Trials@uspto. gov
`571.272.7822
`
`Paper No. 11
`Entered: December 14, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`V.
`
`AS TRAZENECA AB,
`Patent Owner.
`
`Case IPR2016-01325
`
`Patent 8,329,680 B2
`
`Before BRIAN P. MURPHY, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`DECISION
`
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`InnoPharma Exhibit 1011.0001
`
`
`571.272.7822
`
`Paper No. 11
`Entered: December 14, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`V.
`
`AS TRAZENECA AB,
`Patent Owner.
`
`Case IPR2016-01325
`
`Patent 8,329,680 B2
`
`Before BRIAN P. MURPHY, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`DECISION
`
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`InnoPharma Exhibit 1011.0001
`
`
`
`Case IPR2016-01325
`
`Patent 8,329,680 B2
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`1.
`
`INTRODUCTION
`
`Mylan Pharmaceuticals, Inc. (“Petitioner”)1 filed a Petition requesting
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`an interpartes review of claims 1—20 of US. Patent No. 8,329,680 B2
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`(EX. 1001, “the ’680 Patent”). Paper 2 (“Pet.”). AstraZeneca AB (“Patent
`
`Owner”) filed a Preliminary Response to the Petition. Paper 10 (“Prelim.
`
`Resp.”). We havejurisdiction under 35 U.S.C. § 6 and 35 C.F.R. § 4(a).
`
`Institution of an inter partes review is authorized by statute when “the
`
`information presented in the petition .
`
`.
`
`. and any response .
`
`.
`
`. shows that
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`there is a reasonable likelihood that the petitioner would prevail with respect
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`to at least 1 of the claims challenged in the petition.” 35 U.S.C. § 314; see
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`37 C.F.R. §§ 42.4, 42.108. Upon considering the Petition and the
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`Preliminary Response, we determine that Petitioner has not shown a
`
`reasonable likelihood that it would prevail in showing the unpatentability of
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`at least one challenged claim. Accordingly, we decline to institute an inter
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`partes review of claims 1—20 of the ’680 Patent.
`
`A.
`
`Related Applications and Proceedings
`
`The ’680 Patent shares substantially the same specification with US.
`
`Patent Nos. 6,774,122 B2 (“the ’122 Patent”), 7,456,160 B2 (“the ’160
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`Patent”), and 8,466,139 B2 (“the ’139 Patent), which are related as follows.
`
`The ’ 139 Patent issued from Application No. 13/602,667, which is a
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`continuation of Application No. 12/285,877 (now the ’680 Patent), which is
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`a continuation of Application No. 10/872,784 (now the ’ 160 Patent), which
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`is a continuation of Application No. 09/756,291 (now the ’122 Patent).
`
`1 Petitioner further identifies Mylan Institutional LLC, Mylan Laboratories
`Limited, Agila Specialties Inc., Mylan Teoranta, Mylan Inc., and Mylan
`N.V. as real parties-in-interest. Pet. 2.
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`InnoPharma Exhibit 1011.0002
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`Case IPR2016-01325
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`Patent 8,329,680 B2
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`This chain of continuations was first filed on January 9, 2001, and
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`each patent in the family claims benefit of foreign priority to applications
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`filed April 12, 2000, and January 10, 2000. Petitioner acknowledges that the
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`earliest possible priority date for the ’680 Patent is January 10, 2000. See
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`Pet. 10.
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`According to the parties, the ’680 Patent has been the subject of
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`numerous district court litigations. See Pet. 2—3; Paper 4, 2—3; Paper 6, 2—3;
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`Paper 8, 2; Paper 9, 2. The parties further indicate that the ’139, ’160, and
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`’122 Patents are also involved in the district court proceedings. Paper 4, 2,
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`Paper 6, 2; Paper 8, 2; Paper 9, 2.
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`In addition to the instant Petition challenging claims 1—20 of the ’680
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`Patent, Petitioner has submitted Petitions challenging claims of the ’ 122
`
`Patent (IPR2016-01316), the ’160 Patent (IPR2016-01324), and the ’139
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`Patent (IPR2016-01326).
`
`B.
`
`The ’680 Patent and Relevant Background
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`The invention relates to “a novel sustained release pharmaceutical
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`formulation adapted for administration by injection containing the
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`compound 7a-[9-(4,4,5,5 ,5-pentafluoropentylsulphinyl)nonyl]oestra-
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`l,3,5(10)-triene-3,17B-diol,” also known in the art as ICI 182,780 or
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`fulvestrant. EX. 1001, Abstract; 1:65—22 The Specification teaches
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`intramuscular injection of the disclosed fulvestrant formulation for the
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`treatment of “benign or malignant diseases of the breast or reproductive
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`tract, preferably treating breast cancer.” Id. at 11:14—16.
`
`As of the filing date of the ’680 Patent, nonsteroidal antiestrogens,
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`most particularly, tamoxifen, were used in the treatment of hormonal-
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`dependent breast cancers. See Pet. 8—9; Prelim. Resp. 18—19; EX. 1001,
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`InnoPharma Exhibit 1011.0003
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`Case IPR20l6-Ol325
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`Patent 8,329,680 B2
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`1:23—36. In some hormonal-dependent cancers, estrogen bound to estrogen
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`receptors (ERs) stimulates tumor growth. See Pet. 9; Prelim. Resp. 20.
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`Tamoxifen is a selective estrogen receptor modulator or SERM, meaning
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`that it acts as an estrogen antagonist in hormonal-dependent breast cancers,
`
`blocking the binding of estrogen to its receptors; conversely it also acts like
`
`an estrogen agonist in other tissues, providing beneficial effects in bone and
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`heart, and potentially detrimental effects in uterine tissue. See Pet. 9; Prelim
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`Resp. 20—21. In addition, resistance to tamoxifen tends to develop over
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`time, resulting in resumed tumor growth. See Pet. 19; Prelim. Resp. 20;
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`Ex. 1001, 2: 13—19. Accordingly, researchers sought alternative treatments
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`for estrogen-dependent breast cancers. See Prelim. Resp. 21—23. Of these,
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`fulvestrant was under investigation as of the filing date of the ’680 Patent.
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`See Prelim. Resp. 23—24; Ex. lOOl, 2:5—20, 58—64. Unlike tamoxifen,
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`fulvestrant is a steroidal antiestrogen, and does not display the ER agonist
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`activity of tamoxifen. See Pet. 9; Prelim. Resp. 22; Ex. 1001, 2:13—20, 31—
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`39. Rather, fulvestrant is considered a “pure” antiestrogen or ERD (estrogen
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`receptor downregulator). See Pet. 9; Prelim. Resp. 22.
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`The Specification discloses that intramuscular administration of
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`fulvestrant in aqueous suspension results in a clinically insufficient release
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`rate and “extensive local tissue irritation” because fulvestrant particles are
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`present at the injection site. Ex. lOOl, 8:62—9:5. And while the “solvating
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`ability of castor oil for steroidal compounds is known” (id. at 5:48—5 3), a
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`monthly depot injection made by dissolving fulvestrant in castor oil alone
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`would require formulation volumes of at least 10 ml “to achieve a high
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`enough concentration to dose a patient in a low volume injection and
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`InnoPharma Exhibit 1011.0004
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`achieve a therapeutically significant release rate.” Id. at 5:54—62 In
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`addressing these problems, the Patent states that,
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`With the addition of high concentrations of an alcohol
`concentrations of >50 mgml'1 of fulvestrant
`in a castor oil
`formulation is achievable, thereby giving an injection volumes
`of <5 ml. .
`.
`. We have surprisingly found that the introduction
`of a non-aqueous ester solvent which is miscible in the castor oil
`and an alcohol surprisingly eases the solubilisation of fulvestrant
`into a concentration of at least 50 mgml'l. .
`.
`. The finding is
`surprising since the solubility of fulvestrant in non-aqueous ester
`solvent .
`.
`. is significantly lower than the solubility of fulvestrant
`in an alcohol. .
`.
`.
`[or] in castor oil.
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`Id. at 6:3—18 (referencing Tables 2 and 3).
`
`The Specification, thus, describes the extended release fulvestrant
`
`formulation of the invention as comprising
`
`in a ricinoleate vehicle,2 a pharmaceutically
`.
`.
`.
`Fulvestrant
`acceptable nonaqueous ester solvent, and a pharmaceutically
`acceptable alcohol wherein the formulation is adapted for
`intramuscular administration and attaining a therapeutically
`significant blood plasma fulvestrant concentration for at least 2
`weeks.
`
`Ex. 1001, 6:20—27. In preferred embodiments, the ricinolate vehicle is
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`castor oil, the alcohol is a combination of ethanol and benzyl alcohol, and
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`the non-aqueous ester solvent is benzyl benzoate. Id. at 7:43—57; 8:55—58.
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`The Specification explains that “extended release” means that “at least
`
`two weeks, at least three weeks, and, preferably at least four weeks of
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`continuous release of fulvestrant is achieved,” and that “therapeutically
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`2 The Specification defines ricinolate vehicles as castor oil and other
`oils having “at least 20% .
`.
`. of its composition as triglycerides of ricinoleic
`acid.” Id. at 5:47—53, 8:52—27.
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`InnoPharma Exhibit 1011.0005
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`significant” blood plasma levels refer to “blood plasma concentrations of at
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`least 2.5 ngml'l, ideally at least 3 ngml'l, at least 8.5 ngml'l, and up to 12
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`ngml'1 of fulvestrant [] achieved in the patient.” Id at 924—3 1.
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`According to the inventors, “[s]imply solubilizing fulvestrant in an oil
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`based liquid formulation is not predictive of a good release profile or lack of
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`precipitation of drug after injection at the injection site.” Id at 9:42—44.
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`The ’680 Patent states that in vivo testing of the ricinoleate formulations of
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`the invention, however, “surprisingly” demonstrates, “after intra-muscular
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`injection, satisfactory release of fulvestrant over an extended period of
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`time.” Id. at 8:58—60. The disclosed formulations also provide “a
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`particularly even release profile with no evidence of precipitation of
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`fulvestrant at the injection site.” Id. at 10:24—57, Table 4 (second half),
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`Figure l.
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`C.
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`Challenged Claims
`
`Claims 1 and 9 are independent. Claim 1 is illustrative:
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`l. A method for treating a hormonal dependent benign or
`malignant disease of the breast or reproductive tract comprising
`administering intramuscularly to a human in need of such
`treatment a formulation comprising:
`
`about 50 mgml-l of fulvestrant;
`
`about 10% w/v of ethanol;
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`about 10% w/v of benzyl alcohol;
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`about 15% w/v of benzyl benzoate; and
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`a sufficient amount of castor oil vehicle;
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`wherein the method achieves a therapeutically significant
`blood plasma fulvestrant concentration of at least 2.5
`ngml'1 for at least four weeks.
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`InnoPharma Exhibit 1011.0006
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`Case IPR2016-01325
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`Patent 8,329,680 B2
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`D.
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`The Assertea’ Prior art and Grounds of Unpatentability
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`Petitioner asserts the following grounds of unpatentability (Pet. 5):
`
`
`Ground Reference(s)
`Basis
`Claims
`
`
`1
`McLeskey3
`§ 103
`1—20
`
`
`
`
`
`
`
`
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`2
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`Howell 19964 and McLeskey § 103
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`1—20
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`Petitioner also relies on the Declarations of Laird Forrest, Ph.D.
`
`(EX. 1003) and Leslie Oleksowicz, MD. (EX. 1004).
`
`Patent Owner relies on the Declarations of Lisbeth Illum, PhD.
`
`(EX. 2001), John F. R. Robertson, MD. (EX. 2002), and Ronald J. Sawchuk,
`
`Ph.D. (EX. 2003). Drs. Illum and Robertson further rely on Exhibit 2043,
`
`the October 1, 2014, Declaration of Sandra McLeskey, Ph.D. See EX. 2001
`
`11 60, EX. 2002 1111 152—153. Patent Owner further relies on the Sawchuk
`
`§ 1.132 Declaration5 submitted during the prosecution leading to the
`
`issuance of the ‘680 Patent. See Prelim. Resp. 8—1 1.
`
`3 McLeskey et al., Tamoxifen-resistantfibroblast growth factor
`transfectea’MCF—7 cells are cross-resistant in vivo to the antiestrogen [C]
`I 82, 780 and two aromatase inhibitors, 4 CLIN. CANCER RESEARCH 697—711
`(1998). EX. 1005.
`4 Howell et al., Pharmacokinetics, pharmacological and anti-tumour
`eflects 0f the specific anti-oestrogen [C] I 82 780 in women with advanced
`breast cancer, 74 BRIT. J. CANCER 300—308 (1996). EX. 1006.
`5 Declaration under 37 CPR. § 1.132 of Ronald J. Sawchuk, dated
`January 13, 2012. EX. 1002, 357—382.
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`InnoPharma Exhibit 1011.0007
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`E.
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`Overview 0fthe Asserted References
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`l'. McLeskey
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`McLeskey teaches that, in the treatment of clinical breast cancer,
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`“conventional therapy is not usually curative,” and can result in the
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`“development of tamoxifen resistance, in which breast tumors previously
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`growth-inhibited by tamoxifen become refractory.” Ex. 1005, 697.6
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`Moreover, “early results for small numbers of tamoxifen-resistant patients
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`have shown that only about 30—40% of such patients have a positive
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`response to subsequent [fulvestrant] or aromatase inhibitor therapy.” Id. at
`
`698 (citing, inter alia, Howell 1996). To explore the underlying mechanisms
`
`of acquired tamoxifen resistance, McLeskey employs a mouse model of
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`tamoxifen-resistant breast cancer. Id, Abstract.
`
`McLeskey notes that “FGFs [fibroblast growth factors] and their
`
`receptors have been shown to be present with high frequency in breast
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`cancer specimens,” and that there is “[e]vidence of a possible role for FGF
`
`signaling in the estrogen-independent growth of breast tumors.” Id. at 698.
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`McLeskey posits that, “[i]f FGF-mediated growth pathways bypass the ER
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`pathway to affect growth directly, we would expect that [tumor] growth
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`would be unaffected by hormonal treatments devoid of agonist activity. We
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`therefore sought to determine the sensitivity of the estrogen-independent
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`tumor growth of FGF-transfected MCF-7 cells to ICI 182,780 [fulvestrant]
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`or aromatase inhibitors.” Id. Accordingly, McLeskey treats
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`“ovariectomized tumor-bearing mice injected with fibroblast growth factor
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`6 We refer, herein, to the original pagination of the cited references
`rather than to that supplied by the parties.
`
`8
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`InnoPharma Exhibit 1011.0008
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`(FGF)-transfected MCF-7 breast carcinoma cells with the steroidal
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`antiestrogen [fulvestrant] or one of two aromatase inhibitors.” Id.
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`With respect to the fulvestrant arm, McLeskey injects the tumor-
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`bearing mice subcutaneously, once per week, with 5 mg doses of the drug at
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`50 mg/ml in an oil-based formulation. Id. at 698; Fig. 1. Depending on the
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`experiment, the fulvestrant formulations comprise either ethanol and peanut
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`oil (Fig. 1A), or “10% ethanol, 15% benzyl benzoate, 10% benzyl alcohol,
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`brought to volume with castor oil” (Figs. 1B and 1C). Id. “These treatments
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`did not slow estrogen independent growth or prevent metastasis of tumors
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`produced by FGF-transfected MCF-7 cells in ovariectomized nude mice”
`
`(id. at Abstract)—a result McLeskey characterizes as “treatment failure.” Id.
`
`at 706; see id. at 700—01.
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`Because fulvestrant and the aromatase inhibitors were “without
`
`effect” in these experiments, McLeskey “injected reproductively intact
`
`female mice for 2 weeks with these compounds at the same doses used in the
`
`above experiments to observe for activity in preventing effects of
`
`endogenous estrogens on the endometrium.” Id. at 701—02. Upon
`
`examining the effect of these compounds on the uteri of the treated mice,
`
`McLeskey concludes that “these compounds retained activity, although they
`
`had no effect on tumor growth in our experiments.” Id. McLeskey does not
`
`specify whether the peanut oil-based or the castor oil-based fulvestrant
`
`composition was used for this experiment. Nor does McLeskey address
`
`fulvestrant blood plasma levels, or otherwise provide pharrnacokinetic data,
`
`for any experiment.
`
`InnoPharma Exhibit 1011.0009
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`11'. Howell 1996
`
`Howell 1996 discloses the results of a clinical trial in which 19
`
`patients with advanced breast cancer resistant to tamoxifen were
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`administered fulvestrant as “a long-acting formulation contained in a castor
`
`oil-based vehicle7 by monthly i.m. injection (5 ml) into the buttock.”
`
`Ex. 1006, 301; see also id at Abstract (“The agent was administered as a
`
`monthly depot intramuscular injection”). To investigate local and systemic
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`toxicity, “the first four patients received escalating doses of [fulvestrant],
`
`starting with 100 mg in the first month and increasing to 250 mg i.m. from
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`the second month onwards.” Id. The remaining patients received 250 mg
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`doses of fulvestrant, intramuscularly, each month from the outset. Id. As
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`Petitioner’s expert, Dr. Forest, calculates, “by dividing the total dose of
`
`fulvestrant (250 mg) by the injection volume (5 ml) .
`
`.
`
`.
`
`it can be concluded
`
`that the concentration of fulvestrant in the castor oil-based vehicle was 50
`
`mg/ml.” Ex. 1003 11 78.
`
`Howell 1996 reports that “[t]hirteen (69%) patients responded (seven
`
`had partial responses and six showed ‘no change’ responses) to [fulvestrant],
`
`after progression on tamoxifen, for a median duration of 25 months.”
`
`Ex. 1006, Abstract. With respect to pharrnacokinetics, Howell 1996
`
`discloses profiles of fulvestrant serum concentrations in Figure 2. Id. at 303.
`
`Howell 1996 states that “continuous release of drug from the [fulvestrant]
`
`slow release formulation was shown throughout the one month dosing
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`interval.” Id. at 302. “[M]ean exposure to the drug increased slightly after
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`multiple dosing. Mean CmaX (which occurred on day 7) increased from 10.5
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`7 Howell 1996 is silent as to the presence or absence of other
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`components.
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`10
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`InnoPharma Exhibit 1011.0010
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`ng ml'1 to 12.8 ng ml'l, accompanied by increases in mean end-of-month
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`concentrations from 3.1 ng ml'1 to 5.6 ng m1'1.” Id. At page 305 of the
`
`reference, Howell 1996 states:
`
`From studies on inhibition of endometrial proliferation in the
`monkey and inhibition of tumour proliferation in a previous
`phase I study, it was predicted that serum levels of [fulvestrant]
`in the range of 2-3 ng ml'1 were consistent with a therapeutic
`effect in patients with advanced breast cancer. However, a direct
`pharmacokinetic-pharmacodynamic link is not proven with the
`few patients studied to date.
`Serum drug concentrations in
`excess of this were observed with the 250 mg dose used in the
`present study for most of the first and all of the sixth month.
`However,
`there was evidence of drug accumulation after
`multiple dosing, such that after 6 months treatment there was an
`80% increase in mean end of month drug levels and a 50%
`increase in the AUC compared with data from month 1. These
`data suggest that lower doses of the drug may be effective in
`maintaining therapeutic serum drug levels, although further
`clinical studies are required to confirm this hypothesis.
`
`Id. at 305. Howell 1996 concludes that fulvestrant “is well tolerated during
`
`long-term treatment and is active as an anti-tumour agent in patients with
`
`advanced breast cancer who have previously relapsed on tamoxifen.” Id. at
`
`306. However, “[a]t the dose used, there was accumulation of the drug over
`
`time and thus lower doses than those administered in this study may be as
`
`effective.” Id.
`
`F.
`
`Prosecution History Leading to the Issuance of the ’680 Patent
`
`Howell 1996 and McLeskey were considered during the prosecution
`
`leading to the issuance of the ’680 Patent. Applicants first disclosed Howell
`
`1996 in June of 2009. EX. 1002, 270—72. In June 2011, Applicants
`
`disclosed that, in connection with an attempt by Teva Parental Medicines
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`Inc. to gain approval of a generic 50 mg/ml fulvestrant injection, Teva had
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`11
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`InnoPharma Exhibit 1011.0011
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`alleged that the claims of related ’ 122 and ’ 160 Patents were invalid as
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`obvious over inter alia, McLeskey and Howell 1996. Id. at 295—99. Howell
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`1996 and McLeskey were then the subject of an Examiner Interview. See id.
`
`at 336—37 .
`
`Subsequent to the interview, the Examiner rejected the pending claims
`
`as obvious over the combination of McLeskey, Dukes 1989,8 Osborne
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`1995,9 and Wakeling 1992.10 Id. at 313—15. In responding to that rejection,
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`Applicants amended the independent claims (now claims 1 and 9) to recite a
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`formulation comprising “about 50 mgml'1 of fulvestrant; about 10% w/v of
`
`ethanol; about 10% w/v of benzyl alcohol,” and “about 15% w/v of benzyl
`
`benzoate,” wherein the method achieves a therapeutically significant blood
`
`plasma fulvestrant concentration “for at least four weeks.” See id. at 335;
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`Ex. 3001.11 Applicants also relied extensively on arguments set forth in the
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`Sawchuk § 1.132 Declaration. See id. at 339—55.
`
`The Sawchuk § 1.132 Declaration (id. at 357—83) includes the
`
`following three arguments: First, Dr. Sawchuk testified that one of ordinary
`
`skill in the art would have understood that the components in McLeskey’s
`
`castor oil formulation are implicitly described in terms of volume/volume
`
`8 Dukes, EP 0 346 014 B1, published Dec. 13, 1989. Ex. 1007.
`9 Osborne et al., Comparison of the eflects ofa pure steroidal
`antiestrogen with those of tamoxifen in a model ofhuman breast cancer,
`87(20) .1. National Cancer Institute, 746—750 (1995). Ex. 1018.
`10 Wakeling and Bowler, ICI I 82, 780: A new antioestrogen with
`clinical potential, 43 J. Steroid Biochemistry & Molecular Biology, 173—177
`(1992). Ex. 1009.
`11 Exhibit 2001, pages 334—356, contains the comments section of
`Applicants’ January 17, 2012, submission and omits internally numbered
`pages 2—6, setting forth the claim amendments. For completeness, we
`provide a copy of those amendments as Ex. 3001.
`
`12
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`InnoPharma Exhibit 1011.0012
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`percent units, which differ substantially from the weight/volume percentages
`
`of the claimed invention. See EX. 1002 at 361—67, 1111 18—30. Upon
`
`reviewing several prior art sources in which formulations were disclosed in a
`
`% v/v basis, Dr. Sawchuk testified that “one of ordinary skill in the art
`
`would have concluded that the composition [of McLeskey] was described in
`
`terms of volume/volume percent units (% v/v).” 1d. 11 21. Based on the
`
`proposition that McLeskey implicitly disclosed a formulation based on
`
`volume/volume percent units, Dr. Sawchuk calculated the amount of each
`
`component in weight/volume percent units. Id. 1111 23—28 (referencing Table
`
`1). Based on these calculations, Dr. Sawchuk concluded that “McLeskey
`
`described a composition containing about 8.1 % w/v ethanol, about 16.8 %
`
`w/v benzyl benzoate, and about 10.4% w/v benzyl alcohol in a castor oil
`
`vehicle.” Id. 11 29.
`
`Second, Dr. Sawchuk testified that the cited references provide no
`
`motivation to select the disclosed castor oil formulation for intramuscular
`
`administration. See id. at 367—71, 1111 31—41. As compared to the fulvestrant
`
`formulations disclosed in Osborne, Wakeling, or Dukes,
`
`the McLeskey castor oil composition would have been among
`the least favored compositions to select for further development
`.
`.
`. because the McLeskey experiments were ineffective and
`one of ordinary skill in the art would not have been able to
`conclude from the information in McLeskey whether
`fulvestrant, using that composition, was sufficiently
`bioavailable to have an antitumor effect.
`
`Id. at 370—71, 11 41. Moreover, with respect to the two fulvestrant
`
`formulations disclosed in McLeskey,
`
`because of the lack of fulvestrant efficacy and the absence of
`pharmacokinetic data in McLeskey, one of ordinary skill in the
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`13
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`InnoPharma Exhibit 10110013
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`art would have been unable to conclude whether either of the
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`two fulvestrant McLeskey compositions (peanut oil or castor
`oil) was able to deliver a dose of fulvestrant that had an
`antitumour therapeutic effect in the mice when administered
`subcutaneously, nor any insight about fulvestrant absorption
`characteristics (rate and extent) when administered via the
`intramuscular route in any species, including humans.
`
`Id. at 369, 1] 39.
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`Third, Dr. Sawchuk testified that “one of ordinary skill in the art
`
`would not have had a reasonable expectation that the McLeskey castor oil
`
`composition would have been effective when given as an intramuscular
`
`injection” (id. at 381—82, 1] 69) because (1) the composition of a formulation
`
`can have a significant effect on efficacy (id. at 377—82, W 57—69 ), and 2)
`
`because “results from subcutaneous administration in general, and including
`
`those included in McLeskey, cannot be extrapolated to intramuscular
`
`administration,” either with respect to side effects or efficacy (id. at 371—72,
`
`1] 42—43).
`
`Quoting the Specification’s assertion that “[s]imply solubilising
`
`fulvestrant in an oil based liquid formulation is not predictive of a good
`
`release profile or lack of precipitation of drug after injection at the injection
`
`site,” Dr. Sawchuk stated that, “suitable experiments are needed to
`
`determine the pharrnacokinetic performance of any candidate
`
`formulation(s).” Id. at 378—79, 1] 62. To illustrate the unpredictability in the
`
`prior art, Dr. Sawchuk discussed three published examples illustrating that
`
`“the intramuscular and subcutaneous administration of a drug to the same
`
`animal or human may produce very different plasma level curves, and
`
`therefore very different pharrnacologic effects.” Id. at 371—77, W 42—56.
`
`According to Dr. Sawchuk, these references
`
`14
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`InnoPharma Exhibit 10110014
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`
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`Case IPR2016-01325
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`Patent 8,329,680 B2
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`show that there are significant differences in the rate and extent
`of absorption of a drug given by the intramuscular and
`subcutaneous route, even when given to the same animals in a
`crossover study. As a result, it cannot be predicted a priori
`whether intramuscular or subcutaneous dosing will result in
`more rapid and/or complete drug absorption, as examples of both
`cases are found in the scientific literature.
`
`Id. at375,1l 53.
`
`Without citing any one argument as dispositive, the Examiner allowed
`
`the claims to issue. Id. at 717—19, see id. at 650 (withdrawing the
`
`obviousness rejection “in view of the arguments along with the declaration
`
`of Dr. Sawchuk filed 1/17/2012”).
`
`11.
`
`ANALYSIS
`
`A.
`
`Person of Ordinary Skill in the Art.
`
`The parties’ propose similar, albeit non-identical, definitions of one of
`
`ordinary skill in the art, both of which are consistent with the high level of
`
`ordinary skill demonstrated by the prior art asserted in the Petition. See Pet.
`
`14—15; Prelim. Resp. 11—12. Discerning no present conflict between the
`
`parties’ proposals, we rely on the level of ordinary skill in the art of
`
`developing and treating hormone dependent diseases of the breast as
`
`demonstrated by the prior art. See Okajima v. Bourdeau, 261 F.3d 1350,
`
`1355 (Fed. Cir. 2001).
`
`B.
`
`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 CPR. § 42.100(b);
`
`Cuozzo Speed Techs, LLC v. Lee, 136 S. Ct. 2131, 2144—46 (2016)
`
`15
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`InnoPharma Exhibit 1011.0015
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`
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`Case IPR2016-01325
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`Patent 8,329,680 B2
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`(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). Only terms
`
`that are in controversy need be construed, and only to the extent necessary to
`
`resolve the controversy. Vivid Techs., Inc. v. Am. Sci. & Eng ’g, Inc., 200
`
`F.3d 795, 803 (Fed. Cir. 1999). We address the claim terms set forth below;
`
`no other claim terms require construction at this time.
`
`I. Wherein the method achieves a therapeutically significant
`bloodplasmafulvestrant concentration ofat least 2.5 ngml'l for
`at leastfour weeks.
`
`Petitioner contends that the “wherein” clause of independent claims 1
`
`and 9, “wherein the method achieves a therapeutically significant blood
`
`plasma fulvestrant concentration of at least 2.5 nng'1 for at least four
`
`weeks,” is merely a statement of intended result entitled to no patentable
`
`weight. Pet. 16—17. For the reasons set forth at pages 12—16 of Patent
`
`Owner’s Preliminary Response, we do not find Petitioner’s argument
`
`16
`
`InnoPharma Exhibit 1011.0016
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`
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`Case IPR2016-01325
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`Patent 8,329,680 B2
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`persuasive.12 For example, rather than merely stating the result of
`
`intramuscularly administering the recited formulation, as Petitioner argues,
`
`the wherein clause dictates both the administration duration and dose of the
`
`formulation, i.e., an amount sufficient to provide a therapeutically significant
`
`blood plasma fulvestrant concentration of at least 2.5 ngml'1 for at least four
`
`weeks. See Prelim. Resp. 15 (relying on Exhibits 2002 11 37—39, Ex. 2001 W
`
`33—37, and citations therein). That these parameters are further limited in
`
`claims 2, 10 (“the therapeutically significant blood plasma fulvestrant
`
`concentration is at least 8.5 ngml'l”) further indicates that the wherein
`
`clauses provide defining characteristics. See Prelim. Resp. 15 (citing
`
`Ex. 2003 11 60).
`
`2. Therapeutl'cally significant
`
`Petitioner proposes that in the event we accord the wherein clause
`
`patentable weight, the term “therapeutically significant” should be construed
`
`to mean “any blood plasma fulvestrant concentration greater than or equal to
`
`at least 2.5 nng'1 that is achieved for at least 4 weeks after injection.” Pet.
`
`17—18. Patent Owner does not argue that Petitioner’s proposed
`
`interpretation is unreasonable, but contends that the meaning of the term is
`
`clear from the Specification and context of the claim phrase itself. See
`
`Prelim. Resp. 16 (citing Ex. 2003 11 68; Ex. 1001, 9:24—27 (expressly
`
`defining “therapeutically significant” fulvestrant blood plasma levels as “at
`
`least 2.5 ngml'l, ideally at least 3 ngml'l, at least 8.5 ngml'l, and up to 12
`
`12 Our reasoning extends to the wherein clauses of dependent claims 2
`and 10, also challenged by Petitioner at page 16, footnote 9, of the Petition.
`
`l7
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`InnoPharma Exhibit 1011.0017
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`Case IPR2016-01325
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`Patent 8,329,680 B2
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`ngml'1 of fulvestrant [] achieved in the patient”). We agree with Patent
`
`Owner. No express construction of this term is required.
`
`3. Achieves
`
`Petitioner further proposes that the word “achieves” in the wherein
`
`clause be construed as “achieved an average concentration [Cave] in a patient
`
`over the specified period.” Pet. 18 (citing EX. 1003 1111 41—42, EX. 1004
`
`11 35). We do not find Petitioner’s argument persuasive for the reasons set
`
`forth at pages 16 and 17 of the Patent Owner’s Preliminary response, which
`
`we adopt. Most particularly, Petitioner has not shown that any of the claims,
`
`Specification, or prosecution history, define blood plasma fulvestrant levels
`
`in terms of an average concentration over time. Moreover, construing
`
`“achieves” to encompass the range of high and low values that make up an
`
`averaged concentration is inconsistent with the express claim limitation “at
`
`least 2.5 ngml'1 for at least four weeks.” Because the claims on their face
`
`require a blood plasma fulvestrant concentration of at least a specified
`
`concentration over a specified time, we interpret “achieves” in the wherein
`
`clauses as meaning that the concentration of fulvestrant in a patient’s blood
`
`plasma is at or above the specified minimum concentration for the specified
`
`time period.
`
`C.
`
`Principles ofLaw
`
`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 ’1 Co. v. Teleflex Inc. , 550 US. 398, 406
`
`(2007). “The combination of familiar elements according to known methods
`
`18
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`InnoPharma Exhibit 1011.0018
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`Case IPR2016-01325
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`Patent 8,329,680 B2
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`is likely to be obvious when it does no more than yield predictable results.”
`
`Id. at 416. “If a person of ordinary skill can implement a predictable
`
`variation, § 103 likely bars its patentability.” Id. at 417. We are,
`
`nevertheless, cautioned not to “rely on hindsight reasoning to piece together
`
`elements to arrive at the claimed invention.” In re NTP, Inc. 654 F.3d 1279,
`
`1299 (Fed. Cir. 2011) (“Care must be taken to avoid hindsight reconstruction
`
`by using the patent in suit as a guide through the maze of prior art
`
`references, combining the right references in the right way so as to achieve
`
`the result of the claims in suit.” (internal quotations and citations omitted)).
`
`Thus, a finding of obviousness, “cannot be sustained by mere conclusory
`
`statements; instead, there must be some articulated reasoning with some
`
`rational underpinning to support the legal conclusion of obviousness.” Id. at
`
`418 (quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). Accordingly,
`
`a party petitioning the Board for a determination of obviousness must show
`
`that “a skilled artisan would have been motivated to combine the teachings
`
`of the prior art references to achieve the claimed invention, and that the
`
`skilled artisan would have had a reasonable expectation of success in doing
`
`so.” Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 994
`
`(Fed. Cir. 2009) (qu
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