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
`
`
`
`
`
`
`
`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
`
`Phigenix Inc. (“Petitioner”) filed a Petition requesting inter partes
`
`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
`
`Response. Paper 10 (“Prelim. Resp.”). Thereafter, we determined that the
`
`information presented in the Petition demonstrated that there was a
`
`reasonable likelihood that Petitioner would prevail in showing claims 1–8 as
`
`unpatentable. Paper 11 (“Dec. to Inst.”), 2, 23. Pursuant to 35 U.S.C. § 314,
`
`we instituted this proceeding on October 29, 2014, to review whether claims
`
`1–8 of the ’856 patent would have been obvious under 35 U.S.C. § 103 over
`
`Chari 19921 in view of the HERCEPTIN® Label,2 further in view of
`
`Rosenblum 19993 and Pegram 1999.4 Id. at 23.
`
`After institution of trial, Patent Owner filed a Patent Owner Response.
`
`Paper 18 (“PO Resp.”), and Petitioner filed a Reply to the Response. Paper
`
`
`
`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
`
`submitted by Patent Owner. Paper 28. Patent Owner responded by filing an
`
`Opposition to the Motion to Exclude (Paper 29), as well as an unopposed
`
`Motion to Seal two exhibits filed by Patent Owner in connection with the
`
`Opposition (Paper 31, 1). Petitioner filed a Reply to the Opposition to the
`
`Motion to Exclude. Paper 35.
`
`An oral hearing was held on July 9, 2015. A transcript of the hearing
`
`has been entered into the record. Paper 38 (“Tr.”).
`
`We have jurisdiction under 35 U.S.C. § 6(c). This Final Written
`
`Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`
`For the reasons that follow, we determine that Petitioner has not shown by a
`
`preponderance of the evidence that claims 1–8 of the ’856 patent are
`
`unpatentable. We deny Petitioner’s Motion to Exclude Evidence, and we
`
`grant Patent Owner’s Motion to Seal.
`
`A. Related Proceeding
`
`About a month after filing the current Petition, Petitioner filed a
`
`Petition requesting inter partes review of claims 1–20 and 25–27 of U.S.
`
`Patent No. 7,575,748 (“the ’748 patent”) in Case No. IPR2014-00842.
`
`Patent Owner of the ’748 patent, Genentech, Inc., a real party-in-interest in
`
`the current proceeding, filed a Preliminary Response. IPR2014-00842,
`
`Paper 9. On December 9, 2014, we declined to institute review in that case.
`
`Phigenix, Inc. v. Genentech, Inc. and ImmunoGen, Inc., Case IPR2014-
`
`00842 (PTAB Dec. 9, 2014) (Paper 10).
`
`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
`
`U.S. Patent No. 7,097,840 (“the ’840 patent”). IPR2014-00842, Ex. 1001.
`
`The ’856 patent, at issue here, is a divisional application of a continuation
`
`application of the ’840 patent. Ex. 1001.
`
`B. The ’856 Patent (Ex. 1001)
`
`The ’856 patent relates to immunoconjugates comprising an anti-ErbB
`
`antibody, such as the humanized anti-ErbB2 antibody known as
`
`HERCEPTIN® (huMAb4D5-8), linked to a maytansinoid toxin. Ex. 1001,
`
`1:20–52, 35:47–36:39; see also id. at 3:6–16 (discussing HERCEPTIN®),
`
`6:50–67 (defining “ErbB2”), 10:40–52 (defining “humanized”), 16:23–28
`
`(defining “epitope 4D5”).
`
`The term “ErbB2” is synonymous with “HER2,” “p185neu”, or “neu,”
`
`and refers to a member of the ErbB family of receptor tyrosine kinases,
`
`which mediate cell growth, differentiation, and survival. Id. at 1:45–60,
`
`6:50–58. Overexpression of ErbB2 on cell surfaces can lead to cancer in
`
`humans, such as certain breast and ovarian cancers. Id. at 1:54–66, 8:55–60.
`
`The specification teaches that maytansinoids, such as DM1, are highly
`
`cytotoxic, i.e., inhibit or prevent cell function and/or destroy cells, but
`
`induce “severe systemic side-effects primarily attributed to their poor
`
`selectivity for tumors” when administered alone. Id. at 1:38–44, 17:45–52;
`
`see also id. at 5:7–13 (referring to Figure 3, showing the structure of the
`
`maytansinoid designated “DM1”). The specification describes making anti-
`
`ErbB antibody-maytansinoid conjugates using “a variety of bifunctional
`
`protein coupling agents,” i.e., linkers, such as N-succinimidyl-3-(2-
`
`4
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`IPR2014-00676
`Patent 8,337,856 B2
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`pyridyldithio)propionate (“SPDP”), N-succinimidyl-4-(2-
`
`pyridylthio)pentanoate (“SPP”), and succinimidyl-4-(N-maleimidomethyl)-
`
`cyclohexane-1-carboxylate (“SMCC”). Id. at 36:13–31.
`
`The specification states that the “present invention is based on results
`
`obtained in a novel murine HER2-transgenic tumor model in which
`
`HERCEPTIN® or the murine antibody 4D5 from which HERCEPTIN® was
`
`derived, had little effect on tumor growth.” Id. at 21:65–22:1. In this
`
`context, the specification states that “it was surprisingly found that while the
`
`transplanted tumor obtained from such transgenic mice responded poorly to
`
`HERCEPTIN® treatment, the HERCEPTIN®-maytansinoid conjugates were
`
`highly efficacious.” Id. at 22:2–7.
`
`C. The Challenged Claims
`
`Petitioner challenges claims 1–8 of the ’856 patent. Of those, only
`
`claim 1 is independent, which recites:
`
`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
`
`via a disulfide or thioether group at “R” shown in the structure. Id. at 81:31–
`
`53. Dependent claim 3 requires that the immunoconjugate “comprises from
`
`3 to 5 maytansinoid molecules per antibody molecule.” Id. at 82:27–30.
`
`Dependent claim 5 recites a pharmaceutical composition comprising the
`
`immunoconjugate and a pharmaceutically acceptable carrier. Id. at 82:37–
`
`39. Claims 4 and 6–8, which ultimately depend on claim 1 or 2, recite that
`5
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`the antibody and maytansinoid are conjugated by specific chemical linkers,
`
`i.e., SPDP, SPP, or SMCC. Id. at 82:30–36, 39–51.
`
`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.
`
`37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 793 F.3d 1268,
`
`1278–79 (Fed. Cir. 2015). Claim terms are given their ordinary and
`
`customary meaning, as would be understood by one of ordinary skill in the
`
`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
`
`must be set forth in the specification with reasonable clarity, deliberateness,
`
`and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`
`As noted in our Decision to Institute, Petitioner offers claim
`
`construction of the phrase “pharmaceutically-acceptable carrier,” recited in
`
`dependent claim 5, as “including ‘bacteriostatic water for injection (BWFI),
`
`phosphate-buffered saline, Ringer’s solution and dextrose solution.’” Dec.
`
`to Inst. 6–7 (citing Pet. 7 (citing Ex. 1001, 42:4–9)). Patent Owner does not
`
`dispute this claim construction, nor offer construction of other claims terms.
`
`Based on the record currently available, Petitioner’s proposed construction is
`
`the broadest reasonable construction of the phrase. We construe other claim
`
`terms as carrying their ordinary meaning, consistent with their use in the
`
`specification.
`
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`B. Obviousness over Chari 1992 in view of HERCEPTIN® Label,
`further in view of Rosenblum 1999 and Pegram 1999
`
`Petitioner contends that claims 1–8 would have been obvious over
`
`Chari 1992 in view of the HERCEPTIN® Label, further in view of
`
`Rosenblum 1999 and Pegram 1999, relying on a Declaration by Michael G.
`
`Rosenblum, Ph.D. (Ex. 1016). Pet. 8–22. Patent Owner contends otherwise,
`
`relying on a Declaration by Geoffrey A. Pietersz, Ph.D. (Ex. 2134), as well
`
`as Declarations by Linda T. Vahdat, M.D. (Ex. 2103), Joyce
`
`O’Shaughnessy, M.D. (Ex. 2105), and John C. Jarosz (Ex. 2131) in relation
`
`to objective indicia of non-obviousness. PO Resp. 2–60.
`
`1. Chari 1992 (Ex. 1012)
`
`Chari 1992 describes immunoconjugates comprising an anti-ErbB2
`
`mouse monoclonal antibody, TA.1, chemically coupled to the maytansinoid
`
`toxin, DM1, using SPDP or SMCC as a linker. Ex. 1012, 128–129; id. at
`
`Fig. 2 (see maytansinoid 3 and figure legend). As stated in Chari 1992, the
`
`TA.1 antibody binds HER-2/neu oncogene protein (i.e., ErbB2), which is
`
`expressed at high levels on human breast tumor cells. Id. at 129, 1st col.,
`
`1st ¶. The reference discloses conjugates having a range of one to six
`
`maytansinoid molecules per antibody molecule, such as four maytansinoid
`
`molecules per antibody molecule. Id., see also id. at 2nd col., Table 2.
`
`Chari 1992 teaches that the conjugates, called “TA.1(-SS-May)n,”
`
`were cytotoxic when tested in vitro on the human breast cancer cell line, SK-
`
`BR-2. Id. at 129, 1st col., 2nd ¶, 2nd col. Fig. 3. In addition, the reference
`
`teaches that conjugate TA.1(-SS-May)4 was at least 1000-fold less cytotoxic
`
`7
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`toward neu-negative KB cells in tissue culture. Id. It teaches that
`
`cytotoxicity can be increased by linking more maytansinoid molecules per
`
`antibody molecule, “and it reached its maximum value at n = 4 (Table 2).”
`
`Id. at 1st col., 3rd ¶. The reference also discloses that conjugate A7(-SS-
`
`May)6, where A7 is an antibody directed against a human colon cancer cell
`
`line antigen, shows similar cytotoxicity results and is not toxic in mice. Id.
`
`at 1st col., 3rd ¶ – 2nd col., 2nd ¶.
`
`Chari 1992 states that the “high specific cytotoxicity of maytansinoid
`
`conjugates toward tumor cell lines in conjunction with their low systemic
`
`toxicity indicates that these potent conjugates may possess a therapeutic
`
`index sufficient for the effective treatment of human cancer.” Id. at 130, 1st
`
`col., 2nd ¶; see also id. at 127, Abstract (stating that the immunoconjugates
`
`“show high antigen-specific cytotoxicity for cultured human cancer cells
`
`. . . , low systemic toxicity in mice, and good pharmacokinetic behavior”). It
`
`also states that the “development of ‘humanized’ antibodies will offer an
`
`opportunity to produce drug conjugates that would be less immunogenic
`
`than similar conjugates of murine antibodies.” Id. at 130, 1st col., 3rd ¶.
`
`2. HERCEPTIN® Label (Ex. 1008)
`
`The HERCEPTIN® Label describes HERCEPTIN®, also known as
`
`Trastuzumab or huMAB4D5-8, as a humanized form of the mouse
`
`monoclonal antibody 4D5, which binds HER2/ErbB2. Ex. 1008, 1, 1st col.
`
`The Label describes intravenous injection administration of HERCEPTIN®
`
`after reconstitution with “Bacteriostatic Water for Injection (BWFI),” among
`
`other components. Id. at 1st col.
`
`8
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`The Label describes HERCEPTIN® as being indicated for “the
`
`treatment of patients with metastatic breast cancer whose tumors
`
`overexpress the HER2 protein and who have received one or more
`
`chemotherapy regimens for their metastatic disease.” Id. at 2nd col. In
`
`addition, the Label describes HERCEPTIN® in combination with paclitaxel
`
`as being “indicated for treatment of patients with metastatic breast cancer
`
`whose tumors overexpress the HER2 protein and who have not received
`
`chemotherapy for their metastatic disease.” Id.
`
`Table 1 in the Label shows clinical trial data regarding “Phase III
`
`Clinical Efficacy in First-Line Treatment” in patients treated with
`
`chemotherapy alone or chemotherapy combined with HERCEPTIN®. Id. at
`
`1st col. The Label states that “[c]ompared with patients randomized to
`
`chemotherapy alone, the patients randomized to HERCEPTIN and
`
`chemotherapy experienced a significantly longer time to disease progression,
`
`a higher overall response rate (ORR), a longer median duration of response,
`
`and a higher one-year survival rate.” Id. (citing Table 1).
`
`3. Rosenblum 1999 (Ex. 1018)
`
`Rosenblum 1999 discloses an immunoconjugate comprising an anti-
`
`ErbB2 human chimeric antibody (“BACH-250”) chemically coupled to a
`
`ribosomal-inhibiting plant toxin gelonin (“rGel”), using SPDP as a linker.
`
`Ex. 1018, 865, Abstract, 866, 2nd col. Immunoconjugates, antibodies alone,
`
`and toxin alone, were tested in vitro against human tumor cells expressing
`
`various levels of HER2, and in vivo against human tumor xenograft models
`
`(athymic mice bearing s.c. or i.p. SKOV-3 tumors). Id. at Abstract.
`
`9
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`The reference states that although “binding of both BACH-250 and
`
`BACH-250/rGel conjugate to target cells was essentially equivalent,” in
`
`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.”
`
`Id. The reference also states there “was a clear correlation between
`
`expression levels of HER-2/neu and cytoimmunotoxin.” Id.; see also id. at
`
`869, 1st col. (stating that cytotoxic effects of TAB-250/rGel (mouse
`
`antibody conjugate) was greatest against the SKBR-3 cell line having the
`
`highest number of cell surface HER2, as compared to other cell lines
`
`expressing lower levels).
`
`In in vivo xenograft studies in mice using BACH-250 conjugates,
`
`“immunotoxin treatment slowed tumor growth by 99 and 94% at days 35
`
`and 49 after implantation, respectively, and lengthened the median survival
`
`by 40% (from 30 to 50 days) in mice bearing lethal i.p. tumors.” Id. at
`
`Abstract, 871–872 (describing “impressive antitumor effects” as compared
`
`to tumor growth in control groups). Rosenblum 1999 concluded “that
`
`clinical development of BACH-250/rGel may be warranted in patients with
`
`HER2/neu-expressing malignancies.” Id. at Abstract.
`
`4. Pegram 1999 (Ex.1020)
`
`Pegram 1999 states that “[p]revious studies have demonstrated a
`
`synergistic interaction between rhuMAb HER2 and the cytotoxic drug
`
`cisplatin in human breast and ovarian cancer cells.” Ex. 1020, 2241,
`
`Abstract. Pegram 1999 conducted studies in “preclinical models in vitro and
`
`in vivo” using rhuMAb HER2 in combination with other cytotoxic drugs.
`
`10
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`Id., see also id. at 2241, 2nd col., 2242, 2nd col. The reference describes
`
`observing “[s]ynergistic interactions at clinically relevant drug
`
`concentrations” for rhuMAb HER2 in combination with cisplatin, thiotepa,
`
`or etoposide, and “[a]dditive cytotoxic effects” with rhuMAb HER2 plus
`
`doxorubicin, paclitaxel, methotrexate, or vinblastine. Id. at Abstract.
`
`The reference indicates that “rhuMAb HER2” is a recombinant,
`
`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
`
`p185HER-2/neu but has similar specific antiproliferative activity against HER-
`
`2/neu-overexpressing cell lines and xenografts.” Id. The reference also
`
`states that in in vivo studies using human breast cancer xenografts in athymic
`
`mice, vinblastine (“VBL”), a microtubule inhibitor, combined with rhuMAb
`
`HER2 “significantly reduced MCF7/HER-2 xenograft volume compared to
`
`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).
`
`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-
`
`11
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`ErbB2 antibody conjugated to a maytansinoid, such as DMI having the
`
`structure recited in claim 2, where the immunoconjugate comprises four
`
`maytansinoid molecules per antibody molecule (as recited in claim 3), and
`
`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
`
`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
`
`pharmaceutically acceptable carrier, i.e., Bacteriostatic Water for Injection.
`
`Pet. 13 (citing Ex. 1008, 1). Most relevant to our analysis, Petitioner further
`
`contends, relying on the Rosenblum Declaration (Ex. 1016), that it would
`
`have been obvious to the ordinarily skilled artisan, at the time the ’856
`
`patent was filed, to substitute the mouse monoclonal TA.1 antibody in the
`
`immunoconjugate of Chari 1992 with the humanized mAb huMAB4D5-8 to
`
`produce the claim-recited immunoconjugates “based on the teachings of
`
`Chari 1992 and HERCEPTIN® Label, as well as the general knowledge in
`
`the art at that time.” Pet. 13–14.
`
`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
`
`mouse-derived counterparts for clinical applications, as indicated in Chari
`
`1992 (Ex. 1012, 130, 1st col.); (2) huMAB4D5-8 selectively bound with
`
`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
`
`indicated that huMAB4D5-8 worked well in combination with microtubule-
`
`directed chemotherapy agents for the treatment of breast cancer, as indicated
`
`in the HERCEPTIN® Label (Ex. 1008, 1, 1st col.). Pet. 13–15.
`
`In addition, Petitioner contends that an ordinary artisan would have
`
`had a reasonable expectation of success regarding the recited
`
`immunoconjugates because it was known that: (1) huMAB4D5-8 was more
`
`effective in treating breast cancer when used in combination with the
`
`microtubule targeting drug paclitaxel, as described in the HERCEPTIN®
`
`Label; (2) Chari 1992’s maytansinoid conjugates targeted the same cells as
`
`huMAB4D5-8; and (3) an immunoconjugate containing a humanized
`
`antibody was less immunogenic, and therefore more effective in humans,
`
`than an immunoconjugate containing a mouse antibody. Id. at 16.
`
`Petitioner also contends that other prior art references, such as
`
`Rosenblum 1999 and Pegram 1999, provided additional reasons to use the
`
`humanized antibody disclosed in the HERCEPTIN® Label in the
`
`immunoconjugate of Chari 1992, with a reasonable expectation of success.
`
`Id. at 19–22. Petitioner refers to, for example, the in vivo efficacy data of a
`
`similar immunoconjugate, as taught in Rosenblum 1999. Id. at 20 (citing
`
`Ex.1018, Figs. 12 and 13; Ex. 1016 ¶ 18). Petitioner also notes that Pegram
`
`1999 states that “ʻ[t]he synergistic interaction of rhuMab HER2 with
`
`alkylating agents . . . as well as the additive interaction with taxanes, . . . in
`
`HER-2/neu-overexpressing breast cancer cells demonstrates that these are
`
`rational combinations to test in human clinical trials’ (emphasis added).”
`
`13
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`Id. at 22 (quoting Ex. 1020, Abstract). Petitioner contends that Pegram 1999
`
`indicates a reasonable expectation of success because it suggested that
`
`HERCEPTIN® and maytansinoid may act independently and have an
`
`additive effort in inhibiting the growth of breast tumor cells. Id. (citing
`
`Ex. 1016 ¶ 21).
`
`Petitioner also refers to teachings in prior art references, such as in
`
`Pegram 1999 and the HERCEPTIN® Label, which disclose synergistic or
`
`additive effects between HERCEPTIN® and other chemotherapeutic agents,
`
`such as the antimicrotubule agent paclitaxel. Id. at 49. Petitioner also
`
`contends that Chari 1992 taught that “maytansinoid immunoconjugates were
`
`demonstrated to be substantially free of toxicity, based on the same kinds of
`
`assays described in the ’856 patent.” Id. at 54–55 (citing Ex. 1012, Abstract,
`
`129, 1st col., 130 1st col.). Petitioner further cites Liu (Ex. 1023)5 and Chari
`
`1998 (Ex. 1015)6 to rebut the position that one would have expected
`
`“unacceptable cytotoxic side effects for such an immunoconjugate,” and that
`
`nothing before the ’856 patent addressed “the unpredictability in the art” in
`
`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
`
`In response to the Petition, Patent Owner argues that Petitioner has not
`
`established a prima facie case that claims 1–8 would have been obvious over
`
`the cited art. PO Resp. 2–26. Patent Owner contends that an ordinary
`
`artisan would not have had a reason to substitute the mouse monoclonal
`
`TA.1 antibody in the immunoconjugate of Chari 1992 with the humanized
`
`mAb huMAB4D5-8, i.e., Herceptin®. Id. at 1–3.
`
`As noted above, Petitioner argues that an ordinary artisan would have
`
`had reason to substitute the mouse monoclonal TA.1 antibody in the
`
`immunoconjugate of Chari 1992 with huMAB4D5-8 (HERCEPTIN®) in
`
`particular because it was known that (1) humanized antibodies were
`
`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)
`
`clinical studies indicated that huMAB4D5-8 worked well in combination
`
`with microtubule-directed chemotherapy agents for the treatment of breast
`
`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
`
`immunotoxin having humanized ErbB2 extracellular domain-targeted
`
`monoclonal antibody chemically linked to a cytotoxic moiety”); id. at 22
`
`(stating that Pegram 1999 suggested that HERCEPTIN® and maytansinoid
`
`had “an additive effort in inhibiting the growth of breast tumor cells”).
`
`Petitioner also relies on different prior art references when arguing that one
`
`would have had an expectation of success in using the immunoconjugate to
`
`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
`
`had a reason to combine certain teachings in the cited references and,
`
`therefore, prepare a HERCEPTIN®-maytansinoid immunoconjugate,
`
`Petitioner relies on the position that an ordinary artisan would have expected
`
`such an immunoconjugate to work clinically to treat tumors in humans upon
`
`reading the cited references.
`
`Patent Owner provides persuasive evidence, however, that in March
`
`2000, at the time the ’856 patent was filed, prior art indicated that
`
`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
`
`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.
`
`4 (citing Ex. 2029, 2311, 2nd col., Abstract).
`
`Pai-Scherf 1999 indicates that, in a clinical study, human patients
`
`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
`
`the presence of erbB2 on hepatocytes, not detected by immunohistochemical
`
`staining in earlier publications.” Id. at 2314, 1st col., 2315, 1st col. The
`
`reference further discloses that “[d]espite the fact that there is a very large
`
`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
`
`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
`
`tumor cells,” because “mixing within tumors is solely by diffusion and,
`
`therefore, very slow,” and “tumors are often poorly vascularized.” Id.
`
`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
`
`antitumor activity of the antibody in this setting is dependent on genetic
`
`perturbations that alter the configuration of downstream signaling events,”
`
`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,
`
`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
`
`will be principally dependent on the amount of agent delivered to the cell.”
`
`Id. at 2315, 1st col. Thus, Pai-Scherf 1999 indicates that the mechanism of
`
`cytotoxicity of the antibody alone differs from that of the antibody
`
`17
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`IPR2014-00676
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`conjugated to a toxin. In this context, Pai-Scherf 1999 concludes that “the
`
`toxicity observed with erb-38 is most likely due to the presence of erbB2 on
`
`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.
`
`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
`
`patient); PO Resp. 7–8 (citing a number of exhibit references discussing
`
`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
`
`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
`
`injected into the circulation than tumor cells” (Ex. 2029, 2314, 1st and 2nd
`
`col.)—a situation equally applicable when using a full-length anti-HER2
`
`18
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`antibody linked to a toxin, i.e., “an antibody-drug conjugate,” as Petitioner
`
`calls it. Reply 5; PO Resp. 20 (citing Ex. 2111, 8987, 2nd col. (stating that
`
`“treatment of solid tumors presents a potential problem because full-length
`
`antibodies must diffuse into the tumor against a hydrostatic pressure gradient
`
`and into disordered vasculature”)).
`
`Patent Owner persuades us that one would have considered the
`
`teachings of Pai-Scherf 1999 when reading Chari 1992, the HERCEPTIN®
`
`Label, as well as other references cited by Petitioner, such as Rosenblum
`
`1999 and Pegram 1999. Chari 1992 states generally, based on
`
`clearance/degradation studies in mice and in vitro cytotoxicity studies on
`
`human cells in tissue culture, that maytansinoid conjugates “may possess a
`
`therapeutic index sufficient for the effective treatment of human cancer,”
`
`and “development of ‘humanized’ antibodies will offer an opportunity to
`
`produce drug conjugates.” Ex. 1012, 130. Petitioner does not establish by a
`
`preponderance of the evidence that those general statements in Chari 1992,
`
`in view of teachings years later in the HERCEPTIN® Label, Pai-Scherf
`
`1999, and other references regarding liver toxicities, would have motivated
`
`an ordinary artisan to substitute the mouse TA.1 antibody in the
`
`immunoconjugate of Chari 1992 with HERCEPTIN® on the basis that one
`
`would have expected that modified immunoconjugate to work to treat
`
`human tumors. Pet. 14–15 (citing Ex. 1016 ¶¶ 12–15); PO Resp. 5–6, 19;
`
`Ex. 2134 ¶¶ 29, 52–57.
`
`Petitioner’s citation to Rosenblum 1999 and Pegram 1999, which
`
`disclose the testing of other anti-HER2-toxin immunoconjugates or
`
`19
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`IPR2014-00676
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`combinations of antibodies and toxins (using different anti-HER2 antibodies
`
`and different toxins) in in vitro tissue culture, and in vivo in mice expressing
`
`human tumors (mouse xenograft models), does not persuade us otherwise.8
`
`Pet. 17–22; Reply 6–8, 11–12. Patent Owner persuades us that an ordinary
`
`artisan would have understood that such studies would not have provided
`
`adequate information regarding toxicities to normal human cells in vivo. PO
`
`Resp. 12–13, 23–24; Ex. 2134 ¶¶ 22–27, 51. By contrast, the human clinical
`
`study in Pai-Scherf 1999 provided such information and observed
`
`hepatotoxicity when using a relevant immunoconjugate and suggested
`
`“unexpected organ toxicities due to erbB2 [HER2 expression] on normal
`
`cells” in relation to all anti-HER2 antibodies linked to toxins. Ex. 2029,
`
`Abstract.
`
`To establish that t
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