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`Paper No. ____
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`PHIGENIX, INC.
`Petitioner
`
`
`v.
`
`
`IMMUNOGEN, INC.
`Patent Owner
`
`
`Case IPR2014-00676
`U.S. Patent No. 8,337,856
`Title: METHODS OF TREATMENT USING ANTI-ERBB
`ANTIBODY-MAYTANSINOID CONJUGATES
`
`
`
`Before FRANCISCO C. PRATS, JACQUELINE WRIGHT BONILLA, and
`ZHENYU YANG, Administrative Patent Judges
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`
`
`
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`PETITIONER’S NOTICE OF APPEAL
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`PHIGENIX, INC.,
`Petitioner and Appellant,
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`v.
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`IMMUNOGEN, INC.,
`Patent Owner and Appellee,
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`and
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`DIRECTOR, UNITED STATES
`PATENT AND TRADEMARK
`OFFICE,
`Appellee.
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`NOTICE OF APPEAL
`
`
`In re U.S. Patent No. 8,337,856 B2
`Inter Partes Review No. IPR2014-
`00676
`
`
`
`To the Director of the Patent and Trademark Office:
`
`Petitioner Phigenix, Inc. hereby notices its appeal from the Patent Trial and
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`Appeal Board Final Decision dated October 27, 2015 [Paper 39], and all adverse
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`rulings or orders leading up to the Final Decision.
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`In addition to other issues that may be raised on appeal, Petitioner states,
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`pursuant to 37 C.F.R. § 90.2(a)(3)(ii), that the appeal may raise one or more of the
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`following legal issues:
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`(a) Whether the Board erred in ruling that, under the preponderance of the
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`evidence standard, claims 1-8 of the U.S. Patent No. 8,337,856 would not have
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`been obvious over the prior art presented to the Board;
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`
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`(b) Whether the Board erred in denying Petitioner’s motion to exclude
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`certain evidence, including Exhibits 2240-2240, 2256, 2319, and 2320, and the
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`testimony of Patent Owner’s expert witness; and
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`(c) Any finding or determination supporting or related to those issues, as
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`well as all other issues decided adversely to Petitioner in any orders, decisions,
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`rulings, and opinions.
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`In addition to the filing of this Notice of Appeal with the Director, the
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`requisite copies of this notice and all related fees are being filed in the United
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`States Patent Office’s Patent Trial and Appeal Board and in the United States
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`Court of Appeals for the Federal Circuit.
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`No fees are believed to be due to the United States Patent and Trademark
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`Office in connection with this filing, but authorization is hereby given for any
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`required fees to be charged to the Andrews Kurth, LLP Deposit Account No. 50-
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`2849.
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`Respectfully submitted this 22nd day of December, 2015.
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`
`
`Andrews Kurth, LLP
`1350 I Street, NW, Suite 1100
`Washington, DC 20005
`Phone: 202-662-2700
`Fax: 202-662-2736
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`
`
`
`
`
`
`
`
`
`/Matthew J. Dowd/
`Ping Wang, M.D., Esq.
`Reg. No. 48,328
`Matthew J. Dowd, Esq.
`Reg. No. 47,534
`Attorneys for Petitioner
`Phigenix, Inc.
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`
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`
`
` Paper 39
`Trials@uspto.gov
`571-272-7822 Entered: October 27, 2015
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PHIGENIX, INC,
`Petitioner,
`
`v.
`
`IMMUNOGEN, INC.,
`Patent Owner.
`____________
`
`Case IPR2014-00676
`Patent 8,337,856 B2
`____________
`
`
`
`
`Before FRANCISCO C. PRATS, JACQUELINE WRIGHT BONILLA, and
`ZHENYU YANG, Administrative Patent Judges.
`
`
`BONILLA, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`
`
`
`
`IPR2014-00676
`Patent 8,337,856 B2
`
`I.
`
`INTRODUCTION
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`Phigenix Inc. (“Petitioner”) filed a Petition requesting inter partes
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`review of claims 1–8 of U.S. Patent No. 8,337,856 (“the ’856 patent”).
`
`Paper 5 (“Pet.”). Immunogen, Inc. (“Patent Owner”) filed a Preliminary
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`Response. Paper 10 (“Prelim. Resp.”). Thereafter, we determined that the
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`information presented in the Petition demonstrated that there was a
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`reasonable likelihood that Petitioner would prevail in showing claims 1–8 as
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`unpatentable. Paper 11 (“Dec. to Inst.”), 2, 23. Pursuant to 35 U.S.C. § 314,
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`we instituted this proceeding on October 29, 2014, to review whether claims
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`1–8 of the ’856 patent would have been obvious under 35 U.S.C. § 103 over
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`Chari 19921 in view of the HERCEPTIN® Label,2 further in view of
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`Rosenblum 19993 and Pegram 1999.4 Id. at 23.
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`After institution of trial, Patent Owner filed a Patent Owner Response.
`
`Paper 18 (“PO Resp.”), and Petitioner filed a Reply to the Response. Paper
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`
`
`1 Chari et al., Immunoconjugates Containing Novel Maytansinoids:
`Promising Anticancer Drugs, 52 CANCER RES.127–131 (1992) (“Chari
`1992”) (Ex. 1012).
`2 HERCEPTIN® (Trastuzumab) Label, dated September 1998 (“the
`HERCEPTIN® Label”) (Ex. 1008).
`3 Rosenblum et al., Recombinant Immunotoxins Directed against the c-
`erbB-2/HER2/neu Oncogene Product: In Vitro Cytotoxicity,
`Pharmacokinetics, and In Vivo Efficacy Studies in Xenograft Models, 5
`CLIN. CANCER RES. 865–874 (1999) (“Rosenblum 1999”) (Ex. 1018).
`4 Pegram et al., Inhibitory effects of combinations of HER-2/neu antibody
`and chemotherapeutic agents used for treatment of human breast cancers,
`18 ONCOGENE 2241–2251 (1999) (“Pegram 1999”) (Ex. 1020).
`
`2
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`IPR2014-00676
`Patent 8,337,856 B2
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`24 (“Reply”). Petitioner also filed a Motion to Exclude certain evidence
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`submitted by Patent Owner. Paper 28. Patent Owner responded by filing an
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`Opposition to the Motion to Exclude (Paper 29), as well as an unopposed
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`Motion to Seal two exhibits filed by Patent Owner in connection with the
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`Opposition (Paper 31, 1). Petitioner filed a Reply to the Opposition to the
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`Motion to Exclude. Paper 35.
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`An oral hearing was held on July 9, 2015. A transcript of the hearing
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`has been entered into the record. Paper 38 (“Tr.”).
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`We have jurisdiction under 35 U.S.C. § 6(c). This Final Written
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`Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
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`For the reasons that follow, we determine that Petitioner has not shown by a
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`preponderance of the evidence that claims 1–8 of the ’856 patent are
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`unpatentable. We deny Petitioner’s Motion to Exclude Evidence, and we
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`grant Patent Owner’s Motion to Seal.
`
`A. Related Proceeding
`
`About a month after filing the current Petition, Petitioner filed a
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`Petition requesting inter partes review of claims 1–20 and 25–27 of U.S.
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`Patent No. 7,575,748 (“the ’748 patent”) in Case No. IPR2014-00842.
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`Patent Owner of the ’748 patent, Genentech, Inc., a real party-in-interest in
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`the current proceeding, filed a Preliminary Response. IPR2014-00842,
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`Paper 9. On December 9, 2014, we declined to institute review in that case.
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`Phigenix, Inc. v. Genentech, Inc. and ImmunoGen, Inc., Case IPR2014-
`
`00842 (PTAB Dec. 9, 2014) (Paper 10).
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`3
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`IPR2014-00676
`Patent 8,337,856 B2
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`The ’748 patent, at issue in that case, is a continuation application of
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`U.S. Patent No. 7,097,840 (“the ’840 patent”). IPR2014-00842, Ex. 1001.
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`The ’856 patent, at issue here, is a divisional application of a continuation
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`application of the ’840 patent. Ex. 1001.
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`B. The ’856 Patent (Ex. 1001)
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`The ’856 patent relates to immunoconjugates comprising an anti-ErbB
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`antibody, such as the humanized anti-ErbB2 antibody known as
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`HERCEPTIN® (huMAb4D5-8), linked to a maytansinoid toxin. Ex. 1001,
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`1:20–52, 35:47–36:39; see also id. at 3:6–16 (discussing HERCEPTIN®),
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`6:50–67 (defining “ErbB2”), 10:40–52 (defining “humanized”), 16:23–28
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`(defining “epitope 4D5”).
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`The term “ErbB2” is synonymous with “HER2,” “p185neu”, or “neu,”
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`and refers to a member of the ErbB family of receptor tyrosine kinases,
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`which mediate cell growth, differentiation, and survival. Id. at 1:45–60,
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`6:50–58. Overexpression of ErbB2 on cell surfaces can lead to cancer in
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`humans, such as certain breast and ovarian cancers. Id. at 1:54–66, 8:55–60.
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`The specification teaches that maytansinoids, such as DM1, are highly
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`cytotoxic, i.e., inhibit or prevent cell function and/or destroy cells, but
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`induce “severe systemic side-effects primarily attributed to their poor
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`selectivity for tumors” when administered alone. Id. at 1:38–44, 17:45–52;
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`see also id. at 5:7–13 (referring to Figure 3, showing the structure of the
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`maytansinoid designated “DM1”). The specification describes making anti-
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`ErbB antibody-maytansinoid conjugates using “a variety of bifunctional
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`protein coupling agents,” i.e., linkers, such as N-succinimidyl-3-(2-
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`4
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`IPR2014-00676
`Patent 8,337,856 B2
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`pyridyldithio)propionate (“SPDP”), N-succinimidyl-4-(2-
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`pyridylthio)pentanoate (“SPP”), and succinimidyl-4-(N-maleimidomethyl)-
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`cyclohexane-1-carboxylate (“SMCC”). Id. at 36:13–31.
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`The specification states that the “present invention is based on results
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`obtained in a novel murine HER2-transgenic tumor model in which
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`HERCEPTIN® or the murine antibody 4D5 from which HERCEPTIN® was
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`derived, had little effect on tumor growth.” Id. at 21:65–22:1. In this
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`context, the specification states that “it was surprisingly found that while the
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`transplanted tumor obtained from such transgenic mice responded poorly to
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`HERCEPTIN® treatment, the HERCEPTIN®-maytansinoid conjugates were
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`highly efficacious.” Id. at 22:2–7.
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`C. The Challenged Claims
`
`Petitioner challenges claims 1–8 of the ’856 patent. Of those, only
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`claim 1 is independent, which recites:
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`1. An immunoconjugate comprising an anti-ErbB2 antibody
`conjugated to a maytansinoid, wherein the antibody is
`huMAb4D5-8.
`
`Id. at 81:28–31. Dependent claim 2 recites that the maytansinoid is DM1
`
`having a specific structure, where the antibody is linked to the maytansinoid
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`via a disulfide or thioether group at “R” shown in the structure. Id. at 81:31–
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`53. Dependent claim 3 requires that the immunoconjugate “comprises from
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`3 to 5 maytansinoid molecules per antibody molecule.” Id. at 82:27–30.
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`Dependent claim 5 recites a pharmaceutical composition comprising the
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`immunoconjugate and a pharmaceutically acceptable carrier. Id. at 82:37–
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`39. Claims 4 and 6–8, which ultimately depend on claim 1 or 2, recite that
`5
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`IPR2014-00676
`Patent 8,337,856 B2
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`the antibody and maytansinoid are conjugated by specific chemical linkers,
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`i.e., SPDP, SPP, or SMCC. Id. at 82:30–36, 39–51.
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`II. ANALYSIS
`
`A. Claim Construction
`
`For inter partes review, claim terms in an unexpired patent are given
`
`their broadest reasonable interpretation in light of the patent specification.
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`37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 793 F.3d 1268,
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`1278–79 (Fed. Cir. 2015). Claim terms are given their ordinary and
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`customary meaning, as would be understood by one of ordinary skill in the
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`art in the context of the entire disclosure. In re Translogic Tech., Inc., 504
`
`F.3d 1249, 1257 (Fed. Cir. 2007). Any special definition for a claim term
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`must be set forth in the specification with reasonable clarity, deliberateness,
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`and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
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`As noted in our Decision to Institute, Petitioner offers claim
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`construction of the phrase “pharmaceutically-acceptable carrier,” recited in
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`dependent claim 5, as “including ‘bacteriostatic water for injection (BWFI),
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`phosphate-buffered saline, Ringer’s solution and dextrose solution.’” Dec.
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`to Inst. 6–7 (citing Pet. 7 (citing Ex. 1001, 42:4–9)). Patent Owner does not
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`dispute this claim construction, nor offer construction of other claims terms.
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`Based on the record currently available, Petitioner’s proposed construction is
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`the broadest reasonable construction of the phrase. We construe other claim
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`terms as carrying their ordinary meaning, consistent with their use in the
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`specification.
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`6
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`Patent 8,337,856 B2
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`B. Obviousness over Chari 1992 in view of HERCEPTIN® Label,
`further in view of Rosenblum 1999 and Pegram 1999
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`Petitioner contends that claims 1–8 would have been obvious over
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`Chari 1992 in view of the HERCEPTIN® Label, further in view of
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`Rosenblum 1999 and Pegram 1999, relying on a Declaration by Michael G.
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`Rosenblum, Ph.D. (Ex. 1016). Pet. 8–22. Patent Owner contends otherwise,
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`relying on a Declaration by Geoffrey A. Pietersz, Ph.D. (Ex. 2134), as well
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`as Declarations by Linda T. Vahdat, M.D. (Ex. 2103), Joyce
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`O’Shaughnessy, M.D. (Ex. 2105), and John C. Jarosz (Ex. 2131) in relation
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`to objective indicia of non-obviousness. PO Resp. 2–60.
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`1. Chari 1992 (Ex. 1012)
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`Chari 1992 describes immunoconjugates comprising an anti-ErbB2
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`mouse monoclonal antibody, TA.1, chemically coupled to the maytansinoid
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`toxin, DM1, using SPDP or SMCC as a linker. Ex. 1012, 128–129; id. at
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`Fig. 2 (see maytansinoid 3 and figure legend). As stated in Chari 1992, the
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`TA.1 antibody binds HER-2/neu oncogene protein (i.e., ErbB2), which is
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`expressed at high levels on human breast tumor cells. Id. at 129, 1st col.,
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`1st ¶. The reference discloses conjugates having a range of one to six
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`maytansinoid molecules per antibody molecule, such as four maytansinoid
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`molecules per antibody molecule. Id., see also id. at 2nd col., Table 2.
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`Chari 1992 teaches that the conjugates, called “TA.1(-SS-May)n,”
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`were cytotoxic when tested in vitro on the human breast cancer cell line, SK-
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`BR-2. Id. at 129, 1st col., 2nd ¶, 2nd col. Fig. 3. In addition, the reference
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`teaches that conjugate TA.1(-SS-May)4 was at least 1000-fold less cytotoxic
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`7
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`IPR2014-00676
`Patent 8,337,856 B2
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`toward neu-negative KB cells in tissue culture. Id. It teaches that
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`cytotoxicity can be increased by linking more maytansinoid molecules per
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`antibody molecule, “and it reached its maximum value at n = 4 (Table 2).”
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`Id. at 1st col., 3rd ¶. The reference also discloses that conjugate A7(-SS-
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`May)6, where A7 is an antibody directed against a human colon cancer cell
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`line antigen, shows similar cytotoxicity results and is not toxic in mice. Id.
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`at 1st col., 3rd ¶ – 2nd col., 2nd ¶.
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`Chari 1992 states that the “high specific cytotoxicity of maytansinoid
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`conjugates toward tumor cell lines in conjunction with their low systemic
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`toxicity indicates that these potent conjugates may possess a therapeutic
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`index sufficient for the effective treatment of human cancer.” Id. at 130, 1st
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`col., 2nd ¶; see also id. at 127, Abstract (stating that the immunoconjugates
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`“show high antigen-specific cytotoxicity for cultured human cancer cells
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`. . . , low systemic toxicity in mice, and good pharmacokinetic behavior”). It
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`also states that the “development of ‘humanized’ antibodies will offer an
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`opportunity to produce drug conjugates that would be less immunogenic
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`than similar conjugates of murine antibodies.” Id. at 130, 1st col., 3rd ¶.
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`2. HERCEPTIN® Label (Ex. 1008)
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`The HERCEPTIN® Label describes HERCEPTIN®, also known as
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`Trastuzumab or huMAB4D5-8, as a humanized form of the mouse
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`monoclonal antibody 4D5, which binds HER2/ErbB2. Ex. 1008, 1, 1st col.
`
`The Label describes intravenous injection administration of HERCEPTIN®
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`after reconstitution with “Bacteriostatic Water for Injection (BWFI),” among
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`other components. Id. at 1st col.
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`8
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`IPR2014-00676
`Patent 8,337,856 B2
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`The Label describes HERCEPTIN® as being indicated for “the
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`treatment of patients with metastatic breast cancer whose tumors
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`overexpress the HER2 protein and who have received one or more
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`chemotherapy regimens for their metastatic disease.” Id. at 2nd col. In
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`addition, the Label describes HERCEPTIN® in combination with paclitaxel
`
`as being “indicated for treatment of patients with metastatic breast cancer
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`whose tumors overexpress the HER2 protein and who have not received
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`chemotherapy for their metastatic disease.” Id.
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`Table 1 in the Label shows clinical trial data regarding “Phase III
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`Clinical Efficacy in First-Line Treatment” in patients treated with
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`chemotherapy alone or chemotherapy combined with HERCEPTIN®. Id. at
`
`1st col. The Label states that “[c]ompared with patients randomized to
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`chemotherapy alone, the patients randomized to HERCEPTIN and
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`chemotherapy experienced a significantly longer time to disease progression,
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`a higher overall response rate (ORR), a longer median duration of response,
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`and a higher one-year survival rate.” Id. (citing Table 1).
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`3. Rosenblum 1999 (Ex. 1018)
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`Rosenblum 1999 discloses an immunoconjugate comprising an anti-
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`ErbB2 human chimeric antibody (“BACH-250”) chemically coupled to a
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`ribosomal-inhibiting plant toxin gelonin (“rGel”), using SPDP as a linker.
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`Ex. 1018, 865, Abstract, 866, 2nd col. Immunoconjugates, antibodies alone,
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`and toxin alone, were tested in vitro against human tumor cells expressing
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`various levels of HER2, and in vivo against human tumor xenograft models
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`(athymic mice bearing s.c. or i.p. SKOV-3 tumors). Id. at Abstract.
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`9
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`IPR2014-00676
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`The reference states that although “binding of both BACH-250 and
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`BACH-250/rGel conjugate to target cells was essentially equivalent,” in
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`SKOV-3 cells “the IC50 of BACH-250/rGel [conjugate] was 97 pM (17
`
`ng/ml), whereas BACH-250 and rGel alone showed no cytotoxic effects.”
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`Id. The reference also states there “was a clear correlation between
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`expression levels of HER-2/neu and cytoimmunotoxin.” Id.; see also id. at
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`869, 1st col. (stating that cytotoxic effects of TAB-250/rGel (mouse
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`antibody conjugate) was greatest against the SKBR-3 cell line having the
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`highest number of cell surface HER2, as compared to other cell lines
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`expressing lower levels).
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`In in vivo xenograft studies in mice using BACH-250 conjugates,
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`“immunotoxin treatment slowed tumor growth by 99 and 94% at days 35
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`and 49 after implantation, respectively, and lengthened the median survival
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`by 40% (from 30 to 50 days) in mice bearing lethal i.p. tumors.” Id. at
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`Abstract, 871–872 (describing “impressive antitumor effects” as compared
`
`to tumor growth in control groups). Rosenblum 1999 concluded “that
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`clinical development of BACH-250/rGel may be warranted in patients with
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`HER2/neu-expressing malignancies.” Id. at Abstract.
`
`4. Pegram 1999 (Ex.1020)
`
`Pegram 1999 states that “[p]revious studies have demonstrated a
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`synergistic interaction between rhuMAb HER2 and the cytotoxic drug
`
`cisplatin in human breast and ovarian cancer cells.” Ex. 1020, 2241,
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`Abstract. Pegram 1999 conducted studies in “preclinical models in vitro and
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`in vivo” using rhuMAb HER2 in combination with other cytotoxic drugs.
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`10
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`IPR2014-00676
`Patent 8,337,856 B2
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`Id., see also id. at 2241, 2nd col., 2242, 2nd col. The reference describes
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`observing “[s]ynergistic interactions at clinically relevant drug
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`concentrations” for rhuMAb HER2 in combination with cisplatin, thiotepa,
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`or etoposide, and “[a]dditive cytotoxic effects” with rhuMAb HER2 plus
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`doxorubicin, paclitaxel, methotrexate, or vinblastine. Id. at Abstract.
`
`The reference indicates that “rhuMAb HER2” is a recombinant,
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`humanized form of 4D5. Id. at 2241, 2nd col. It states that when “compared
`
`to murine 4D5, rhuMAb HER2 exhibits a stronger binding affinity for
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`p185HER-2/neu but has similar specific antiproliferative activity against HER-
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`2/neu-overexpressing cell lines and xenografts.” Id. The reference also
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`states that in in vivo studies using human breast cancer xenografts in athymic
`
`mice, vinblastine (“VBL”), a microtubule inhibitor, combined with rhuMAb
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`HER2 “significantly reduced MCF7/HER-2 xenograft volume compared to
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`treatment with VBL alone or single agent rhuMAb HER2 (Figure 6b).” Id.
`
`at 2245, 2nd col.; see also id. at 2248, ¶ spanning 1st and 2nd col.
`
`(describing “significantly superior anti-tumor efficacy” of rhuMAb HER2
`
`when combined with different chemotherapy drugs, such as VBL, as
`
`compared to effects of each drug alone).
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`5. Petitioner’s Contentions
`
`Petitioner contends that Chari 1992 teaches all limitations recited in
`
`claims 1–8 of the ’856 patent, except that it does not disclose huMAB4D5-8
`
`(as recited in independent claim 1) or a pharmaceutically acceptable carrier
`
`(as recited in claim 5). Pet. 13; see id. at 9–13. For example, Petitioner
`
`contends that Chari 1992 discloses an immunoconjugate comprising an anti-
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`11
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`IPR2014-00676
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`ErbB2 antibody conjugated to a maytansinoid, such as DMI having the
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`structure recited in claim 2, where the immunoconjugate comprises four
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`maytansinoid molecules per antibody molecule (as recited in claim 3), and
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`where the antibody and maytansinoid are conjugated by chemical linkers,
`
`such as SPDP or SMCC (as recited in claims 4 and 6–8). Pet. 9–12 (citing
`
`Ex. 1012).
`
`Petitioner also contends that the HERCEPTIN® Label describes the
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`use of huMAB4D5-8 (i.e., HERCEPTIN®) for the treatment of patients with
`
`metastatic breast cancer, as well as the combination of HERCEPTIN® with a
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`pharmaceutically acceptable carrier, i.e., Bacteriostatic Water for Injection.
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`Pet. 13 (citing Ex. 1008, 1). Most relevant to our analysis, Petitioner further
`
`contends, relying on the Rosenblum Declaration (Ex. 1016), that it would
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`have been obvious to the ordinarily skilled artisan, at the time the ’856
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`patent was filed, to substitute the mouse monoclonal TA.1 antibody in the
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`immunoconjugate of Chari 1992 with the humanized mAb huMAB4D5-8 to
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`produce the claim-recited immunoconjugates “based on the teachings of
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`Chari 1992 and HERCEPTIN® Label, as well as the general knowledge in
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`the art at that time.” Pet. 13–14.
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`Specifically, Petitioner contends that an ordinary artisan would have
`
`been motivated to do such a substitution because it was known that:
`
`(1) humanized mAbs, such as huMAB4D5-8, were preferred over their
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`mouse-derived counterparts for clinical applications, as indicated in Chari
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`1992 (Ex. 1012, 130, 1st col.); (2) huMAB4D5-8 selectively bound with
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`high affinity to HER2 and had been approved for use to treat breast tumors
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`in humans, as indicated in the HERCEPTIN® Label; and (3) clinical studies
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`indicated that huMAB4D5-8 worked well in combination with microtubule-
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`directed chemotherapy agents for the treatment of breast cancer, as indicated
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`in the HERCEPTIN® Label (Ex. 1008, 1, 1st col.). Pet. 13–15.
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`In addition, Petitioner contends that an ordinary artisan would have
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`had a reasonable expectation of success regarding the recited
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`immunoconjugates because it was known that: (1) huMAB4D5-8 was more
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`effective in treating breast cancer when used in combination with the
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`microtubule targeting drug paclitaxel, as described in the HERCEPTIN®
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`Label; (2) Chari 1992’s maytansinoid conjugates targeted the same cells as
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`huMAB4D5-8; and (3) an immunoconjugate containing a humanized
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`antibody was less immunogenic, and therefore more effective in humans,
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`than an immunoconjugate containing a mouse antibody. Id. at 16.
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`Petitioner also contends that other prior art references, such as
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`Rosenblum 1999 and Pegram 1999, provided additional reasons to use the
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`humanized antibody disclosed in the HERCEPTIN® Label in the
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`immunoconjugate of Chari 1992, with a reasonable expectation of success.
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`Id. at 19–22. Petitioner refers to, for example, the in vivo efficacy data of a
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`similar immunoconjugate, as taught in Rosenblum 1999. Id. at 20 (citing
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`Ex.1018, Figs. 12 and 13; Ex. 1016 ¶ 18). Petitioner also notes that Pegram
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`1999 states that “ʻ[t]he synergistic interaction of rhuMab HER2 with
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`alkylating agents . . . as well as the additive interaction with taxanes, . . . in
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`HER-2/neu-overexpressing breast cancer cells demonstrates that these are
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`rational combinations to test in human clinical trials’ (emphasis added).”
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`Id. at 22 (quoting Ex. 1020, Abstract). Petitioner contends that Pegram 1999
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`indicates a reasonable expectation of success because it suggested that
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`HERCEPTIN® and maytansinoid may act independently and have an
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`additive effort in inhibiting the growth of breast tumor cells. Id. (citing
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`Ex. 1016 ¶ 21).
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`Petitioner also refers to teachings in prior art references, such as in
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`Pegram 1999 and the HERCEPTIN® Label, which disclose synergistic or
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`additive effects between HERCEPTIN® and other chemotherapeutic agents,
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`such as the antimicrotubule agent paclitaxel. Id. at 49. Petitioner also
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`contends that Chari 1992 taught that “maytansinoid immunoconjugates were
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`demonstrated to be substantially free of toxicity, based on the same kinds of
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`assays described in the ’856 patent.” Id. at 54–55 (citing Ex. 1012, Abstract,
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`129, 1st col., 130 1st col.). Petitioner further cites Liu (Ex. 1023)5 and Chari
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`1998 (Ex. 1015)6 to rebut the position that one would have expected
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`“unacceptable cytotoxic side effects for such an immunoconjugate,” and that
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`nothing before the ’856 patent addressed “the unpredictability in the art” in
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`relation to a reasonable expectation of success. Pet. 55–57 (citing Ex. 1028
`
`¶ 14).
`
`
`
`5 Liu et al., Eradication of large colon tumor xenografts by targeted
`delivery of maytansinoids, 93 PROC. NATL. ACAD. SCI., USA 8618–8623
`(1996) (Ex. 1023).
`6 Chari, Targeted delivery of chemotherapeutics: tumor-activated prodrug
`therapy, 31 ADV. DRUG DEL. REV. 89–104 (1998) (Ex. 1015).
`
`14
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`6. Analysis regarding claims 1–8
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`In response to the Petition, Patent Owner argues that Petitioner has not
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`established a prima facie case that claims 1–8 would have been obvious over
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`the cited art. PO Resp. 2–26. Patent Owner contends that an ordinary
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`artisan would not have had a reason to substitute the mouse monoclonal
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`TA.1 antibody in the immunoconjugate of Chari 1992 with the humanized
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`mAb huMAB4D5-8, i.e., Herceptin®. Id. at 1–3.
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`As noted above, Petitioner argues that an ordinary artisan would have
`
`had reason to substitute the mouse monoclonal TA.1 antibody in the
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`immunoconjugate of Chari 1992 with huMAB4D5-8 (HERCEPTIN®) in
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`particular because it was known that (1) humanized antibodies were
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`preferred over mouse counterparts for clinical applications, (2) huMAB4D5-
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`8 had been FDA approved for use to treat breast tumors in humans, and (3)
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`clinical studies indicated that huMAB4D5-8 worked well in combination
`
`with microtubule-directed chemotherapy agents for the treatment of breast
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`cancer. Pet. 14–15 (citing Ex. 1012, 130; Ex. 1008, 1); see also id. at 19–20
`
`(stating that “Rosenblum 1999 teaches the use, efficacy and safety of an
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`immunotoxin having humanized ErbB2 extracellular domain-targeted
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`monoclonal antibody chemically linked to a cytotoxic moiety”); id. at 22
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`(stating that Pegram 1999 suggested that HERCEPTIN® and maytansinoid
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`had “an additive effort in inhibiting the growth of breast tumor cells”).
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`Petitioner also relies on different prior art references when arguing that one
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`would have had an expectation of success in using the immunoconjugate to
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`treat breast cancer in humans. Id. at 16–17; Ex. 1016 ¶ 16.
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`15
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`In other words, when asserting that an ordinary artisan would have
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`had a reason to combine certain teachings in the cited references and,
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`therefore, prepare a HERCEPTIN®-maytansinoid immunoconjugate,
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`Petitioner relies on the position that an ordinary artisan would have expected
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`such an immunoconjugate to work clinically to treat tumors in humans upon
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`reading the cited references.
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`Patent Owner provides persuasive evidence, however, that in March
`
`2000, at the time the ’856 patent was filed, prior art indicated that
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`HERCEPTIN®-maytansinoid immunoconjugates would have been expected
`
`to exhibit unacceptable levels of antigen-dependent toxicity in normal
`
`human liver tissue in patients. PO Resp. 1–13. For example, Patent Owner
`
`points to Pai-Scherf 1999 (Ex. 2029),7 which describes a Phase I clinical
`
`study of human patients receiving an immunoconjugate (erb-38) comprising
`
`a portion of the anti-HER2 monoclonal antibody e23 fused to a truncated
`
`form of Pseudomonas exotoxin A. As stated by Patent Owner, although the
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`Pai-Scherf group “initiated the study in humans based on ‘excellent
`
`antitumor activity and acceptable animal toxicities,’” it nonetheless observed
`
`unacceptable hepatotoxicity in all patients in the treatment group. PO Resp.
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`4 (citing Ex. 2029, 2311, 2nd col., Abstract).
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`Pai-Scherf 1999 indicates that, in a clinical study, human patients
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`experienced “hepatic injury” when exposed to erb-38. Ex. 2029, 2313–14.
`
`
`
`7 Pai-Scherf et al., Hepatotoxicity in Cancer Patients Receiving erb-38, a
`Recombinant Immunotoxin That Targets the erbB2 Receptor, 5 CLINICAL
`CANCER RESEARCH 2311–15 (1999) (Ex. 2029).
`
`16
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`Pai-Scherf 1999 discloses that the “toxicity of erb-38 is most likely due to
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`the presence of erbB2 on hepatocytes, not detected by immunohistochemical
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`staining in earlier publications.” Id. at 2314, 1st col., 2315, 1st col. The
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`reference further discloses that “[d]espite the fact that there is a very large
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`difference in the amount of erbB2 on the surface of cancer cells relative to
`
`the small amount present on liver cells, liver toxicity was the first biological
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`effect seen in this study.” Id. at 2314, 2nd col. Pai-Scherf 1999 explains
`
`that a factor contributing to this finding is that “hepatocytes [normal liver
`
`cells] are more rapidly exposed to agents injected into the circulation than
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`tumor cells,” because “mixing within tumors is solely by diffusion and,
`
`therefore, very slow,” and “tumors are often poorly vascularized.” Id.
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`Pai-Scherf 1999 also discusses HERCEPTIN® in particular, noting
`
`that the “antibody alone has been found to produce objective responses in
`
`breast cancer and when combined with chemotherapy results in an increased
`
`response rate.” Id. Pai-Scherf 1999 states that “[i]t is likely that the
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`antitumor activity of the antibody in this setting is dependent on genetic
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`perturbations that alter the configuration of downstream signaling events,”
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`where “the mechanism of killing depends on a genetic abnormality present
`
`in the cancer cells.” Id. at 2314, 2nd col. – 2315, 1st col. By contrast,
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`according to Pai-Scherf 1999, “if the antibody is used to deliver a cytotoxic
`
`agent, such as a bacterial toxin or radioisotope, the death of the target cell
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`will be principally dependent on the amount of agent delivered to the cell.”
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`Id. at 2315, 1st col. Thus, Pai-Scherf 1999 indicates that the mechanism of
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`cytotoxicity of the antibody alone differs from that of the antibody
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`17
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`conjugated to a toxin. In this context, Pai-Scherf 1999 concludes that “the
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`toxicity observed with erb-38 is most likely due to the presence of erbB2 on
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`hepatocytes,” and the “targeting of tumors with antibodies to erbB2 that are
`
`armed with . . . toxic agents may result in unexpected organ toxicities due to
`
`erbB2 expression on normal tissues.” Id. at 2315, 2nd col.
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`Patent Owner further cites evidence indicating that HERCEPTIN® and
`
`maytansinoids each caused toxicity to normal human cells, including liver
`
`cells, on their own. PO Resp. 7–13; Ex 1008, 1, 2nd col., 2, 2nd col.
`
`(observing heart toxicity generally, and “hepatic failure” in at least one
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`patient); PO Resp. 7–8 (citing a number of exhibit references discussing
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`hepatic toxicity and injury upon administering maytansinoids to patients).
`
`In response, Petitioner contends that Pai-Scherf 1999 is not relevant to
`
`our analysis because it describes the use of a “fusion protein,” not an
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`antibody-drug conjugate. Reply 4–6. We disagree that Pai-Scherf 1999 is
`
`not relevant. Although the reference discloses clinical studies using a
`
`“single-chain” immunoconjugate comprising a portion of an anti-
`
`HER2/erbB2 antibody and a truncated form of a toxin, Pai-Scherf 1999
`
`discusses generally the “targeting of tumors with antibodies to erbB2 armed
`
`with radioisotopes or other toxic agents.” Ex. 2029, 2311, Abstract, 2315,
`
`2nd col. As noted above, the reference also expressly states that the
`
`“toxicity of erb-38 is most likely due to the presence of erbB2 on
`
`hepatocytes,” i.e., normal liver cells that “are more rapidly exposed to agents
`
`in