`571.272.7822
`
`Paper No. 7
`Entered: August 30, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`INNOPHARMA LICENSING, LLC,
`
`Petitioner,
`
`V.
`
`AS TRAZENECA AB,
`Patent Owner.
`
`Case IPR2017-OO904
`
`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
`
`AstraZeneca Exhibit 2173 p. 1
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01910
`
`
`
`IPR2017-00904
`
`Patent 6,774,122 B2
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`1.
`
`INTRODUCTION
`
`Petitioner InnoPharma Licensing, LLC (“Petitioner”)1 filed a Petition
`
`requesting an inter partes review of claims 1, 2, 5, and 9 US. Patent No.
`
`6,774,122 B2 (EX. 1001, “the ’122 Patent”). Paper 2 (“Pet.”). AstraZeneca
`
`AB (“Patent Owner”) filed a Preliminary Response to the Petition. Paper 6
`
`(“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 CPR. §§ 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
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`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 US.
`
`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
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`Application No. 10/872,784 (“the ’784 Application”) (now the ’160 Patent),
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`1 Petitioner further identifies InnoPharma, Inc., Pfizer Inc., Pfizer Australia
`Pty Ltd., Hospira Pty Ltd., and Hospira, Inc. as real parties-in-interest.
`Pet. 4.
`
`AstraZeneca Exhibit 2173 p. 2
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`
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`IPR2017-00904
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`Patent 6,774,122 B2
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`which is a continuation of Application No. 09/75 6,291(“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
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`numerous district court litigations. See Pet. 4—5; Paper 3, 2—3. According to
`
`Patent Owner, the related ’ 160, ’680, and ’ 139 Patents have also been
`
`involved in district court proceedings. Paper 3, 3. Each of the four related
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`patents have also been the subject of inter partes review proceedings filed
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`by Mylan Pharmaceuticals, Inc. (“Mylan”). Of these, IPR2016-01316 on the
`
`’122 patent, IPR2016-01324 on the ’ 160 patent, and IPR2016-01326 on the
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`’ 139 patent were terminated before we issued a decision regarding
`
`institution. In IPR2016-01325 (“the Mylan IPR”) on the ’680 patent,
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`however, we issued a Decision denying institution (“Mylan Decision”),
`
`which Petitioner submits in this proceeding as Exhibit 1011 and discusses
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`extensively in the Petition.
`
`In addition to the instant Petition challenging claims 1, 2, 5, and 9 of
`
`the ’ 122 Patent, Petitioner has submitted Petitions challenging claims of the
`
`’139 Patent (IPR2017-00905) and the ’680 Patent (IPR2017-00900).
`
`Petitioner does not presently challenge the ’ 160 Patent.
`
`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
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`AstraZeneca Exhibit 2173 p. 3
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`
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`IPR2017-00904
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`Patent 6,774,122 B2
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`fulvestrant” 2 for the treatment of “benign or malignant disease[s]of the
`
`breast or reproductive tract, preferably treating breast cancer.” Ex. 1001,
`
`10:56—1 1 :22. Fulvestrant is also known in the art as 1C1 182,780 or 70t-[9-
`
`(4,4,5 ,5 ,5-pentafluoropentylsulphinyl)nonyl]oestra-1 ,3 ,5(10)-triene-3 ,17-[3-
`
`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. 1021,3 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: 1 1—3 1;
`
`Prelim. Resp. 19—21; Ex. 1015 1111 61—74. Unlike tamoxifen, fulvestrant is a
`
`“pure” antiestrogen or ERD (estrogen receptor downregulator), which does
`
`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 9:17—9.
`
`3 FASLODEX Prescribing Information, Rev. 11/2012.
`
`4
`
`AstraZeneca Exhibit 2173 p. 4
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`
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`IPR2017-00904
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`Patent 6,774,122 B2
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`not display the partial ER agonist activity of tamoxifen. See Ex. 1001, 2: 12—
`
`19, Ex. 1015 W 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
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`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 5:25—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'l. .
`.
`. 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
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`AstraZeneca Exhibit 2173 p. 5
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`
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`IPR2017-00904
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`Patent 6,774,122 B2
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`site.” Id at 9:20—22. But according to the inventors, in vivo testing of the
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`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.
`
`The Specification, thus, describes the extended release fulvestrant
`
`formulation of the invention as comprising
`
`. in a ricinoleate vehicle,[4] a pharmaceutically
`.
`Fulvestrant .
`acceptable nonaqueous ester solvent, and a pharmaceutically
`acceptable alcohol wherein the formulation is adapted for
`intramuscular administration and attaining a therapeutically
`significant[5] blood plasma fulvestrant concentration for at least
`2 weeks.
`
`Ex. 1001 , 5:5 8—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.
`
`4 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.
`5 The Specification explains that “therapeutically significant” blood
`plasma levels refer to “blood plasma concentrations of at least 2.5 ngml'l,
`ideally at least 3 ngml'l, at least 8.5 ngml'l, and up to 12 nng'1 of
`fulvestrant [] achieved in the patient.” Id. at 9: 1—4.
`
`6
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`AstraZeneca Exhibit 2173 p. 6
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`
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`IPR20l7-OO904
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`Patent 6,774,122 B2
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`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
`
`injection of
`
`a pharmaceutical
`
`formulation
`
`intramuscular
`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,
`
`plasma
`blood
`significant
`therapeutically
`a
`whereby
`fulvestrant concentration of at least 2.5 nng'1 is attained
`for at least 2 weeks after injection.
`
`EX.1001,12:55—65.
`
`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.
`
`AstraZeneca Exhibit 2173 p. 7
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`IPR2017-00904
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`Patent 6,774,122 B2
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`D.
`
`The Assertea’ Prior art and Grounds of Unpatentability
`
`Petitioner asserts the following grounds of unpatentability (Pet. 8—9):
`
`
`Ground Reference(s)
`Basis
`Claims
`
`
`1
`Howell6
`§ 103
`1, 2, 5, and 9
`
`
`
`
`
`
`
`
`
`
`2
`Howell and McLeskey7
`§ 103
`1, 2, 5, and 9
`
`
`3
`
`Howell, lgcheskey, and
`O Regan
`
`103
`
`§
`
`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,
`
`PhD. (EX. 2003).
`
`6 Howell et al., Pharmacokinetics, pharmacological and anti-tumour
`eflects 0f the specific anti-oestrogen [C] l 82 780 in women with advanced
`breast cancer, 74 BRIT. J. CANCER 300—308 (1996). EX. 1007.
`7 McLeskey et al., Tamoxifen-resistantfibroblast growth factor
`transfectea’MCF—7 cells are cross-resistant in vivo to the antiestrogen [C]
`l 82, 780 and two ar0matase inhibitors, 4 CLIN. CANCER RESEARCH 697—711
`(1998). EX. 1008.
`8 O’Regan et al. , Eflects 0f the Antiestrogens Tamoxifen, T0remifene,
`and [C] l 82, 780 on Endometrial Cancer Growth, 90 J. NAT’L CANCER INST.
`
`1552—58 (1998). EX. 1009.
`
`AstraZeneca Exhibit 2173 p. 8
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`Patent 6,774,122 B2
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`The parties also discuss the Sawchuk § 1.132 Declaration9 and the
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`Gellert § 1.132 Declaration10 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,
`
`PhD. See Ex. 1014 11 3; Ex. 2001 11 61, Ex. 2002 11 150; Ex. 2003 11 58.
`
`E.
`
`Overview 0ftlze Asserted References
`
`l. 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;11
`
`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.12 Id. Howell
`
`9 Declaration under 37 C.F.R. § 1.132 of Ronald J. Sawchuk, dated
`January 13, 2012. Ex. 1019.
`10 Declaration under 37 C.F.R. § 1.132 of Paul Richard Geller, dated
`August 8, 2008. Ex. 1020.
`11 We refer, herein, to the original pagination of the cited references
`rather than to that supplied by the parties.
`12 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 1111 78, 83, 85. Howell is
`silent as to the presence or absence of other components in the formulation.
`
`9
`
`AstraZeneca Exhibit 2173 p. 9
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`Patent 6,774,122 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 pharrnacokinetics, 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 ml'1 to 12.8 ng ml'l, accompanied by increases in
`
`mean end-of-month concentrations from 3.1 ng ml'1 to 5.6 ng ml'l.” Id.
`
`In addressing the relationship between fulvestrant blood levels and
`
`efficacy, Howell states:
`
`investigation of long-term
`study represents the first
`This
`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 ml'1 were consistent with a therapeutic
`effect in patients with advanced breast cancer. However, a direct
`pharmacokinetic-pharmacodynamic link is not proven with the
`few patients studied to date.
`Serum drug concentrations in
`excess of this were observed with the 250 mg dose used in the
`
`10
`
`AstraZeneca Exhibit 2173 p. 10
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`Patent 6,774,122 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.
`
`11'. 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
`
`11
`
`AstraZeneca Exhibit 2173 p. 11
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`Patent 6,774,122 B2
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`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.
`
`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
`
`12
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`AstraZeneca Exhibit 2173 p. 12
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`examining the effect of these compounds on the uteri of the treated mice,
`
`McLeskey concludes that “these compounds retained activity, although they
`
`had no effect on tumor growth in our experiments.” Id. McLeskey does not
`
`specify whether the peanut oil-based or the castor oil-based fulvestrant
`
`composition was used for this experiment. Nor does McLeskey address
`
`fulvestrant blood plasma levels, or otherwise provide pharrnacokinetic data,
`
`for any experiment.
`
`l'l'l'. 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
`
`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.
`
`13
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`AstraZeneca Exhibit 2173 p. 13
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`Patent 6,774,122 B2
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`F.
`
`Prosecution History
`
`As set forth in section 1(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
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`have used benzyl benzoate in view of “the very low solubility of fulvestrant
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`in such ester,” as shown in the Specification. Id. at 523—530. The Examiner
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`found allowable subject matter in light of the “[u]nexpected increase of
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`solubility of fulvestrant by adding 15% of benzyl benzoate into the
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`composition with ethanol, benzyl alcohol, and castor oil .
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`.
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`. .” Id. at 540—
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`541; see also id. at 5 72 (Examiner’s Reasons For Allowance stating that
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`“[t]he herein recited ratio of ethanol, benzyl alcohol, and benzyl benzoate is
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`demonstrated to have unexpected increase of solubility of fulvestrant”).
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`Addressing a similar argument during the prosecution of the ’784
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`Application, Applicants relied on the Gellert § 1.132 Declaration. Ex. 1046,
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`150—181; see id. at 182—496; Ex. 1020. Dr. Gellert testified that, although it
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`14
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`AstraZeneca Exhibit 2173 p. 14
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`was known to use benzyl benzoate in castor oil-based formulations, an
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`experienced forrnulator
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`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.
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`Ex. 1020 1111 18—20, 24. According to Dr. Gellert, the inventors’ discovery
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`“that the addition of benzyl benzoate to the castor oil/alcohol mixture
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`actually increases the solubility of fulvestrant such that more fulvestrant
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`could be dissolved in a given volume of formulation, was unexpected and
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`truly surprising.” Id. 11 25. In allowing the ’160 Patent to issue, the
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`Examiner stated that “the unexpected solubility and the bioavailability of
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`using the specific solvent mixture as recited have been demonstrated.”
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`Ex. 1046, 729.
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`During the prosecution of the ’887 Application, Applicants disclosed
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`that, in connection with an attempt by Teva Parenteral Medicines Inc. to
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`gain approval of a generic 50 mg/ml fulvestrant injection, Teva had alleged
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`that the claims of the then-issued ’ 122 and ’ 160 Patents were invalid as
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`obvious over, inter alia, McLeskey and Howell. Ex. 1042, 295—99. Howell
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`and McLeskey were then the subject of an Examiner Interview. See id. at
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`336—37. Subsequent to the interview, the Examiner entered a rejection
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`under § 103 over McLeskey in combination with three other references. Id.
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`at 313—15. In responding to that rejection, Applicants amended the
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`independent claims (now claims 1 and 9) to recite a formulation comprising
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`“about 50 mgml'1 of fulvestrant; about 10% w/v of ethanol; about 10% w/v
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`15
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`of benzyl alcohol,” and “about 15% w/v of benzyl benzoate,” wherein the
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`method achieves a therapeutically significant blood plasma fulvestrant
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`concentration “for at least four weeks.” See id. at 335 ; Ex. 3001.13
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`Applicants also relied extensively on arguments set forth in the Sawchuk
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`§ 1.132 Declaration. Ex. 1042, 339—55; see id at 357—83; Ex. 1019.
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`Dr. Sawchuk testified that the cited references provide no motivation
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`to select the disclosed castor oil formulation for intramuscular
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`administration. Ex. 1019, 1111 31—41. McLeskey, for example, “did not
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`disclose plasma or blood levels of fulvestrant in mice after subcutaneous
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`administration of either the peanut oil or the castor oil compositions” and,
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`thus presents “no information regarding the rate and/or extent of absorption
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`of fulvestrant from the subcutaneous injection site.” Id. 11 32. Dr. Sawchuk
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`further testified that “McLeskey concluded that treatment with fulvestrant
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`(ICI 182,780), using either of the disclosed compositions was not effective
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`in that it ‘did not slow estrogen-independent growth or prevent metastasis of
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`tumors’” in the mouse model and, thus, would not have informed one of
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`ordinary skill in the art “about the usefulness of either fulvestrant
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`formulation when administered subcutaneously to a mouse for the treatment
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`of cancerous tumors.” Id. 11 33; see also id. 11 34 (noting that although
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`McLeskey demonstrated that fulvestrant had activity in mice uteri, the
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`reference did not specify which formulation was used in that experiment).
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`Dr. Sawchuk concluded that
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`13 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. 3001.
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`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
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`fulvestrant McLeskey compositions (peanut oil or castor oil) was
`able to deliver a dose of fulvestrant that had an antitumour
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`administered
`the mice when
`in
`effect
`therapeutic
`subcutaneously, nor any insight about fulvestrant absorption
`characteristics (rate and extent) when administered via the
`intramuscular route in any species, including humans.
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`Id. 1] 35.
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`Expanding on that conclusion, Dr. Sawchuk testified that “one of
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`ordinary skill in the art would not have had a reasonable expectation that the
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`McLeskey castor oil composition would have been effective when given as
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`an intramuscular injection” (id. 1] 69) because (1) the composition of a
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`formulation can have a significant effect on efficacy (id. W 57—69), and (2)
`
`because “results from subcutaneous administration in general, and including
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`those included in McLeskey, cannot be extrapolated to intramuscular
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`administration,” either with respect to side effects or efficacy (id. 1] 42—43).
`
`Quoting the Specification’s assertion that “[s]imply solubilising
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`fulvestrant in an oil based liquid formulation is not predictive of a good
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`release profile or lack of precipitation of drug after injection at the injection
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`site,” Dr. Sawchuk stated that “suitable experiments are needed to determine
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`the pharmacokinetic performance of any candidate formulation(s).” Id. 1] 62.
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`To illustrate the unpredictability in the prior art, Dr. Sawchuk discussed
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`three published examples illustrating that “the intramuscular and
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`subcutaneous administration of a drug to the same animal or human may
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`produce very different plasma level curves, and therefore very different
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`pharrnacologic effects.” Id. 1111 42—56. According to Dr. Sawchuk, these
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`references14
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`show that there are significant differences in the rate and extent
`of absorption of a drug given by the intramuscular and
`subcutaneous route, even when given to the same animals in a
`crossover study. As a result, it cannot be predicted a priori
`whether intramuscular or subcutaneous dosing will result in
`more rapid and/or complete drug absorption, as examples of both
`cases are found in the scientific literature.
`
`Id. 11 53.
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`Dr. Sawchuk also testified that one of ordinary skill in the art would
`
`have understood that the components in McLeskey’s castor oil formulation
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`are implicitly described in terms of volume/volume percent units, which
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`differ substantially from the weight/volume percentages of the claimed
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`invention. See id. 1111 16—30. Upon reviewing several prior art sources in
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`which formulations were disclosed in a % v/v basis, Dr. Sawchuk testified
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`that “one of ordinary skill in the art would have concluded that the
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`composition [of McLeskey] was described in terms of volume/volume
`
`percent units (% v/v).” Id. 11 21. Based on the proposition that McLeskey
`
`implicitly disclosed a formulation based on volume/volume percent units,
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`Dr. Sawchuk calculated the amount of each component in weight/volume
`
`percent units. Id. 1111 23—28 (referencing Table 1). Based on these
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`14 Guerrini et al., Pharmacokinetics ofprobenecid 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).
`
`18
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`AstraZeneca Exhibit 2173 p. 18
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`calculations, Dr. Sawchuk concluded that “McLeskey described a
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`composition containing about 8.1% w/v ethanol, about 16.8 % w/v benzyl
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`benzoate, and about 10.4% w/v benzyl alcohol in a castor oil vehicle.” Id.
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`11 29.
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`Without citing any one argument as dispositive, the Examiner
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`withdrew the obviousness rejection “in view of the arguments along with the
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`declaration of Dr. Sawchuk filed 1/17/2012” (Ex. 1042, 650) and allowed
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`the ’680 Patent to issue (id. at 717—19).
`
`1].
`
`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.
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`17; Prelim. Resp. 18. Discerning no present conflict between the parties’
`
`proposals, we rely on the level of ordinary skill in the art of developing and
`
`treating hormone-dependent diseases of the breast as demonstrated by the
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`prior art. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001).
`
`B.
`
`Claim Construction
`
`In an inter partes review, claim terms in an unexpired patent are
`
`interpreted according to their broadest reasonable construction in light of the
`
`specification of the patent in which they appear. 37 CPR. § 42.100(b);
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`Cuozzo Speed Techs, LLC v. Lee, 136 S. Ct. 2131, 2144—46 (2016)
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`(upholding the use of the broadest reasonable interpretation stand