Trials@uspto.gov
`Tel: 571-272-7822
`
`
`Paper 17
`Entered: July 27, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`HOSPIRA, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`_______________
`
`Case IPR2017-00737
`Patent 7,892,549 B2
`_______________
`
`
`Before ZHENYU YANG, CHRISTOPHER G. PAULRAJ, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Instituting Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`

`

`IPR2017-00737
`Patent 7,892,549 B2
`
`I.
`INTRODUCTION
`Hospira, Inc. (“Petitioner”)1 filed a Petition requesting an inter partes review
`of claims 1–17 of U.S. Patent No. 7,892,549 B2 (Ex. 1001, “the ’549 patent”).
`Paper 1 (“Pet.”). Genentech, Inc. (“Patent Owner”) filed a Preliminary Response
`to the Petition. Paper 9 (“Prelim. Resp.”).
`Institution of an inter partes review is authorized by statute when “the
`information presented in the petition . . . and any response . . . shows that there is a
`reasonable likelihood that the petitioner would prevail with respect to at least 1 of
`the claims challenged in the petition.” 35 U.S.C. § 314; see 37 C.F.R. §§ 42.4,
`42.108. Upon considering the Petition and the Preliminary Response, we
`determine that Petitioner has shown a reasonable likelihood that it would prevail in
`showing the unpatentability of at least one challenged claim. For the reasons that
`follow, we institute an inter partes review of claims 1–17 of the ’549 patent.
`
`A.
`
`Related Applications and Proceedings
`The ’549 Patent issued from Application No. 10/356,824, filed February 3,
`2003, which is a continuation of Application No. 09/208,649, filed Dec. 10, 1998
`(the “649 Application”). U.S. Patent No. 7,846,441 B2 (“the ’441 Patent) issued
`from the ’649 Application on December 7, 2010. The ’549 and ’441 Patents claim
`benefit of priority to Provisional Application No. 60/069,346, filed Dec. 12, 1997
`(“the ’346 application”). See e.g., Ex. 1001, (21), (63) (60), 1:4–9.
`In addition to this proceeding, Petitioner has challenged claims 1–11 and
`14–17 of the ’549 Patent in IPR2017-00739. The related ’441 Patent is presently
`the subject of IPR2017-00731.
`
`
`1 Petitioner identifies Pfizer, Inc. as “the real party in interest for Petitioner.”
`Paper 10, 2.
`
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`2
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`IPR2017-00737
`Patent 7,892,549 B2
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`Petitioner has also filed IPR2017-00804 and IPR2017-00805 involving the
`claims of U.S. Patent Nos. 6,627,196 and 7,371,379, respectively. These two
`patents are not in the chain of priority of the ’549 and ’441 Patents but involve
`subject matter similar to that at issue here.
`Petitioner further directs us to invalidation and revocation proceedings
`involving European Patent EP 1,037,926, which, like the ’549 Patent at issue here,
`claims benefit of priority to the ’346 application. See Pet. 1–2 (citing Ex. 1004,
`1026, and 1049).
`
`B.
`
`The ’549 Patent and Relevant Background
`According to the Specification, 25% to 30% of human breast cancers
`overexpress a 185-kD transmembrane glycoprotein receptor (p185HER2), also
`known as HER2 (human epidermal growth factor receptor-2) or ErbB2. Ex. 1001,
`1:21–32, 5:16–21. These HER2-positive cancers are associated with poor
`prognoses and resistance to many chemotherapeutic regimens including
`anthracyclines (e.g., doxorubicin or epirubicin). Id. at 3:43–52; 4:11–12, 11:41–
`45. Conversely, patients with HER2-positive cancers are three times more likely
`to respond to treatment with taxanes than those with HER2 negative tumors. Id. at
`3:52–56 (citing Baselga ’97 (Ex. 1007)).
`Although “ErbB2 overexpression is commonly regarded as a predictor of
`poor prognosis,” “a humanized version of the murine anti-ErbB2 antibody 4D5,
`referred to as rhuMAb HER2 or HERCEPTIN® [or trastuzumab] has been
`clinically active in patients with ErbB2-overexpressing metastatic breast cancers
`that had received extensive prior anti-cancer therapy.” Ex. 1001, 3:35–61 (citing
`Baselga ’96 (Ex. 1005)). Anti-ErbB2 4D5 antibodies also “enhance the activity of
`paclitaxel (TAXOL®) and doxorubicin against breast cancer xenographs in nude
`
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`Patent 7,892,549 B2
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`mice injected with BT-474 human breast adenocarcinoma cells, which express
`high levels of HER2.” Id. at 3:56–61 (citing Baselga ’94 (Ex. 1006)).
`According to the Specification,
`treatment of disorders
`the
`The present
`invention concerns
`characterized by overexpression of ErbB2, and is based on the
`recognition that while treatment with anti-ErbB2 antibodies markedly
`enhances the clinical benefit of the use of chemotherapeutic agents in
`general, a syndrome of myocardial dysfunction that has been observed
`as a side-effect of anthracycline derivatives is increased by the
`administration of anti-ErbB2 antibodies.
`Id. at 3:65–4:5.
`The ’549 Patent thus relates to the treatment of breast cancers that
`overexpress HER2/ErbB2 “comprising administering a therapeutically effective
`amount[2] of a combination of an anti-ERbB2 antibody and a chemotherapeutic
`agent other than an anthracycline derivative, e.g. doxorubicin or epirubicin, in the
`absence of an anthracycline derivative to the human patient.” Id. at 4:6–13. In
`some embodiments, the anti-ERbB2 antibody of the combination is Herceptin®
`and the chemotherapeutic agent “is a taxoid, such as TAXOL® (paclitaxel) or a
`TAXOL® derivative.” Id. at 4:23–25. The combination may further include one
`or more additional anti-ErbB2 antibodies, “antibodies which bind to the EGFR . . .
`ErbB3, ErbB4, or vascular endothelial factor (VEGF),” “one or more cytokines,”
`or “a growth inhibitory agent.” Id. at 23:60–24:5, 25:20–34; see also id. at 11:4–
`40 (defining “chemotherapeutic agent” and “growth inhibitory agent”).
`
`
`2 The Specification defines a “therapeutically effective amount” of the combination
`as “an amount having an antiproliferative effect,” which can be measured by
`assessing the time to disease progression (TTP) or determining the response rates
`(RR).” Id. at 10:41–50.
`
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`Patent 7,892,549 B2
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`The ’549 Patent also provides an Example disclosing the conduct and results
`of a clinical trial involving 469 women with metastatic HER2-positive breast
`cancer Id. at 26:34–30:25. All patients were treated with one of two
`chemotherapy regimens (CRx) designated either “AC” for anthracycline
`(doxorubicin or epirubicin) and cyclophosphamide, or “T” for Taxol (paclitaxel).
`See id. at 28:5–47; 29:13–30:12. Half of the patients were also treated with the
`anti-ERbB2 antibody Herceptin, designated “H”. Id. The Specification discloses
`that “[a]t a median follow-up of 10.5 months, assessments of time to disease
`progression (TTP in months) and response rates (RR) showed a significant
`augmentation of the chemotherapeutic effect by HERCEPTIN®, without increase
`in overall severe adverse events (AE).” Id. at 29:13–18. In addition, “[a]
`syndrome of myocardial dysfunction similar to that observed with anthracyclines
`was reported more commonly with a combined treatment of AC-H (18% Grade ¾)
`than with AC alone (3%), T (0%), or T+H (2%).” Id. at 30:13–16. According to
`the inventors:
`These data indicate that the combination of anti-ErbB2 antibody
`treatment with chemotherapy markedly increases the clinical benefit,
`as assessed by response rates and the evaluation of disease progression.
`However, due to the increased cardiac side-effects of doxorubicin or
`epirubicin, the combined use of anthracyclines with anti-ErbB2
`antibody therapy is contraindicated. The results, taking into account
`risk and benefit, favor the combined treatment with HERCEPTIN® and
`paclitaxel (TAXOL®).
`Id. at 30:17–25.
`
`C.
`
`Challenged Claims
`Petitioner challenges claims 1–17. Pet. 4. Claims 1, 5, and 16 are
`independent. Claim 1, reproduced below, requires “administering a combination”
`of three agents—an anti-ErbB2 antibody, a taxoid, and “a further growth inhibitory
`agent”— “in an amount effective to extend the time to disease progression:”
`5
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`Patent 7,892,549 B2
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`1. A method for the treatment of a human patient with breast cancer that
`overexpresses ErbB2
`receptor,
`comprising
`administering
`a
`combination of an antibody that binds ErbB2, a taxoid, and a further
`growth inhibitory agent to the human patient in an amount effective to
`extend the time to disease progression in the human patient, wherein
`the antibody binds to epitope 4D5 within the ErbB2 extracellular
`domain sequence
`
`Independent claim 16 is similar to claim 1, but further includes a negative
`limitation requiring the administration of an anti-ErbB2 antibody, a taxoid, and a
`further growth inhibitory agent “in the absence of an anthracycline derivative.”
`Independent claim 5 is also similar to claim 1, but recites “administering an
`effective amount” of an anti-ErbB2 antibody, a taxoid, and “a further therapeutic
`agent,” and further specifies that the taxoid is paclitaxel. Depending from claim 5,
`claims 12, 13, and 14, respectively, specify that this “further therapeutic agent” is
`another anti-ErbB2 antibody, a vascular endothelial growth factor (VEGF), or “a
`growth inhibitory agent.” Depending from claims 1 and 5, respectively, claims 2
`and 7 require that the 4D5 anti-ErB2 antibody is humanized.
`
`D.
`
`Asserted Prior Art and Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability (Pet. 7):
`
`References
`Ground Claim(s)
`1
`1–11 and 14–17 Baselga ’973 and Gelmon4
`2
`12
`Baselga ’97, Gelmon, and
`Drebin5
`Baselga ’97, Gelmon, and
`Presta6
`
`13
`
`3
`
`Basis
`§ 103
`§ 103
`
`§ 103
`
`
`3 Baselga et al., 11(3) (Suppl. 2) ONCOLOGY 43–48 (1997). Ex. 1007.
`4 Gelmon et al., 14(4) J. CLIN. ONCOL. 1185–91 (1996). Ex. 1025.
`5 Drebin et al., 2(3) ONCOGENE 273–77 (1988). Ex. 1010.
`6 Presta et al., 57(20) CANCER RES. 4593–99 (1997). Ex. 1012.
`6
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`Patent 7,892,549 B2
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`5
`
`6
`
`12
`
`13
`
`References
`Ground Claim(s)
`4
`1–11 and 14–17 Baselga ’96,7 Baselga ’94,8 and
`Gelmon
`Baselga ’96, Baselga ’94,
`Gelmon, and Drebin
`Baselga ’96, Baselga ’94,
`Gelmon, and Presta
`Petitioner also relies on Ex. 1011, the declaration of its technical expert,
`Allan Lipton, MD.
`
`Basis
`§ 103
`
`§ 103
`
`§ 103
`
`II.
`
`ANALYSIS
`
`A.
`
`Principles of Law
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences between
`the subject matter sought to be patented and the prior art are such that the subject
`matter as a whole would have been obvious at the time the invention was made to a
`person having ordinary skill in the art to which that subject matter pertains. KSR
`Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007). The question of obviousness is
`resolved based on underlying factual determinations including: (1) the scope and
`content of the prior art; (2) any differences between the claimed subject matter and
`the prior art; (3) the level of ordinary skill in the art; and (4) objective evidence of
`nonobviousness, if present. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`“[T]he [obviousness] analysis need not seek out precise teachings directed to
`the specific subject matter of the challenged claim, for a court can take account of
`the inferences and creative steps that a person of ordinary skill in the art would
`employ.” KSR, 550 U.S. at 418. “[I]nterrelated teachings of multiple patents; the
`
`7 Baselga et al., 14(3) J. CLIN. ONCOL. 737–44 (1996). Ex. 1005.
`8 Baselga et al., 13 Proc. AM. SOC. CLIN. ONCOL. 63 (Abstract 53)
`(1994). Ex. 1006.
`
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`effects of demands known to the design community or present in the marketplace;
`and the background knowledge possessed by a person having ordinary skill in the
`art, all [can provide] . . . an apparent reason to combine the known elements in the
`fashion claimed.” Id.
`“In an [inter partes review], the petitioner has the burden from the onset to
`show with particularity why the patent it challenges is unpatentable.” Harmonic
`Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed. Cir. 2016) (citing 35 U.S.C.
`§ 312(a)(3) (requiring inter partes review petitions to identify “with particularity
`. . . the evidence that supports the grounds for the challenge to each claim”)). This
`burden of persuasion never shifts to Patent Owner. See Dynamic Drinkware, LLC
`v. Nat’l Graphics, Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015) (discussing the
`burden of proof in inter partes review). Furthermore, Petitioner cannot satisfy its
`burden of proving obviousness by employing “mere conclusory statements.” In re
`Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1380 (Fed. Cir. 2016). Thus, to
`prevail in an inter partes review, Petitioner must explain how the proposed
`combinations of prior art would have rendered the challenged claims unpatentable.
`At this preliminary stage, we determine whether the information presented in the
`Petition and Preliminary Response shows there is a reasonable likelihood that
`Petitioner would prevail in establishing that at least one challenged claim would
`have been obvious over the proposed combinations of prior art. 35 U.S.C. §
`314(a).
`We analyze the challenges presented in the Petition in accordance with the
`above-stated principles.
`
`B.
`
`Person of Ordinary Skill in the Art
`Petitioner argues that a person of ordinary skill in the art as of the effective
`filing date of the ’549 patent “would be a clinical or medical oncologist
`
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`specializing in breast cancer with several years of experience with breast cancer
`research or clinical trials.” Pet. 6 (citing Ex. 1011 ¶¶ 15–17; Ex. 1004 ¶¶ 29–31).
`Patent Owner does not dispute Petitioner’s proposed definition. Prelim. Resp. 36.
`Based on our review of the ’549 Patent, the cited art, and the testimony of
`Dr. Lipton, we adopt Petitioner’s definition for the purposes of this Decision. We
`further note that the prior art itself demonstrates the level of skill in the art at the
`time of the invention. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir.
`2001) (explaining that specific findings regarding ordinary skill level are not
`required “where the prior art itself reflects an appropriate level and a need for
`testimony is not shown”) (quoting Litton Indus. Prods., Inc. v. Solid State Sys.
`Corp., 755 F.2d 158, 163 (Fed. Cir. 1985)).
`
`C.
`
`Claim Construction
`In an inter partes review, claim terms in an unexpired patent are interpreted
`according to their broadest reasonable construction in light of the specification of
`the patent in which they appear. 37 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC
`v. Lee, 136 S. Ct. 2131, 2144–46 (2016) (upholding the use of the broadest
`reasonable interpretation standard). Under that standard, we presume that a claim
`term carries its “ordinary and customary meaning,” which “is the meaning the term
`would have to a person of ordinary skill in the art in question” at the time of the
`invention. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007); see
`also Trivascular, Inc. v. Samuels, 812 F.3d 1056, 1062 (Fed. Cir. 2016) (“Under a
`broadest reasonable interpretation, words of the claim must be given their plain
`meaning, unless such meaning is inconsistent with the specification and
`prosecution history.”). Any special definition for a claim term must be set forth in
`the specification with reasonable clarity, deliberateness, and precision. In re
`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). Limitations, however, are not to be
`
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`read from the specification into the claims (In re Van Geuns, 988 F.2d 1181, 1184
`(Fed. Cir. 1993)), nor may the Board “construe claims during [an inter partes
`review] so broadly that its constructions are unreasonable under general claim
`construction principles” (Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1298
`(Fed. Cir. 2015)).
`
`“administering a combination”
`1.
`Patent Owner proposes that we interpret “administering a combination” as
`requiring “a single treatment regimen in which the patient receives all drugs that
`are part of the claimed combination” and sets forth a reasoned explanation of why
`this definition is supported by the Specification and claim language. Prelim. Resp.
`36–37. Patent Owner argues, for example, that “the absence of an anthracycline
`derivative” language in dependent claims 16 and 17, “would make no sense if
`‘administering a combination’ included drugs received as part of a different
`treatment regimen [because] [i]n the ’549 patent’s working example, patients were
`administered the combination of the anti-ErbB2 antibody and a taxoid in the
`absence of an anthracycline derivative only if they had ‘received any anthracycline
`therapy in the adjuvant setting’” Id. at 37). For the purpose of this Decision, and
`based on the present record, we adopt Patent Owner’s presently unopposed
`argument and proposed definition of “administering a combination” as requiring “a
`single treatment regimen in which the patient receives all drugs that are part of the
`claimed combination.”
`
`2.
`
`“in an amount effective to extend the time of disease progression in
`the human patient”
`Independent claims 1 and 16 require administering a combination of an anti-
`ErbB2 antibody, a taxoid, and a further agent, “in an amount effective to extend the
`time to disease progression in the human patient” (claims 1 and 16), or more
`
`
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`Patent 7,892,549 B2
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`generically, administering the three-part combination to a human patient in “an
`effective amount” (claim 5).
`Although Petitioner proposes no express construction of any claim term (see
`Pet. 14), it reasonably asserts that the language of claims 1 and 16 “purports to
`capture any ‘amount effective to extend the time to disease progression’” (id. at 29
`(citing Ex. 1011 ¶ 83)) and that, “‘an amount effective to extend the time to disease
`progression would be an ‘effective amount’” as set forth in claim 5 (id. at 34
`(citing Ex. 1011 ¶¶ 98–99); id. at 39). Patent Owner has not disputed these
`assertions but merely states that the language of claim 5 requires “clinically
`‘effective’ results.” See Prelim. Resp. 44.
`The claim language “an amount effective to extend the time to disease
`progression” implies that time to disease progression is extended in relation to
`some metric, but we do not discern that the claims, standing alone, identify the
`intended comparator. The facial ambiguity of this phrase was expressly addressed
`by the Examiner during the prosecution leading to the issuance of the ’549 Patent.
`In particular, during the prosecution of the ’649 Application (the direct predecessor
`to the ’842 Application, from which the ’549 Patent issued), the Examiner rejected
`then-pending claims under 35 U.S.C. § 112, second paragraph because:
`The phrase “extend the time to disease progression” . . . is a relative
`term which renders the claim[s] indefinite. The term “extend time to
`disease progression” is not defined by the claim, the specification does
`not provide a standard for ascertaining the requisite degree, and one of
`ordinary skill in the art would not be reasonably apprised of the scope
`of the invention. Specifically, it is never set forth what the extension
`of time to disease progress is relative to, for example, is the extension
`of time to disease progress relative to untreated patients? Patients who
`received antibody or taxoid alone? Patients who received antibody and
`an anthracycline?
`
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`Ex. 3000,9 3–4 (OA dated 7/17/01). Applicants responded that
`the expression[] “extend the time to disease progression”. . . [is] clear
`from the specification (see, in particular, page 15, lines 15-17; and
`pages 42-43) and would be readily understood by the skilled oncologist.
`Clearly, the combination of anti-ErbB2 antibody and taxoid is
`administered in an amount effective to extend the time to disease
`progression relative to an untreated patient.
`
`Id. at 17–18 (Response dated 1/17/2001); see Ex. 1021, 19 (15:12–17), 46–47 (42–
`43). The Examiner stated that “[a]ll claims were allowable” in the next office
`action. Ex. 3000, 24 (OA dated 3/27/2002) (suspending prosecution due to
`potential interference); see also id. at 28 (OA dated 8/12/2003) (new grounds of
`rejection not relating to the phrase “extend the time to disease progression”).
`We further note that the language at issue references administration “to the
`human patient,” where “the human patient” is identified in the preamble as one
`having “breast cancer that overexpresses ErbB2 receptor.” “When limitations in
`the body of the claim rely upon and derive antecedent basis from the preamble,
`then the preamble may act as a necessary component of the claimed invention.”
`Eaton Corp. v. Rockwell Int'l Corp., 323 F.3d 1332, 1339 (Fed. Cir. 2003). In the
`present case, we read the preamble as defining and, thus, limiting “the human
`patient” recited in the body of the claim.
`In view of the above, and for the purpose of this Decision, we interpret “an
`amount effective to extend the time to disease progression in the human patient” in
`independent claims 1 and 16 as an amount sufficient to extend the time to disease
`progression in a human patient having breast cancer that overexpresses ErbB2
`receptor as compared to one receiving no treatment. We further construe the
`
`
`9 Excerpts of prosecution history of US Application No. 09/208,649.
`12
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`language “an effective amount” of independent claim 5 as encompassing “an
`amount effective to extend the time to disease progression in the human patient.”
`
`D. Grounds 1–3
`In Ground 1, Petitioner challenges claims 1–11 and 14–17 as obvious under
`35 U.S.C. § 103 based on Baselga ’97 and Gelmon. In Grounds 2 and 3,
`respectively, Petitioner further asserts Drebin (claim 12) and Presta (claim 13).
`
`1.
`Overview of Baselga ’97 (Ex. 1007)10
`Baselga ’97 reviews the relationship and clinical implications of HER2
`overexpression and chemotherapeutics, most particularly taxanes, in the treatment
`of breast cancers. Baselga ’97 states that HER2 positive tumors “have increased
`resistance to adjuvant CMF (cyclophosphamide, methotrexate, and fluorouracil)-
`based therapy and, conversely, increased dose-response effects to an anthracycline-
`containing regimen.” Ex. 1007, 6. Moreover, the “[a]vailable data . . . suggest
`that HER2 overexpression may influence the response to paclitaxel in patients with
`metastatic breast cancer and that anti-HER2 monoclonal antibodies significantly
`increase the antitumor activity of paclitaxel in vitro and in vivo.” Id.
`Baselga ’97 teaches that “[t]he murine monoclonal antibody (MoAb) 4D5,
`directed against the extracellular domain of p185HER2 (ECDHER2), is a potent
`inhibitor of in vitro growth and, in xenograft models, of human breast cancer cells
`overexpressing HER2.” Id. at 7. For example, in a mouse model using HER2-
`expressing BT-474 cell implants, Baselga ’97 states:
`
`10 In IPR2017-00731 we declined to revisit the Examiner’s determination that
`Baselga ’97 was not prior art with respect to the two-drug combination treatment
`claimed in the ’441 patent. See IPR2017-00731, Paper 19, 7–8, 10, n.5. With
`respect to the three-drug combination treatments of the ’549 claims at issue here,
`however, Applicants did not antedate Baselga ’97 during prosecution and Patent
`Owner does not contest Petitioner’s assertion that Baselga ’97 is prior art.
`13
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`Therapy with MoAb 4D5 alone produced a 35% growth inhibition,
`and paclitaxel alone resulted in a 35% growth inhibition when
`compared with animals treated with a control MoAb. The treatment
`with paclitaxel plus 4D5 resulted in major antitumor activity, with 93%
`inhibition of growth. This result was markedly better than an equipotent
`dose of doxorubicin (10 mg/kg IP) and 4D5 (70% inhibition). In
`addition, paclitaxel combined with 4D5 resulted in the disappearance
`of well-established xenografts.
`Id. at 9.
`According to Baselga ’97, because the potential for immunogenic response
`limits the clinical application of murine antibodies such as 4D5, Genentech
`scientists developed a recombinant, humanized version of this antibody, rhuMoAb
`HER2, “to facilitate further clinical investigations.” Id. at 44, 46. Phase II clinical
`trials have shown that rhuMoAb HER2, alone, “is clinically active in patients who
`have metastatic breast cancers that overexpress HER2 and have received extensive
`prior therapy” and further suggest that the antibody may be synergistic in
`combination with cisplatin therapy. Id. at 9–10. In addition:
`Results from the phase II studies and the activity of rhuMoAb HER2
`against xenografts when given in combination with doxorubicin and
`paclitaxel have been encouraging. These positive results have led to
`the design of a phase III multinational study of chemotherapy in
`combination with
`rhuMoAb HER2
`in patients with HER2-
`overexpressing breast
`tumors who have not
`received prior
`chemotherapy for metastatic disease.
`Id. at 10. “The main goal of this study is to determine whether the addition of this
`anti-HER2 antibody increases the time to disease progression compared with the
`group of patients treated with antibody alone [sic., chemotherapy alone].” Id.; see,
`e.g, id. at Figure 2 (showing randomization to either chemotherapy alone
`(“AC/Paclitaxel”) or chemotherapy “+ rhuMab HER2”); see also id. (“The study
`end point is time to disease progression.”).
`
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`Treatment consists of either cytotoxic chemotherapy or chemotherapy plus
`treatment with rhuMoAb HER2. Id. at 10. The chemotherapy regimen is selected
`based on whether the patients have been previously treated with anthracyclines
`(e.g., doxorubicin or epirubicin). Id. Patients that have not previously been treated
`with anthracyclines are administered a combination of cyclophosphamide and
`doxorubicin or epirubicin, whereas patients that have received anthracycline
`therapy in the adjuvant setting are treated with paclitaxel. Id. Besegla ’97 notes
`that “[b]ecause anthracyclines are widely used in the adjuvant setting, it is likely
`that a significant number of patients will be treated with paclitaxel ± rhuMoAb
`HER2.” Id. Baselga ’97 describes the phase III trial as “ongoing” and presents no
`results from this study. Id.11
`
`2.
`Overview of Gelmon (Ex. 1025)
`Gelmon states that, “Phase II studies have shown paclitaxel to be an active
`single agent in metastatic breast cancer, with reported response rates of 17% to
`62% . . . . Promising results have also been reported with combinations of
`paclitaxel with other active agents such as doxorubicin, cyclophosphamide, and
`edatrexate.” Ex. 1025 at 9. “We were also interested in combining [paclitaxel]
`with a non-cross-resistant drug with a different spectrum of toxicity. Cisplatin
`seemed to be an appropriate choice.” Id. Accordingly, Gelmon presents the
`results of a Phase I/II clinical study designed
`(1) to determine the toxicity of paclitaxel and cisplatin in a biweekly
`schedule, (2) to establish the maximum-tolerated dose of paclitaxel in
`combination with a fixed dose of cisplatin (60 mg/m2) for patients with
`metastatic breast cancer, (3) to determine the feasibility of repeated
`
`
`11 As pointed out by Petitioner, the results of the Phase III clinical trial discussed in
`Baselga ’97 are disclosed in the ’549 Patent. See Pet. 8–9.
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`biweekly administrations, and (4) to evaluate the activity of this
`combination in this disease setting.
`Id. at 10.
`According to Gelmon, “[a]ll but two of the women in our trial had been
`treated with previous adjuvant chemotherapy, and 23 of 29 patients had previous
`exposure to anthracyclines.” Id. at 13. Of the 27 patients assessed for efficacy,
`three showed a complete response with a time to disease progression of 110 to 200
`days, and 20 showed a partial response with a time to disease progression of 96 to
`377+ days. See, e.g., id. at Abstract. Overall, patients treated with the
`paclitaxel/cisplatin regimen showed an overall response rate of 85% and a median
`time to disease progression of 7.1 months. Id. Gelmon concludes that “Biweekly
`paclitaxel and cisplatin is an active combination in the treatment of metastatic
`breast cancer, including for patients with previous exposure to anthracyclines.” Id.
`
`3.
`Overview of Drebin (Ex. 1010)
`Drebin discloses that administering combinations of anti-ErbB2 antibodies
`“reactive with two distinct regions on the p185 molecule” in a mouse model,
`“resulted in synergistic anti-tumor effects and complete eradication of tumors.”
`Ex. 1010, Abstract, 5. Drebin concludes that antibodies specific for human p185
`may “find application as adjuvant therapy for diseases like breast cancer.” Id. at 7.
`
`4.
`Overview of Presta (Ex. 1012)
`Presta describes the preparation of recombinant, humanized anti-VEGF
`antibodies that inhibit VEGF-induced proliferation of endothelial cells in vitro and
`the growth of breast carcinoma cell tumors in a mouse model. See, e.g., Ex. 1012,
`abstract, 11. According to Presta, “[t]his humanized MAb is suitable for clinical
`trials to test the hypothesis that inhibition of VEGF action is an effective strategy
`for the treatment of cancer and other disorders in humans.” Id. at 8.
`
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`5.
`Analysis
`Petitioner has provided a claim-by-claim explanation for the basis of its
`contention that claims 1–11 and 14–17 are obvious under 35 U.S.C. § 103 based on
`Baselga ’97 and Gelmon and that claims 12 and 13 are obvious further in view of
`Drebin and Presta, respectively. Pet. 25–43. In short, Petitioner argues that
`“[e]very component of the claimed three-drug combination was known in the prior
`art.” Pet. 15.
`According to Petitioner:
`Anti-ErbB2 antibodies, paclitaxel, and cisplatin had all been used in
`human patients in the prior art, and two-drug combinations of each of
`them were shown to be synergistic. Drug combinations generally,
`including two- and three- agent combinations, were routinely used to
`fight cancer, including breast cancer. And it was well known that
`combination chemotherapies were superior to single agent therapies.
`Combinations, like anti-ErbB2 antibodies, paclitaxel, and cisplatin,
`acting on different and complementary pathways were known to have
`a greater probability of exhibiting synergy without resulting in drug
`resistance or enhanced toxicity.
`Id. at 17 (internal citations omitted). We find Petitioner’s argument persuasive.
`Further, as set forth in section II(D)(1),(2), the combination of Baselga ’97
`and Gelmon teaches the clinical efficacy of anti-ErbB2 antibodies in treating
`HER2-positive breast cancer; that paclitaxel in combination with another
`chemotherapeutic compound is clinically active in treating metastatic breast
`cancer; that anti-ErbB2 antibodies are synergistic with paclitaxel in inhibiting
`tumor growth in a mouse model of HER2-positive breast cancer; and that an on-
`going clinical trial involves the treatment of HER2-positive breast cancer with a
`combination of anti-ErbB2 antibodies and paclitaxel. On the present record, we
`agree with Petitioner that “[t]he thought to combine these known treatments was
`nothing more than the exercise of routine skill.” Id. at 15.
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`Focusing on the two-drug combination of anti-ErbB2 antibodies and a
`taxoid, Patent Owner argues that “[t]he ’549 Specification contains the first
`disclosure of clinical results showing that combination therapies that include an
`anti-ErbB2 antibody and a taxoid are effective at extending the time to disease
`progression in patients with HER2-positive breast cancer,” whereas, “[n]one of
`Petitioner’s cited references disclose results for that clinical outcome.” Prelim.
`Resp. 1–2. Thus, according to Patent