`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`SWISS PHARMA INTERNATIONAL AG,
`Petitioner
`
`v.
`
`BIOGEN IDEC,
`Patent Owner
`
`Case IPR2016-00916
`Patent 8,900,577
`
`PATENT OWNER PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Mylan v. Genentech
`IPR2016-00710
`Merck Ex. 1123, Pg. 1
`
`

`

`LIST OF EXHIBITS
`
`EXHIBIT
`
`DESCRIPTION
`
`Ex. 2001
`
`Ex. 2002
`
`Ex. 2003
`
`Ex. 2004
`
`Ex. 2005
`
`Ex. 2006
`
`Ex. 2007
`
`Ex. 2008
`
`Ex. 2009
`
`Ex. 2010
`
`Ex. 2011
`
`Ex. 2012
`
`Ex. 2013
`
`Ex. 2014
`
`Ex. 2015
`
`Ex. 2016
`
`Ex. 2017
`
`CURRENT TRENDS IN MONOCLONAL ANTIBODY DEVELOPMENT AND
`MANUFACTURING (Steven J. Shire, et al., eds., 2010)
`Theodore W. Randolph & John F. Carpenter, Engineering
`Challenges of Protein Formulations, 53 AIChe J. 1902-07 (2007)
`RATIONAL DESIGN OF STABLE PROTEIN FORMULATIONS: THEORY
`AND PRACTICE (John F. Carpenter & Mark C. Manning, eds., 2002)
`Elizabeth R. Proos, et al., Long-term Stability and in vitro Release
`of hPTH(1−34) from a Multi-reservoir Array, 25(6) Pharm. Res.
`1387-95 (2008)
`HERCEPTIN® FDA Approved Drug Label, dated September 25,
`1998
`SYNAGIS®, in PHYSICIANS’ DESK REFERENCE 2028-29 (2002)
`XOLAIR® FDA Approved Drug Label, dated June 20, 2003
`RAPTIVA® FDA Approved Drug Label, dated October 24, 2003
`REMICADE® FDA Approved Drug Label, dated October 2, 2015
`ENTYVIO® FDA Approved Drug Label, dated May 20, 2014
`David Ouellette, et al., Comparison of the in vitro and in vivo
`stability of a succinimide intermediate observed on a therapeutic
`IgG1 molecule, 5(3) mAbs 432-44 (2013)
`LH Stockwin & S Holmes, Antibodies as therapeutic agents: vive
`la renaissance!, 3(7) Expert Opin. Biol. Ther. 1133-52 (2003)
`Robert G. Hamilton, THE HUMAN IGG SUBCLASSES (2001)
`
`The Generation of Antibody Diversity, in MOLECULAR BIOLOGY OF
`THE CELL 1385-92 (Bruce Alberts, et al., eds., 4th ed. 2002)
`PROTEIN FORMULATION AND DELIVERY (Eugene J. McNally, ed.,
`2000)
`Wei Wang, Instability, stabilization, and formulation of liquid
`protein pharmaceuticals, 185 Int. J. Pharm. 129-88 (1999)
`Samir Mitagotri, et al., Overcoming the challenges in administering
`biopharmaceuticals: formulation and delivery strategies, 13 Nat.
`
`Merck Ex. 1123, Pg. 2
`
`

`

`EXHIBIT
`
`Ex. 2018
`
`Ex. 2019
`
`Ex. 2020
`
`Ex. 2021
`
`Ex. 2022
`
`Ex. 2023
`
`Ex. 2024
`
`Ex. 2025
`
`Ex. 2026
`
`DESCRIPTION
`
`Rev. Drug Discov. 655-72 (2014)
`Jeffrey L. Cleland, et al., The Development of Stable Protein
`Formulations: A Close Look at Protein Aggregation, Deamidation,
`and Oxidation, in CRITICAL REVIEWS IN THERAPEUTIC DRUG
`CARRIER SYSTEMS 307-77 (Stephen D. Bruck, ed., 1993)
`Romain Rouet, et al., Stability engineering of the human antibody
`repertoire, 588 FEBS Lett. 269-77 (2013)
`PHARMACEUTICAL FORMULATION DEVELOPMENT OF PEPTIDES AND
`PROTEINS (Sven Frokjaer & Lars Hovgaard, eds., e-Library ed.
`2003)
`Shihong Li, Christian Schöneich, et al., Chemical Instability of
`Proteins, 2(5) Pharm. News 12-16 (1995)
`Olivier Mozziconacci, Christian Schöneich, et al., Comparative
`Evaluation of the Chemical Stability of 4 Well-Defined
`Immunoglobulin G1-Fc Glycoforms, 105 J. Pharm. Sci. 575-87
`(2016)
`United States Top 25 Neurological Therapies, 49(11) Medical
`Marketing & Media 38 (2014)
`Tecfidera Will Be Leading MS Drug In 2015, BMI Research, May
`6, 2015
`Ingrid Loma & Rock Heyman, Multiple Sclerosis: Pathogenesis
`and Treatment, 9 Curr. Neuropharmacol. 409-16 (2011)
`Prosecution History of U.S. Patent No. 8,349,321
`
`Ex. 2027
`
`REMICADE® approval letter from the FDA, dated August 24, 1998
`
`Ex. 2028
`
`Ex. 2029
`
`Ex. 2030
`
`Ex. 2031
`
`Ex. 2032
`
`Sumit Goswami et al., Developments and Challenges for mAb-
`Based Therapeutics, 2 Antibodies 452-500 (2013)
`SIMULECT®, in PHYSICIANS’ DESK REFERENCE 2399-401 (2002)
`
`Reed J. Harris, et al., Commercial Manufacturing Scale
`Formulation and Analytical Characterization of Therapeutic
`Recombinant Antibodies, 61 Drug Dev. Res. 137-54 (2004)
`RITUXAN® FDA Approved Drug Label, dated November 26, 1997
`
`WJ Pan, et al., Pharmacology of AMG 181, a human anti- α4β7
`antibody that specifically alters trafficking of gut-homing T cells,
`
`Merck Ex. 1123, Pg. 3
`
`

`

`EXHIBIT
`
`Ex. 2033
`
`Ex. 2034
`
`Ex. 2035
`
`Ex. 2036
`
`Ex. 2037
`
`Ex. 2038
`
`Ex. 2039
`
`Ex. 2040
`
`Ex. 2041
`
`Ex. 2042
`
`Ex. 2043
`
`Ex. 2044
`
`DESCRIPTION
`
`169 Br. J. Pharmacol. 51-68 (2013)
`Sampathkumar Krishnan, et al., Development of Formulations for
`Therapeutic Monoclonal Antibodies and Fc Fusion Proteins, in
`FORMULATION AND PROCESS DEVELOPMENT STRATEGIES FOR
`MANUFACTURING PHARMACEUTICALS 383-427 (Feroz Jameel &
`Susan Hershenson, eds., 2010)
`Marco van de Weert & Theodore W. Randolph, Physical Instability
`of Peptides and Proteins, in PHARMACEUTICAL FORMULATION
`DEVELOPMENT OF PEPTIDES AND PROTEINS 107-29 (Lars Hovgaard,
`et al., eds., 2013)
`Jasmin F. Sydow, et al., Structure-Based Prediction of Asparagine
`and Aspartate Degradation Sites in Antibody Variable Regions,
`9(6) PLoS ONE e100736 (2014)
`Josef Vlasak, et al., Identification and characterization of
`asparagine deamidation in the light chain CDR1 of a humanized
`IgG1 antibody, 392 Anal. Biochem. 14554 (2009)
`Genentech: Survivor Strutting Its Stuff, The New York Times, Oct.
`1, 2000
`Jerry Cacia, et al., Isomerization of an Aspartic Acid Residue in the
`Complementarity-Determining Regions of a Recombinant Antibody
`to Human IgE: Identification and Effect on Binding Affinity, 35
`Biochem. 1897-903 (1996)
`Stuart Rudikoff, et al., Single amino acid substitution altering
`antigen-binding specificity, 79 Proc. Natl. Acad. Sci. USA 1979-83
`(1982)
`E. Morrey Atkinson & Wolfgang Klum, Formulation Strategies for
`Biopharmaceuticals Ensuring Success to Market, 4 IDrugs 557-60
`(2001)
`Genentech, Xoma seeking FDA approval for psoriasis drug, RBC
`News, Dec. 24, 2002
`CD18 trials disappoint again, 18 Nature Biotechnology 817−20
`(2000)
`EP Patent Application No. 04709508.8, Grounds in Support of
`Appeal, Nov. 4, 2010
`Wim Jiskoot, et al., Protein Instability and Immunogenicity:
`Roadblocks to Clinical Application of Injectable Protein Delivery
`Systems for Sustained Release, 101 J. Pharm. Sci. 946-54 (2012)
`
`Merck Ex. 1123, Pg. 4
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`INTRODUCTION .......................................................................................... 1
`
`CLAIM CONSTRUCTION UNDER “BROADEST REASONABLE
`INTERPRETATION” .................................................................................... 5
`
`PETITIONER FAILS TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT ANY CLAIM OF THE ’577 PATENT IS
`UNPATENTABLE. ........................................................................................ 6
`
`A.
`
`The prior art taught that antibody formulations were
`unpredictable, highly specific, and challenging to develop. ................ 6
`
`1.
`
`2.
`
`3.
`
`The art taught that liquid antibody formulations were
`difficult and that lyophilized formulations were preferred. ....... 7
`
`Antibodies are incredibly diverse, and small differences
`among antibodies result in profound functional changes. ....... 10
`
`Formulation of proteins, particularly antibodies,
`including IgGs, was (and remains) complicated and
`unpredictable. ........................................................................... 14
`
`a)
`
`b)
`
`c)
`
`d)
`
`e)
`
`There was no direction as to which combination of
`formulation components would be successful for a
`specific antibody. ........................................................... 15
`
`It is critical to understand antibody properties and
`degradation pathways for successful development
`of a stable formulation. .................................................. 16
`
`A stable formulation of one antibody would not
`have been expected to work for a different
`antibody. ........................................................................ 17
`
`Developing stable, high-concentration liquid
`antibody formulations was particularly difficult to
`achieve. .......................................................................... 20
`
`Reference pages omitted by Petitioner and Dr.
`Schöneich show that antibody formulation
`components were not routine. ........................................ 22
`
`Merck Ex. 1123, Pg. 5
`
`

`

`f)
`
`Dr. Schöneich’s own work confirms that the
`unique structures of antibodies render their
`successful formulation unpredictable. ........................... 23
`
`B.
`
`The inventions claimed by the ’577 patent are not merely a
`compilation of “result-effective variables” subject to routine
`optimization. ....................................................................................... 25
`
`1.
`
`2.
`
`3.
`
`Petitioner fails to show that protein concentration of
`liquid antibody formulations is a result-effective variable. ..... 26
`
`Petitioner fails to show that buffer, salt, and polysorbate
`80 concentrations are result-effective variables. ..................... 27
`
`Petitioner’s arguments further fail because the result-
`effective variable doctrine does not apply in these
`circumstances. .......................................................................... 28
`
`IV. PETITIONER FAILS TO SHOW THE CHALLENGED CLAIMS
`ARE UNPATENTABLE OVER VAN OOSTEN OR ZENAPAX IN
`VIEW OF SORBERA. ................................................................................. 30
`
`A.
`
`van Oosten, Zenapax, and Sorbera fail to disclose a stable,
`high-concentration liquid formulation of any antibody. .................... 32
`
`B.
`
`Petitioner relies on impermissible hindsight. ..................................... 35
`
`1.
`
`2.
`
`Petitioner fails to show why a POSA would have had
`reason to select the formulation of van Oosten or
`Zenapax over other possible formulations and
`combinations of components (Ground 1). ............................... 35
`
`Petitioner fails to show why a POSA would have had
`reason to select the antibody and excipient concentrations
`claimed in the ’577 patent based on Sorbera, van Oosten,
`and Zenapax. ............................................................................ 39
`
`C.
`
`The documents cited by Petitioner for Ground 1 fail to establish
`a reasonable expectation of success of achieving the claimed
`invention. ............................................................................................ 41
`
`Merck Ex. 1123, Pg. 6
`
`

`

`1.
`
`2.
`
`Petitioner fails to establish a reasonable expectation of
`success of achieving a stable, high-concentration liquid
`formulation of natalizumab. ..................................................... 42
`
`Petitioner fails to establish a reasonable expectation of
`success that natalizumab can be “simp[ly] substitute[d]”
`for the antibodies disclosed by van Oosten or Zenapax. ......... 47
`
`V.
`
`PETITIONER FAILS TO SHOW THE CHALLENGED CLAIMS
`ARE UNPATENTABLE OVER GORDON IN VIEW OF
`ORTHOCLONE OR AVERSANO. ............................................................. 49
`
`A. Gordon, Orthoclone, and Aversano fail to disclose a stable,
`high-concentration liquid formulation of any antibody. .................... 52
`
`B.
`
`Petitioner relies on impermissible hindsight. ..................................... 53
`
`1.
`
`2.
`
`Petitioner fails to show why a POSA would have had
`reason to select the formulation of Orthoclone or
`Aversano over other possible formulations and
`combinations of components (Ground 2). ............................... 54
`
`Petitioner fails to show why a POSA would have had
`reason to select the antibody and excipient concentrations
`claimed in the ’577 patent based on Gordon, Orthoclone,
`and Aversano. ........................................................................... 57
`
`C.
`
`The documents cited by Petitioner for Ground 2 fail to establish
`a reasonable expectation of success of achieving the claimed
`invention. ............................................................................................ 58
`
`1.
`
`2.
`
`Petitioner fails to establish a reasonable expectation of
`success of achieving a stable, high-concentration liquid
`formulation of natalizumab. ..................................................... 58
`
`Petitioner fails to establish a reasonable expectation of
`success that natalizumab can be “simply substituted” for
`the antibodies disclosed in Orthoclone or Aversano. .............. 59
`
`VI. THE PETITION FURTHER LACKS ARTICULATED
`REASONING SUPPORTED BY EVIDENCE FOR ADDITIONAL
`CLAIM ELEMENTS.................................................................................... 62
`
`Merck Ex. 1123, Pg. 7
`
`

`

`VII. CONCLUSION ............................................................................................. 62
`
`VII. CONCLUSION ........................................................................................... .. 62
`
`
`
`Merck Ex. 1123, Pg. 8
`
`Merck Ex. 1123, Pg. 8
`
`

`

`TABLE OF AUTHORITIES
`
`CASES
`
`Page(s)
`
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955) ...................................................................... 26, 28
`
`In re Antonie,
`559 F.2d 618 (C.C.P.A. 1977) ............................................................................ 26
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) .................................................................... 26, 27
`
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015), aff’d, 2016 WL 33699425 (U.S.
`June 20, 2016) ....................................................................................................... 5
`
`In re Cyclobenzaprine,
`676 F.3d 1063 (Fed. Cir. 2012) .............................................................. 46, 47, 59
`
`In re Haase,
`542 Fed. App’x 962 (Fed. Cir. 2013) ................................................................. 26
`
`In re ICON Health and Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007) ............................................................................ 5
`
`In re Patel,
`566 Fed. App’x 1005 (Fed. Cir. 2014) ......................................................... 28, 29
`
`Procter & Gamble v. Teva Pharm.,
`566 F.3d 989 (Fed. Cir. 2009) ............................................................................ 41
`
`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007) ............................................................................ 5
`
`OTHER AUTHORITIES
`37 C.F.R. § 42.65(a) ..........................................................................................passim
`
`37 C.F.R. § 42.100(b) ................................................................................................ 5
`
`37 C.F.R. § 42.104(b) ........................................................................................ 32, 51
`
`Merck Ex. 1123, Pg. 9
`
`

`

`37 C.F.R. § 42.104(b)(2) .............................................................................. 43, 55, 59
`37 CPR. § 42.104(b)(2) ............................................................................ ..43, 55, 59
`
`
`
`Merck Ex. 1123, Pg. 10
`
`Merck Ex. 1123, Pg. 10
`
`

`

`I.
`
`INTRODUCTION
`
`Petitioner’s allegations that the ’577 patent merely claims “an old
`
`therapeutically active agent paired with a standard well-known formulation” and
`
`that all IgG antibodies can be “simply substituted” for one another is flatly
`
`contradicted by the prior art. As discussed in detail below, the art taught that
`
`formulation of proteins, including IgG antibodies, was highly complex because
`
`various degradation pathways, including deamidation, oxidation, aggregation, and
`
`denaturation, can result in loss of therapeutic effectiveness. Moreover, the art
`
`showed that IgG antibodies are an incredibly broad class of compounds that do not
`
`lend themselves to a generic approach to formulation. Most importantly, Petitioner
`
`completely ignores that developing a stable, high-concentration liquid antibody
`
`formulation, like the one claimed by the ’577 patent, was a particularly difficult
`
`challenge.
`
`Despite the complexities and unpredictability of antibody formulation
`
`development, Biogen was the first to invent and commercialize a stable, high-
`
`concentration liquid antibody formulation for use in treating multiple sclerosis
`
`(“MS”). The unique formulation contains natalizumab, a humanized monoclonal
`
`IgG4 antibody, and is claimed by the ’577 patent. It is commercialized as
`
`TYSABRI®, one of the top-selling neurology drugs in the United States to treat
`
`MS. See Ex. 2023 at 39; Ex. 2024. In MS, the patient’s own immune system
`
`Merck Ex. 1123, Pg. 11
`
`

`

`attacks the central nervous system, causing a chronic condition with progressively
`
`devastating symptoms throughout a patient’s lifetime. See Ex. 2025 at 409.
`
`Before TYSABRI® launched in 2004, there were no antibody therapeutics
`
`available to treat MS, despite the long-felt need and recognition that antibody
`
`therapeutics would be of tremendous value for MS treatment due to their
`
`selectivity and potency compared to small molecule drugs. See Exhibit 2012 at
`
`1134, 1136–37 (Table 1); Ex. 2001 at 103; Ex. 2017 at 655. The inventors of the
`
`’577 patent overcame substantial development obstacles to achieve a highly
`
`concentrated liquid antibody formulation, including facing complex degradation
`
`reactions in initial natalizumab formulations containing histidine as a buffer. See
`
`’577 patent at 11:15–25.1 TYSABRI® is the first antibody formulation successfully
`
`1 Petitioner argues that, during prosecution, applicant relied on pre-formulation
`
`study results to support unexpected results of the claimed formulation, and then
`
`“publicly admitted” during EP prosecution that the study results were inaccurate
`
`and not reproducible. Pet. at 2, 9–10, 57–58. But Petitioner mischaracterizes both
`
`the US and EP prosecution records where the pre-formulation study was cited to
`
`illustrate the level of experimentation required, and whether the study data could
`
`be reproduced or were described as “not accurate” is irrelevant. See Ex. 2026 at
`
`145−52 ; Ex. 2043 at 10–12.
`
`Merck Ex. 1123, Pg. 12
`
`

`

`developed and approved to treat patients suffering from multiple sclerosis. See Ex.
`
`2025 at 411 (Table 3). As recognized by experts at the Department of Neurology at
`
`the University of Pittsburgh Medical Center, TYSABRI® “has robust benefits on
`
`relapse rate, disability progression, and MRI activity.” Ex. 2025 at 412–13.
`
`Petitioner identifies no specific evidence from the prior art showing there
`
`would have been a reasonable expectation of success in formulating the claims that
`
`cover the TYSABRI® product—i.e., a stable, high-concentration liquid formulation
`
`of natalizumab. Petitoner fails to identify any high-concentration natalizumab
`
`formulation. Further, neither Petitioner’s cited “Prior Art IgG mAb Formulations”
`
`(Orthoclone, Aversano, van Oosten, and Zenapax) nor the contemporaneous
`
`literature cited by both parties (e.g. Wang (Ex. 2016), McNally (Ex. 2015), and
`
`Frokjaer (Ex. 2020)) would have provided a reasonable expectation of success in
`
`achieving the claimed high-concentration formulation. The cited mAb formulations
`
`do not contain natalizumab and are not high-concentration, and the literature at the
`
`time taught that formulating antibodies at high-concentration in solution was
`
`unpredictable.
`
`Merck Ex. 1123, Pg. 13
`
`

`

`Petitioner instead resorts to hindsight, cherry-picking prior art without
`
`providing any reason why a person of ordinary skill in the art (“POSA”)2 would
`
`have selected and combined those references as opposed to any of the numerous
`
`other prior art describing antibody products that did not contain components of the
`
`claimed invention. Petitioner then proceeds to make broad conclusions that each
`
`claim element is obvious because the identity, amount, or concentration of a
`
`particular component could have been achieved by “routine optimization of a result
`
`effective variable” and/or by “simple substitution.” Petitioner, however, fails to
`
`provide any evidence as to why the particular identity, amount, or concentration of
`
`a particular component was a “result-effective variable” that could be achieved
`
`through “routine optimization” and/or by “simple substitution.”
`
`Recognizing that it has failed to meet its burden, Petitioner turns to
`
`numerous additional prior art references in an attempt to plug the holes in Grounds
`
`1 and 2—nineteen and eight references, respectively. Despite relying on
`
`twenty-two prior art references for Ground 1 and eleven prior art references for
`
`Ground 2, Petitioner still fails to demonstrate a reasonable likelihood that any
`
`2 Patent Owner submits that any disagreement it may have with Petitioner’s
`
`definition of a POSA does not change the analysis below.
`
`Merck Ex. 1123, Pg. 14
`
`

`

`claim of the ’577 patent is unpatentable. Simply put, Petitioner’s allegations lack
`
`any merit and the Board should deny institution of the Petition.
`
`II. CLAIM CONSTRUCTION UNDER “BROADEST REASONABLE
`INTERPRETATION”
`A claim subject to Inter Partes Review is given its “broadest reasonable
`
`construction in light of the specification of the patent in which it appears.” 37
`
`C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1278 (Fed.
`
`Cir. 2015), aff’d, 2016 WL 33699425 (U.S. June 20, 2016).
`
`Under this standard, claim terms are given their ordinary and customary
`
`meaning as would be understood by a POSA at the time of the invention and in the
`
`context of the entire patent disclosure. In re Translogic Tech., Inc., 504 F.3d 1249,
`
`1257 (Fed. Cir. 2007). If an inventor acts as his or her own lexicographer and
`
`provides a definition of a term, that definition will control. See In re ICON Health
`
`and Fitness, Inc., 496 F.3d 1374, 1379 (Fed. Cir. 2007).
`
`As Petitioner concedes:
`
`The ’577 patent expressly defines [stable] by stating that “[a] ‘stable’
`formulation is one in which the protein therein essentially retains its
`physical stability and/or chemical stability and/or biological activity
`upon storage. By ‘stable’ is also meant a formulation which exhibits
`little or no signs of instability, including aggregation and/or
`deamidation.” (Ex. 1001 at 5:55–60.)
`
`Merck Ex. 1123, Pg. 15
`
`

`

`Pet. at 11 (emphasis added). Petitioner does not offer any reason why the explicit
`
`definition should not control. Petitioner, instead, simply asserts that stable “merely
`
`requires that the formulation retains any one of physical, chemical, or biological
`
`stability upon storage.” Pet. at 11. Petitioner’s interpretation of “stable” is flawed
`
`because it treats the definition above as “alternate definitions” rather than a single
`
`definition. Id. However, even if the Board adopts Petitioner’s definition, Petitioner
`
`still fails to establish that there is a reasonable likelihood it would prevail with
`
`respect to any of the challenged claims, as detailed below in Sections III.–VI.
`
`III. PETITIONER FAILS TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT ANY CLAIM OF THE ’577 PATENT IS
`UNPATENTABLE.
`formulations were
`that antibody
`taught
`A. The prior art
`unpredictable, highly specific, and challenging to develop.
`
`Despite Petitioner’s allegations to the contrary, there was overwhelming
`
`scientific evidence in 2003, and still today, that achieving a stable liquid
`
`formulation of a monoclonal antibody was an unpredictable and highly
`
`antibody-specific challenge. As discussed in detail below, the art taught that liquid
`
`antibody formulations were difficult and that lyophilized formulations were
`
`preferred. The art also taught that IgG antibodies are an incredibly broad class of
`
`compounds that do not lend themselves to a generic approach to formulation such
`
`that they could be seen as “simple substitutes.” Most importantly, the art taught
`
`that stable, high-concentration (e.g., 20 mg/mL) liquid antibody formulations, like
`
`Merck Ex. 1123, Pg. 16
`
`

`

`the formulations recited in the ’577 patent, were particularly difficult to achieve.
`
`See Ex. 2004 at 1394 (reporting that therapeutic formulations having >10 mg/mL
`
`protein are considered highly concentrated); infra Sections III.A.1–4. Indeed,
`
`Petitioner all but admits this conclusion by failing to identify any stable, high-
`
`concentration
`
`antibody
`
`formulation
`
`in
`
`the
`
`prior
`
`art.
`
`
`
`Excerpt from Pet. at 16, Table 1, 1st row.
`
`1.
`
`The art taught that liquid antibody formulations were
`difficult and that lyophilized formulations were preferred.
`
`Formulating antibodies as liquids (as opposed to a lyophilized, or
`
`freeze-dried, formulation) is unpredictable and challenging because the protein
`
`must retain its physical and chemical stability in solution for months or years. See
`
`Ex. 2001 at 106–112. This unpredictability is further exacerbated with the high
`
`antibody concentrations claimed in the ’577 patent (20–150 mg/mL). Id. at 110; Ex.
`
`2002 at 1905.
`
`These challenges are highlighted in the literature both before and after 2003.
`
`“[F]or most proteins maintaining physical and chemical stabilities in aqueous
`
`Merck Ex. 1123, Pg. 17
`
`

`

`solution for an extended period of time is extremely difficult.” Ex. 2003 at 184
`
`(emphasis added). In fact, “[i]t can be assumed that most proteins will not exhibit
`
`sufficient stability in aqueous solution to allow a liquid formulation to be
`
`developed.” Id. at 188. Even in 2007, four years after the priority date, it was
`
`understood that the “[d]evelopment of these [high protein concentration]
`
`formulations poses a number of serious obstacles to commercialization.” Ex. 2002
`
`at 1905.
`
`As a result of the challenges with liquid formulations, it was well-known
`
`just prior to the filing date that the primary way to stabilize protein formulations
`
`was lyophilization into powders. Ex. 2003 at 188. This was the case despite the
`
`fact that a POSA would have otherwise preferred liquid formulations due to
`
`“simple processing, less manipulation, and easy application.” Ex. 2016 at 175; see
`
`also Ex. 2001 at 112. Even after the filing date lyophilization is the most prevalent
`
`method of stabilization. Ex. 2004 at 1394; see also Ex. 2001 at 112−114, 123. This
`
`is because “water is the common culprit” in antibody degradation events. Ex. 2001
`
`at 112. Even the 2000 Frokjaer text relied upon by Dr. Schöneich and Petitioner
`
`teaches that lyophilization was the preferred method for stabilizing proteins. Only
`
`four (4) of the twenty-two (22) commercialized protein products reported in 2000
`
`were formulated as liquids for storage. Ex. 1029 at 146. The remainder of the
`
`products at the time were lyophilized powders. Id.
`
`Merck Ex. 1123, Pg. 18
`
`

`

`In fact, Dr. Schöneich also provides direction toward the development of
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`lyophilized formulations: “In designing a protein formulation, formulators
`
`generally prefer to select excipients that have been used in marketed products….”
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`Ex. 1002 ¶ 38 (citing Ex. 1029 at 146–147) (emphases added). As Exhibit 1029
`
`reports, the vast majority of marketed protein products were lyophilized
`
`formulations. Ex. 1029 at 146. And one excipient—histidine buffer—was
`
`predominantly used in the marketed lyophilized antibody formulations. See Ex.
`
`2005 at 1; Ex. 2006 at 1; Ex. 2007 at 1; Ex. 2008 at 2; Ex. 2037; Ex. 2041.
`
`The teachings toward lyophilization by Dr. Schöneich and others run
`
`contrary to Dr. Schöneich’s hindsight-driven assertions about achieving the stable
`
`formulation of the ’577 patent claims. For example, Dr. Schöneich states—with no
`
`citation support—that “the [van Oosten] formulation would have to remain stable
`
`at least for the length of time required to be shipped.” Ex. 1002 ¶ 96. But the
`
`reality was that developing a stable liquid antibody formulation, particularly at a
`
`high concentration, was extremely challenging. See, e.g., Ex. 2001 at 110; Ex.
`
`2002 at 1905. Indeed, the liquid antibody formulation of van Oosten was
`
`abandoned and replaced with a lyophilized formulation for commercial purposes,
`
`which Dr. Schöneich fails to recognize, despite his assertion that a formulator
`
`would look to marketed products. See Ex. 2009 at 1. Confirming the prevalence of
`
`lyophilized formulations even to this day, the only other approved α4 integrin-
`
`Merck Ex. 1123, Pg. 19
`
`

`

`binding antibody, besides TYSABRI®, is ENTYVIO® (vedolizumab), a lyophilized
`
`formulation. See Ex. 2010 at 1.
`
`The marketed products in early 2003, as well as the established literature,
`
`demonstrate the strong preference for high-concentration lyophilized formulations
`
`over liquid formulations.
`
`2.
`
`Antibodies are incredibly diverse, and small differences
`among antibodies result in profound functional changes.
`
`Therapeutic antibodies encompass a platform of glycoproteins with a
`
`tremendous array of variations resulting in exquisite specificity for target antigens.
`
`See Ex. 2011 at 432; Ex. 2012 at 1133−35. Human antibodies (immunoglobulins)
`
`consist of five different classes, IgA, IgD, IgE, IgG, and IgM, each evolved for
`
`different physiological roles. Ex. 2012 at 1134.
`
`The IgG class of antibodies has been the focus for therapeutic antibody
`
`development. See id. One reason is due to the substantial versatility among IgG
`
`subclasses (IgG1-4). Id. at 1134–35; Ex. 2013 at 7−11. The amino terminal regions
`
`of the heavy and light chains contain highly variable amino acid compositions (VH
`
`and VL regions) that are involved in antigen binding. Ex. 2013 at 8. It was well-
`
`known that IgG antibodies contain major structural differences in other regions as
`
`well, which result in significant functional diversity. In different IgG subclasses,
`
`unique antigenic determinants are found in the constant fragment (Fc) region and
`
`hinge region. Id. at 8–9. Besides the protein components, another distinguishing
`
`Merck Ex. 1123, Pg. 20
`
`

`

`feature among IgG antibodies is the presence of different carbohydrates at the
`
`antibody’s glycosylated sites, which participate in cell response events and affect
`
`clinical efficacies. See Ex. 2001 at 105; Ex. 2016 at 145 (“The effect of
`
`glycosylation on stability of proteins is highly protein-dependent.”). Additionally,
`
`although overlooked by Dr. Schöneich, see infra at Section III.A.2.f, there are
`
`differences in the higher-order three-dimensional structures among IgG antibodies,
`
`resulting in significant challenges to prevent unfolding and loss of physical
`
`stability. See Ex. 2013 at 7–9; Ex. 2015 at 28; Ex. 2001 at 243–44.
`
`Dr. Schöneich contradicts this well-established art by asserting that IgG
`
`monoclonal antibodies are nothing more than “simple substitut[es].”3 See, e.g., Ex.
`
`3 Petitioner ignores the clear language of the claims and mischaracterizes the
`
`specification by asserting that “[t]he ’577 patent states that virtually all proteins are
`
`interchangeable in this [phosphate-buffer, polysorbate, and sodium chloride]
`
`formulation.” Pet at 8. The specification states “other proteins are contemplated,”
`
`yet the claims recite natalizumab, not “other proteins.” Thus, the scope of the
`
`claims does not encompass “other proteins.” And Petitioner’s unsupported leap
`
`from “other proteins” to “virtually all proteins” confirms the absurdity of its
`
`position. Id. Further, the quoted specification language is directed to “the
`
`formulations disclosed” in the patent specification, not only in the particular
`
`Merck Ex. 1123, Pg. 21
`
`

`

`1002 ¶ 14; see also id. ¶ 34 (“[A]ll IgG mAbs … share up to 95% homology….”).
`
`While IgG antibodies are greater than 95% homologous in the constant regions of
`
`the heavy chains (CH), Ex. 2013 at 8, they encompass an enormous number of
`
`antibodies. Differences in the variable regions lead to antibodies with very
`
`different functions. For example, vedolizumab (commercialized as ENTYVIO®
`
`(Ex. 2010)) and natalizumab are both humanized monoclonal antibodies that target
`
`the same antigen, namely, the α4 subunit of integrin proteins found on the surface
`
`of immunoregulatory cells. Ex. 2032 at 52. But while vedolizumab targets the
`
`α4β7 integrin subunit and is used to treat ulcerative colitis and Crohn’s disease,
`
`natalizumab targets both the α4β7 and α4β1 integrin subunits and treats multiple
`
`sclerosis, in addition to Crohn’s disease. Id.
`
`Furthermore, the human body can likely make over ten trillion different
`
`types of antibodies due to the evolution of unique genetic mechanisms. See Ex.
`
`2014. And molecular engineering made the vast spectrum of monoclonal IgG
`
`antibodies exponentially more complex and diverse. See Ex. 2001 at 105–06. Such
`
`formulation [containing phosphate-buffer, polysorbate, and sodium chloride] that
`
`Petitioner plucks from a different section of the