Paper No. 51
`
`
`Trials@uspto.gov
` Date: November 18, 2020
`
`
`571.272.7822
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`TEVA PHARMACEUTICALS USA, INC.,
`Petitioner,
`v.
`CORCEPT THERAPEUTICS, INC.,
`Patent Owner.
`____________
`
`PGR2019-00048
`Patent 10,195,214 B2
`____________
`
`
`Before JAQUELINE WRIGHT BONILLA, Deputy Chief Administrative
`Patent Judge, ROBERT A. POLLOCK, and DAVID COTTA,
`Administrative Patent Judges.
`
`COTTA, Administrative Patent Judge.
`
`
`
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. § 328
`Dismissing Patent Owner’s Motion to Exclude Evidence
`37 C.F.R. § 42.64
`
`
`
`
`
`
`
`
`
`

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`PGR2019-00048
`Patent 10,195,214 B2
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`I.
`INTRODUCTION
`On May 7, 2019, Teva Pharmaceuticals USA, Inc., (“Petitioner”) filed
`a Petition for Post Grant Review of claims 1–13 of U.S. Patent No.
`10,195,214 B2 (“the ’214 patent”).1 Paper 2 (“Pet.”). On August 23, 2019,
`Corcept Therapeutics, Inc. (“Patent Owner”) filed a Preliminary Response to
`the Petition.2 Paper 8 (“Prelim. Resp.”). On September 23, 2019, with the
`authorization of the Board, Paper 14, Petitioner filed a Reply to Patent
`Owner’s Preliminary Response. Paper 15 (“Reply”). On October 3, 2019,
`also with the authorization of the Board, Patent Owner filed a Sur-Reply to
`Petitioner’s Reply. Paper 17 (“Sur-reply”). We determined, based on the
`information presented in papers and evidence before us at that time, that
`there was a reasonable likelihood that Petitioner would prevail in showing
`that at least one of the challenged claims was unpatentable over the cited art.
`Pursuant to 35 U.S.C. § 324, the Board instituted trial on November 20,
`2019. Paper 19 (“Institution Decision” or “Inst. Dec.”).
`After institution, Patent Owner filed a Response to the Petition (Paper
`29, “PO Resp.”), Petitioner filed a Reply to Patent Owners’ Response (Paper
`34, “Reply”), and Patent Owner filed a Sur-Reply (Paper 43, “Sur-Reply”).
`Patent Owner also filed a Motion to Exclude (Paper 44, “Mot.”),
`Petitioner filed an Opposition to Patent Owner’s Motion to Exclude (Paper
`45, “Mot. Opp.”), and Patent Owner filed a Reply in Support of its Motion
`to Exclude (Paper 47, “Mot. Reply”).
`
`
`1 Petitioner identifies Teva Pharmaceutical USA Inc. as the real party in
`interest. Pet. 65.
`2 Patent Owner identifies Corcept Therapeutics, Inc. as the real party in
`interest. Paper 5, 1.
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`On September 2, 2020, the parties presented arguments at an oral
`hearing. The transcript of the hearing has been entered into the record.
`Paper 50 (“Tr.”).
`We have jurisdiction under 35 U.S.C. § 6. We issue this Final Written
`Decision pursuant to 35 U.S.C. § 328(a) and 37 C.F.R. § 42.73. Based on
`the record before us, we conclude that Petitioner has not demonstrated by a
`preponderance of the evidence that claims 1–13 are unpatentable. We
`dismiss Patent Owners’ Motion to Exclude as moot.
`A.
`Related Proceedings
`Petitioner and Patent Owner represent that the ’214 patent was
`asserted in district court in Corcept Therapeutics, Inc. v. Teva
`Pharmaceuticals USA, Inc., Civil Action No. 18-3632 (SDW) (CLW)
`(D.N.J.). Pet. 65; Paper 5, 1. Petitioner additionally identifies pending U.S.
`Patent Application Nos. 16/219,564 and 15/627,368 as relating to the ’214
`patent. Pet. 65.
`
`The ’214 Patent (Ex. 1001)
`B.
`The ’214 patent, entitled “Concomitant Administration of
`Glucocorticoid Receptor Modulators and CYP3A Inhibitors,” issued
`February 5, 2019, identifying Joseph K. Belanoff as the inventor. Ex. 1001,
`codes (45), (54), (72). The ’214 patent discloses “methods of treating
`diseases including Cushing’s syndrome and hormone-sensitive cancers by
`concomitant administration of a glucocorticoid receptor antagonist (GRA)
`and steroidogenesis inhibitors, and by concomitant administration of [] GRA
`and CYP3A inhibitors.” Ex. 1001, Abstract.
`
`The ’214 patent teaches that Cushing’s syndrome is a disorder caused
`by dysregulation of cortisol. Id. at 1:27–37. “Clinical manifestations of
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`Cushing’s syndrome include abnormalities in glucose control, requirement
`for anti-diabetic medication, abnormalities in insulin level, abnormal
`psychiatric symptoms, cushingoid appearance, acne, hirsutism, and
`increased or excessive body weight, and other symptoms.” Id. at 1:37–42.
`
`The ’214 patent discloses that “[o]ne effective treatment of cortisol
`dysregulation is to block the binding of cortisol to cortisol receptors, or to
`block the effect of cortisol binding to cortisol receptors.” Id. at 1:43–45.
`The ’214 patent also discloses that “[m]ifepristone binds to cortisol
`receptors, and acts to block such binding and to block the effect of cortisol
`on tissues.” Id. at 1:45–49.
`
`According to the ’214 patent, “[a]nother effective treatment of cortisol
`dysregulation is to reduce the synthesis of cortisol, e.g., by reducing or
`blocking steroid synthesis.” Id. at 1:50–53. “CYP3A enzymes play
`important roles in the synthesis of steroid hormones such as cortisol.” Id. at
`1:61–62. The ’214 patent discloses a number of drugs that inhibit CYP3A
`including, inter alia, ketoconazole, itraconazole, and clarithromycin. Id. at
`1:63–2:12.
`The ’214 patent teaches that “[t]he simultaneous, or nearly
`simultaneous (e.g., concomitant) presence of two drugs in a subject may
`alter the effects of one or the other, or both, drugs.” Id. at 2:64–66. More
`specifically, “[c]oncomitant administration of different drugs often leads to
`adverse effects since the metabolism and/or excretion of each drug may
`reduce or interfere with the metabolism and/or excretion of the other drug(s),
`thus increasing the effective concentrations of those drugs as compared to
`the effective concentrations of those drugs when administered alone.” Id. at
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`Patent 10,195,214 B2
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`3:15–22. In addition, “the risk of . . . toxic effects is believed to be increased
`when other drugs are concomitantly administered.” Id. at 3:24–29.
`The ’214 patent discloses that “CYP3A inhibitors such as, e.g.,
`ketoconazole, may be concomitantly administered with glucocorticoid
`receptor modulators (GRMs) such as the GR antagonik [sic, antagonist]
`(GRA) mifepristone.” Id. at 3:47–50; see also id. at 4:1–21. For example,
`the ’214 patent asserts that “concomitant administration of ketoconazole and
`mifepristone surprisingly does not increase the risk of ketoconazole toxicity
`in the patient, and is believed to be safe for the patient.” Id. at 4:51–55.
`Challenged Claims
`C.
`Petitioner challenges claims 1–13 of the ’214 patent. Claim 1 is
`representative and is reproduced below.
`
`1.
`A method of treating Cushing’s syndrome in a patient who
`is taking an original once-daily dose of 1200 mg or 900 mg per
`day of mifepristone, comprising the steps of:
`reducing the original once-daily dose to an adjusted once-
`daily dose of 600 mg mifepristone,
`administering the adjusted once-daily dose of 600 mg
`mifepristone and a strong CYP3A inhibitor to the patient,
`wherein said strong CYP3A inhibitor is selected from the
`group consisting of ketoconazole, itraconazole, nefazodone,
`ritonavir, nelfmavir,
`indinavir, boceprevir, clarithromycin,
`conivaptan, lopinavir, posaconazole, saquinavir, telaprevir,
`cobicistat,
`troleandomycin,
`tipranivir,
`paritaprevir
`and
`voriconazole.
`Ex. 1001, 68:2–16.
`D. The Asserted Ground of Unpatentability
`Petitioner challenges the patentability of claims 1‒13 of the ’214
`patent on the following grounds:
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`35 U.S.C. §
`103(a)
`103(a)
`
`Reference(s)/Basis
`Korlym Label,3 Lee4
`Korlym Label, Lee, FDA Guidance5
`
`Claim(s)
`Challenged
`1–13
`1–13
`
`Petitioner submits two Declarations of Dr. David J. Greenblatt
`(Ex. 1002; Ex. 1067) and the Declaration of Dr. Adrian Dobs (Ex. 1068) in
`support of its Petition and Reply to Patent Owners’ Response. Patent Owner
`submits the Declarations of Dr. F. Peter Guengerich (Ex. 2056), Dr. Ty
`Carroll (Ex. 2057), and Dr. Laurence Katznelson (Ex. 2058) in support of its
`Response to the Petition and Sur-Reply to Petitioner’s Reply.
`E. Person of Ordinary Skill in the Art
`Factual indicators of the level of ordinary skill in the art include “the
`various prior art approaches employed, the types of problems encountered in
`the art, the rapidity with which innovations are made, the sophistication of
`the technology involved, and the educational background of those actively
`working in the field.” Jacobson Bros., Inc. v. U.S., 512 F.2d 1065, 1071 (Ct.
`Cl. 1975); see also Orthopedic Equip. Co., v. U.S., 702 F.2d 1005, 1011
`(Fed. Cir. 1983) (quoting with approval Jacobson Bros.).
`
`
`3 Corcept Therapeutics Inc., KorlymTM (mifepristone) 300 mg Tablets, (2012)
`(Ex. 1004, “Korlym Label”).
`4 Lee et al., Office of Clinical Pharmacology Review NDA 20687
`(Addendum, KorlymTM, Mifepristone) (2012) (Ex. 1005, “Lee”).
`5 U.S. Department of Health and Human Services, Food and Drug
`Administration (FDA), Center for Drug Evaluation and Research (CDER),
`Center for Biologics Evaluation and Research (CBER), Guidance for
`Industry, Drug Interaction Studies — Study Design, Data Analysis, and
`Implications for Dosing and Labeling, (2006) (Ex. 1041, “FDA Guidance”).
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`Petitioner contends that the person of ordinary skill in the art
`(“POSA”) “would have had an M.D., a Pharm. D., and/or a Ph.D. in
`pharmacology or a related discipline” as well as “at least four years of
`experience either treating patients with mifepristone and/or CYP3A
`inhibitors or, alternatively, studying drug-drug interactions involving
`CYP3A inhibitors.” Pet. 22. Petitioner further contends that a POSA might
`also “have worked as part of a multidisciplinary team that included
`researchers and clinicians in the field and drawn upon not only her own
`skills, but also the specialized skills of others, to solve a given problem.” Id.
`Petitioner’s proposal thus embraces three distinct possibilities: 1) that the
`POSA is just a clinician with experience treating patients, 2) that the POSA
`is just a researcher with experience studying drug-drug interactions, and
`3) that the POSA is part of a multidisciplinary team including researchers
`and clinicians.
`Patent Owner contends that Petitioner’s definition of the POSA is
`“incomplete.” PO Resp. 20. According to Patent Owner, “the POSA for
`purposes of the ’214 patent needs to include an M.D. or related medical
`professional with at least four years of experience treating patients with
`Cushing’s syndrome with mifepristone.” Id. at 22. Patent Owner does not
`otherwise object to Petitioner’s definition and, in fact, notes that Petitioner’s
`definition allows for the inclusion of a POSA having such experience, but
`does not require it. Id. at 21 n. 2.
`We agree with Petitioner that the “problem” addressed in the ’214
`patent focused on “determining the extent and clinical significance of the
`DDI [drug-drug interaction] between mifepristone and strong CYP3A
`inhibitors.” Pet. Reply. 3–4 (citing Ex. 1001, 3:40–57; Ex. 1035, 339). This
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`supports that the POSA should include someone having experience studying
`drug-drug interactions. In addition, we agree with Patent Owner that the
`POSA should have some experience treating patients with Cushing’s
`syndrome because all of the claims of the ’214 relate to treating patients with
`Cushing’s syndrome,6 and because both of the prior art references relied
`upon in connection with Ground 1, and two of the three prior art references
`relied upon in connection with Ground 2, relate to Cushing’s syndrome.
`Ex. 1004, 1 (prescribing information for Korlym, a drug indicated for
`treating “patients with endogenous Cushing’s syndrome”); Ex. 1005 (an
`FDA Office of Clinical Pharmacology Review Memorandum, included in
`the 2012 drug approval package for Korlym). See Okajima v. Bourdeau,
`261 F.3d 1350, 1355 (Fed. Cir. 2001) (the prior art itself can reflect the
`appropriate level of ordinary skill in the art).
`The definition of a POSA that best incorporates both experience with
`drug-drug interaction and experience treating patients is Petitioner’s
`proposed multidisciplinary team. Patent Owner does not object to defining
`the POSA as part of a multidisciplinary team, so long as that team includes a
`person with experience treating Cushing’s syndrome, which, as discussed
`above, is appropriate. Tr. 38. Accordingly, we define the POSA as: a
`multidisciplinary team that includes researchers and clinicians in the field
`and is able to draw upon not only the individual skills of each team member,
`but also the specialized skills of others to solve a given problem. The
`
`6 Claim 5 and its dependents are directed to “[a] method of treating
`symptoms associated with elevated cortisol levels.” Cushing’s syndrome is
`“caused by excess levels of cortisol.” Ex. 1001, 1:31–33. Accordingly,
`claim 5 relates to Cushing’s syndrome even if it does not specifically recite
`that the patient has Cushing’s syndrome. All of the other claims expressly
`recite Cushing’s syndrome.
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`researchers and clinicians would have an M.D., a Pharm. D., and/or a Ph.D.
`in pharmacology or a related discipline. The clinician would have at least
`four years of experience treating patients with Cushing’s syndrome using
`mifepristone and/or CYP3A inhibitors. The researcher would have at least
`four years of experience studying drug-drug interactions involving CYP3A
`inhibitors.
`Notwithstanding the parties’ differences with respect to whether the
`POSA must have experience treating patients with Cushing’s syndrome, we
`do not perceive our identification of the POSA to impact our patentability
`analysis. In this regard, we note that while some of the individuals who
`have offered testimony in this proceeding may lack certain attributes
`encompassed within the multi-disciplinary team, all are qualified to
`contribute to the multidisciplinary team. We further note that by
`incorporating experience with treating Cushing’s syndrome in the definition
`of the POSA, as proposed by Patent Owner, we have adopted a higher level
`of skill than proposed by Petitioner.
`F.
`Claim Construction
`In a post-grant review, we construe the claims “using the same claim
`construction standard that would be used to construe the claim in a civil
`action under 35 U.S.C. § 282(b).” See Changes to the Claim Construction
`Standard for Interpreting Claims in Trial Proceedings Before the Patent Trial
`and Appeal Board, 83 Fed. Reg. 51,340, 51,340, 51,358 (Oct. 11, 2018)
`(amending 37 C.F.R. § 42.200(b) effective November 13, 2018) (now
`codified at 37 C.F.R. § 42.200(b) (2019)). Therefore, we construe the
`challenged claims under the framework set forth in Phillips v. AWH Corp.,
`415 F.3d 1303, 1312–19 (Fed. Cir. 2005) (en banc) and its progeny. Under
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`this framework, claim terms are given their ordinary and customary
`meaning, as would be understood by a person of ordinary skill in the art, at
`the time of the invention, in light of the language of the claims, the
`specification, and the prosecution history of record. Id. Only those terms
`that are in controversy need be construed, and only to the extent necessary to
`resolve the controversy. See Nidec Motor Corp. v. Zhongshan Broad Ocean
`Motor Co., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (citing Vivid Techs., Inc. v.
`Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
`As discussed in more detail below, the Petition, Patent Owner’s
`Response, the testimonial evidence, and our Institution Decision implicitly
`treat the claims as requiring co-administering mifepristone with a strong
`CYP3A inhibitor in a manner that is safe for the patient being treated.
`Pet. 33; id. at 41; Ex. 1002 ¶¶ 61, 69, 86, 105; Inst. Dec. 21; PO Resp. 29–
`33. In its Reply, Petitioner argues, for the first time, that “the claims do not
`require safety; they require only ‘treating’ Cushing’s syndrome or its
`symptoms.” Reply 14. We address this argument infra p. 16–21. Other
`than our discussion of claim construction in connection with this new
`argument, for purposes of resolving whether Petitioner has demonstrated
`that claims 1–13 of the ’214 patent are unpatentable, we need not expressly
`construe any claim terms.
`
`
` GROUND 1: OBVIOUSNESS OVER
`KORLYM LABEL AND LEE
`Petitioner asserts that the combination of the Korlym Label and Lee
`renders claims 1–13 of the ’214 patent obvious. Pet. 24–41. Patent Owner
`opposes. PO Resp. 29–77. We have considered the question of patentability
`in view of all the evidence and arguments presented in this proceeding.
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`Based on the record developed during this proceeding, we determine that
`Petitioner has not shown by a preponderance of the evidence that claims 1–
`13 of the ’214 patent would have been obvious over the combination of the
`Korlym Label and Lee.
`A. Disclosures of the Asserted Prior Art
`The Korlym Label
`The Korlym Label is “the original FDA-approved prescribing
`information for Korlym® from February 2012.” Prelim. Resp. 28. It
`discloses that Korlym (mifepristone) is “a cortisol receptor blocker indicated
`to control hyperglycemia secondary to hypercortisolism in adult patients
`with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or
`glucose intolerance and have failed surgery or are not candidates for
`surgery.” Ex. 1004, 1. “The recommended starting dose is 300 mg once
`daily.” Id. “Based on clinical response and tolerability, the dose may be
`increased in 300 mg increments to a maximum of 1200 mg once daily.” Id.
`The Korlym Label cautions:
`Medications that inhibit CYP3A could increase plasma mifepristone
`concentrations and dose reduction of Korlym may be required.
`
`Ketoconazole and other strong inhibitors of CYP3A, such as
`itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir,
`amprenavir and fosamprenavir, boceprevir, clarithromycin,
`conivaptan, lopinavir, mibefradil, nefazodone, posaconazole,
`ritonavir, saquinavir, telaprevir, telithromycin, or voriconazole may
`increase exposure to mifepristone significantly. The clinical impact of
`this interaction has not been studied. Therefore, extreme caution
`should be used when these drugs are prescribed in combination with
`Korlym. The benefit of concomitant use of these agents should be
`carefully weighed against the potential risks. The dose of Korlym
`should be limited to 300 mg and used only when necessary.
`Id. at 9–10.
`
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`Lee
`Lee is “an FDA Office of Clinical Pharmacology Review
`
`Memorandum, included in the 2012 drug approval package for Korlym®.”
`Prelim. Resp. 30. Lee discloses that there is a “high potential of
`[ketoconazole’s] concomitant use with mifepristone.” Ex. 1005, 4.7 In view
`of the high potential for concomitant use, Lee recommends a drug-drug
`interaction (“DDI”) study. It states:
`The degree of change in exposure of mifepristone when co-
`administered with strong CYP3A inhibitors is unknown and
`may present a safety risk or deprive the patients on strong
`inhibitors the use of Mifepristone due to lack of accurate
`knowledge of this potential drug interaction. Thus the
`quantitative data for effect of ketoconazole on the
`pharmacokinetics of mifepristone would be beneficial to the
`target populations. A drug-drug interaction study with
`ketoconazole is recommended as a Post Marketing Requirement
`(PMR). The goal of this study is to get a quantitative estimate
`of the change in exposure of mifepristone following co-
`administration with ketoconazole. Based on the results of this
`study, the effect of moderate CYP3A inhibitors on mifepristone
`pharmacokinetics may need to be addressed. This will help
`provide more therapeutic options available to Cushing’s
`patients and appropriate labeling of mifepristone when co-
`administered with CYP3A inhibitors.
`Id. at 4–5.
`
`Lee also discloses that the FDA recommended a DDI study, and that
`the drug-drug interaction data provided by the sponsor (Patent Owner) did
`not allow for “reasonable interpretation.” Lee explains:
`The Agency recommended a drug-drug interaction study with a
`strong CYP3A4 inhibitor prior to the submission because the
`DDI study with a cimetidine, could not adequately address the
`DDI with CYP3A4 inhibitors. Instead of conducting a DDI
`
`7 All references to Lee are to the exhibit page numbers added by Petitioner.
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`study with ketoconazole, the sponsor provided two randomly-
`timed concentrations of mifepristone obtained from one patient
`who w[as] on the concomitant use of 400 mg TID ketoconazole
`during [a] Phase 3 clinical trial on page 122 in [the] Clinical
`Pharmacology Summary. Those concentrations were 8,520 and
`8,770 ng/mL (75 minutes apart between the two samples),
`which were more than 4 times higher than average trough
`concentrations (~2,000 ng/mL). However, reasonable
`interpretation of these concentrations was not possible, because
`detailed information was not provided further.
`Id. at 38. Lee notes, however, that “[t]he mechanism-based inhibition of
`mifepristone on its own metabolism, may not allow an adequate assessment
`of drug-interaction at steady state or the remaining capacity of metabolizing
`enzyme may not be sensitive to any influence by inhibitors.” Id. at 76.
`B.
`The Parties’ Positions
`Petitioner contends that the Korlym Label and Lee disclose
`administering mifepristone in doses ranging from 300–1200 mg to treat
`Cushing’s syndrome. Pet 30–31 (citing Ex. 1004, 3; Ex. 1005, 3, 11).
`Petitioner also contends that the Korlym Label and Lee disclose co-
`administration of mifepristone and a strong CYP3A inhibitor, such as
`ketoconazole, to treat Cushing’s syndrome. Id. at 32 (citing Ex. 1004, 9;
`Ex. 1005, 37). Petitioner acknowledges, however, that “[t]he Korlym Label
`does not expressly teach lowering the once-daily dose from 1200 or 900 mg
`to 600 mg, specifically, when used in combination with strong CYP3A
`inhibitors . . . [i]nstead . . . recommend[ing] limiting mifepristone
`dosages to 300 mg per day in such cases.” Id. (citing Ex. 1004, 6).
`Petitioner contends that “arriving at the specific once-daily dose of
`600 mg in conjunction with strong CYP3A inhibitors would have been
`merely the product of routine optimization.” Pet. 32. Petitioner provides the
`testimony of Dr. David J Greenblatt, who testifies that,
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`a POSA would have expected that co-administration of strong
`CYP3A inhibitors and mifepristone—at some dose—would be
`safe and effective to treat Cushing’s syndrome and other
`symptoms associated with elevated cortisol levels, and it would
`be a matter of routine experimentation to determine precisely
`how much to adjust the dosage of mifepristone when co-
`administered with a strong CYP3A inhibitor to achieve the
`optimum balance of safety and therapeutic efficacy.
`Ex. 1002 ¶ 61.
`Petitioner contends that the POSA would have been motivated to
`optimize mifepristone dosage with a reasonable expectation of success for
`three reasons. First, “the label instructs clinicians to make dosage
`adjustments ‘based on a clinical assessment of tolerability and degree of
`improvement in Cushing’s syndrome manifestations.’” Pet. 33. According
`to Petitioner, the label thus “explicitly contemplates that physicians
`prescribing Korlym will optimize the dosage on a trial-and-error basis.” Id.
`Second, Petitioner contends that the label “expressly permits once-daily
`doses up to 1200 mg per day, and skilled artisans would have known from
`prior studies that mifepristone was well tolerated and effective in patients
`with Cushing’s syndrome at doses even higher than that.” Id. (internal
`citations omitted). Petitioner thus argues that “a skilled artisan would have
`had a reasonable expectation that 600 mg could be administered safely, even
`in combination with a strong CYP3A inhibitor.” Id. Third, Petitioner notes
`that the POSA would have known exactly how to test an optimized dosage
`of mifepristone using studies that were “routine in the art.” Id. at 34.
`Patent Owner argues, inter alia, that Petitioner “failed to show that a
`POSA would have had a reasonable expectation of success of developing the
`methods claimed in the ’214 patent based on the Korlym Label and Lee,
`with or without FDA Guidance.” PO Resp. 29. Patent Owner contends that
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`Dr. Greenblatt, upon whom Petitioner relied to establish a reasonable
`expectation of success, testified that “a POSA at the time of invention would
`have no expectation regarding whether co-administration of greater than 300
`mg mifepristone with a strong CYP3A inhibitor would be safe and
`effective.” Id. at 33. According to Patent Owner, this is dispositive because
`“[i]f a POSA does not have any expectation based on the prior art, he or she
`cannot have a reasonable expectation of successfully arriving at the claimed
`inventions.” Id. at 34.
`
`Analysis
`C.
`This case turns on whether Petitioner has carried its burden to
`establish that a POSA had a reasonable expectation of success in performing
`the claimed methods. We begin our analysis by considering the argument,
`advanced by Petitioner for the first time in its Reply, that the claims do not
`require safety. For the reasons discussed below, we determine that
`Petitioner has waived this argument and that, even if it is not waived, it is
`not persuasive.
`We then consider the three reasons identified in the Petition as to why
`“[a] skilled artisan would have been motivated to [optimize the treatment
`regimen as claimed], and the skilled artisan would have had a reasonable
`expectation of success of using that optimized treatment regimen to treat
`Cushing’s syndrome.” Pet. 33. As noted above, these reasons are: 1) that
`the Korlym label “explicitly contemplates that physicians prescribing
`Korlym will optimize dosage on a trial-and-error basis”; 2) that “the label
`expressly permits once-daily doses of up to 1200 mg per day” in
`monotherapy; and 3) that “a skilled artisan would have known exactly how
`to . . . run a clinical study to determine the extent and significance of the
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`drug-drug interaction” and “how to adjust the dosage based on the results of
`the DDI study.” Id. at 33–35.
`We next consider below Petitioner’s argument that the 300 mg/day
`limitation recited in the Korlym Label is not supported by clinical
`experience. Id. 35–37. It appears that Petitioner relies on this argument to
`support the notion that the 300 mg/day limitation would not have
`discouraged the POSA from trying higher doses, rather than as support for
`an expectation that such doses would be safe and effective. See id. at 35
`(“Nor would the 300-mg-per-day dose limitation on the Korlym Label have
`discouraged a skilled artisan from titrating the dose to 600 mg when used in
`combination with strong CYP3A inhibitors.”). Nevertheless, for
`completeness, and so as not to omit discussion of any evidence potentially
`supporting a reasonable expectation of success, we consider below whether
`this argument supports an expectation of success.
`Finally, we also address below evidence identified for the first time in
`Petitioner’s Reply disclosing administration of more than 300 mg of
`mifepristone with ketoconazole.
`After considering all of the evidence before us, we find that Petitioner
`has not carried its burden to establish a reasonable expectation of success.
`Because we find that Petitioner has not carried its burden, we decline to
`consider Patent Owner’s arguments that the POSA would have expected
`failure in co-administering mifepristone with a strong CYP3A inhibitor and
`that objective indicia support the non-obviousness of the claimed methods.
`
`
`
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`PGR2019-00048
`Patent 10,195,214 B2
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`
`1. Petitioner’s new argument that the claims do not require safety
`
`Prior to the filing of Petitioner’s Reply, the parties implicitly agreed
`that the claims required co-administering mifepristone with a strong CYP3A
`inhibitor in a manner that is safe for the patient being treated. For example,
`when asserting a reasonable expectation of success in the Petition, the
`Petitioner posits that the POSA “would have had a reasonable expectation
`that 600 mg could be administered safely, even in combination with a strong
`CYP3A inhibitor.” Pet. 33 (emphasis added); see also id. at 41 (arguing that
`“a skilled artisan would have had a reasonable expectation that the resulting
`method of treatment would be successful in effectively and safely treating
`these conditions.”) (emphasis added); PO Resp. 29–33 (arguing that the
`POSA would have lacked an expectation of success because there was no
`expectation that mifepristone could be co-administered safely with a strong
`CYP3A inhibitor). Similarly, Dr. Greenblatt’s initial testimony (pre-
`institution) supporting a reasonable expectation of success states that it was
`“reasonably likely that 600 mg would be well tolerated and therapeutically
`effective when co-administered with a strong CYP3A inhibitor.” Ex. 1002
`¶¶ 69, 86, 105 (emphasis added); see also id ¶ 61 (“[A] POSA would have
`expected that co-administration of strong CYP3A inhibitors and
`mifepristone—at some dose—would be safe and effective to treat Cushing’s
`syndrome and other symptoms associated with elevated cortisol levels, and it
`would be a matter of routine experimentation to determine precisely how
`much to adjust the dosage of mifepristone when co-administered with a
`strong CYP3A inhibitor to achieve the optimum balance of safety and
`therapeutic efficacy.”) (emphasis added). Based on the parties’ implicit
`construction of the challenged claims as requiring safety, our Institution
`
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`PGR2019-00048
`Patent 10,195,214 B2
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`Decision also treated the claims as requiring safety. See, e.g., Inst. Dec. 21
`(crediting Dr. Greenblatt’s testimony in rejecting Patent Owner’s argument
`that there was “nothing in the prior art that would have indicated to a POSA
`that 600 mg of mifepristone could safely be administered to a patient
`concomitantly being treated with a strong CYP3A inhibitor”).
`In its Reply, Petitioner changed its position, arguing for the first time
`that “the claims do not require safety; they require only ‘treating’ Cushing’s
`syndrome or its symptoms.” Reply 14. Not only is this an inappropriate
`new argument (see Pet. 23 (arguing that the claims should be given their
`plain and ordinary meaning and that “no further claim construction is
`required for purposes of this PGR”)), it contradicts the obviousness rationale
`set forth in the Petition. See supra p. 16–17.
`Our regulations require the Petition to identify “[h]ow the challenged
`claim is to be construed” and “[h]ow the construed claim is unpatentable.”
`37 C.F.R. § 42.104(b)(3),(4). A reply is not an opportunity to start anew, to
`fill in gaps or to remedy omissions in a petition. See SAS Inst., Inc. v. Iancu,
`138 S. Ct. 1348, 1357 (2018) (explaining that “petitioner’s contentions [in a
`petition] ... define the scope of the litigation all the way from institution
`through to conclusion.”); see also Patent Trial and Appeal Board
`Consolidated Trial Practice Guide 73 (Nov. 2019),
`https://www.uspto.gov/sites/default/files/documents/tpgnov.pdf. We
`therefore decline to consider Petitioner’s belatedly presented new argument
`in its Reply that the claims do not require safety. See Acceleration Bay, LLC
`v. Activision Blizzard Inc., 908 F.3d 765, 775 (Fed. Cir. 2018) (concluding
`that the Board did not abuse its discretion in refusing to consider portions of
`a reply declaration “rais[ing] a new obviousness argument for [a claim]
`
`17
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`PGR2019-00048
`Patent 10,195,214 B2
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`limitation that could have been made in the petition” but was not);
`Intell