`571.272.7822
`
` Paper No.
` Entered:
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`FRESENIUS-KABI USA LLC,
`Petitioner,
`
`v.
`
`ASTRAZENECA AB,
`Patent Owner.
`____________
`
`Case IPR2017-01910
`Patent 6,774,122 B2
`____________
`
`Before GRACE KARAFFA OBERMANN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`OBERMANN, Administrative Patent Judge.
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`IPR2017-01910
`Patent 6,774,122 B2
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` INTRODUCTION
`I.
`Petitioner Fresenius-Kabi USA LLC (“Petitioner”) filed a Petition requesting
`an inter partes review of claims 1, 2, 5, and 9 U.S. Patent No. 6,774,122 B2
`(Ex. 1001, “the ’122 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 ’122 Patent.
`
`A. Related Applications and Proceedings
`The ’122 Patent shares substantially the same specification with U.S. Patent
`Nos. 7,456,160 B2 (“the ’160 Patent”), 8,329,680 B2 (“the ’680 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 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 ’122 Patent has been the subject of numerous
`district court litigations. See Pet. 4–5; Paper 6, 2–3. According to Patent Owner, the
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`related ’160, ’680, 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 (“the 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 ’122 patent and two related patents also have been the subject of petitions
`for inter partes review filed by InnoPharma Licensing, LLC: IPR2017-00904 on the
`’122 patent, IPR2017-00900 on the ’680 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 ’122 Patent,
`Petitioner has submitted Petitions challenging claims of the ’139 Patent (IPR2017-
`01912) and the ’680 Patent (IPR2017-01913). These petitions are virtually identical
`to the three petitions filed by InnoPharma Licensing and denied by the Board in
`IPR2017-00900, IPR2017-00904, and 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 ’122 Patent and Relevant Background
`The Specification of the ’122 Patent discloses “an extended release
`pharmaceutical formulation adapted for intra-muscular injection comprising
`fulvestrant” 1 for the treatment of “benign or malignant disease[s]of the breast or
`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.”
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`reproductive tract, preferably treating breast cancer.” Ex. 1001, 10:56–11:22.
`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; 1:64–2:2; Ex. 1021,2 1,
`13.
`
`As of the filing date of the ’122 Patent, nonsteroidal antiestrogens, most
`particularly, tamoxifen, were used in the treatment of hormone-dependent breast
`cancers. See Ex. 1001, 1:16–32; Prelim. Resp. 19–20. In some hormone-dependent
`cancers, estrogen bound to estrogen receptors (ERs) stimulates tumor growth. See
`Pet. 12; Prelim. Resp. 19. 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. 19–20. As of the filing date of the
`’122 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, 2:11–31; Prelim. Resp. 19–21; Ex. 1015
`¶¶ 61–74. 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, 2:12–19; Ex. 1015 ¶¶ 61, 77.
`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, 8:36–46. And while the “solvating ability of castor oil for steroidal
`compounds is known” (id. at 5:19–24), a monthly depot injection made by dissolving
`
`Id. at 9:17–9.
`2 FASLODEX Prescribing Information, Rev. 11/2012.
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`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 5:25–41. In addressing these
`problems, the ’122 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 5:44–57 (referencing Tables 2 and 3); see also id. at 9:23–47 (“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 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 9:20–22. 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 8:29–32. 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 9:54–10:55,
`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 10:52–55; see id. at Fig. 1 and Table 4, second half.
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`The Specification, thus, describes the extended release fulvestrant formulation
`of the invention as comprising
`Fulvestrant . . . in a ricinoleate vehicle,[3] a pharmaceutically acceptable
`nonaqueous 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.
`Ex. 1001, 5:58–67. 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 7:12–31; 8:23–33.
`
`C. Challenged Claims
`Petitioner challenges claims 1, 2, 5, and 9 of the ’122 Patent. Pet. 1. Claims 1
`and 5 are independent. Claim 1 recites (paragraphing added):
`1. A method of treating a hormonal dependent benign or malignant
`disease of the breast or reproductive tract by administration to a human
`in need of such treatment an intramuscular injection of a pharmaceutical
`formulation comprising
`fulvestrant,
`a mixture of 10% weight of ethanol per volume of formulation,
`10% weight of benzyl alcohol per volume of formulation and
`15% weight of benzyl benzoate per volume of formulation and
`a sufficient amount of a castor oil vehicle,
`whereby a therapeutically significant blood plasma fulvestrant
`concentration of at least 2.5 ngml-1 is attained for at least 2 weeks
`after injection.
`
`Ex. 1001, 12:55–65.
`
`3 The Specification defines ricineolate vehicles as castor oil and other oils having “at least
`20% . . . of its composition as triglycerides of ricinoleic acid.” Id. at 8:23–27; see id. at 5:47–53.
`4 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 9:1–4.
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`Claim 5 is similar but in place of the “whereby” clause of claim 1, recites:
`“whereby the formulation comprises at least 45 mgml of fulvestrant.” Id. at 13:15–
`16. Depending from claims 1 and 5, respectively, claims 2 and 9 specify that “the
`benign or malignant disease is breast cancer.” Id. at 12:66–67, 14:13–14.
`
`D. The Asserted Prior art and Grounds of Unpatentability
`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, 2, 5, and 9
`
` 1, 2, 5, and 9
`
` 1, 2, 5, and 9
`
`Petitioner also relies on the Declarations of 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 300–308
`(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, Vol. 90 No. 20 J. NAT’L CANCER INST. 1552–58 (1998). Ex. 1009.
`7
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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. 15–16; Prelim. Resp. 8–12.
`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 ¶ 150; 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
`reports that “[t]hirteen (69%) patients responded (seven had partial responses and six
`
`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 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.
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`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 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.
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`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 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
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`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, 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
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`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 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, ’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 523–530. 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
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`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
`182–496; 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 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
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`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. 3001.12 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 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
`
`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.
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`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
`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
`
`13 Guerrini et al., Pharmacokinetics of probenecid in sheep, 8(2) J. VET. PHARMACOL.
`THER. 128–135 (1985) (Ex. 1042 at 549–556); Lavy et al., Pharmacokinetics of clindamycin HCl
`administered intravenously, intramuscularly and subcutaneously to dogs, 22(4) J. VET.
`PHARMACOL. THER. 261–265 (1999) (Ex. 1042 at 482–486); Ismail, Disposition kinetics of
`difloxacin after intravenous, intramuscular and subcutaneous administration in calves, 31(4) VET.
`RES. COMMUN. 467–476 (2007) (Ex. 1042 at 487–496).
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`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 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).
`
`II.
`
` 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. 18; Prelim. Resp. 20.
`Discerning no present conflict between the parties’ proposals, we rely on the level of
`
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`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 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131, 2144–46 (2016) (upholding the use of the broadest re