenius-kabi.com,
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`leena.contarino@fresenius-kabi.com, and rcuriel@goodwinlaw.com.
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`IV. THE ’039 PATENT DISCLOSURE
` The Alleged Invention of the ’039 Patent
`The ’039 patent is entitled “Stable Aqueous Formulations of Adalimumab”
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`and is generally directed to “stable” adalimumab antibody formulations suitable for
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`“long-term storage.” Ex. 1001 at 1:6-10; See Ex. 1002 ¶¶ 62-71 for a tutorial on
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`antibody structure). The patent notes that while “[v]arious formulations of
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`adalimumab are known in the art,” there is “still need for stable liquid formulations
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`of adalimumab that allow its long term storage without substantial loss in efficacy.”
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`Ex. 1001 at 1:66-2:3. As the inventors explain, when aqueous formulations of
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`adalimumab “are stored on a long-term basis, the activity of adalimumab can be lost
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`or decreased due to aggregation and/or degradation.” Id. at 10:42-46. According to
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`the inventors, “the present invention provides aqueous formulations of adalimumab
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`that allow stable long-term storage of adalimumab, so that [it] is stable over the
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`course of storage either in liquid or frozen states.” Id. at 10:46-50. The patent
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`defines “stability” in terms of activity of adalimumab. Id. at 9:28-33; Ex. 1002 ¶¶
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`44-51.
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`The Claims of the ’039 Patent
`The ’039 patent has 12 claims directed to “stable” adalimumab formulations.
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`Independent claim 1 embraces a broad genus of all “stable” and “aqueous”
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`pharmaceutical compositions comprising
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`(a)
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`(b)
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`(c)
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`(d)
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`adalimumab;
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`a buffer;
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`polysorbate 80; and
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`a sugar,
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`wherein the composition is free of i) mannitol; ii) citrate and phosphate buffers,
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`and iii) sodium chloride, and wherein the composition has a pH of about 5 to about
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`6. Ex. 1001 at 87:33-41.
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`Claims 2 and 3 depend from claim 1 and are almost as broad. Claim 2 limits
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`the compositions of claim 1 to those containing “about 40 mg of adalimumab,” are
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`“suitable for administration to a subject as a single dose,” and have an osmolality of
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`“about 180 to 420 mOsM,” but does not limit the concentration of adalimumab or
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`any other ingredient. Id. at 87:42-45. Claim 3 limits the compositions of claim 1 to
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`those “wherein the pH is about 5.2.” Id. at 88:1-2. Claim 4 depends from claim 3
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`and combines the limitations of claims 2 and 3. Id. at 88:3-6.
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`Claim 5 is independent. It is identical to claim 1 except that it limits the
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`“sugar” to “sucrose.” Id. at 88:7-15. Claims 6 and 7 depend from claim 5, and claim
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`8 depends from claim 7. They are identical to claims 2, 3 and 4, respectively, except
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`that the “sugar” must comprise “sucrose.” Id. at 88:16-25.
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`Claim 9 is independent. It is identical to claim 5 except that it limits the
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`“buffer” to comprising “acetate buffer”. Id. at 88:26-34. Claims 10 and 11 depend
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`from claim 9, and claim 12 depends from claim 11. They are identical to claims 6,
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`7 and 8, respectively, except that the “buffer” must comprise “acetate buffer.” Id. at
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`88:35-44.
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` Relevant Prosecution History
`During prosecution, the Examiner rejected claims 1-12 as being obvious over
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`U.S. Patent 6,090,382 (“Salfeld”) (Ex. 1003) in light of U.S. Patent 6,171,586
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`(“Lam”) (Ex. 1004). Ex. 1005 at 177. Salfeld taught combinations of adalimumab
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`and various pharmaceutical excipients. Lam taught formulations of anti-TNF-α
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`antibodies (a class that includes adalimumab) with a two-year shelf life, comprising
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`acetate buffer, surfactant (a class of compound that includes polysorbate 80) and
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`trehalose, and free of NaCl, mannitol and citrate and phosphate buffers in a pH of
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`about 5 to about 6. Ex. 1004 at 28: Table 2 (formula F2), reproduced below.
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`The Examiner reasoned that a POSA would have been motivated to use the
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`anti-TNF-α antibody formulation in Lam, which describes an embodiment
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`encompassed by the ’039 patent claims other than it does not describe adalimumab
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`and it does not specify polylsorbate 80—adalimumab was disclosed in Salfeld—
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`because “the addition of acetate, sucrose and polysorbate in the antibody formulation
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`is known to improve stability and reduce aggregates.” Ex. 1005 at 178. The
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`Examiner further reasoned that because of this motivation, “there would have been
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`a reasonable expectation of success in producing the claimed invention.” Id.
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`The applicant countered that a POSA “would not have reasonably expected”
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`from the disclosures in Salfeld and Lam that a formulation containing adalimumab,
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`a buffer, polysorbate 80 and a sugar, such as sucrose, that is also free of mannitol,
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`citrate and phosphate buffers and NaCl, and has a pH of about 5 to about 6, “would
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`be stable.” Ex. 1005 at 192 (emphasis in original). The applicant asserted that,
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`contrary to the Examiner’s view, “the formulation of proteins was known to be
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`unpredictable.” Id. (emphasis added). In support, the applicant cited the following
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`passage in United States Patent No. 8,420,081 (“Fraunhofer”) (Ex. 1006) explaining
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`that testing is required before one can know whether a particular formulation is
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`stable:
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`Since the stabilizing effects of additives are protein- and concentration-
`dependent, each additive being considered for use in a pharmaceutical
`formulation must be carefully tested to ensure that it does not cause
`instability or have other negative effects on the chemical or physical
`make-up of the formulation. Ingredients used to stabilize the protein
`may cause problems with protein stability over time or with protein
`stability in changing environments during storage.
`Ex. 1005 at 192 (emphasis in original) (citing Fraunhofer at 2:7-15). The applicant
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`also later asserted that due to the unpredictability in formulating proteins, “extensive
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`experimentation was known to be required for formulating a stable protein
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`composition.” Id. at 216 (emphasis in original). The applicant emphasized that Lam
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`did not contain any stability test data for formulations containing adalimumab, and
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`that while Salfeld describes formulations of adalimumab, it “does not provide any
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`data regarding the stability of any particular formulation of adalimumab (much less
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`the specific aqueous formulations of adalimumab that are presently claimed).” Id.
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`at 217.
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`The applicant also distinguished Salfeld and Lam (alone or in combination)
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`from the claimed formulations on the ground that neither Salfeld nor Lam disclosed
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`“with any specificity the presently claimed compositions.” Id. at 193. The applicant
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`argued that Salfeld does not “provide any specific examples of an adalimumab
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`formulation, and instead provides a general description of pharmaceutical
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`formulations.” Id. Likewise, Lam does not “teach or suggest with any specificity
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`an aqueous formulation that includes adalimumab, a buffer, polysorbate 80, and a
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`sugar (such as sucrose), where the composition is free of i) mannitol, ii) citrate and
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`phosphate buffers, and iii) sodium chloride, and the composition has a pH of about
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`5 to about 6.” Id. at 194 (emphasis added).
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`In the summary of the interview conducted on August 15, 2018, the applicant
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`asserted that the Examiners “agreed that [the art already of record] and the lack of
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`data for aqueous adalimumab pharmaceutical compositions in Salfeld and Lam
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`indicate that one skilled in the art would not have reasonably expected that the
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`presently claimed compositions would be stable.” Id. at 210.
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`The Examiner allowed claims 1-12, noting that “the most pertinent prior art
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`neither teaches nor suggests any stable antibody formulations without mannitol,
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`citrate/phosphate combination and NaCl.” Id. at 224 (emphasis added).
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` Construction of Claim Terms