Paper 11
`Trials@uspto.gov
`571-272-7822 Entered: October 29, 2014
`
`
`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.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`

`

`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.”). We have jurisdiction under 35 U.S.C. § 314(a), which provides
`
`that an inter partes review may not be instituted “unless . . . there is a reasonable
`
`likelihood that the petitioner would prevail with respect to at least 1 of the claims
`
`challenged in the petition.”
`
`Upon consideration of the Petition and the Preliminary Response, and for the
`
`reasons explained below, we determine that Petitioner has shown that there is a
`
`reasonable likelihood that it would prevail with respect to at least one of the
`
`challenged claims. We institute an inter partes review of claims 1-8 of the ’856
`
`patent.
`
`A. Related Proceeding
`
`On May 29, 2014, five weeks 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. The ’748 patent 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. Claims of
`
`the ’748 patent are directed to methods for treating a tumor comprising
`
`administering an immunoconjugate. IPR2014-00842, Ex. 1001, cols. 81-84. As
`
`2
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`IPR2014-00676
`Patent 8,337,856 B2
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`discussed below, the claims of the ’856 patent are directed to immunoconjugate
`
`compounds.
`
`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
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`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-pyridyldithio)propionate (“SPDP”), N-succinimidyl-
`
`4-(2-pyridylthio)pentanoate (“SPP”), and succinimidyl-4-(N-maleimidomethyl)-
`
`cyclohexane-l-carboxylate (“SMCC”). Id. at 36:13-31.
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`3
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`IPR2014-00676
`Patent 8,337,856 B2
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`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
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`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 the antibody and maytansinoid are
`
`conjugated by specific chemical linkers, i.e., SPDP, SPP, or SMCC. Id. at 82:30-
`
`36, 39-51.
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`4
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`IPR2014-00676
`Patent 8,337,856 B2
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`D. Asserted Grounds of Unpatentability
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`Petitioner contends that the challenged claims are unpatentable under
`
`35 U.S.C. § 103(a) based on the following grounds. Pet. 8.
`
`
`
`References
`
`Basis Claims Challenged
`
`1 Chari 1992 (Ex. 1012)1 in view of HERCEPTIN®
`Label (Ex. 1008)2
`
`2 Chari 1992 and HERCEPTIN® Label, further in
`view of Hudziak 1998 (Ex. 1017)3 and/or
`Rosenblum 1999 (Ex. 1018)4
`
`3 Chari 1992 and HERCEPTIN® Label, further in
`view of Hudziak 1998 and/or Rosenblum 1999,
`and further in view of Baselga 1998 (Ex. 1019)5
`and/or Pegram 1999 (Ex.1020)6
`
`§ 103 1-8
`
`§ 103 1-8
`
`§ 103 1-8
`
`4 Chari 1992 and HERCEPTIN® Label, further in view
`of Morgan 1990 (Ex. 1021)7
`
`§ 103 6, 8
`
`
`
`1 Chari et al., “Immunoconjugates Containing Novel Maytansinoids: Promising
`Anticancer Drugs,” 52 CANCER RES.127-131 (1992).
`2 HERCEPTIN® (Trastuzumab) Label, dated September 1998.
`3 U.S. Patent No. 5,770,195 (Hudziak, et al.), issued June 23, 1998.
`4 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).
`5 Baselga et al., “Recombinant Humanized Anti-HER2 Antibody (HerceptinTM)
`Enhances the Antitumor Activity of Paclitaxel and Doxorubicin against HER2/neu
`Overexpressing Human Breast Cancer Xenografts,” 58 CANCER RES. 2825-2831
`(1998).
`6 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).
`
`5
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`IPR2014-00676
`Patent 8,337,856 B2
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`
`
`
`References
`
`Basis Claims Challenged
`
`5 Chari 1992 and Carter 1992 (Ex. 1022)8 and
`common knowledge in the art
`6 Liu 1996 (Ex. 1023)9 in view of HERCEPTIN®
`Label
`
`§ 103 1-8
`
`§ 103 1-5, 7
`
`7 Liu 1996 and HERCEPTIN® Label, further in view
`of Morgan 1990
`8 Cohen 1999 (Ex. 1025)10 in view of Chari 1992
`
`§ 103 6, 8
`
`§ 103 1-8
`
`
`
`II.
`
`ANALYSIS
`
`A. Claim Construction
`
`The Board interprets claims in an unexpired patent using the “broadest
`
`reasonable construction in light of the specification of the patent in which [they]
`
`appear[].” 37 C.F.R. § 42.100(b); see also Office Patent Trial Practice Guide
`
`(“Practice Guide”), 77 Fed. Reg. 48756, 48766 (Aug. 14, 2012). There is a “heavy
`
`presumption” that a claim term carries its ordinary and customary meaning. CCS
`
`Fitness, Inc. v. Brunswick Corp., 288 F.3d 1359, 1366 (Fed. Cir. 2002).
`
`Petitioner offers claim construction of the phrase “pharmaceutically-
`
`acceptable carrier,” recited in dependent claim 5, as “including ‘bacteriostatic
`
`
`7 Morgan et al., “IMMUNOTOXINS OF PSEUDOMONAS EXOTOXIN A (PE):
`EFFECT OF LINKAGE ON CONJUGATE YIELD, POTENCY, SELECTIVITY
`AND TOXICITY,” 27(3) MOL. IMMUNOL. 273-282 (1990).
`8 Carter et al., “Humanization of an anti-p185HER2 antibody for human cancer
`therapy,” 89 PROC. NATL. ACAD. SCI., USA 4285-4289 (1992).
`9 Liu et al., “Eradication of large colon tumor xenografts by targeted delivery of
`maytansinoids,” 93 PROC. NATL. ACAD. SCI., USA 8618-8623 (1996).
`10 Cohen, U.S. Pat. Appl. Publ. No. 2003/0170235 A1, published Sept. 11, 2003.
`
`6
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`IPR2014-00676
`Patent 8,337,856 B2
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`water for injection (BWFI), phosphate-buffered saline, Ringer’s solution and
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`dextrose solution.’” 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. 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.
`
`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, among other alternative references, relying on a Declaration by Dr.
`
`Michael G. Rosenblum (Ex. 1016). Pet. 8-22.
`
`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.
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`7
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`IPR2014-00676
`Patent 8,337,856 B2
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`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 toward neu-
`
`negative KB cells. 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 was an antibody directed against a human
`
`colon cancer cell line antigen, showed similar cytotoxicity results and was 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. Ex. 1008, 1, 1st col. The Label describes
`
`intravenous injection administration of HERCEPTIN® after reconstitution with
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`Patent 8,337,856 B2
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`“Bacteriostatic Water for Injection (BWFI),” among other components. Id. at 1st
`
`col.
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`The Label describes HERCEPTIN® as being indicated for “the treatment of
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`patients with metastatic breast cancer whose tumors overexpress the HER2 protein
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`and who have received one or more chemotherapy regimens for their metastatic
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`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
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`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 xenograph models (athymic mice bearing s.c. or i.p.
`
`SKOV-3 tumors). Id. at Abstract.
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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 xenograph 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.
`
`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. Id., see also id. at 2241, 2nd col., 2242,
`
`2nd col. The reference describes observing “synergistic interactions at clinically
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`relevant drug concentrations” for rhuMAb HER2 in combination with cisplatin,
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`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 4421, 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 xenographs in athymic mice, vinblastine (“VBL”), a microtubule
`
`inhibitor, combined with rhuMAb HER2 “significantly reduced MCF7/HER-2
`
`xenograph 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 activity” of rhuMAb HER2
`
`when combined with different chemotherapy drugs, such as VBL, as compared to
`
`effects of each drug alone).
`
`5. Petition and Preliminary Response
`
`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-ErbB2 antibody conjugated to a
`
`maytansinoid, such DMI having the structure recited in claim 2, where the
`
`immunoconjugate comprises four maytansinoid molecules per antibody molecule
`
`(as recited in claim 3), where the antibody and maytansinoid are conjugated by
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`chemical linkers, such as SPDP or SMCC (as recited in claims 4 and 6-8). Pet. 9-
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`12 (citing Ex. 1012). Patent Owner does not contend otherwise. See Prelim. Resp.
`
`generally.
`
`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). Again, Patent Owner does not contend otherwise. See
`
`Prelim. Resp. generally.
`
`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
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`mouse monoclonal TA.1 antibody in the immunoconjugate of Chari 1992 with the
`
`humanized mAb huMAB4D5-8 to produce the 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.
`
`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 in humans, as indicated in the HERCEPTIN® Label; and (3)
`
`clinical studies indicated that huMAB4D5-8 worked well in combination with
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`microtubule-directed chemotherapy agents for the treatment of breast cancer, as
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`indicated in the HERCEPTIN® Label (Ex. 1008, 1, 1st col.). Id. at 13-14.
`
`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).” 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).
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`Petitioner also discusses the prosecution history of the ’856 patent as it
`
`relates to a reasonable expectation of success, and assertions of unexpected results,
`
`as discussed in Declarations by Dr. Mark X. Sliwkowski (Ex. 1028) and Dr.
`
`Barbara Klencke (Ex. 1029) submitted during prosecution. Id. at 48-59. Petitioner
`
`acknowledges that Dr. Sliwkowski concluded that an ordinarily skilled artisan
`
`would not have been motivated to select huMAb4D5-8 as a humanized anti-HER2
`
`antibody for conjugation to a maytansinoid, such as DM1, because “it would have
`
`expected that huMAb4D5-8 would arrest cancer cells in the pre-mitotic G0/G1
`
`phase of the cell cycle before DM1 would even have the opportunity to act.” Id. at
`
`48-49 (quoting Ex. 1028 ¶ 12).
`
`Petitioner refers to teachings in prior art references, however, such as in
`
`Pegram 1999 and the HERCEPTIN® Label, which discloses synergistic or
`
`additive effect between HERCEPTIN® and other chemotherapeutic agents, such as
`
`the antimicrotubule agent paclitaxel. Id. at 49. Petitioner also relies on the
`
`Rosenblum Declaration and Chari 1992 when stating that “there was no evidence
`
`that internalized maytansinoid would not kill breast cancer cells in G0/G1 phase.”
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`Id. at 49-51 (citing Ex. 1016 ¶¶ 35-37; Ex. 1012, Abstract). Petitioner also
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`contends that “Dr. Sliwkowski’s statement that HERCEPTIN® is cytostatic (i.e.,
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`causing arrest of cycle but not cell death, Ex. 1028, para. 11) provides further
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`motivation for combining HERCEPTIN® with a more potent cytotoxic agent such
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`as maytansinoid,” again relying on the Rosenblum Declaration. Id. at 51-52 (citing
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`Ex. 1016 ¶ 38, Ex. 1004).11
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`11 Ex. 1004, Phillips et al., 68 CANCER RES. 9280-9290 (2008) (“Phillips 2008”),
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`Petitioner acknowledges a review article by Trail and Bianchi (Ex. 1028,
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`Exhibit H), submitted during prosecution to support Dr. Sliwkowski’s position that
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`“it would have been unpredictable whether [the claimed immunoconjugate] would
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`effectively and safely treat a HER2 overexpressing cancer with a reasonable
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`expectation of success.” Id. at 53. Petitioner counters that Chari 1992 indicated to
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`the contrary when it taught that “maytansinoid immunoconjugates were
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`demonstrated to be substantially free of toxicity, based on the same kinds of assays
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`described in the ’856 patent.” Id. at 54-55 (citing Ex. 1012, Abstract, 129, 1st col.,
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`130 1st col.). Petitioner further cites Liu et al. (Ex. 1023) and Chari 1998 (Ex.
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`1015)12 to rebut Dr. Sliwkowski’s 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 relation
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`to a reasonable expectation of success. Id. at 55-56 (citing Ex. 1028 ¶ 14).
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`Petitioner also acknowledges an Amendment dated July 6, 2010 (Ex. 1027)
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`and the Klencke Declaration (Ex. 1029), submitted during prosecution, which
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`discusses results of a Phase II clinical trial of “T-DM1,” a huMAb4D5-8-
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`maytansinoid conjugate within the scope of the present claims. Id. at 57-59.
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`
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`was published in November 2008. Petitioner cites and quotes this reference in its
`discussion of a motivation to combine elements in the prior art. Pet. 51-53. We
`are not persuaded that Petitioner has established that this reference constitutes prior
`art to the ’856 patent, which claims priority to applications filed in 2000. While
`Phillips 2008 cites Chari 1992 (Ex. 1012), Baselga 1998 (Ex. 1019), and Pegram
`1999 (Ex. 1020), we are not persuaded that the cited statements in Phillips 2008,
`by themselves, establish what would have been obvious in 2000.
`12 Chari, “Targeted delivery of chemotherapeutics: tumor-activated prodrug
`therapy,” 31 ADV. DRUG DEL. REV. 89-104 (1998).
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`Petitioner argues, however, that unexpected results relevant to non-obviousness are
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`those “different in kind and not merely in degree from the results of the prior art,”
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`quoting Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir.
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`2004). Petitioner contends that the increase in objective response rate (“ORR”)
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`from 23.7% to 32.7%, as described in the Klencke Declaration, does not represent
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`a “difference in kind” required to show unexpected results. Pet. 58.
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`In response to the Petition, Patent Owner argues that Petitioner fails to
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`establish a reason to combine the cited art with a reasonable expectation of success
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`regarding the claimed immunoconjugates, and fails to properly account for
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`objective indicia of nonobviousness, such as unexpected results, praise in the
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`industry, long-felt need, and commercial success. Prelim. Resp. 1-4. The Patent
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`Owner relies on, inter alia, the Sliwkowski (Ex. 1028) and Klencke (Ex. 1029)
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`Declarations submitted during prosecution.
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`In relation to a motivation to use HERCEPTIN® in the immunoconjugate of
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`Chari 1992, Patent Owner contends that Petitioner “repeatedly emphasizes the
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`‘clinical applications’ of the invention, e.g., ‘treating breast cancer’ in ‘humans.’”
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`Prelim. Resp. 4. Patent Owner argues that Petitioner fails address “the numerous
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`challenges POSAs faced in developing therapeutic immunoconjugates as of the
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`’856 patent’s priority date,” as discussed during prosecution of the patent. Id. at 5-
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`10. In this regard, Patent Owner contends that, to be therapeutically useful, a
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`relevant immunoconjugate must kill tumor cells effectively enough to outweigh
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`toxicities that result from killing normal cells. Id. at 5-6.
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`Patent Owner contends that Petitioner does not show sufficiently a
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`reasonable expectation of success regarding an immunoconjugate that included
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`“maytansinoid, an extremely toxic compound that had already failed clinical trials
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`due to its toxicity” (id. at 6-7 (citing Ex. 2001-2005; Ex. 1029 ¶ 9)), especially
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`when only four other immunoconjugates had been tested in clinical trials, and none
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`had been successful in treating a solid tumor (id. at 6-8). Patent Owner points out
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`that T-DM1 was the first immunoconjugate to be approved by the FDA to treat a
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`solid tumor, and that the Klencke Declaration explains that this ability to treat solid
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`tumors was “an important advance in the field of immunoconjugates.” Id. at 8
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`(citing Ex. 1029 ¶ 26). Patent Owner contends that solid tumors, such as breast
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`cancer, were considered particularly difficult to treat because, for example, it was
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`known that target antigens were expressed on both tumor and normal cells, as
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`discussed in Chari 1998, a reference dated six years after Chari 1992. Id. at 9-10
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`(citing Exs. 1015 and 1029).
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`Patent Owner also contends that Petitioner “fails to properly account” for
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`objective indicia of nonobviousness.” Id. at 11-12. Patent Owner discusses the
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`Klencke and Sliwkowski Declarations cited during the prosecution history, stating
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`that those experts demonstrated that T-DM1 exhibited unexpected results, received
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`significant professional acclaim, satisfied a long-felt, and met an unmet need in
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`terminally ill breast cancer patients. Id. at 12.
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`Patent Owner refers to “unexpected results exhibited by T-DM1 over
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`trastuzumab and a chemotherapeutic agent in first-line and second-line therapy;
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`over lapatinib and capecitabine in second-line therapy; and over ixabepilone in
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`third-line therapy.” Id. at 12-13. Patent Owner describes statements and data
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`presented in the Klencke Declaration, such as her statement that “[t]he fact that the
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`ORR of T-DM1 in [the clinical trial] (32.7%) significantly exceeded that of current
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`second-line therapies (23.7%), and well surpassed that of current third-line
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`therapies (12.4%), was a better result than expected.” Id. at 15-16 (quoting Ex.
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`1029 ¶ 18).
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`Patent Owner argues that the Petition “proffers no substantiated rebuttal to
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`this unexpected results evidence.” Id. at 16-22. Along these lines, Patent Owner
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`contends that Dr. Rosenblum, Petitioner’s witness, “provides no rationale for why
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`the claimed immunoconjugates, which include the trastuzumab antibody, would
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`have been expected to be effective in treating tumors that fail to respond to
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`unconjugated trastuzumab antibody.” Id. at 13-23. For example, Patent Owner
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`argues:
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`Offering an “apples-to-oranges” comparison, Dr. Rosenblum states
`“[t]he observed increase from standard second-line therapies of 23.7% to
`32.7% with TDM1 did occur but whether this represents a statistically-
`significant increase over second-line treatment with Herceptin in addition to
`Taxol is not clear.” (Ex. 1016: ¶ 46, discussing Dr. Klencke’s Declaration.)
`(Again, Dr. Rosenblum disregards the 12.4% to 32.7% ORR comparison as
`a third-line therapy.) But, the data to which Dr. Klencke’s declaration refers
`involved second-line therapy with lapatinib and capecitabine, not
`trastuzumab and Taxol.
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`Id. at 18. According to Patent Owner, the Petition “does not even mention a
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`comparison of T-DM1 to trastuzumab and Taxol®.” Id. at 19.
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`Patent Owner also cites Wildiers (Ex. 2009)13 as providing “evidence that T-
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`DM1 represents a statistically significant improvement over a combination of
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`
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`13 Wildiers, H., et al., “Late Breaking Abstract: T-DM1 for HER2-positive
`metastatic breast cancer (MBC): Primary result from TH3RESA, a phase 3 study
`of T-DM1 vs treatment of physician's choice,” The European Cancer Congress
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`trastuzumab and other anti-cancer agents in second-line therapy.” Id. at 20. Patent
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`Owner also argues that “[w]hile Dr. Rosenblum mentions the Trail article in the
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`context of safety (Ex. 1016 ¶¶ 41-43), he fails to provide any rebuttal to Trail’s
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`prediction that the major role of immunoconjugates for treating solid tumors would
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`lie only in minimal disease settings.” Id. at 22.
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`In addition, Patent Owner provides evidence of “praise T-DM1 has received
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`in the industry,” as well as the commercial success of T-DM1 (Kadcyla). Id. at 23-
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`26, 29-30. Patent Owner also discusses “a long-felt, unmet need for HER2-
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`positive breast cancer patients who do not respo