Paper No. 19
`
`
`Trials@uspto.gov
` Entered: November 20, 2019
`
`
`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.
`
`
`
`DECISION
`Granting Institution of Post Grant Review
`35 U.S.C. § 324(a)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Trials@uspto.gov
` Entered: November 20, 2019
`
`
`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.
`
`
`
`DECISION
`Granting Institution of Post Grant Review
`35 U.S.C. § 324(a)
`
`
`
`
`
`
`
`
`
`
`
`
`PGR2019-00048
`Patent 10,195,214 B2
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`
`INTRODUCTION
`I.
`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”).
`Institution of post grant review is authorized by statute only when “the
`information presented in the petition . . . demonstrate[s] that it is more likely
`than not that at least 1 of the claims challenged in the petition is
`unpatentable.” 35 U.S.C. § 324(a) (2012); see 37 C.F.R. § 42.4 (2012).
`Upon considering the Petition, the Preliminary Response, and the cited
`evidence, we conclude that Petitioner has satisfied the burden under 35
`U.S.C. § 324(a) to show that it is more likely than not that at least one of the
`claims challenged in the petition is unpatentable.
`Related Proceedings
`A.
`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.
`
`
`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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`2
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`PGR2019-00048
`Patent 10,195,214 B2
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`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,
`code (54), (45), (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 a 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
`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 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
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`Patent 10,195,214 B2
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`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
`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 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.
`
`
`
`C. Challenged Claims
`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
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`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:
`Claim(s)
`35 U.S.C. §
`Challenged
`1–13
`103(a)
`1–13
`103(a)
`
`Reference(s)/Basis
`Korlym Label,3 Lee4
`Korlym Label, Lee, and FDA
`Guidance5
`
`
` Petitioner submits the Declaration of Dr. David J. Greenblatt
`(Ex. 1002) in support of institution of post grant review.
`
`
`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, 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”).
`5
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`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.).
`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.
`At this stage in the proceeding, Patent Owner does not challenge
`Petitioner’s definition of the POSA. Prelim. Resp. 35 (“For the limited
`purpose of this Preliminary Response only, Patent Owner does not dispute
`Petitioner’s contention regarding the level of ordinary skill in the art.”)
`Accordingly, for purposes of this Decision and based on the present record,
`we accept Petitioner’s definition, which is consistent with the level of skill
`reflected in the asserted prior art references. 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).
`
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`Claim Construction
`F.
`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).” 37 C.F.R. § 42.200 (2018). 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 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)). For purposes
`of resolving whether Petitioner has demonstrated that it is more likely than
`not that at least one claim of the ’214 patent is unpatentable, we need not
`expressly construe any claim term.
`II. ELIGIBILITY FOR POST GRANT REVIEW
`The AIA’s post grant review provisions apply to patents that
`“contain[] or contained at any time . . . a claim to a claimed invention that
`has an effective filing date . . . that is on or after [March 16, 2013].” Leahy-
`Smith America Invents Act (AIA) §§ 3(n)(1), 6(f)(2)(A) (2011). In addition,
`“[a] petition for a post-grant review may only be filed not later than the date
`that is 9 months after the date of the grant of the patent or of the issuance of
`a reissue patent (as the case may be).” 35 U.S.C. § 321(c) (2012); see also
`37 C.F.R. § 42.202(a) (2019).
`
`7
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`Here, the ‘214 patent is eligible for post grant review because the
`
`Petition was filed within nine months of the ’214 patent’s issue date and the
`earliest possible priority date of the ’214 patent is after March 16, 2013 (the
`effective date for the first inventor to file provisions of the Leahy-Smith
`America Invents Act). Ex. 1001, code (45) (showing an issue date of
`February 5, 2019); id. at 1:8–13 (claiming priority to two provisional
`applications, the earliest of which was filed on March 1, 2017); id. at code
`(60); Paper 3 (according the Petition a filing date of May 7, 2019).
`III. 35 U.S.C. § 324(a)
`Before addressing the merits of the Petition, we consider Patent
`Owner’s contention that we should exercise our discretion under 35 U.S.C.
`§ 324(a) and deny institution.
`As discussed above, the ’214 patent has been asserted in litigation
`before the District Court of New Jersey, which has not yet set a trial date.
`See supra, at 2–3; Ex. 1063. Patent Owner explains that the district court
`litigation “concerns Petitioner’s filing of an ANDA [Abbreviated New Drug
`Application] seeking approval to market a generic version of Patent Owner’s
`Korlym® drug product prior of the expiration of certain patents, including
`the ’214 patent.” Prelim. Resp. 6. The filing of ANDA litigation serves to
`trigger a thirty-month stay under which, without a court judgment, the FDA
`may not approve the generic’s ANDA application until that stay expires. 21
`U.S.C. § 355(j)(5)(B)(iii) (2018). The thirty-month stay triggered by the
`district court litigation expires on August 2, 2020. Prelim. Resp. 6; Reply 3.
`Petitioner has represented that it has received tentative approval from the
`FDA to market its proposed generic product and thus “the only thing
`preventing Teva’s launch . . . is the 30-month stay.” Ex. 2003.
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`Patent Owner contends that the District Court is “well of aware of the
`ramifications of not issuing a trial decision prior to the August 2020
`expiration of the 30-month stay.” Sur-reply. 1. Moreover, Patent Owner
`argues, Petitioner will not agree not to launch its proposed generic product at
`risk until after the issuance of the district court’s decision, and therefore,
`“before the stay expires, the [District] Court will necessarily issue a
`decision, if not after trial then on a PI [preliminary injunction].” Id.
`According to Patent Owner, such a decision would come “months before the
`November 2020 date for the Board to enter a final written decision (“FWD”)
`in this PGR.” Id.
`Patent Owner contends that “Petitioner has served invalidity
`contentions regarding the ’214 patent that include identical arguments
`based on the same references relied upon by Petitioner in the instant
`proceeding.” Prelim. Resp. 6 (citing Ex. 2002). Patent Owner thus argues
`that we should exercise our discretion to deny the Petition because
`“institution here . . . would be an inefficient use of Board resources.” Id. at
`8–9. As support, Patent Owner cites NHK Spring Co., Ltd. v. Intri-Plex
`Techs., Inc., IPR2018-00752, Paper 8 (precedential), Mylan Pharm., Inc. v.
`Bayer Intellectual Property GMBH, IPR2018-01143, Paper 13, and E-One,
`Inc. v. Oshkosh Corp., IPR2019-00161, Paper 16.
`The Board will consider the “advanced state of [a] district court
`proceeding” as a “factor that weighs in favor of denying the Petition under
`§ 314(a).” NHK Spring, IPR2018-00752, Paper 8, at 20. Here, however, it
`is not clear that the District Court litigation is in an “advanced state.” As
`discussed above, no trial date has been set. Ex. 1063. In addition, the
`District Court has not yet set dates for the completion of fact or expert
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`discovery, events which we expect would necessarily precede trial. Id.6
`While we acknowledge that the thirty-month stay provides reason to
`complete trial before August 2, 2020, absent clear indication from the
`District Court as to when trial – or conditions precedent to trial – will occur,
`we can only speculate as to when the District Court will provide a final
`decision.
`Similarly, we acknowledge that the expiration of the thirty-month stay
`would provide reason for Patent Owner to seek a preliminary injunction
`prior to August 2, 2020. However, at this point in time, Patent Owner has
`not yet moved for a preliminary injunction, leaving us to speculate as to
`whether and when a preliminary injunction will be filed and, if filed, what
`issues it would address. Moreover, while we have considered a district
`court’s familiarity with the issues gained in resolving a motion for a
`preliminary injunction as a factor in determining whether to exercise our
`discretion to deny institution, see E-One, IPR2019-00161, Paper 16, 7–9, we
`are also mindful that, even if a motion for a preliminary injunction were
`filed, the District Court’s decision here with respect to that motion would not
`provide a final resolution regarding the validity of the ’214 patent.
`Accordingly, we are not persuaded that institution would be an inefficient
`use of Board resources.
`
`
`6 The parties have proposed widely divergent dates for when these events
`must be completed. Ex. 1064. For example, Petitioner propose that expert
`discovery be completed by February 28, 2020 while Patent Owner proposes
`that expert discovery extend at least through mid-October. Id. The
`November 1, 2019 fact discovery date proposed by Petitioner has passed
`with no indication from the District Court that it will proceed based upon on
`Petitioner’s proposed schedule. Indeed, a recent docket entry suggests that
`fact discovery is ongoing. Ex. 3002.
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`Patent Owner argues that “Petitioner is seeking a second bite at the
`apple on the validity of the ’214 patent.” Prelim. Resp. 5. Patent Owner
`argues that post grant reviews were intended as alternatives to litigation, that
`institution would potentially result in multiple adjudications on the
`obviousness arguments presented in the Petition, and that “Congress did not
`intend for PGR to result in such duplication.” Sur-reply 2. The AIA
`explicitly contemplates, however, that a party may choose to seek post grant
`review of a patent that is involved in concurrent litigation. 35 U.S.C.
`§ 325(a)(3) (2012) (providing that counterclaim challenging patent validity
`does not count as a “civil action,” which would otherwise trigger an
`automatic stay of a pending civil action). Moreover, Petitioner filed its
`Petition promptly––a little more than three months––after patent issuance,
`and Patent Owner does not apprise us of any tactical advantage, or
`opportunity for tactical advantage, that Petitioner gained through the timing
`of its Petition.7
`We acknowledge Patent Owner’s argument that the district court
`litigation and the present proceeding involve the same or substantially
`similar issues. See Ex. 2002. However, a trial date in the district court
`litigation has not been set, and it is not clear that the district court litigation
`will have concluded by the time our final decision is due. These facts
`distinguish the present proceeding from NHK. In NHK, the Board denied
`institution under 35 U.S.C. § 325(d), finding that the arguments advanced in
`the petition were substantially similar to those made by the Examiner during
`prosecution, before considering the “advanced state of the district court
`
`7 Given the prompt filing of this petition, denying Petitioner the opportunity
`to seek post-grant review under these circumstances would effectively deny
`them the opportunity to ever seek post-grant review.
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`proceeding” as an additional factor that weighed in favor of denying the
`petition. NHK, Paper 8 at 20. Thus, the district court timeline was merely
`one of many factors considered by the Board when denying institution of the
`petition. Id. Here, Patent Owner does not contend that the arguments
`advanced in the Petition are substantially similar to those made during
`prosecution. In addition, the district court proceeding in NHK, where trial
`was set to conclude six months before a final Board decision would be due
`(id.), appears to have been substantially more advanced than the district
`court proceeding is here.
`The facts in this case are also distinguishable from E-One and Mylan.
`In E-One, the Board exercised its discretion to deny institution where the
`District Court had already “received briefing, heard oral argument, and
`issued detailed decisions” on claim construction and on a motion for a
`preliminary injunction, and where the issues in the Petition “essentially
`duplicate[d]” these issues. IPR2019-00161, Paper 16 at 7. In addition, the
`district court in E-One, unlike the district court here (which has not even
`scheduled a trial date), was scheduled to complete trial in the parallel district
`court case “before a final [Board] decision would be due.” Id. at 6. The
`facts here are similarly distinguishable from those in Mylan. In that case, the
`Board exercised its discretion to deny institution where trial was set to occur
`more than eight months before a Final Written Decision would be due.
`IPR2018-01143, Paper
`Accordingly, we decline to exercise our discretion under 35 U.S.C.
`§ 324(a) on the basis that the issues duplicate those at issue in the pending
`ANDA litigation.
`
`
`
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`IV. GROUND 1: OBVIOUSNESS OVER KORELYM 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. Prelim. Resp. 9–62, 65–74. We have reviewed Petitioner’s and
`Patent Owner’s assertions, as well as the evidence of record, and, for the
`reasons discussed below, we conclude that Petitioner has demonstrated that
`it is more likely than not that at least claim 1 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 Krolym 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 warns:
`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,
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`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.
`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, 1.8 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.
`
`8 All references to Lee are to the page numbers provided on the original
`document not the exhibit page number.
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`Id. at 1–2.
`
`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
`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 32/100. 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 70/100.
`
`B.
`
`Analysis
`
`Claim 1
`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 and Ex. 1005, 3/100,
`11/100). 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 and
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`Ex. 1005, 31/100). 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
`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
`because “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. In addition, 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
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`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. Finally, 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.
`
`Based on the information presented at this stage of the proceeding,
`Petitioner has shown sufficiently in the Petition that it is more likely than not
`to prevail in showing the unpatentability of claim 1 over the combination of
`the Korlym Label and Lee. We focus our further analysis on Patent Owner’s
`arguments against institution in its Preliminary Response.
`
`Much of the discussion in the Preliminary Response focuses on the
`statement in the Korlym label regarding concomitant use with strong
`inhibitors of CYP3A. Our decision on institution thus turns, in large part, on
`how the POSA would have interpreted the following statement on the
`Korlym Label:
`Korlym should be used with extreme caution in patients taking
`ketoconazole and other strong inhibitors of CYP3A. . . .
`Mifepristone should be used in combination with strong
`CYP3A inhibitors only when necessary, and in such cases the
`dose should be limited to 300 mg per day.
`Ex. 1004, 6. Accordingly, we begin our analysis by considering this
`statement (the “300 mg limitation”).
`Patent Owner argues that Petitioner cannot establish a reasonable
`expectation of success that mifepristone could successfully be used with a
`strong CYP3A inhibitor at doses above 300 mg/day because the “Korlym
`Label explicitly states that ‘the dose of Korlym [or mifepristone] should be
`limited to 300 mg and used only when necessary.’” Prelim. Resp. 36.
`Patent Owner further argues that this statement, and similar statements in the
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`art, teach away from administering concomitant administration of
`mifepristone and a strong CYP3A inhibitor at doses above 300 mg. Id. at
`41–45, 66–70. Based on the current record, we do not find these arguments
`persuasive.
`We acknowledge that the Korlym Label states that when mifepristone
`is administered with a strong CYP3A inhibitor, it should be limited to 300
`mg per day. Ex. 1004, 6. However, Lee teaches that “the degree of change
`in exposure of mifepristone when co-administered with strong CYP3A
`inhibitors is unknown,” and recommends conducting a drug-drug interaction
`study with the goal of generating “a quantitative estimate of the change in
`exposure of mifepristone following co-administration with ketoconazole.”
`Ex. 1005, 1–2. Consistent with these teachings, the Korlym Label suggests
`that its instruction to limit the dosage of mifepristone, when used together
`with a strong CYP3A inhibitor, is based on the absence of clinical data. It
`states:
`Ketoconazole and other strong inhibitors of CYP3A . . . 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.
`Ex. 1004, 9–10 (emphasis added). Based on these teachings, Dr.
`Greenblatt testifies that “[a] A POSA at the time of the claimed invention
`would have in fact known that the 300-mg limitation was not founded in
`clinical experience.” Ex. 1002, ¶ 129. Accordingly, the current record,
`which does not include testimonial evidence from Patent Owner, tends to
`support Petitioner’s position that a POSA would have known that the 300
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`mg limitation was “put on the label as a precautionary measure pending the
`completion of the [FDA required DDI study]” because, at the time, “there
`was no evidence a
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