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` Paper No. 27
`Trials@uspto.gov
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`
`
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`571.272.7822
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`Filed: December 1, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PFIZER, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01489
`Patent 6,407,213 B1
`____________
`
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`INTRODUCTION
`I.
`Pfizer, 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. 1501). Paper 1 (“Pet.”).
`Genentech, Inc. (“Patent Owner”) timely filed a Preliminary Response.
`
`
`
`
`
`
` Paper No. 27
`Trials@uspto.gov
`
`
`
`
`571.272.7822
`
`
`
`Filed: December 1, 2017
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PFIZER, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01489
`Patent 6,407,213 B1
`____________
`
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`INTRODUCTION
`I.
`Pfizer, 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. 1501). Paper 1 (“Pet.”).
`Genentech, Inc. (“Patent Owner”) timely filed a Preliminary Response.
`
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`Paper 7 (“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 demonstrated a reasonable likelihood that at least claim 1 of
`the ’213 patent is unpatentable, we institute an inter partes review of the
`challenged claims.
`
`A. Related Proceedings
`According to Petitioner, 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.). Paper 16, 1.
`The ’213 patent was the subject of two earlier IPR proceedings filed
`by Mylan Pharmaceuticals Inc., IPR2016–01693 and IPR2016–01694,
`which we terminated on March 10, 2017, in response to the parties’ Joint
`Motion to Terminate. See IPR2016–01693, Paper 24; IPR2016–01694,
`Paper 23.
`In addition to the present case, the ’213 patent is presently the subject
`of seven pending matters: IPR2017-01488, brought by Pfizer, Inc.;
`IPR2017-01373 and IPR2017-01374, brought by Celltrion, Inc.; IPR2017-
`02031 and IPR2017-02032 brought by Boehringer Ingelheim
`Pharmaceuticals, Inc.; and IPR2017-02139 and IPR2017-02140, brought by
`Samsung Bioepis Co., Ltd. Paper 4, 4; Paper 16, 1.
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`B.
`
`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. 1501, 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
`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).
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`
`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.
`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.
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`C.
`
`
`
`Illustrative Claims
`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.[1]
`D. Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability (Pet. 5–6):
`Claim(s)
`Basis
`Reference(s)
`1, 2, 12, 25, 29, 63, 64,
`§ 103 Queen 19892 and Protein Data Bank
`66, 67, and 71–81
`(PDB database)
`1, 2, 4, 12, 25, 29, 62–64,
`Queen 19903 and PDB database
`66, 67, 69, and 71–81
`65, 75–77, and 79
`
`§ 103
`
`§ 103
`
`65, 75–77, and 79
`
`§ 103
`
`Queen 1989, PDB database, and
`Tramontano4
`Queen 1990, PDB database, and
`Tramontano
`
`
`1 See Ex. 1501, 10:45–56 (indicating that the Kabat numbering scheme for
`antibodies “assign[s] a residue number to each amino acid in a listed
`sequence”).
`2 Cary Queen et al., A humanized antibody that binds to the interleukin 2
`Receptor, 86 PRO. NAT’L ACAD. SCI. 10029–33 (1989). Ex. 1534.
`3 Cary L. Queen et al., International Publication No. WO 90/07861 A1,
`published July 26, 1990. Ex. 1550.
`4 Anna Tramontano 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. 1551.
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`
`Reference(s)
`Queen 1989, PDB database, and
`Kabat 19875
`Queen 1989, PDB database, and
`Hudziak6
`Queen 1990, PDB database, and
`Hudziak
`
`Claim(s)
`4, 62, 64, and 69
`
`Basis
`§ 103
`
`30, 31, 42, and 60
`
`§ 103
`
`30, 31, 33, 42, and 60
`
`§ 103
`
`In support of its patentability challenges, Petitioner relies on the
`Declarations of its technical experts, Dr. Jefferson Foote (Ex. 1503) and
`Mr. Timothy Buss (Ex. 1504). Petitioner further relies on the Declarations
`of Amanda Hollis, Christopher Lowden, and Karen Younkins for record
`authentication. Exs. 1687, 1688, and 1684, respectively.
`Patent Owner relies on the Declarations of named inventors
`Dr. Leonard G. Presta and Dr. Paul J. Carter (Exs. 2016 and 2017,
`respectively), research technician Mr. John Ridgway Brady (Ex. 2018), and
`Ms. Irene Loeffler (Ex. 2019) with respect to authentication of records.
`
`II. ANALYSIS
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`between the subject matter sought to be patented and the prior art are such
`that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which that
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`
`
`5 Elvin A. Kabat, et al., Sequences of Proteins of Immunological Interest 1–
`23 (1987) (4th Ed.) (NIH, Bethesda, Md.). Ex. 1552.
`6 Robert M. 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. 1521.
`6
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`(2007). In analyzing the obviousness of a combination of prior art elements,
`it can be important to identify a reason that would have prompted one of
`skill in the art “to combine . . . known elements in the fashion claimed by the
`patent at issue.” Id. at 418.
`A precise teaching directed to the specific subject matter of a
`challenged claim is not necessary to establish obviousness. Id. Rather, “any
`need or problem known in the field of endeavor at the time of invention and
`addressed by the patent can provide a reason for combining the elements in
`the manner claimed.” Id. at 420. Accordingly, a party that petitions the
`Board for a determination of unpatentability based on obviousness must
`show that “a skilled artisan would have been motivated to combine the
`teachings of the prior art references to achieve the claimed invention, and
`that the skilled artisan would have had a reasonable expectation of success in
`doing so.” In re Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1381 (Fed.
`Cir. 2016) (internal quotations and citations omitted).
`
`A.
`
`Person of Ordinary Skill in the Art
`The parties propose similar definitions of a person of ordinary skill for
`the ’213 patent. See Pet. 16; 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
`experience with antibody structural characterization, engineering, and/or
`biological testing, or an M.D. with practical academic or industrial
`experience in antibody development.” Id.
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`We further note that the prior art itself demonstrates this 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)).
`
`B.
`
`Claim Construction
`In an inter partes review, claim terms in an unexpired patent are
`interpreted according to their broadest reasonable construction in light of the
`specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016)
`(upholding the use of the broadest reasonable interpretation standard).
`Under that standard, we presume that a claim term carries its “ordinary and
`customary meaning,” which “is the meaning that the term would have to a
`person of ordinary skill in the art in question” at the time of the invention.
`In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007) (internal
`quotations and citation omitted); see also Trivascular, Inc. v. Samuels, 812
`F.3d 1056, 1062 (Fed. Cir. 2016) (“Under a broadest reasonable
`interpretation, words of the claim must be given their plain meaning, unless
`such meaning is inconsistent with the specification and prosecution
`history”). Any special definition for a claim term must be set forth in the
`specification with reasonable clarity, deliberateness, and precision. In re
`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). Limitations, however, may
`not be read from the specification into the claims (In re Van Geuns, 988 F.2d
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`1181, 1184 (Fed. Cir. 1993)), nor may the Board “construe claims during [an
`inter partes review] so broadly that its constructions are unreasonable under
`general claim construction principles” (Microsoft Corp. v. Proxyconn, Inc.,
`789 F.3d 1292, 1298 (Fed. Cir. 2015) (overruled on other grounds by Aqua
`Products, Inc. v. Matal, 872 F.3d 1290 (Fed. Cir. 2017)).
`On pages 17–19 of its Petition, Petitioner proposed the construction of
`“humanized” (see claims 1, 30, 62–64, 66, 79, 80); “and further comprising
`a framework region (FR) amino acid substitution at a site selected from the
`group consisting of” (claims 1, 30, 62, 63, 66, 79, and 80); “numbering
`system set forth in Kabat” (claims 1, 30, 62, 63, 66, 79, and 80); and “up to
`3-fold more” (claim 65). Patent Owner does not dispute Petitioner’s
`proposed constructions “for purposes of this proceeding,” but asserts that
`“[n]o construction of those terms is necessary.” See Prelim. Resp. 18. On
`the present record, we agree with Patent Owner that the terms identified by
`Petitioner need not be construed to resolve the issues presently before us.
`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. 17–18. Patent
`Owner correctly points out that this “construction comes directly from the
`definition provided in the ’213 patent.” Id. at 18 (citing Ex. 1501, 11:32–
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`38). For purposes of this Decision, we adopt Patent Owner’s proposed
`construction.
`
`
`
`C.
`
`Prior-Art Status of Queen 1990 and Tramontano
`Petitioner asserts that Queen 1990 and Tramontano are prior art. See,
`e.g., Pet. 5–6. Patent Owner disagrees. 19–42.
` “In an [inter partes review], the petitioner has the burden from the
`onset to show with particularity why the patent it challenges is
`unpatentable.” Harmonic Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed.
`Cir. 2016) (citing 35 U.S.C. § 312(a)(3) (requiring inter partes review
`petitions to identify “with particularity . . . the evidence that supports the
`grounds for the challenge to each claim”)). This burden of persuasion never
`shifts to Patent Owner. See 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 1379. 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)). We, therefore, address the threshold issue of whether Petitioner
`has met its initial burden to show that Tramontano and Queen 1990 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 the national stage on
`November 17, 1993, from a PCT application filed on June 15, 1992. Ex.
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`1501, (21), (22), (86). The ’206 application is also a continuation-in-part of
`the ’272 application, filed on June 14, 1991. Id. at (63). Tramontano was
`published on September 5, 1990 (Exs. 1551, 2027), and Queen 1990 was
`published on July 26, 1990 (Ex. 1550, (43)), both of which predate the
`earliest possible priority date shown on the face of the ’213 patent. Thus, we
`determine that Petitioner has satisfied its initial burden of showing that
`Tramontano and Queen 1990 qualify as prior art to the challenged claims.
`Patent Owner attempts to disqualify Tramontano and Queen 1990 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
`this 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).
`According to Patent Owner, even though the ’213 patent issued from a
`continuation-in-part of the ’272 application, the challenged claims are only
`entitled to the priority date of June 14, 1991, the filing date of the ’272
`application. Prelim. Resp. 40–42. Thus, Patent Owner argues, Tramontano
`and Queen 1990 do not qualify as prior art under § 102(b). Id. at 39. For
`purposes of this Decision, we assume, without deciding, that the challenged
`claims are entitled to the priority date of June 14, 1991. Nevertheless, based
`on the current record, Patent Owner has not sufficiently shown that the
`challenged claims were actually reduced to practice before the July 26, 1990,
`publication of Queen 1990.
`Reduction to practice is a question of law predicated on subsidiary
`factual findings. Brown v. Barbacid, 276 F.3d 1327, 1332 (Fed. Cir. 2002).
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`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
`determining the credibility of an inventor’s testimony. Medichem, S.A. v.
`Rolabo, S.L., 437 F.3d 1157, 1170 (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. at
`1171.
`
`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. 19–39 (citing Exs. 2001–2015); see also Paper 6
`(seeking to seal Exhibits 2001–2015). Patent Owner also relies on the
`Declarations of the inventors and another employee scientist. Id. (citing
`Exs. 2016 (Presta Declaration), 2017 (Carter Declaration), 2018 (Brady
`Declaration)). These declarations, according to Patent Owner, “pertain[] to
`confidential research and development activities related to the invention
`described and claimed.” Paper 6, 3–4 (seeking to seal Exhibits 2016–2018).
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`At this early stage of the proceeding, none of the antedating evidence
`has been developed or tested. Merely by way of example, Petitioner relies
`on Queen 1989’s disclosure for creating humanized mouse monoclonal
`antibodies in which the framework residues at 4L and 69H are murine, as set
`forth in claim 1. Pet. 34–35. It is not clear whether any of the antedating
`evidence relates to those substitutions. See Prelim. Resp. 19–39. To the
`contrary, Patent Owner states that the antedating evidence does not show
`substitution at 69H “because the murine . . . antibody and human consensus
`sequences are the same at those positions.” Prelim. Resp. 35. It appears the
`substitution at 69H was only made “subsequently,” as evinced in a 1997
`publication. Id. at 35 n.6; Ex. 2016 ¶ 52; Ex. 2021.7 As a result, based on
`the current record, we determine that Patent Owner’s evidence of prior
`invention is insufficient to disqualify Tramontano and Queen 1990 as prior
`art.
`
`D. Disclosures of the Asserted Prior Art
`Queen 1989
`1.
`Queen 1989 teaches constructing a humanized antibody by combining
`the CDRs of a murine antibody with human framework and constant
`regions. Ex. 1534, Abstract, 5–6. 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 3. In
`
`
`7 Leonard G. Presta et al., Humanization of an Anti-Vascular Endothelial
`Growth Factor Monoclonal Antibody for the Therapy of Solid Tumors and
`Other Disorders, 57 Cancer Res. 4593–99 (1997).
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`Queen 1989, the human framework regions were chosen to maximize
`homology with the murine antibody sequence. Id. at Abstract, 5. 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. Further, Queen 1989 teaches substituting an unusual amino
`acid in the human framework region if the corresponding positions in the
`murine antibody “actually has a residue much more typical of human
`sequences.” Id. at 6.
`
`Queen 1990
`2.
`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
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`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
`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. 1550, 14:9–16:25 (some formatting added). 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
`3.
`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. 23; Ex. 1503 ¶ 140 (citing Ex. 1580).
`The purpose of the Bank “is to collect, standardize, and distribute atomic co-
`ordinates and other data from crystallographic studies.” Ex. 1080, 3.
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`Dr. Foote testifies that the PDB database “is a repository of protein crystal
`atomic co-ordinates available to the public.” Ex. 1503 ¶ 140. According to
`Dr. Foote, “‘. . . [s]killed artisans relied on and contributed to the PDB
`database, retrieving computer-readable data that could be directly input into
`distance calculation and graphic programs for use in visualization and
`comparison studies, before the earliest priority date of the ’213 patent.’” Id.
`at 24–25 (quoting Ex. 1503 ¶ 140).
`
`Tramontano
`4.
`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. 1551, 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
`5.
`Kabat 1987 is a compilation of known antibody sequences. Ex. 1552.
`For a given type of immunoglobulin, Kabat 1987 identifies the most
`common amino acids occurring at each position. See, e.g., id. at 13. It also
`teaches the FR and CDR boundaries within the variable domains. See, e.g.,
`id. at 9.
`
`Hudziak
`6.
`Hudziak teaches p185HER2’s role in carcinoma development.
`Ex. 1521, Abstract. Hudziak shows that 4D5, “a monoclonal antibody
`directed against the extracellular domain of p185HER2 specifically inhibits the
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`growth of breast tumor-derived cell lines overexpressing the HER2/c-erbB-2
`gene product.” Id. emphasis omitted). 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. (emphasis
`omitted). Hudziak states that “[m]onoclonal antibodies specific for p185HER2
`may therefore be useful therapeutic agents for the treatment of human
`neoplasias.” Id. at 14.
`
`E. Obviousness over Queen 1989 and PDB Database (Ground 1)
`Petitioner argues that claims 1, 2, 12, 25, 29, 63–65,8 66, 67, and 71–
`81 would have been obvious over the combination of Queen 1989 and PDB
`database. Pet. 31–53. 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. Foote, 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) [and] are suitable for
`substitution.
`Pet. 31–32 (citing Ex. 1534, 5–6; Ex. 1503 ¶ 254). According to Petitioner,
`an ordinary artisan “would have used those simple rules to determine which
`
`
`8 See Ex. 3001 (communications regarding the omission of claim 65 from
`the box identifying Proposed Statutory Rejections).
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`residues in a human FR region could be switched back to mouse.” Id. at 32
`(citing Ex. 1503 ¶¶ 255–259).
`“Following the teachings of Queen 1989” and using antibodies well-
`known prior to the ’213 patent, Petitioner continues, Dr. Foote was able to
`identify CDR-contacting framework residues that were targets for
`substitution. Pet. 34 (citing Ex. 1503 ¶¶ 263–266). These include residues
`4L, 58L, 62L, 66L, 67L, 69L, 73L, 85L, and 105L in the light chain, and
`residues 2H, 24H, 39H, 45H, 69H, 71H, 73H, 76H, 78H, 93H, and 103H in
`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. According to Patent Owner, Queen
`1989 teaches nine substitutions, none of which corresponds to those recited
`in the challenged claims. Id. (citing Ex. 1534, 3). We are not persuaded by
`Patent Owner’s argument.
`First, Queen 1989 teaches more than the nine substitutions to which
`Patent Owner refers. For example, Queen 1989 teaches substituting 93H,
`which is a residue recited in claim 66. Ex. 1534, 6. Second, a person of
`ordinary skill would have read a reference for all that it teaches, including
`uses beyond its primary purpose. KSR, 550 U.S. at 418–21; 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
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`’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,
`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.
`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 recognizes the need to substitute
`framework residues in order to “reduce immunogenicity while retaining high
`binding affinity.” See Ex. 1534, 3. Based on that design need, the finite
`number of potential substitutions, and the methodolo
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