Trials@uspto.gov
`571-272-7822
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`Paper No. 16
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`Entered: December 1, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`CELLTRION, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01373
`Patent 6,407,213 B1
`____________
`
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
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`571-272-7822
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`Paper No. 16
`
`Entered: December 1, 2017
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`CELLTRION, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01373
`Patent 6,407,213 B1
`____________
`
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`
`
`IPR2017-01373
`Patent 6,407,213 B1
`
`
`INTRODUCTION
`Celltrion, Inc. (“Petitioner”) filed a Petition for an inter partes review
`of claims 1, 2, 4, 12, 25, 29–31, 33, 42, 60, 62–67, 69, and 71–81 of U.S.
`Patent No. 6,407,213 B1 (“the ’213 patent,” Ex. 1001). Paper 2 (“Pet.”).
`Genentech, Inc. (“Patent Owner”) timely filed a Preliminary Response.
`Paper 9 (“Prelim. Resp.”). We review the Petition, Preliminary Response,
`and accompanying evidence under 35 U.S.C. § 314.
`For the reasons provided below, we determine Petitioner has satisfied
`the threshold requirement set forth in 35 U.S.C. § 314(a). Because
`Petitioner has established a reasonable likelihood that it would prevail in
`showing the unpatentability of at least one challenged claims, we institute an
`inter partes review of the challenged claims.
`Related Proceedings
`Petitioner has concurrently filed IPR2017-01374, challenging the
`same claims of the ’213 patent based on different prior art references. Paper
`3, 4.
`
`The ’213 patent is the subject of IPR2016-01693 and IPR2016-01694,
`filed by Mylan Pharmaceuticals Inc. Paper 3, 4. Those two proceedings
`were terminated before institution due to settlement. Mylan
`Pharmaceuticals Inc. v. Genentech, Inc., IPR2016-01693 (PTAB March 10,
`2017) (Paper 24); IPR2016-01694 (PTAB March 10, 2017) (Paper 23).
`The ’213 patent is also the subject of the following pending matters:
`IPR2017-01488 and IPR2017-01489, brought by Pfizer, Inc.; IPR2017-
`02031 and IPR2017-02032 brought by Boehringer Ingelheim
`Pharmaceuticals, Inc.; and IPR2017-02139 and IPR2017-02140, brought by
`Samsung Bioepis Co., Ltd.
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`IPR2017-01373
`Patent 6,407,213 B1
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`
`The parties have identified no district court cases involving the ’213
`patent. We note, however, that the petitioner in IPR2017-01488 represents
`that the ’213 Patent is at issue in Amgen Inc. v. Genentech, Inc., No. 2-17-
`cv-07349 (C.D. Cal.); Genentech, Inc. v. Amgen Inc., No. 1-17-cv-01407 (D.
`Del.); Genentech, Inc. v. Amgen Inc., No. 1-17-cv-01471 (D. Del.).
`IPR2017-01488, Paper 16, 1. The parties are encouraged to update their
`mandatory disclosures.
`The ’213 Patent and Relevant Background
`The ’213 patent relates to “methods for the preparation and use of
`variant antibodies and finds application particularly in the fields of
`immunology and cancer diagnosis and therapy.” Ex. 1001, 1:12–14.
`A naturally occurring antibody (immunoglobulin) comprises two
`heavy chains and two light chains. Id. at 1:18–20. Each heavy chain has a
`variable domain (VH) and a number of constant domains. Id. at 1:21–23.
`Each light chain has a variable domain (VL) and a constant domain. Id. at
`1:23–24.
`The variable domains are involved directly in binding the antibody to
`the antigen. Id. at 1:36–38. Each variable domain “comprises four
`framework (FR) regions, whose sequences are somewhat conserved,
`connected by three hyper-variable or complementarity determining regions
`(CDRs).” Id. at 1:40–43. The constant domains are not involved directly in
`binding the antibody to an antigen, but are involved in various effector
`functions. Id. at 1:33–34.
`Before the ’213 patent, monoclonal antibodies targeting a specific
`antigen, obtained from animals, such as mice, had been shown to be
`antigenic in human clinical use. Id. at 1:51–53. The ’213 patent recognizes
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`Patent 6,407,213 B1
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`efforts to construct chimeric antibodies and humanized antibodies in the
`prior art. Id. at 1:59–2:52. According to the ’213 patent, chimeric
`antibodies are “antibodies in which an animal antigen-binding variable
`domain is coupled to a human constant domain” (id. at 1:60–62), whereas
`“humanized antibodies are typically human antibodies in which some CDR
`residues and possibly some FR residues are substituted by residues from
`analogous sites in rodent antibodies” (id. at 2:32–35).
`The ’213 patent also acknowledges the following as known in the
`prior art:
`In certain cases, in order to transfer high antigen binding
`1.
`affinity, it is necessary to not only substitute CDRs, but also replace one or
`several FR residues from rodent antibodies for the human CDRs in human
`frameworks. Id. at 2:53–61.
`“For a given antibody[,] a small number of FR residues are
`2.
`anticipated to be important for antigen binding” because they either directly
`contact antigen or “critically affect[] the conformation of particular CDRs
`and thus their contribution to antigen binding.” Id. at 2:62–3:8.
`In a few instances, a variable domain “may contain
`3.
`glycosylation sites, and that this glycosylation may improve or abolish
`antigen binding.” Id. at 3:9–12.
`The function of an antibody is dependent on its three-
`4.
`dimensional structure, and amino acid substitutions can change the three-
`dimensional structure of an antibody. Id. at 3:40–43.
`The antigen binding affinity of a humanized antibody can be
`5.
`increased by mutagenesis based upon molecular modelling. Id. at 3:44–46.
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`Patent 6,407,213 B1
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`
`Despite such knowledge in the field, according to the ’213 patent, at
`the time of its invention, humanizing an antibody with retention of high
`affinity for antigen and other desired biological activities was difficult to
`achieve using then available procedures. Id. at 3:50–52. The ’213 patent
`purportedly provides methods for rationalizing the selection of sites for
`substitution in preparing humanized antibodies and, thereby, increasing the
`efficiency of antibody humanization. Id. at 3:53–55.
`Illustrative Claim
`Among the challenged claims, claims 1, 30, 62–64, 66, 79, and 80 are
`independent. Claim 1 is illustrative and is reproduced below:
`1.
`A humanized antibody variable domain comprising non-
`human Complementarity Determining Region (CDR) amino acid
`residues which bind an antigen incorporated into a human
`antibody variable domain, and further comprising a Framework
`Region (FR) amino acid substitution at a site selected from the
`group consisting of: 4L, 38L, 43L, 44L, 58L, 62L, 65L, 66L,
`67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H, 36H, 39H, 43H, 45H,
`69H, 70H, 74H, and 92H, utilizing the numbering system set
`forth in Kabat.
`Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability:
`Claim(s)
`Basis
`Reference(s)
`1, 2, 12, 25, 29, 63,
`§ 103
`Queen 19891 and Protein Data Bank
`66, 67, and 71–81
`(PDB database)
`1, 2, 4, 12, 25, 29,
`Queen 19902 and PDB database
`62–67, 69, and 71–81
`
`§ 103
`
`
`1 Queen et al., A Humanized Antibody that Binds to the Interleukin 2
`Receptor, 86 PRO. NAT’L ACAD. SCI. 10029–33 (1989) (Ex. 1034).
`2 Queen et al., International Publication No. WO 90/07861 A1, published
`July 26, 1990 (Ex. 1050).
`
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`Patent 6,407,213 B1
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`Claim(s)
`65, 75–77, and 79
`
`Basis
`§ 103
`
`65, 75–77, and 79
`
`§ 103
`
`4, 62, 64, and 69
`
`§ 103
`
`30, 31, 42, and 60
`
`§ 103
`
`30, 31, 33, 42, and 60
`
`§ 103
`
`Reference(s)
`Queen 1989, PDB database, and
`Tramontano3
`Queen 1990, PDB database, and
`Tramontano
`Queen 1989, PDB database, and
`Kabat 19874
`Queen 1989, PDB database, and
`Hudziak5
`Queen 1990, PDB database, and
`Hudziak
`
`Pet. 4.
`In support of its patentability challenges, Petitioner relies on the
`Declarations of Dr. Lutz Riechmann (Ex. 1003) and Dr. Robert Charles
`Fredrick Leonard (Ex. 1004).
`Patent Owner relies on the Declarations of named inventors Dr.
`Leonard G. Presta (Ex. 2016) and Dr. Paul J. Carter (Ex. 2017), and research
`technician Mr. John Ridgway Brady (Ex. 2018)
`
`
`3 Tramontano, A. et al., Framework Residue 71 is a Major Determinant of
`the Position and Conformation of the Second Hypervariable Region in the
`VH Domains of Immunoglobulins, 215 J. MOL. BIOL. 175–82 (1990)
`(Ex. 1051).
`4 Kabat, et al., Sequences of Proteins of Immunological Interest 4th Ed.,
`Tabulation and Analysis of Amino Acid and Nucleic Acid Sequences of
`Precursors, V-Regions, C-Regions, J-Chain, T-Cell Receptor for Antigen, T-
`Cell Surface Antigens (National Institutes of Health, Bethesda, Md.) (1987)
`(Ex. 1052).
`5 Hudziak et al., p185HER2 Monoclonal Antibody Has Antiproliferative
`Effects In Vitro and Sensitizes Human Breast Tumor Cells to Tumor
`Necrosis Factor, 9 MOL. CELL BIOL. 1165–72 (1989) (Ex. 1021).
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`
`ANALYSIS
`Claim Construction
`In an inter partes review, the Board interprets a claim term in an
`unexpired patent according to its broadest reasonable construction in light of
`the specification of the patent in which it appears. 37 C.F.R. § 42.100(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016). Under
`that standard, and absent any special definitions, we assign claim terms their
`ordinary and customary meaning, as would be understood by one of ordinary
`skill in the art at the time of the invention, in the context of the entire patent
`disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.
`2007).
`Petitioner proposes the construction of several claim terms. Pet. 13–
`16. Patent Owner states that “[n]o construction of those terms is necessary,
`but Patent Owner does not dispute Celltrion’s proposed constructions for
`purposes of this proceeding.” Prelim. Resp. 18. We agree with Patent
`Owner that those terms do not need express construction. See Wellman, Inc.
`v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011) (instructing
`that claim terms need only be construed to the extent necessary to resolve
`the controversy).
`Patent Owner proposes that we construe the term “consensus human
`variable domain,” which appears in claims 4, 33, 62, and 69, to mean “a
`human variable domain which comprises the most frequently occurring
`amino acid residues at each location in all human immunoglobulins of any
`particular subclass or subunit structure.” Prelim. Resp. 17. According to
`Patent Owner, “[t]hat construction comes directly from the definition
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`provided in the ’213 patent.” Id. at 17–18 (citing Ex. 1001, 11:32–38). For
`purposes of this Decision, we adopt Patent Owner’s proposed construction.
`Prior-Art Status of Queen 1990 and Tramontano
`Petitioner asserts that Queen 1990 and Tramontano are prior art. See,
`e.g., Pet. 4. Patent Owner disagrees. Prelim. Resp. 19–42.
`In an inter partes review, the burden of persuasion is on the petitioner
`to prove unpatentability by a preponderance of the evidence, and that burden
`never shifts to the patentee. Dynamic Drinkware, LLC v. Nat’l Graphics,
`Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015). The petitioner also has the
`initial burden of production to show that an asserted reference qualifies as
`prior art under 35 U.S.C. § 102. Id. at 1378–79. Once the petitioner has met
`that initial burden, the burden of production shifts to the patent owner to
`argue or produce evidence that either the asserted reference does not render
`the challenged claims unpatentable, or the reference is not prior art. Id.
`(citing Tech. Licensing Corp. v. Videotek, Inc., 545 F.3d 1316, 1327 (Fed.
`Cir. 2008)).
`A threshold issue, then, is whether Petitioner has met its initial burden
`to show that Queen 1990 and Tramontano are prior art to the challenged
`claims. The ’213 patent issued from application number 08/146,206 (“the
`’206 application), which is an application that entered national stage on
`November 17, 1993, from a PCT application filed on June 15, 1992.
`Ex. 1001, (22), (86). The ’206 application is also a continuation-in-part of
`application No. 07/715,272 (“the ’272 application”), filed on June 14, 1991.
`Id. at (21), (63). Queen 1990 was published on July 26, 1990 (Ex. 1050,
`(43)), and Tramontano was published on September 5, 1990 (Exs. 1051,
`2027), both of which predate the earliest possible priority date shown on the
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`face of the ’213 patent. Thus, we determine that Petitioner has satisfied its
`initial burden of showing that Queen 1990 and Tramontano qualify as prior
`art to the challenged claims.
`Patent Owner attempts to disqualify Queen 1990 and Tramontano as
`prior art, arguing that the challenged claims were actually reduced to
`practice before either Tramontano or Queen 1990 was published, i.e., before
`July 26, 1990. Prelim. Resp. 19–42. As a preliminary matter, we note that
`the avenue of antedating a reference is unavailable if the reference qualifies
`as prior art under 35 U.S.C. § 102(b). See 37 C.F.R. § 1.131(a)(2). Patent
`Owner argues that Queen 1990 and Tramontano do not qualify as prior art
`under § 102(b). Prelim. Resp. 40. According to Patent Owner, even though
`the ’213 patent issued from a continuation-in-part of the ’272 application,
`the challenged claims are entitled to the priority date of June 14, 1991, the
`filing date of the ’272 application. Id. at 40–42. For purposes of this
`Decision, we assume, without deciding, that the challenged claims are
`entitled to the priority date of June 14, 1991.
`Reduction to practice is a question of law predicated on subsidiary
`factual findings. Brown v. Barbacid, 276 F.3d 1327, 1332 (Fed. Cir. 2002).
`To establish an actual reduction to practice, the inventor must prove that:
`(1) an embodiment of the invention was constructed that meets all the
`limitations of the claim-at-issue; and (2) the inventor appreciated that the
`invention would work for its intended purpose. Cooper v. Goldfarb, 154
`F.3d 1321, 1327 (Fed. Cir. 1998). A showing of prior invention requires
`corroboration. Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1577 (Fed. Cir.
`1996). Sufficiency of corroboration is determined by using a “rule of
`reason” analysis, under which all pertinent evidence is examined when
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`determining the credibility of an inventor’s testimony. Medichem, S.A. v.
`Rolabo, S.L., 437 F.3d 1157, 1170–71 (Fed. Cir. 2006). Corroboration may
`be testimony of a witness, other than the inventor, to the actual reduction to
`practice, or it may consist of evidence of surrounding facts and
`circumstances independent of information received from the inventor. Id.
`To support its argument of prior invention, Patent Owner relies on
`numerous confidential internal documents, including laboratory notebooks
`or excerpts of laboratory notebooks, and other documents relating to internal
`research. Prelim. Resp. 20–39 (citing Exs. 2001–2015); see also Paper 8
`(seeking to seal Exhibits 2001–2015). Patent Owner also relies on the
`Declarations of the inventors and another employee scientist. Prelim. Resp.
`20–39 (citing Exs. 2016–2018). These declarations, according to Patent
`Owner, “pertain[] to confidential research and development activities related
`to the invention described and claimed.” Paper 8, 3–4 (seeking to seal
`Exhibits 2016–2018).
`At this early stage of the proceeding, none of Patent Owner’s
`witnesses has been cross-examined regarding the antedating evidence. Thus,
`the better course of action is to permit the parties to fully develop the record
`during trial before determining whether Patent Owner’s evidence of prior
`invention is sufficient to disqualify Queen 1990 and Tramontano as prior art.
`Level of Ordinary Skill in the Art
`The parties propose similar definitions of a person of ordinary skill for
`the ’213 patent. See Pet. 12; Prelim. Resp. 17. For purposes of this
`Decision, we adopt Patent Owner’s proposed definition that “[a] person of
`ordinary skill for the ’213 patent would have had a Ph.D. or equivalent in
`chemistry, biochemistry, structural biology, or a closely related field, and
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`experience with antibody structural characterization, engineering, and/or
`biological testing, or an M.D. with practical academic or industrial
`experience in antibody development.” Prelim. Resp. 17.
`We further note that, in this case, the prior art itself demonstrates the
`level of skill in the art at the time of the invention. See Okajima v.
`Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (explaining that specific
`findings regarding ordinary skill level are not required “where the prior art
`itself reflects an appropriate level and a need for testimony is not shown”)
`(quoting Litton Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158,
`163 (Fed. Cir. 1985)).
`Disclosures of the Asserted Prior Art
`
`Queen 1989
`Queen 1989 teaches constructing a humanized antibody by combining
`the CDRs of a murine antibody with human framework and constant
`regions. Ex. 1034, Abstract, 3–4. According to Queen 1989, “[f]or the
`humanized antibody, sequence homology and molecular modeling were used
`to select a combination of mouse and human sequence elements that would
`reduce immunogenicity while retaining high binding affinity.” Id. at 1. In
`Queen 1989, the human framework regions were chosen to maximize
`homology with the murine antibody sequence. Id. at Abstract, 3. In
`addition, based on a computer model, Queen 1989 identified “several amino
`acids which, while outside the CDRs, are likely to interact with the CDRs or
`antigen. These mouse amino acids were also retained in the humanized
`antibody.” Id. at Abstract, 3. Further, Queen 1989 teaches substituting an
`unusual amino acid in the human framework region if the corresponding
`
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`positions in the murine antibody “actually has a residue much more typical
`of human sequences.” Id. at 4.
`Queen 1990
`Queen 1990 teaches the following four criteria for designing
`humanized antibodies that “have a very strong affinity for a desired
`antigen:”
`
`Criterion I: As acceptor, use a framework from a particular
`human immunoglobulin that is unusually homologous to the
`donor immunoglobulin to be humanized, or use a consensus
`framework from many human antibodies . . . .
`. . . .
`Criterion II: If an amino acid in the framework of the
`human acceptor immunoglobulin is unusual (i.e. “rare”, which as
`used herein indicates an amino acid occurring at that position in
`no more than about 10% of human heavy (respectively light)
`chain V region sequences in a representative data bank), and if
`the donor amino acid at that position is typical for human
`sequences (i.e. “common”, which as used herein indicates an
`amino acid occurring in at least about 25% of sequences in a
`representative data bank), then the donor amino acid rather than
`the acceptor may be selected . . . .
`Criterion III: In the positions immediately adjacent to one
`or more of the 3 CDR[]s in the primary sequence of the
`humanized immunoglobulin chain, the donor amino acid(s)
`rather than acceptor amino acid may be selected. These amino
`acids are particularly likely to interact with the amino acids in
`the CDR[]s and, if chosen from the acceptor, to distort the donor
`CDR[]s and reduce affinity. Moreover, the adjacent amino acids
`may interact directly with the antigen . . . and selecting these
`amino acids from the donor may be desirable to keep all the
`antigen contacts that provide affinity in the original antibody.
`Criterion IV: A 3-dimensional model, typically of the
`original donor antibody, shows that certain amino acids outside
`of the CDR[]s are close to the CDR[]s and have a good
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`probability of interacting with amino acids in the CDR[]s by
`hydrogen bonding, Van der Waals forces, hydrophobic
`interactions, etc. At those amino acid positions, the donor amino
`acid rather than the acceptor immunoglobulin amino acid may be
`selected. Amino acids according to this criterion will generally
`have a side chain atom within about 3 angstrom units of some
`site in the CDR[]s and must contain atoms that could interact
`with the CDR atoms according to established chemical forces,
`such as those listed above.
`Ex. 1050, 14:9–16:25. According to Queen 1990, “[w]hen combined into an
`intact antibody, the humanized light and heavy chains of the present
`invention will be substantially non-immunogenic in humans and retain
`substantially the same affinity as the donor immunoglobulin to the antigen.”
`Id. at 8:21–25.
`PDB Database
`According to Petitioner, the Protein Data Bank (PDB) database was
`established in 1971 as a computer archival service managed by the
`Brookhaven National Laboratory. Pet. 19–20; Ex. 1003 ¶ 129 (citing
`Ex. 1080). “The purpose of the Bank is to collect, standardize, and
`distribute atomic co-ordinates and other data from crystallographic studies.”
`Ex. 1080, 1. Dr. Riechmann testifies that the PDB database “is a repository
`of protein crystal atomic co-ordinates available to the public.” Ex. 1003
`¶ 129. “The information provided in the PDB database was only a list of
`residues and their coordinates, but this was computer-readable data that
`could be directly inputted into distance calculation and graphic programs . . .
`for use in visualization and comparison studies.” Id. According to
`Dr. Riechmann, in 1991, an ordinary artisan “relied on and contributed to the
`PDB database.” Id.
`
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`Tramontano
`Tramontano teaches that “the major determinant of the position of H2
`[i.e., CDR2 of the heavy chain] is the size of the residue at site 71, a site that
`is in the conserved framework of the VH domain.” Ex. 1051, Abstract.
`According to Tramontano, “[u]nderstanding the relationship between the
`residue at position 71 and the position and conformation of H2 has
`applications to the prediction and engineering of antigen-binding sites of
`immunoglobulins.” Id.
`Kabat 1987
`Kabat 1987 is a compilation of known antibody sequences. Ex. 1052.
`For a given type of immunoglobulin, Kabat 1987 identifies the most
`common amino acids occurring at each position. See, e.g., id. at 8. It also
`teaches the FR and CDR boundaries within the variable domains. See, e.g.,
`id. at 6–11.
`Hudziak
`Hudziak teaches p185HER2’s role in carcinoma development.
`Ex. 1021, Abstract. Hudziak shows that 4D5, “a monoclonal antibody
`directed against the extracellular domain of p185HER2 specifically inhibits the
`growth of breast tumor-derived cell lines overexpressing the HER2/c-erbB-2
`gene product.” Id. In addition, Hudziak reports that “resistance to the
`cytotoxic effect of tumor necrosis factor alpha, which has been shown to be
`a consequence of HER2/c-erbB-2 overexpression, is significantly reduced in
`the presence of this antibody.” Id. Hudziak states that “[m]onoclonal
`antibodies specific for p185HER2 may therefore be useful therapeutic agents
`for the treatment of human neoplasias.” Id. at 7.
`
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`Obviousness over Queen 1989 and PDB Database
`Petitioner argues that claims 1, 2, 12, 25, 29, 63, 66, 67, and 71–81
`would have been obvious over the combination of Queen 1989 and PDB
`database. Pet. 26–49. Based on the current record, we determine Petitioner
`has established a reasonable likelihood that it would prevail in this assertion
`with respect to at least claim 1.
`Relying on the Declaration of Dr. Riechmann, Petitioner asserts that
`Queen 1989 taught that framework residues that (1) are close
`enough to influence CDR conformation; (2) interact directly with
`the antigen; and/or (3) are more ‘human’ in the mouse or donor
`immunoglobulin than the residue at the same position in human
`antibody variable domain (i.e., conserved) are candidates for
`substitution with the donor antibody residue in the humanization
`process.
`Pet. 27 (citing Ex. 1034, 3–4; Ex. 1003 ¶ 247). According to Petitioner, an
`ordinary artisan “would have used those simple rules to determine which
`residues in a human FR region could be switched back to mouse.” Id.
`(citing Ex. 1003 ¶¶ 247–250).
`“[F]ollowing the teachings of Queen 1989” and using antibodies well-
`known prior to the ’213 patent, Petitioner continues, Dr. Riechmann was
`able to identify CDR-contacting framework residues that were targets for
`substitution. Pet. 30 (citing Ex. 1003 ¶¶ 254–258). These include residues
`4L, 58L, 62L, 66L, 67L, 69L,6 73L, 85L, and 105L in the light chain, and
`residues 2H, 24H, 39H, 45H, 69H, 71H, 73H, 76H, 78H, 93H, and 103H in
`
`
`6 Even though the Petition states that Dr. Riechmann found “8 light (L)
`chain” residues and does not lists 69L (Pet. 30), Dr. Riechmann actually
`testifies he found nine residues, including 69L, in the light chain (Ex. 1003
`¶ 255).
`
`15
`
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`IPR2017-01373
`Patent 6,407,213 B1
`
`the heavy chain. Id. As Petitioner points out, residues 4L, 58L, 66L, 67L,
`69L, 73L, 2H, 45H, and 69H are recited in claim 1. Id.
`Patent Owner argues that Queen 1989 contradicts Petitioner’s
`obviousness theory. Prelim. Resp. 44–45. According to Patent Owner,
`Queen 1989 teaches nine substitutions, none of which corresponds to those
`recited in the challenged claims. Id. at 44 (citing Ex. 1034, 3). We are not
`persuaded by Patent Owner’s argument.
`First, Queen 1989 teaches more than the nine substitutions referred to
`by Patent Owner. For example, Queen 1989 teaches substituting 93H,
`which is a residue recited in claim 66. Ex. 1034, 4. Second, a person of
`ordinary skill would have read a reference for all that it teaches, including
`uses beyond its primary purpose. KSR Int’l Co. v. Teleflex, Inc., 550 U.S.
`398, 418–21 (2007); see also Beckman Instruments, Inc. v. LKB Produkter
`AB, 892 F.2d 1547, 1551 (Fed. Cir. 1989) (stating that a prior art reference is
`relevant “for all that it teaches” to those of ordinary skill in the art). Here,
`Queen 1989 teaches a general method to humanize antibodies. We agree
`with Petitioner that applying the criteria taught in Queen 1989 to antibodies
`known before the ’213 patent, one of ordinary skill in the art would have
`identified nine positions in the light chain and eleven in the heavy chain as
`candidates for substitution, including those recited in the challenged claims.
`Patent Owner next contends that 20 is a “large number” of possible
`framework substitutions. Prelim. Resp. 46. According to Patent Owner,
`because only “[l]ess than half” of them are claimed, Petitioner has not
`explained why an ordinary artisan “would have been drawn to the specific
`substitutions recited in the challenged claims.” Id. We are not persuaded by
`this argument, either.
`
`
`
`16
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`IPR2017-01373
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`
`
`As the Supreme Court instructed,
`When there is a design need or market pressure to solve a
`problem and there are a finite number of identified, predictable
`solutions, a person of ordinary skill has good reason to pursue
`the known options within his or her technical grasp. If this leads
`to the anticipated success, it is likely the product not of
`innovation but of ordinary skill and common sense.
`KSR, 550 U.S. at 421. Here, Queen 1989 recognize the need to substitute
`framework residues in order to “reduce immunogenicity while retaining high
`binding affinity.” See Ex. 1034, 1. Based on that design need, the finite
`number of potential substitutions, and the methodology taught in Queen
`1989, we are persuaded by Petitioner that an ordinary artisan would have
`had a reason to combine the teachings of Queen 1989 and PDB database,
`and that the combination teaches or suggests all limitations in claim 1.
`We acknowledge the evidence of secondary considerations and Patent
`Owner’s argument that such evidence establishes the non-obviousness of the
`challenged claims. Prelim. Resp. 63–65. Indeed, evidence of secondary
`considerations, when present, “must always . . . be considered en route to a
`determination of obviousness.” Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d
`1530, 1538–39 (Fed. Cir. 1983). Here, the secondary-considerations
`evidence Patent Owner relies on is first presented together with the
`Preliminary Response (see Prelim. Resp. 63–65 (citing Exs. 2025, 2029)),
`and Petitioner has not yet had an opportunity to respond to the evidence and
`arguments. Thus, in this case, a better course of action is to permit the
`parties to fully develop the record during trial before further weighing the
`alleged evidence of secondary considerations.
`
`
`
`17
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`Patent 6,407,213 B1
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`
`In sum, based on the current record, we are satisfied that Petitioner
`has shown a reasonable likelihood to prevail in its assertion that claim 1
`would have been obvious over the combination of Queen 1989 and PDB
`database. We, thus, institute an inter partes review of the claims challenged
`under this ground.
`Obviousness over Queen 1990 and PDB Database
`Petitioner argues that claims 1, 2, 4, 12, 25, 29, 62–67, 69, and 71–81
`would have been obvious over the combination of Queen 1990 and PDB
`database. Pet. 32–49. Based on the current record, we determine Petitioner
`has established a reasonable likelihood that it would prevail in this assertion
`with respect to at least claim 1.
`Petitioner asserts that Queen 1990 teaches substituting “framework
`region positions that are adjacent to or can contact the CDRs” and
`“maintaining conserved residues in the human acceptor framework” in order
`to decrease immunogenicity. Pet. 33 (citing Ex. 1003 ¶¶ 123, 259–260;
`Ex. 1050, 15:22–37, 16:1–36). Petitioner contends “Queen 1990 thus
`provided a detailed rationale for substituting particular amino acids, and how
`to do it in a detailed and objective way.” Id. Petitioner further points out
`that Queen 1990 “explicitly instructed” an ordinary artisan to look to the
`PDR Database to identify candidate framework residues for substitution. Id.
`(citing Ex. 1050, 14:21–25, 15:22–37, 16:1–12). According to Petitioner,
`following this roadmap, an ordinary artisan would have determined 19 light
`chain residues and 23 heavy chain residues as candidates. Id. at 33–34.
`Among those, 4L, 58L, 66L, 67L, 69L, 73L, 98L, 2H, 36H, 45H, and 69H
`are recited in claim 1. Id. at 34 (citing Ex. 1003 ¶¶ 164–165, 259–260).
`
`
`
`18
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`
`Patent Owner’s arguments in rebuttal are similar to those advanced in
`countering the obviousness ground based on Queen 1989. Prelim. Resp. 48–
`50. As explained above, we are not persuaded by those arguments. See
`supra at 15–18. After reviewing the record, we are satisfied that Petitioner
`has met its burden at this stage with regard to at least claim 1.
`In sum, based on the current record, we are satisfied that Petitioner
`has shown a reasonable likelihood to prevail in its assertion that claim 1
`would have been obvious over the combination of Queen 1990 and PDB
`database. We, thus, institute an inter partes review of the claims challenged
`under this ground.
`Obviousness over Queen 1989 or Queen 1990, PDB Database, and
`Tramontano
`Petitioner argues that claims 65, 75–77, and 79 would have been
`obvious over the combination of Queen 1989 or Queen 1990, PDB database,
`and Tramontano. Pet. 49–51. Claim 75 specifies substitution at site 71H.
`According to Petitioner, Tramontano independently confirms the criticality
`of residue 71H “to maintain the H2 loop and antigen binding.” Id. at 50
`(citing Ex. 1051, Abstract). Based on the current record, we determine
`Petitioner has established a reasonable likelihood that it would prevail in this
`obviousness assertion with respect to at least claim 75. We, thus, institute an
`inter partes review of the claims challenged under this ground.
`Obviousness over Queen 1989, PDB Database, and Kabat 1987
`Each of claims 4, 62, 64, and 69 requires “a consensus human variable
`domain.” Petitioner argues that these claims would have been obvious over
`the combination of Queen 1989, PDB Database, and Kabat 1987. Pet. 51–
`52. Specifically, Petitioner asserts:
`
`
`
`19
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`
`[R]ecognizing the importance of maintaining FR conserv
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