Trials@uspto.gov
`571-272-7822
`
` Paper No. 34
`Entered: January 11, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PFIZER, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01488
`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
`
`
`571-272-7822
`
` Paper No. 34
`Entered: January 11, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PFIZER, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01488
`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
`
`
`
`IPR2017-01488
`Patent 6,407,213 B1
`
`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. 1001). Paper 1 (“Pet.”).
`Genentech, Inc. (“Patent Owner”) timely filed a Preliminary Response.
`Paper 6 (“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: IPR2017-01489, brought by Pfizer, Inc.;
`IPR2017-01373 and IPR2017-01374, brought by Celltrion, Inc.; IPR2017-
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`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.
`
`The ’213 Patent and Relevant Background
`B.
`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
`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
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`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.
`2.
`“For a given antibody[,] a small number of FR residues are
`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.
`3.
`In a few instances, a variable domain “may contain
`glycosylation sites, and that this glycosylation may improve or abolish
`antigen binding.” Id. at 3:9–12.
`4.
`The function of an antibody is dependent on its three-
`dimensional structure, and amino acid substitutions can change the three-
`dimensional structure of an antibody. Id. at 3:40–43.
`5.
`The antigen binding affinity of a humanized antibody can be
`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
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`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 Claims
`C.
`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. 6–7):
`Ground
`Claim(s)
`Basis
`Reference(s)
`1
`1, 2, 25, 29, 63, 66,
`§ 102 Kurrle2
`67, 71, 72, 75, 76, 80,
`and 81
`1, 2, 4, 29, 62–64, 80,
`and 81
`
`§ 102 Queen 19903
`
`2
`
`1 See Ex. 1001, 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 Kurrle, et al., European Patent Application Publication No. 0403156,
`published December 19, 1990. Ex. 1071.
`3 Queen, et al., International Publication No. WO 1990/07861, published
`July 26, 1990. Ex. 1050.
`
`5
`
`
`
`Claim(s)
`1, 2, 4, 25, 29, 62–64,
`66, 67, 69, 71, 72, 75,
`76, 78, 80, and 81
`12
`
`73 and 77
`
`74
`
`79 and 65
`
`30, 31, 33, and 42
`42
`
`4
`
`5
`
`6
`
`7
`
`8
`9
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`Ground
`3
`
`Reference(s)
`Basis
`§ 103 Kurrle and Queen 1990 and
`
`§ 103 Kurrle, Queen 1990, and
`Furey 4
`§ 103 Kurrle, Queen 1990, and
`Chothia & Lesk5
`§ 103 Kurrle, Queen 1990, and
`Chothia 19856
`§ 103 Kurrle, Queen 1990, Chothia
`& Lesk, and Chothia 1985
`§ 103 Queen 1990 and Hudziak7
`§ 103 Queen 1990, Hudziak and
`Furey
`§ 103 Queen 1990, Hudziak, and
`Chothia & Lesk
`In support of its patentability challenges, Petitioner relies on the
`Declarations of its technical experts, Dr. Jefferson Foote (Ex. 1003) and Mr.
`Timothy Buss (Ex. 1004). Petitioner further relies on the Declarations of
`Amanda Hollis, Christopher Lowden, and Karen Younkins for record
`authentication. Exs. 1187, 1188, and 1184, respectively.
`
`10
`
`60
`
`4 Furey et al., Structure of a Novel Bence-Jones Protein (Rhe) Fragment at
`1.6 Å Resolution, 167 J. MOL. BIOL. 661–92 (1983). Ex. 1125.
`5 Chothia and Lesk, Canonical Structures for the Hypervariable Regions of
`Immunoglobulins, 196 J. MOL. BIOL. 901–17 (1987). Ex. 1062.
`6 Chothia et al., Domain Association in Immunoglobulin Molecules: The
`Packing of Variable Domains, 186 J. MOL. BIOL. 651–63 (1985). Ex. 1063.
`7 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.
`6
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`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.
`
`ANALYSIS
`II.
`To anticipate a claim under 35 U.S.C. § 102, “a single prior art
`reference must expressly or inherently disclose each claim limitation.”
`Finisar Corp. v. DirecTV Group, Inc., 523 F.3d 1323, 1334 (Fed. Cir. 2008).
`That “single reference must describe the claimed invention with sufficient
`precision and detail to establish that the subject matter existed in the
`prior art.” Verve, LLC v. Crane Cams, Inc., 311 F.3d 1116, 1120 (Fed. Cir.
`2002).
`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
`(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
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`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).
`
`Person of Ordinary Skill in the Art
`A.
`The parties propose similar definitions of a person of ordinary skill for
`the ’213 patent. See Pet. 15–16; Prelim. Resp. 18. 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.
`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)).
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`Claim Construction
`B.
`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); 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 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 16–18 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
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`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.” Prelim. Resp. 19. 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).
`1. “consensus human variable domain”
`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. 18–19. Patent
`Owner correctly points out that this “construction comes directly from the
`definition provided in the ’213 patent.” Id. at 19 (citing Ex. 1001, 11:32–
`38). For purposes of this Decision, we adopt Patent Owner’s proposed
`construction.
`2. “lacks immunogenicity compared to a non-human parent
`antibody”
`Independent claim 63 is directed to “[a] humanized antibody which
`lacks immunogenicity compared to a non-human parent antibody upon
`repeated administration to a human patient.” Although neither party
`proposes an express definition of this phrase, Patent Owner appears to
`suggest that it refers to a complete lack of immunogenicity. See Prelim.
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`Resp. 45 (arguing that “lack[ing] immunogenicity compared to a non-human
`parent antibody” cannot be an inherent property of humanized antibodies
`because “even humanized antibodies may produce an immunogenic
`response”); see also, id. at 45–46 (arguing that Petitioner must show that
`antibodies produced according to techniques disclosed in [Kurrle and/or
`Queen 1990] will necessarily lack immunogenicity”). We find no support
`for this construction in the Specification or in the plain reading of the claim
`language.
`Claim 63 does not merely recite “[a] humanized antibody which lacks
`immunogenicity,” but expressly compares the immunogenicity of the
`claimed humanized antibody to that of its parent. Consistent with the plain
`language of the claim, the Specification states that one object of the
`invention is to “to provide methods for the preparation of antibodies which
`are less antigenic in humans than non-human antibodies but have desired
`antigen binding and other characteristics and activities.” Ex. 1001, 4:24–28.
`The Specification similarly states that embodiments within the scope of the
`claims have “low immunogenicity,” or are designed to “minimize the
`potential immunogenicity of the resulting humanized antibody in the clinic.”
`Id. at 52:54–58, 61:56–61. Moreover, with reference to claim 63 in
`particular, Patent Owner states that “[t]he ’272 application explains that the
`purpose of humanizing antibodies using its consensus sequence approach is
`to reduce immunogenicity versus the non-human parent antibody. (Id., 6:24–
`30, 84:24–30.).” Prelim. Resp. 42 (citing Ex. 2032 (File History for U.S.
`Patent Application No. 07/715,272 (“the ’272 application”)); see also id. at
`38 (indicating that the limitation is satisfied where “[o]nly 1 out of 885
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`patients experienced an immunogenic response . . . which was a substantial
`improvement over the murine 4D5 antibody”). Accordingly, for the purpose
`of institution, we interpret “[a] humanized antibody which lacks
`immunogenicity compared to a non-human parent antibody upon repeated
`administration to a human patient,” as referring to a humanized antibody
`having reduced immunogenicity in a human patient as compared to its non-
`humanized parent antibody.
`
`Prior-Art Status of Kurrle and Queen 1990
`C.
`Petitioner asserts that Kurrle and Queen 1990 are prior art. Pet. 1–2 &
`n.3, 13, 19–23, 27. Patent Owner disagrees. Prelim. Resp. 2, 12, 14, 20–43.
`“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
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`has met its initial burden to show that Kurrle 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. 1001, (21), (22), (86). The ’206 application is also a continuation-in-
`part of the ’272 application, filed on June 14, 1991. Id. at (63). Kurrle was
`published on December 19, 1990 (Ex. 1071, (43)), and Queen 1990 was
`published on July 26, 1990 (Ex. 1050, (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
`Kurrle and Queen 1990 qualify as prior art to the challenged claims.
`Patent Owner attempts to disqualify Kurrle and Queen 1990 as prior
`art, arguing that the challenged claims were actually reduced to practice
`before either Kurrle or Queen 1990 was published, i.e., before July 26, 1990.
`Prelim. Resp. 20–43. 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, Kurrle and Queen 1990 do not qualify as
`prior art under § 102(b). Id. at 40. 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,
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`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).
`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. 20–40 (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. Id. (citing
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`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 8, 3–4 (seeking to seal Exhibits 2016–2018).
`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 Kurrle’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. 19–20. It is not clear whether any of the antedating evidence
`relates to those substitutions. See Prelim. Resp. 20–40. 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. 36. It appears the
`substitution at 69H was only made “subsequently,” as evinced in a 1997
`publication. Id., n.6; Ex. 2016 ¶ 52; Ex. 2021.8 As a result, based on the
`current record, we determine that Patent Owner’s evidence of prior invention
`is insufficient to disqualify Kurrle and Queen 1990 as prior art.
`
`D. Anticipation by Kurrle (Ground 1)
`Kurrle discloses “humanised and civilised versions” of monoclonal
`antibodies against the human alpha/beta T-cell receptor. Ex. 1071, Abstract;
`see Ex. 1003 ¶ 122. In particular, Kurrle discloses the production of
`chimeric antibodies, i.e., those “having mixed murine and human
`
`8 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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`IPR2017-01488
`Patent 6,407,213 B1
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`characteristics in order to improve their effectiveness and/or lower their
`immunogenicity in patients.” Ex. 1071, 3:3–5. In one embodiment, “[o]nly
`the complementarity deter[min]ing regions and selected framework amino
`acids necessary for antigen binding are maintained murine. The remaining
`framework regions are converted to human sequences.” Id. at 3:9–11. Such
`alterations to the framework regions “can advantageously be made in the
`sequence immediately before and after the CDRs.” Id. at 8:25–26. In
`particular,
`Molecular models of antibodies have shown that the actual CDR
`loops can contain amino acids up to 4 amino acids away from the
`“Kabat” CDRs. Therefore, maintaining at least the major amino
`acid differences (in size or charge) within 4 amino acids of the
`CDRs as murine may be beneficial.
`Id. at 8:27–29.
`Kurrle also discloses using “a simplified computer model . . . based on
`sequence homology to other antibodies with solved structures” to “judge
`proximity of framework amino acids to the CDRs.” Id. at 8:33–35. Kurrle
`further discloses changing existing framework residues in accord with the
`consensus sequences for particular human antibody subgroups. Id. at 8:36–
`47. Applying the subgroup consensus model, Kurrle discloses substitution
`of human framework residues for mouse residues, including at positions 4L,
`69H, 71H, 73H, and 76H. Id. at Tables 6A, 6B; Ex. 1003 ¶¶ 111, 123–124,
`158, Exhibit D.
`Relying on these disclosures, Petitioner asserts that Kurrle anticipates
`claims 1, 2, 25, 29, 63, 66, 67, 71, 72, 75, 76, 80, and 81. Pet. 12, 28–34.
`Patent Owner only challenges the merits of Petitioner’s assertion regarding
`claim 63. Prelim. Resp. 45–46; see also id. at 2 (“even if Pfizer could rely
`
`16
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`IPR2017-01488
`Patent 6,407,213 B1
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`on Kurrle . . . Pfizer has failed to demonstrate a reasonable likelihood of
`success for claim 63 in Ground 1”); Prelim. Resp. 44, n.8. On this record,
`we are satisfied that Petitioner has established a reasonable likelihood that
`Kurrle anticipates at least claim 1.
`We also are satisfied that Petitioner has shown sufficiently that Kurrle
`discloses all the elements of claim 63. Claim 63 recites:
`63. A humanized antibody which
`lacks
`immunogenicity
`compared to a non-human parent antibody upon repeated
`administration to a human patient in order to treat a chronic
`disease in that patient, wherein the humanized antibody
`comprises non-human Complementarity Determining Region
`(CDR) amino acid residues which bind an antigen incorporated
`into a human antibody variable domain, and further comprises an
`amino acid substitution at a site selected from the group
`consisting of: 4L, 38L, 43L, 44L, 46L, 58L, 62L, 65L, 66L, 67L,
`68L, 69L, 73L, 85L, 98L, 2H, 4H, 36H, 39H, 43H, 45H, 69H,
`70H, 74H, 75H, 76H, 78H and 92H, utilizing the numbering
`system set forth in Kabat.
`Ex. 1001, 88:36–48.
`Petitioner presents evidence that Kurrle discloses substitution of
`framework residues at positions 4L, 69H, 71H, and 76H, thus encompassing
`four of the amino acid substitutions recited in claim 63. See Pet. at 20;
`Ex. 1071, Tables 6A, 6B; Ex. 1003 ¶¶ 111, 123, 124 & n.12, 155–172,
`Exhibit D.
`Petitioner further contends that “lacking immunogenicity compared to
`a non-human parent [antibody is] an inherent aspect of the claimed
`humanized antibodies.” Pet. 31; see Ex. 1003 ¶¶ 162–164. According to
`Petitioner, “because the structural components are the same, the same
`function (i.e., ‘which lacks immunogenicity compared to a non-human
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`IPR2017-01488
`Patent 6,407,213 B1
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`parent antibody upon repeated administration to a human patient in order to
`treat a chronic disease in that patient’) is also present.” Pet. 30–31.
`Petitioner also refers to Kurrle for stating that after humanization of the
`variable regions, the resulting chimeric antibody is “essentially a human
`antibody with a much lower immunogenicity in patients.” Id. (quoting
`Ex. 1071, 3:8–12).
`Patent Owner argues that Petitioner has failed to establish inherent
`anticipation because Petitioner has not shown that “antibodies produced
`according to techniques disclosed in [Kurrle] will necessarily lack
`immunogenicity.” Prelim. Resp. 45–46. According to Patent Owner,
`Kurrle’s assertion that “[t]he humanized immunoglobulins of the present
`invention will be substantially non-immunogenic in humans,” is merely an
`“aspirational statement[] of intended results,” and an “unsupported
`prediction.” Id. at 45. Patent Owner argues that during prosecution,
`Applicants successfully distinguished similar aspirational statements in
`Riechmann,9 and “[t]he same result should apply here.” Id. at 46 (citing
`Ex. 1002, 2485, 3431–3432; Ex. 1069, 1). We are not persuaded.
`During prosecution of the ’213 patent, the examiner rejected certain
`claims as obvious over the combination of several references, including
`Riechmann. Ex. 1002, 2483–87. According to the examiner, those
`references “clearly teach reduced immunogenicity associated with the
`humanized antibody.” Id. at 2485. Specifically, the examiner relied on a
`passage from Riechmann, which states that “the use of human rather than
`
`9 Riechmann, et al., Reshaping Human Antibodies for Therapy, 332 NATURE
`323–27 (1988) (Ex. 1069).
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`mouse isotypes should minimize the anti-globulin responses during therapy
`by avoiding anti-isotypic antibodies.” Ex. 1069, 323; Ex. 1002, 245 (citing
`“Riechmann et al. page 323, column 2, lines 5–8”); see also Prelim. Resp. 6,
`46 (explaining anti-globulin responses are immunogenic response).
`Applicants argued that in Isaacs,10 a follow-on publication of Riechmann,
`“three out of four patients treated with [Riechmann’s] humanized . . .
`antibody . . . developed antiglobulins that were able to inhibit the binding of
`[the antibody] to its antigen.” Ex. 1002, 3432 (citing Ex. 2025, 751). Patent
`Owner now relies on the same statement in Isaacs to support the proposition
`that “even humanized antibodies may produce an immunogenic response.”
`Prelim. Resp. 45 (citing Ex. 2025, 751).
`We note, however, that claim 63 does not require an absolute lack of
`immunogenicity, but only a reduction in immunogenicity as compared to a
`non-humanized parent antibody. See section II(B)(ii), above. Accordingly,
`Petitioner need not demonstrate that antibodies produced according to Kurrle
`“lack immunogenicity” as Patent Owner asserts.
`We further note that Patent Owner does not argue that the humanized
`antibody taught in Riechmann and tested in Isaacs contains any substitution
`of framework residues at positions recited in claim 63. In contrast, Kurrle
`explicitly discloses the substitution of framework residues at positions 4L,
`69H, or 76H, as recited in claim 63. See Pet. 20 (citing Ex. 1071, 25–26,
`Tables 6A and 6B; Ex. 1003 ¶¶ 123, 155–172). Moreover, Kurrle
`recognizes that the humanized antibody disclosed therein is “essentially a
`
`10 Isaacs, et al., Humanised Monoclonal Antibody Therapy for Rheumatoid
`Arthritis, 340 THE LANCET 748–52 (1992). Ex. 2025.
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`human antibody with a much lower immunogenicity in patients.” Ex. 1071,
`3:11–12. And even if, as Patent Owner argues, the statement in Kurrle is
`merely aspirational, “the discovery of a previously unappreciated property of
`a prior art composition, or of a scientific explanation for the prior art’s
`functioning, does not render the old composition patentably new to the
`discoverer.” Atlas Powder Co. v. Ireco, Inc., 190 F.3d 1342, 1347 (Fed. Cir.
`1999). Thus, on the current record, we are persuaded that Petitioner has
`established a reasonable likelihood that Kurrle discloses all the elements of
`claim 63.
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