Trials@uspto.gov
`571.272.7822
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` Paper No. 9
` Entered: December 11, 2017
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`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`FRESENIUS-KABI USA LLC,
`Petitioner,
`v.
`ASTRAZENECA AB,
`Patent Owner.
`____________
`
`Case IPR2017-01912
`Patent 8,466,139 B2
`____________
`
`
`Before GRACE KARAFFA OBERMANN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`571.272.7822
`
`
`
`
`
`
`
`
`
`
` Paper No. 9
` Entered: December 11, 2017
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`FRESENIUS-KABI USA LLC,
`Petitioner,
`v.
`ASTRAZENECA AB,
`Patent Owner.
`____________
`
`Case IPR2017-01912
`Patent 8,466,139 B2
`____________
`
`
`Before GRACE KARAFFA OBERMANN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`IPR2017-01912
`Patent 8,466,139 B2
`
`
` INTRODUCTION
`Petitioner Fresenius-Kabi USA LLC (“Petitioner”) filed a Petition
`requesting an inter partes review of claims 1, 3, 10, 11, 13, and 20 of U.S.
`Patent No. 8,466,139 B2 (Ex. 1001, “the ’139 Patent”). Paper 1 (“Pet.”).
`AstraZeneca AB (“Patent Owner”) filed a Preliminary Response. Paper 8
`(“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 not shown a
`reasonable likelihood that it would prevail in showing the unpatentability of
`at least one challenged claim. Accordingly, we decline to institute an inter
`partes review of the ’139 Patent.
`A.
`Related Applications and Proceedings
`The ’139 Patent shares substantially the same specification with U.S.
`Patent Nos. 6,774,122 B2 (“the ’122 Patent”), 7,456,160 B2 (“the ’160
`Patent”), and 8,329,680 B2 (“the ’680 Patent), which are related as follows.
`The ’139 Patent issued from Application No. 13/602,667 (“the ’667
`Application”), which is a continuation of Application No. 12/285,887 (“the
`’887 Application”) (now the ’680 Patent), which is a continuation of
`Application No. 10/872,784 (“the ’784 Application”) (now the ’160 Patent),
`which is a continuation of Application No. 09/756,291(“the ’291
`Application”) (now the ’122 Patent). This chain of continuations was first
`
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`IPR2017-01912
`Patent 8,466,139 B2
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`filed on January 9, 2001, and each patent in the family claims benefit of
`foreign priority to applications filed April 12, 2000, and January 10, 2000.
`According to the parties, the ’139 Patent has been the subject of
`numerous district court litigations. See Pet. 5–6; Paper 6, 2–3. According to
`Patent Owner, the related ’122, ’160, and ’680 Patents have also been
`involved in district court proceedings. Paper 6, 3.
`Each of the four related patents has been the subject of a petition for
`inter partes review filed by Mylan Pharmaceuticals, Inc. (“Mylan”). Of
`these, IPR2016-01316 on the ’122 patent, IPR2016-01324 on the ’160
`patent, and IPR2016-01326 on the ’139 patent were terminated before we
`issued a decision regarding institution. In IPR2016-01325 (“Mylan IPR”) on
`the ’680 patent, however, we issued a Decision denying institution (“Mylan
`Decision”), which Petitioner submits in this proceeding as Exhibit 1011 and
`discusses extensively in the Petition.
`The ’139 patent and two related patents also have been the subject of
`petitions for inter partes review filed by InnoPharma Licensing, LLC:
`IPR2017-00900 on the ’680 patent, IPR2017-00904 on the ’122 patent, and
`IPR2017-00905 on the ’139 patent. We previously denied each of those
`petitions.
`In addition to the instant Petition challenging claims of the ’139
`Patent, Petitioner has submitted Petitions challenging claims of the ’122
`Patent (IPR2017-01910) and the ’680 Patent (IPR2017-01913). Petitioner
`seeks joinder with the respective inter partes review filed by InnoPharma.
`Paper 3. We previously denied Petitioner’s motion to join. Paper 7.
`Petitioner does not presently challenge the ’160 Patent.
`
`3
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`IPR2017-01912
`Patent 8,466,139 B2
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`
`The ’139 Patent and Relevant Background
`B.
`The Specification of the ’139 Patent discloses “an extended release
`pharmaceutical formulation adapted for intramuscular injection comprising
`fulvestrant” 1 for the treatment of “benign or malignant diseases of the breast
`or reproductive tract, preferably treating breast cancer.” Ex. 1001, 10:33–
`67. Fulvestrant is also known in the art as ICI 182,780 or 7α-[9-(4,4,5,5,5-
`pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17-β-diol, and is
`the active ingredient in AstraZeneca’s FASLODEX product for “[t]reatment
`of hormone receptor positive metastatic breast cancer in postmenopausal
`women with disease progression following antiestrogen therapy.” Id. at
`Abstract, 2:1–6; Ex. 1021,2 1, 13.
`As of the filing date of the ’139 Patent, nonsteroidal antiestrogens,
`most particularly, tamoxifen, were used in the treatment of hormonal-
`dependent breast cancers. See Ex. 1001, 1:25–39; Prelim. Resp. 21. In
`some hormonal-dependent cancers, estrogen bound to estrogen receptors
`(ERs) stimulates tumor growth. See Pet. 12; Prelim. Resp. 21. Tamoxifen is
`a selective estrogen receptor modulator or SERM, meaning that it acts as an
`estrogen antagonist in these cancers, blocking the binding of estrogen to its
`receptors. Prelim Resp. 22. As of the filing date of the ’680 Patent,
`however, researchers were seeking alternative treatments, including
`fulvestrant, for estrogen-dependent breast cancers because resistance to
`tamoxifen tends to develop over time, and because tamoxifen treatment
`
`
`1 The Specification defines “extended release” to mean that “at least
`two weeks, at least three weeks, and, preferably at least four weeks of
`continuous release of fulvestrant is achieved.” Id. at 9:6–13.
`2 FASLODEX Prescribing Information, Rev. 11/2012.
`4
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`IPR2017-01912
`Patent 8,466,139 B2
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`could adversely affect bone and uterine tissue. See Ex. 1001, 2:14–32;
`Prelim. Resp. 21; Ex. 1015 ¶¶ 69–74. Unlike tamoxifen, fulvestrant is a
`“pure” antiestrogen or ERD (estrogen receptor downregulator), which does
`not display the partial ER agonist activity of tamoxifen. See Ex. 1001, 2:14–
`21; Ex. 1015 ¶¶ 71, 87.
`The Specification discloses that intramuscular administration of
`fulvestrant in aqueous suspension results in a clinically insufficient release
`rate and “extensive local tissue irritation” because fulvestrant particles are
`present at the injection site. Ex. 1001, 8:38–49. And while the “solvating
`ability of castor oil for steroidal compounds is known” (id. at 5:30–35), a
`monthly depot injection made by dissolving fulvestrant in castor oil alone
`would require formulation volumes of at least 10 ml “to achieve a high
`enough concentration to dose a patient in a low volume injection and
`achieve a therapeutically significant release rate.” Id. at 5:36–51. In
`addressing these problems, the ’139 Patent states:
`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-1. . . . The finding is
`surprising since the solubility of fulvestrant in non-aqueous ester
`solvents . . . is significantly lower than the solubility of
`fulvestrant in an alcohol. . . . [or] in castor oil.
`Id. at 5:54–67 (referencing Tables 2 and 3); see also id. at 9:22–44 (“Table 3
`shows . . . . the positive effect of benzyl benzoate on fulvestrant solubility in
`castor oil, despite fulvestrant having a lower solubility in benzyl benzoate
`than in either alcohol or castor oil.”).
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`IPR2017-01912
`Patent 8,466,139 B2
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`The Specification further discloses 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.” Id. at 9:19–21. But according to the inventors, in vivo testing of the
`castor oil-based formulations of the invention “surprisingly” demonstrates,
`“after intra-muscular injection, satisfactory release of fulvestrant over an
`extended period of time.” Id. at 8:34–36. In particular, Figure 1 shows
`release profiles after intramuscular injection into rabbits of 5% fulvestrant
`formulations comprising 10% ethanol, 10% benzyl alcohol and 15% benzyl
`benzoate made to volume with various oil components. See id. at 9:52–
`10:32, Fig. 1. The inventors conclude that “the castor oil formulation
`showed a particularly even release profile with no evidence of precipitation
`of fulvestrant at the injection site.” Id. at 10:30–32; see id. at Fig. 1 and
`Table 4, second half.
`The Specification, thus, describes the extended release fulvestrant
`formulation of the invention as comprising
`fulvestrant . . . in a ricinoleate vehicle,[3] a pharmaceutically
`acceptable non-aqueous ester solvent, and a pharmaceutically
`acceptable alcohol wherein the formulation is adapted for
`intramuscular administration and attaining a therapeutically
`significant[4] blood plasma fulvestrant concentration for at least
`2 weeks.
`
`
`3 The Specification defines ricinoleate vehicles as castor oil and other
`oils having “at least 20% . . . of its composition as triglycerides of ricinoleic
`acid.” Ex. 1001, 8:28–33; see id. at 5:29–35.
`4 The Specification explains that “therapeutically significant levels”
`blood plasma levels refer to “blood plasma concentrations of at least 2.5
`ngml-1, ideally at least 3 ngml-1, at least 8.5 ngml-1, and up to 12 ngml-1 of
`fulvestrant [] achieved in the patient.” Id. at 9:1–5.
`6
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`IPR2017-01912
`Patent 8,466,139 B2
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`Ex. 1001, 6:1–9. In preferred embodiments, the ricinoleate vehicle is castor
`oil, the alcohol is a combination of ethanol and benzyl alcohol, and the non-
`aqueous ester solvent is benzyl benzoate. Id. at 7:19–34; 8:28–33.
`C.
`Challenged Claims
`Petitioner challenges claims 1, 3, 10, 11, 13, and 20 of the ’139
`Patent, of which claims 1 and 11 are independent. Claim 1/11 recites:
`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/consisting essentially of:
`about 50 mgml-1 of fulvestrant;
`a mixture of from 17–23% w/v of ethanol and benzyl alcohol;
`12–18% w/v of benzyl benzoate; and
`a sufficient amount of castor oil vehicle;
`wherein the method achieves a blood plasma fulvestrant
`concentration of at least 2.5 ngml-1 for at least two weeks.
`Ex. 1001, 12:11–22, 48–59.
`The asserted dependent claims limit claims 1/11 to a method wherein
`the formulation comprises/consists essentially of: about 10% w/v of ethanol;
`about 10% w/v of benzyl alcohol; about 15% w/v of benzyl benzoate (claims
`3, 13); and wherein the hormonal dependent benign or malignant disease of
`the breast or reproductive tract is breast cancer and the blood plasma
`fulvestrant concentration is attained for at least 4 weeks (claims 10, 20).
`Ex. 1001, 12:26–29, 12:63–67, 12:44–47, 13:15–18.
`
`7
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`IPR2017-01912
`Patent 8,466,139 B2
`
`
`The Asserted Prior art and Grounds of Unpatentability
`D.
`Petitioner asserts the following grounds of unpatentability (Pet. 8–9):
`
`Ground Reference(s)
` 1
`Howell5
`
` 2
`
` 3
`
`Howell and McLeskey6
`
`Howell, McLeskey, and
`O’Regan7
`
`Basis
`§ 103
`
`§ 103
`
`§ 103
`
` Claims
`1, 3, 10, 11, 13, and 20
`1, 3, 10, 11, 13, and 20
`
`1, 3, 10, 11, 13, and 20
`
`The parties also rely on the declarations prepared for and filed in
`IPR2017-00905 to support their respective positions. Petitioner relies on the
`Declarations Diane Burgess, Ph.D. (Ex. 1012), Richard Bergstrom, Ph.D.
`(Ex. 1013), Dorraya El-Ashry, Ph.D. (Ex. 1014), and Dr. Adrian Harris
`(Ex. 1015). Patent Owner relies on the Declarations of Lisbeth Illum, Ph.D.
`(Ex. 2001), John F. R. Robertson, M.D. (Ex. 2002), and Ronald J. Sawchuk,
`Ph.D. (Ex. 2003).
`
`
`5 Howell et al., Pharmacokinetics, pharmacological and anti-tumour
`effects of the specific anti-oestrogen ICI 182780 in women with advanced
`breast cancer, 74 BRIT. J. CANCER 300–08 (1996). Ex. 1007.
`6 McLeskey et al., Tamoxifen-resistant fibroblast growth factor
`transfected MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI
`182,780 and two aromatase inhibitors, 4 CLIN. CANCER RESEARCH 697–711
`(1998). Ex. 1008.
`7 O’Regan et al., Effects of the Antiestrogens Tamoxifen, Toremifene,
`and ICI 182,780 on Endometrial Cancer Growth, 90 J. NAT’L CANCER INST.
`1552–58 (1998). Ex. 1009.
`
`8
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`IPR2017-01912
`Patent 8,466,139 B2
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`
`The parties also discuss the Sawchuk § 1.132 Declaration8 and the
`Gellert § 1.132 Declaration9 submitted during the prosecution leading to the
`issuance of the ‘680 Patent. See, e.g., Pet. 16–17; Prelim. Resp. 10–14.
`Dr. El-Ashry, Dr. Illum, Dr. Robertson, and Dr. Sawchuk also opine
`on Exhibit 2043, the October 1, 2014, Declaration of Sandra McLeskey,
`Ph.D. See Ex. 1014 ¶ 3; Ex. 2001 ¶ 61; Ex. 2002 ¶ 149; Ex. 2003 ¶ 58.
`E. Overview of the Asserted References
`i. Howell (Ex. 1007)
`Howell discloses the results of a clinical trial in which 19 patients
`with advanced breast cancer resistant to tamoxifen were administered
`fulvestrant as “a long-acting formulation contained in a castor oil-based
`vehicle by monthly i.m. injection (5 ml) into the buttock.” Ex. 1007, 301;10
`see also id. at Abstract (“The agent was administered as a monthly depot
`intramuscular injection.”). To investigate local and systemic 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 the second month
`onwards.” Id. at 301. The remaining patients received 250 mg doses of
`fulvestrant, intramuscularly, each month from the outset.11 Id. Howell
`
`
`8 Declaration under 37 C.F.R. § 1.132 of Ronald J. Sawchuk, dated
`January 13, 2012. Ex. 1019.
`9 Declaration under 37 C.F.R. § 1.132 of Paul Richard Geller, dated
`August 8, 2008. Ex. 1020.
`10 We refer, herein, to the original pagination of the cited references
`rather than to that supplied by the parties.
`11 As Dr. Burgess indicates, one of ordinary skill in the art would have
`understood that the concentration of fulvestrant in the castor oil-based
`vehicle was 50 mg/ml. Ex. 1012 ¶¶ 78, 83, 85. Howell is silent as to the
`presence or absence of other components in the formulation.
`9
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`IPR2017-01912
`Patent 8,466,139 B2
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`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. 1007,
`Abstract.
`With respect to pharmacokinetics, Figure 2 of the reference shows
`fulvestrant serum concentration profiles over time during the first and sixth
`months of treatment. Id. at 303. Howell states that “continuous release of
`drug from the [fulvestrant] slow release formulation was shown throughout
`the one month dosing interval.” Id. at 302. “[M]ean exposure to the drug
`increased slightly after multiple dosing. Mean Cmax (which occurred on day
`7) increased from 10.5 ng m1-1 to 12.8 ng ml-1, accompanied by increases in
`mean end-of-month concentrations from 3.1 ng m1-1 to 5.6 ng m1-1.” Id.
`In addressing the relationship between fulvestrant blood levels and
`efficacy, Howell states:
`This study represents the first investigation of long-term
`administration of the specific anti-oestrogen, ICI 182780, to
`patients with breast cancer and demonstrates that predicted
`therapeutic levels of ICI 182780, as judged from animal
`experiments . . . and our previous short phase I study (DeFriend
`et al., 1994b) can be achieved and maintained for 1 month
`following a single i.m. injection of the long-acting formulation
`used.
`
`* * *
`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 m1-1 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
`
`10
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`IPR2017-01912
`Patent 8,466,139 B2
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`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 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.
`ii. McLeskey (Ex. 1008)
`McLeskey teaches that, in the treatment of clinical breast cancer,
`“conventional therapy is not usually curative,” and can result in the
`“development of tamoxifen resistance, in which breast tumors previously
`growth-inhibited by tamoxifen become refractory.” Ex. 1008, 697.
`Moreover, “early results for small numbers of tamoxifen-resistant patients
`have shown that only about 30–40% of such patients have a positive
`response to subsequent [fulvestrant] or aromatase inhibitor therapy.” Id. at
`698 (citing, inter alia, Howell). To explore the underlying mechanisms of
`acquired tamoxifen resistance, McLeskey employs a mouse model of
`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
`cancer specimens,” and that there is “[e]vidence for a possible role for FGF
`
`11
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`IPR2017-01912
`Patent 8,466,139 B2
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`signaling in the estrogen-independent growth of breast tumors.” Id. at 698.
`McLeskey posits that, “[i]f FGF-mediated growth pathways bypass the ER
`pathway to affect growth directly, we would expect that [tumor] growth
`would be unaffected by hormonal treatments devoid of agonist activity.” Id.
`McLeskey “therefore sought to determine the sensitivity of the estrogen-
`independent tumor growth of FGF-transfected MCF-7 cells to [fulvestrant]
`or aromatase inhibitors,” by treating “ovariectomized tumor-bearing mice
`injected with fibroblast growth factor (FGF)-transfected MCF-7 breast
`carcinoma cells with the steroidal antiestrogen [fulvestrant] or one of two
`aromatase inhibitors.” Id. at 698, Abstract.
`With respect to the fulvestrant arm, McLeskey injects the tumor-
`bearing mice subcutaneously, once per week, with 5 mg doses of the drug at
`50 mg/ml in an oil-based formulation. Id. at 698, Fig. 1. Depending on the
`experiment, the fulvestrant formulations comprise either ethanol and peanut
`oil (Fig. 1A), or “10% ethanol, 15% benzyl benzoate, 10% benzyl alcohol,
`brought to volume with castor oil” (Figs. 1B and 1C). Id. “These treatments
`did not slow estrogen independent growth or prevent metastasis of tumors
`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.
`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,
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`12
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`Patent 8,466,139 B2
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`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 pharmacokinetic data,
`for any experiment.
`iii. O’Regan (Ex. 1009)
`Noting that tamoxifen has been associated with an increased risk of
`endometrial cancers, O’Regan explores the effect of a tamoxifen derivative
`and fulvestrant in a mouse model of human endometrial cancer. See
`Ex. 1009, Abstract. With respect to fulvestrant, O’Regan states that this
`compound “has shown promising results clinically in Europe, with high
`response rates of almost 70% in tamoxifen-failed, advanced breast cancer”
`(id. at 1553 (citing Howell)) and that “[c]linically, it must be given by depot
`intramuscular injection because of low oral potency” (id.). In the context of
`the mouse model, O’Regan administers fulvestrant by subcutaneous
`injection in peanut oil. Id.
`O’Regan concludes that “[fulvestrant] inhibits endometrial cancer,
`both in the presence and in the absence of estrogen, suggesting that it will
`prevent further tumor growth in patients with tamoxifen-stimulated
`endometrial cancer.” Id. at 1557. According to O’Regan, “[fulvestrant]
`should not be associated with an increase in endometrial cancer and could
`even be considered in the treatment of endometrial cancer.” Id.
`F.
`Prosecution History
`As set forth in section I(A), above, the ’122, ’160, ’680, and ’139
`Patents derive from a series of continuation applications (the ’291, ’789,
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`Patent 8,466,139 B2
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`’887, and ’667 Applications, respectively) and share essentially the same
`Specification. Applicants first disclosed Howell during the prosecution of
`the ’291 Application. See Ex. 1006, 461. The Examiner did not address
`Howell in any rejection, but argued that the then-pending claims were
`obvious because, inter alia, “combining one or more agents, which are
`known to be useful as commonly used solvents, such as benzyl benzoate,
`ethanol, castor oil, and benzyl alcohol, together and incorporated such
`combination with an estrogen derivatives, fulvestrant, would be reasonably
`expected to be useful in formulating a pharmaceutical composition.” Id. at
`508.
`
`Applicants responded that one of ordinary skill in that art would not
`have used benzyl benzoate in view of “the very low solubility of fulvestrant
`in such ester,” as shown in the Specification. Id. at 523–30. The Examiner
`found allowable subject matter in light of the “[u]nexpected increase of
`solubility of fulvestrant by adding 15% of benzyl benzoate into the
`composition with ethanol, benzyl alcohol, and castor oil . . . .” Id. at 540–
`41; see also id. at 572 (Examiner’s Reasons For Allowance stating that
`“[t]he herein recited ratio of ethanol, benzyl alcohol, and benzyl benzoate is
`demonstrated to have unexpected increase of solubility of fulvestrant.”).
`Addressing a similar argument during the prosecution of the ’784
`Application, Applicants relied on the Gellert § 1.132 Declaration. Ex. 1046,
`150–81; see id. at 182–470; Ex. 1020. Dr. Gellert testified that, although it
`was known to use benzyl benzoate in castor oil-based formulations, an
`experienced formulator
`would have expected that benzyl benzoate would not act as a co-
`solvent for fulvestrant in castor oil because the solubility of
`fulvestrant in benzyl benzoate was significantly lower than its
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`solubility in castor oil. . . . [and] would have been expected to
`decrease, rather than increase, the solubility of fulvestrant in the
`resulting castor oil/benzyl benzoate mixture.
`Ex. 1020 ¶¶ 18–20, 24. According to Dr. Gellert, the inventors’ discovery
`“that the addition of benzyl benzoate to the castor oil/alcohol mixture
`actually increases the solubility of fulvestrant such that more fulvestrant
`could be dissolved in a given volume of formulation, was unexpected and
`truly surprising.” Id. ¶ 25. In allowing the ’160 Patent to issue, the
`Examiner stated that “the unexpected solubility and the bioavailability of
`using the specific solvent mixture as recited have been demonstrated.”
`Ex. 1046, 729.
`During the prosecution of the ’887 Application, Applicants disclosed
`that in connection with an attempt by Teva Parenteral Medicines Inc. to gain
`approval of a generic 50 mg/ml fulvestrant injection, Teva had alleged that
`the claims of the then-issued ’122 and ’160 Patents were invalid as obvious
`over, inter alia, McLeskey and Howell. Ex. 1042, 295–99. Howell and
`McLeskey were then the subject of an Examiner Interview. See id. at 336–
`37. Subsequent to the interview, the Examiner entered a rejection under
`§ 103 over McLeskey in combination with three other references. Id. at
`313–15. In responding to that rejection, Applicants amended the
`independent claims (now claims 1 and 9) to recite a 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
`
`15
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`concentration “for at least four weeks.” See id. at 335; Ex. 3002.12
`Applicants also relied extensively on arguments set forth in the Sawchuk
`§ 1.132 Declaration. Id. at 339–55; see id at 357–83; Ex. 1019.
`Dr. Sawchuk testified that the cited references provide no motivation
`to select the disclosed castor oil formulation for intramuscular
`administration. Ex. 1019, ¶¶ 31–41. McLeskey, for example, “did not
`disclose plasma or blood levels of fulvestrant in mice after subcutaneous
`administration of either the peanut oil or the castor oil compositions” and,
`thus presents “no information regarding the rate and/or extent of absorption
`of fulvestrant from the subcutaneous injection site.” Id. ¶ 32. Dr. Sawchuk
`further testified that “McLeskey concluded that treatment with fulvestrant
`(ICI 182,780), using either of the disclosed compositions was not effective
`in that it ‘did not slow estrogen-independent growth or prevent metastasis of
`tumors’” in the mouse model and, thus, would not have informed one of
`ordinary skill in the art “about the usefulness of either fulvestrant
`formulation when administered subcutaneously to a mouse for the treatment
`of cancerous tumors.” Id. ¶ 33; see also id. ¶ 34 (noting that although
`McLeskey demonstrated that fulvestrant had activity in mice uteri, the
`reference did not specify which formulation was used in that experiment).
`Dr. Sawchuk concluded that
`because of the lack of fulvestrant efficacy and the absence of
`pharmacokinetic data in McLeskey, one of ordinary skill in the
`art would have been unable to conclude whether either of the two
`fulvestrant McLeskey compositions (peanut oil or castor oil) was
`
`12 Exhibit 1042, 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. 3002.
`16
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`IPR2017-01912
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`
`
`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. ¶ 35.
`Expanding on that conclusion, 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. ¶ 69) because (1) the composition of a
`formulation can have a significant effect on efficacy (id. ¶¶ 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. ¶¶ 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 pharmacokinetic performance of any candidate formulation(s).” Id. ¶ 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
`
`17
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`IPR2017-01912
`Patent 8,466,139 B2
`
`pharmacologic effects.” Id. ¶¶ 42–56. According to Dr. Sawchuk, these
`references13
`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. ¶ 53.
`Dr. Sawchuk also 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 percent units, which
`differ substantially from the weight/volume percentages of the claimed
`invention. See id. ¶¶ 16–30. 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).” Id. ¶ 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. ¶¶ 23–28 (referencing Table 1). Based on these
`
`
`13 Guerrini et al., Pharmacokinetics of probenecid in sheep, 8(2) J.
`VET. PHARMACOL. THER. 128–35 (1985) (Ex. 1042 at 549–56); Lavy et al.,
`Pharmacokinetics of clindamycin HCl administered intravenously,
`intramuscularly and subcutaneously to dogs, 22(4) J. VET. PHARMACOL.
`THER. 261–65 (1999) (Ex. 1042, 482–86); Ismail, Disposition kinetics of
`difloxacin after intravenous, intramuscular and subcutaneous
`administration in calves, 31(4) VET. RES. COMM. 467–76 (2007) (Ex. 1042,
`487–96).
`
`18
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`IPR2017-01912
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`
`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. ¶ 29.
`Without citing any one argument as dispositive, the Examiner
`withdrew the obviousness rejection “in view of the arguments along with the
`declaration of Dr. Sawchuk filed 1/17/2012” (Ex. 1042, 650), and allowed
`the ’680 Patent to issue (id. at 717–19).
` ANALYSIS
`Person of Ordinary Skill in the Art
`A.
`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.
`17–18; Prelim. Resp. 20. Discerning no present conflict between the parties’
`proposals, we rely on the level of ordinary skill in the art of developing and
`tre
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