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 IPR2017-01913
`Patent 8,329,680 B2
`____________
`
`
`Before GRACE KARAFFA OBERMANN, 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
`
`
`
`
`
`
`
`
`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 IPR2017-01913
`Patent 8,329,680 B2
`____________
`
`
`Before GRACE KARAFFA OBERMANN, 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
`
`
`
`
`
`
`
`
`
`IPR2017-01913
`Patent 8,329,680 B2
`
`
` INTRODUCTION
`Petitioner Fresenius-Kabi USA LLC (“Petitioner”) filed a Petition
`requesting an inter partes review of claims 1–3 and 6 of U.S. Patent No.
`8,329,680 B2 (Ex. 1001, “the ’680 Patent”). Paper 1 (“Pet.”). AstraZeneca
`AB (“Patent Owner”) filed a Preliminary Response to the Petition. 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 ’680 Patent.
`
`A.
`
`Related Applications and Proceedings
`The ’680 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 8,466,139 B2 (“the ’139 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
`
`2
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`IPR2017-01913
`Patent 8,329,680 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 ’680 Patent has been the subject of
`numerous district court litigations. See Pet. 4–5; Paper 6, 2–3. According to
`Patent Owner, the related ’122, ’160, and ’139 Patents have also been
`involved in district court proceedings. Paper 6, 3.
`Each of the four related patents have also been the subject of inter
`partes review proceedings 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 ’680 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 ’680
`Patent, Petitioner has submitted Petitions challenging claims of the ’122
`Patent (IPR2017-01910), and the ’139 Patent (IPR2017-01912).1 These
`petitions are virtually identical to the three petitions filed by InnoPharma
`Licensing and denied by the Board in IPR2017-00900, IPR2017-00904, and
`
`1 Petitioner does not presently challenge any claim of the ’160 Patent.
`
`
`3
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`Patent 8,329,680 B2
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`IPR2017-00905, respectively. Paper 7, 3–4; see id. at 4 (“Petitioner copied
`verbatim the earlier-filed petitions, and supporting declarations, submitted
`by InnoPharma Licensing.”). Petitioner filed requests for joinder with the
`respective inter partes reviews filed by InnoPharma (Paper 3), which we
`denied (Paper 7).
`
`B.
`
`The ’680 Patent and Relevant Background
`The Specification of the ’680 Patent discloses “an extended release
`pharmaceutical formulation adapted for intramuscular injection comprising
`fulvestrant” 2 for the treatment of “benign or malignant diseases of the breast
`or reproductive tract, preferably treating breast cancer.” Ex. 1001, 10:65–
`11:32. 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, 1:65–2:6; Ex. 1021,3 1, 13.
`As of the filing date of the ’680 Patent, nonsteroidal antiestrogens,
`most particularly, tamoxifen, were used in the treatment of hormonal-
`dependent breast cancers. See Ex. 1001, 1:23–36; Prelim. Resp. 21. In
`some hormonal-dependent cancers, estrogen bound to estrogen receptors
`(ERs) stimulates tumor growth. See Pet. 12; Prelim. Resp. 20. Tamoxifen is
`a selective estrogen receptor modulator or SERM, meaning that it acts as an
`
`
`2 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 9:29–31.
`3 FASLODEX Prescribing Information, Rev. 11/2012.
`4
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`IPR2017-01913
`Patent 8,329,680 B2
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`estrogen antagonist in these cancers, blocking the binding of estrogen to its
`receptors. Prelim Resp. 21–22. 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
`could adversely affect bone and uterine tissue. See Ex. 1001, 2:13–31; Pet.
`22; Prelim. Resp. 21; Ex. 1015 ¶¶ 68–74. 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, 2:13–
`19; Ex. 1015 ¶¶ 68, 85.
`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, 8:62–9:5. And while the “solvating
`ability of castor oil for steroidal compounds is known” (id. at 5:48–53), 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 5:54–6:2. In
`addressing these problems, the ’680 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
`
`5
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`Patent 8,329,680 B2
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`
`solvents . . . is significantly lower than the solubility of
`fulvestrant in an alcohol. . . . [or] in castor oil.
`Id. at 6:3–18 (referencing Tables 2 and 3); see also id. at 9:45–65 (“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.”).
`The Specification further discloses that “[s]imply solubili[z]ing
`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 9:42–44. 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 8:58–60. 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 10:5–51,
`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 10:49–51; see id. at Fig. 1 and Table
`4, second half.
`The Specification, thus, describes the extended release fulvestrant
`formulation of the invention as comprising:
`[F]ulvestrant . . . in a ricinoleate vehicle,[4] a pharmaceutically
`acceptable non-aqueous ester solvent, and a pharmaceutically
`
`
`4 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, 8:52–57; see id. at 5:47–53.
`6
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`
`acceptable alcohol wherein the formulation is adapted for
`intramuscular administration and attaining a therapeutically
`significant[5] blood plasma fulvestrant concentration for at least
`2 weeks.
`Ex. 1001, 6:19–27. In preferred embodiments, the ricinolate 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 7:43–57; 8:51–58.
`
`C.
`
`Challenged Claims
`Petitioner challenges claims 1–3 and 6 of the ’680 Patent. Pet. 1.
`Claim 1 recites:
`1. 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-1 of fulvestrant;
`about 10% w/v of ethanol;
`about 10% w/v of benzyl alcohol;
`about 15% w/v of benzyl benzoate; and
`a sufficient amount of castor oil vehicle;
`wherein the method achieves a therapeutically significant
`blood plasma fulvestrant concentration of at least 2.5
`ngml-1 for at least four weeks.
`Ex. 1001, 12:42–53.
`Claim 2 specifies that “the therapeutically significant blood plasma
`fulvestrant concentration is at least 8.5 ngml-1.” Ex. 1001, 12:54–56.
`
`
`5 The Specification explains that “therapeutically significant” 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 9:24–28.
`
`7
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`IPR2017-01913
`Patent 8,329,680 B2
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`Depending from claims 1 and 2, respectively, claims 3 and 6 specify that the
`hormonal dependent benign or malignant disease is breast cancer. Ex. 1001,
`12:57–59, 12:65–67.
`
`D.
`
`The Asserted Prior art and Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability (Pet. 9):
`
`Ground Reference(s)
` 1
`Howell6
`
` 2
`
` 3
`
` 4
`
`Howell and McLeskey7
`
`Howell, McLeskey, and
`O’Regan
`Howell, McLeskey, O’Regan,8
`and DeFriend9
`
`Basis
`§ 103
`
`§ 103
`
`§ 103
`
`§ 103
`
` Claims
` 1–3, 6
` 1–3, 6
`
` 1–3, 6
`
` 2, 6
`
`Petitioner also 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).
`
`
`6 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.
`7 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.
`8 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.
`9 DeFriend et al., Investigation of a New Pure Antiestrogen (ICI 182780) in
`Women with Primary Breast Cancer, 54 CANCER RES. 408–14 (1994).
`Ex. 1038.
`
`8
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`IPR2017-01913
`Patent 8,329,680 B2
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`
`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).
`The parties also discuss the Sawchuk § 1.132 Declaration10 and the
`Gellert § 1.132 Declaration11 submitted during the prosecution leading to the
`issuance of the ’680 Patent. See, e.g., Pet. 16-17; Prelim. Resp. 9–14.
`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 ¶ 59; Ex. 2002 ¶¶ 154–55; 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;12
`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
`
`
`10 Declaration under 37 C.F.R. § 1.132 of Ronald J. Sawchuk, dated January
`13, 2012. Ex. 1019.
`11 Declaration under 37 C.F.R. § 1.132 of Paul Richard Geller, dated August
`8, 2008. Ex. 1020.
`12 We refer, herein, to the original pagination of the cited references rather
`than to that supplied by the parties.
`
`9
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`IPR2017-01913
`Patent 8,329,680 B2
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`fulvestrant, intramuscularly, each month from the outset.13 Id. Howell
`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)[14] can be achieved and maintained for 1 month
`following a single i.m. injection of the long-acting formulation
`used.
`
`* * *
`
`
`13 As Petitioner’s expert, 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.
`14 Ex. 1038, discussed in section I(E)(iv), below.
`10
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`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
`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
`
`11
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`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
`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.
`
`12
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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 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 reports 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, however, O’Regan administers fulvestrant by
`subcutaneous injection in peanut oil. Id.
`O’Regan concludes that in the mouse model, “[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
`
`13
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`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.
`
`iv. DeFriend (Ex. 1038)15
`DeFriend describes the results of a clinical trial of fulvestrant “to
`assess its tolerance, pharmacokinetics, and short term biological effects in
`women with primary breast cancer.” Ex. 1038, Abstract. In this study,
`“[fulvestrant] was administered by i.m. injection into the buttock as a short-
`acting formulation, containing 20 mg/ml drug in a propylene glycol-based
`vehicle.” Id. at 409.
`[P]atients were randomized to either a control group (n = 19), in
`which they received no preoperative treatment, or a treatment
`group (n = 37), in which they received daily i.m. injections of
`[fulvestrant] at doses of 6 mg (n = 21) or 18 mg (n = 16) for 7
`days prior to surgery.
`
`
`Id.
`
`With respect to pharmacokinetics,
`mean serum drug levels versus time achieved in patients
`receiving the 6-mg and 18-mg daily doses of [fulvestrant] are
`shown in Fig. 1. The serum concentration of [fulvestrant] was
`dose dependent but showed some variation between individual
`patients. An approximately 3-fold drug accumulation was seen
`over the 7-day dosing period, although steady state serum levels
`were not reached by the end of the study.
`Id. at 410.
`
`
`15 As noted by Patent Owner, “DeFriend is cited in Howell, and Drs.
`DeFriend and Howell were authors on both publications.” See Prelim. Resp.
`27 (citing Ex. 2002 ¶¶ 208, 216; Ex. 1007, 300, 305–306).
`14
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`According to DeFriend, “the short-acting formulation of [fulvestrant]
`used in this study [was] well tolerated at the two doses studied over a 7-day
`treatment period and to be associated with minimal local or systemic
`toxicity.” Id. at 412. The treatment “produced a significant decline in the
`expression of [estrogen receptors] and [progesterone receptors] in primary
`breast cancers, as determined by immunohistochemistry on pre- and post-
`treatment tumor samples.” Id. at 412. DeFriend concludes that “[t]his small
`study has shown [fulvestrant] to be well tolerated after short term
`administration and has produced preliminary evidence to suggest that this
`novel agent does exhibit biological activity as an estrogen antagonist in
`primary breast tumors, without producing demonstrable agonist effects.” Id.
`at 413.
`
`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,
`’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.
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`15
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`Patent 8,329,680 B2
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`
`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 523–530. 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–
`541; 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,
`150–181; 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
`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
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`IPR2017-01913
`Patent 8,329,680 B2
`
`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
`concentration “for at least four weeks.” See id. at 335; Ex. 3002.16
`Applicants also relied extensively on arguments set forth in the Sawchuk
`§ 1.132 Declaration. Ex. 1042, 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
`
`
`16 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 Exhibit 3002.
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`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
`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
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`IPR2017-01913
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`those reported 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 solubili[z]ing
`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
`pharmacologic effects.” Id. ¶¶ 42–56. According to Dr. Sawchuk, these
`references17
`show that there are signif
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