Filed on behalf of: Corcept Therapeutics, Inc.
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`TEVA PHARMACEUTICALS USA, INC.,
`Petitioner
`
`v.
`
`CORCEPT THERAPEUTICS, INC.,
`Patent Owner
`_______________________
`
`Case PGR2019-00048
`U.S. Patent No. 10,195,214
`_______________________
`
`PATENT OWNER PRELIMINARY RESPONSE
`
`

`

`Table of Contents
`
`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`Page
`
`I.
`
`II.
`
`III.
`
`INTRODUCTION ...........................................................................................1
`
`THE BOARD SHOULD DENY THE PETITION UNDER 35 U.S.C.
`§ 324(A) BECAUSE PARALLEL DISTRICT COURT LITIGATION
`RENDERS INSTITUTION INEFFICIENT....................................................5
`
`THE BOARD SHOULD DENY INSTITUTION BECAUSE
`PETITIONER DOES NOT DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT ANY CHALLENGED CLAIM WOULD
`HAVE BEEN OBVIOUS................................................................................9
`
`A.
`
`The State of the Art and the ʼ214 Patent...............................................9
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Cushing’s Syndrome is a Debilitating and Difficult-to-
`Treat Disorder .............................................................................9
`
`Korlym® (Mifepristone) Is a First-in-Class
`Glucocorticoid Receptor Antagonist with a Complex
`Pharmacokinetic Profile............................................................10
`
`Patients with Cushing’s Syndrome Often Take Multiple
`Drugs, Including Strong CYP3A Inhibitors .............................13
`
`The Dangers of Concomitantly Administering
`Mifepristone and Strong CYP3A Inhibitors Were Well-
`Known in the Art.......................................................................16
`
`Because of these Known Dangers, the Art Taught to
`Never Administer More Than 300 mg of Mifepristone in
`Combination With a Strong CYP3A Inhibitor .........................20
`
`Patent Owner Unexpectedly Found That 600 mg
`Mifepristone Could Safely and Effectively Be Dosed in
`Combination With Strong CYP3A Inhibitors...........................23
`
`B.
`
`Scope and Content of the Asserted References ..................................28
`
`1.
`
`2012 Korlym Label...................................................................28
`
`- i -
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`2.
`
`3.
`
`Lee.............................................................................................30
`
`2006 FDA Guidance .................................................................32
`
`Level of Ordinary Skill in the Art.......................................................35
`
`Claim Construction..............................................................................35
`
`Petitioner Does Not Demonstrate a Reasonable Likelihood of
`Success on Ground 1 ...........................................................................35
`
`1.
`
`2.
`
`The Petition Fails to Establish a Reasonable Expectation
`of Success..................................................................................36
`
`Petitioner’s Invocation of “Routine Optimization” Does
`Not Provide the Missing Reasonable Expectation of
`Success ......................................................................................39
`
`a.
`
`b.
`
`c.
`
`Petitioner’s “Routine Optimization” Argument
`Ignores the Teaching Away in the Prior Art ..................41
`
`Petitioner’s “Routine Optimization” Argument
`Ignores the Well-Known Safety Concerns
`Associated With Both Mifepristone and Strong
`CYP3A Inhibitors Disclosed in the Art..........................45
`
`The FDA’s Requirement that Patent Owner Carry
`Out Additional Drug-Drug Interaction Studies as
`Part of the Korlym® Approval Process Does Not
`Provide a Reasonable Expectation of Success ...............54
`
`Petitioner Does Not Demonstrate a Reasonable Likelihood of
`Success on Ground 2 ...........................................................................62
`
`Secondary Indicia of Non-Obviousness Further Support the
`Patentability of the Challenged Claims...............................................65
`
`1.
`
`2.
`
`The Prior Art Teaches Away from the Claimed
`Inventions..................................................................................66
`
`The Claimed Inventions Produced Unexpected Results...........70
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`IV. CONCLUSION..............................................................................................74
`
`- ii -
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`Page
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Abbott Labs., Inc. v. Sandoz, Inc.,
`544 F.3d 1341 (Fed. Cir. 2009) ..........................................................................60
`Alcon Research, Ltd. v. Watson Labs., Inc.,
`No. 15-1159, 2018 WL 1115090 (D. Del. Mar. 1, 2018)............................ 39, 54
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent
`Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) ..........................................................................60
`Endo Pharm. Inc. v. Actavis LLC,
`922 F.3d 1365 (Fed. Cir. 2019) ..........................................................................61
`E-One, Inc. v. Oshkosh Corp.,
`IPR2019-00161, Paper 16 (PTAB May 15, 2019) ...............................................8
`Honeywell Int’l Inc. v. Mexichem Amanco Holding S.A.,
`865 F.3d 1348 (Fed. Cir. 2017) ..........................................................................56
`Hospira, Inc. v. Genentech, Inc.,
`IPR2017-00804, Paper No. 83 (PTAB Oct. 3, 2018) .................................. 38, 62
`Impax Labs., Inc. v. Lannett Holdings Inc.,
`246 F. Supp. 3d 1024 (D. Del. 2017)..................................................................44
`Initiative for Meds., Access & Knowledge (I-MAK), Inc. v. Gilead
`Pharmasset LLC,
`IPR2018-00103, Paper 7 (PTAB June 13, 2018) ...............................................44
`Initiative for Meds., Access & Knowledge (I-MAK), Inc. v. Gilead
`Pharmasset LLC,
`IPR2018-00119, Paper 7 (PTAB May 4, 2018) .................................................45
`Janssen Pharm., Inc. v. Watson Labs., Inc.,
`No. 08-5103, 2012 WL 3990221 (D.N.J. Sept. 11, 2012)..................................43
`Janssen Prods., L.P. v. Lupin Ltd.,
`109 F. Supp. 3d 650 (D.N.J. 2014).....................................................................39
`Leo Pharm. Prods. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ..........................................................................38
`
`- iii -
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`Luye Pharma Grp. Ltd. v. Alkermes Pharma Ireland Ltd.,
`IPR2016-01096, Paper 74 (PTAB Nov. 28, 2017).............................................65
`Mylan Pharm., Inc. v. Bayer Intellectual Property GMBH,
`IPR2018-01143, Paper 13 (PTAB Dec. 3, 2018) .................................................8
`E.I. DuPont de Nemours & Co. v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018) ............................................................................55
`NHK Spring Co., Ltd. v. Intri-Plex Techs., Inc.,
`IPR2018-00752, Paper 8 (PTAB Sept. 12, 2018)........................................ 5, 7, 8
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988) ............................................................................55
`Par Pharm., Inc., v. Jazz Pharm. Ireland Ltd.,
`IPR2016-00002, Paper No. 12 (PTAB Apr. 12, 2016)................................ 61, 62
`Pfizer Inc. v. Apotex Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ..........................................................................57
`Pfizer Inc. v. Sandoz Inc.,
`No. 13-1110, 2016 WL 1611377 (D. Del. Apr. 20, 2016) .................................66
`Sandoz, Inc. v. AbbVie Biotech. Ltd.,
`IPR2017–01823, Paper No. 16 (PTAB Feb. 9, 2018) ........................................38
`In re Stepan Co.,
`868 F.3d 1342 (Fed. Cir. 2017) ............................................................. 40, 54, 56
`Unified Patents Inc. v. Custom Media Techs. LLC,
`IPR2015-00516, Paper 9 (PTAB June 25, 2015) ........................................ 44, 45
`Vanda Pharm. Inc. v. Roxane Labs,
`203 F. Supp. 3d 412 (D. Del. 2016)............................................................. 39, 60
`
`Rules / Statutes
`35 U.S.C. § 103........................................................................................................57
`35 U.S.C. § 324(a) .................................................................................................1, 5
`
`- iv -
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`Exhibits
`
`Description
`EX
`2001 August 2018 Update to the Office Patent Trial Practice Guide, 83 Fed.
`Reg. 39,989 (Aug. 13, 2018)
`2002 Chart Comparing Arguments Made By Petitioner in PGR2019-00048 and
`in the District Court Litigation
`2003
`January 16, 2019 Email from U. Everett to Counsel
`2004 Corcept Therapeutics, Inc. v. Teva Pharmaceuticals USA, Inc., No. 18-cv-
`3632, D.I. 31 (D.N.J. Oct. 23, 2018)
`2005 Corcept Therapeutics, Inc. v. Teva Pharmaceuticals USA, Inc., No. 18-cv-
`3632, D.I. 73 (D.N.J. June 4, 2019)
`2006 R. Pivonello et al., “The Treatment of Cushing’s Disease,” Endocrine
`Rev., 36(4):385-486 (2015)
`2007 D. Guelho & A. Grossman, “Emerging Drugs for Cushing’s disease,” Exp.
`Op. on Emerging Drugs, 20(3):463-78 (2015)
`2008 M. Fleseriu & S. Petersenn, “New Avenues in the medical treatment of
`Cushing’s disease: corticotroph tumor targeted therapy,” J. Neurooncol.,
`114:1-11 (2013)
`2009 R.A. Feelders et al., “The burden of Cushing’s disease: clinical and health-
`related quality of life aspects,” Eur. J. Endocrinol., 167:311-26 (2012)
`“Hyperglycemia in Diabetes,” The Mayo Clinic (Nov. 3, 2018),
`https://www.mayoclinic.org/diseases-conditions/hyperglycemia/
`symptoms-causes/syc-20373631
`2011 D. Cuevas-Ramos et al., “Update on medical treatment for Cushing’s
`disease,” Clin. Diabetes & Endocrinol., 2:16 (2016)
`2012 M. Fleseriu et al., “A New Therapeutic Approach in the Medical
`Treatment of Cushing’s Syndrome: Glucocorticoid Receptor Blockade
`with Mifepristone,” Endocrine Practice, 19(2):313-26 (2013)
`2013 O. Heikinheimo et al., “The pharmacokinetics of mifepristone in humans
`reveal insights into differential mechanisms of antiprogestin action,”
`Contraception, 68:421-26 (2003)
`
`2010
`
`- v -
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`2016
`
`2014 U.S. Patent No. 8,921,348 (“Optimizing Mifepristone Levels in Plasma
`Serum of Patients Suffering from Mental Disorders Treatable with
`Glucocorticoid Receptor Antagonists”)
`2015 X. Bertagna et al., “Chapter 16: Cushing’s Disease,” in THE PITUITARY
`(Shlomo Melmed ed., 3rd ed. 2011)
`J.K. Oosterhuis et al., “Life-threatening Pneumocystis jiroveci pneumonia
`following treatment of severe Cushing’s syndrome,” Netherlands J. Med.,
`65(6):215-17 (2007)
`2017 Biaxin (clarithromycin) Full Prescribing Information (May 2016)
`2018
`Sporanox (itraconazole) Full Prescribing Information (April 2015)
`2019 Nizoral (ketoconazole) Full Prescribing Information (2013)
`E. Charmandari et al., “Adrenal Insufficiency,” Lancet, 383(9935):2152-
`2020
`67 (2014)
`2021 A. Viera et al., “Potassium Disorders: Hypokalemia and Hyperkalemia,”
`American Family Physician, 92(6):487-95 (2015)
`2022 M. Basina et al., “Successful Long-Term Treatment of Cushing Disease
`with Mifepristone (RU486),” Endocrine Practice, 18(5):114-20 (2012)
`2023 D. Greenblatt & J. Harmatz, “Ritonavir is the best alternative to
`ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug
`interaction studies,” Brit. J. Clin. Pharmacol., 80(3):342-50 (2015)
`2024
`Incivek (telaprevir) Full Prescribing Information (October 2013)
`2025 VFEND (voriconazole) Full Prescribing Information (February 2015)
`2026 Victrelis (boceprevir) Full Prescribing Information (January 2017)
`2027
`Tybost (cobicistat) Full Prescribing Information (June 2016)
`2028 Vaprisol (conivaptan hydrochloride) Full Prescribing Information (October
`2016)
`2029 Crixivan (indinavir sulfate) Full Prescribing Information (September 2016)
`2030 Kaletra (lopinavir and ritonavir) Full Prescribing Information (November
`2016)
`2031 Viracept (nelfinavir mesylate) Full Prescribing Information (September
`2016)
`
`- vi -
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`2032
`
`2035
`
`2036
`
`2033
`
`Technivie (ombitasvir, paritaprevir and ritonavir) Full Prescribing
`Information (February 2017)
`Invirase (saquinavir mesylate) Full Prescribing Information (September
`2016)
`2034 D. Cuevas-Ramos & M. Fleseriu, “Treatment of Cushing’s disease: a
`mechanistic update,” J. Endocrinol., 223(2):R19-39 (2014)
`T. Carroll & J.W. Findling, “The Use of Mifepristone in the Treatment of
`Cushing’s Syndrome,” Drugs of Today, 48(8):509-18 (2012)
`E. Dunnigan et al., “Mifepristone (RU-486) in the treatment of Refractory
`Cushing’s Disease,” Endocrine Rev., Suppl. 1, 31(3):S1201 (2010)
`2037 Nefazodone Hydrochloride Tablets Full Prescribing Information (May
`2014)
`2038 Noxafil (posaconazole) Full Prescribing Information (September 2016)
`2039 Norvir (ritonavir) Full Prescribing Information (December 2016)
`2040
`Excerpts of Physician’s Desk Reference (58th ed. 2004)
`2041
`“The Hazards of Seldane,” N.Y. TIMES (January 17, 1997)
`2042
`European Medicines Agency, “European Medicines Agency recommends
`suspension of marketing authorisations for oral ketoconazole,” July 26,
`2013
`2043 M. Tran & J. Grillo, “Translation of Drug Interaction Knowledge to
`Actionable Labeling,” Clin. Pharmacol. & Therapeutics, 105(6):1292-95
`(2019)
`2044 M. Fleseriu et al., “Changes in Plasma ACTH Levels and Corticotroph
`Tumor Size in Patients With Cushing’s Disease During Long-term
`Treatment With the Glucocorticoid Receptor Antagonist Mifepristone,” J.
`Clin. Endocrinol. Metab., 99(10):3718-27 (2014)
`“Treatment for Aspergillosis,” Centers for Disease Control and Prevention
`(Jan. 2, 2019), https://www.cdc.gov/fungal/diseases/aspergillosis/
`treatment.html
`“Drug Development and Drug Interactions: Table of Substrates, Inhibitors
`and Inducers,” U.S. Food and Drug Administration (Nov. 14, 2017),
`https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-
`and-drug-interactions-table-substrates-inhibitors-and-inducers
`
`2045
`
`2046
`
`- vii -
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`I.
`
`INTRODUCTION
`
`The Petition should not be instituted. As an initial matter, the Board should
`
`decline to institute the Petition under 35 U.S.C. § 324(a) because institution would
`
`be an inefficient use of the Board’s resources. U.S. Patent No. 10,195,214 (“the
`
`’214 patent”), the subject of the petition at issue here, is also the subject of district
`
`court litigation between Patent Owner and Petitioner. In both the Petition and the
`
`litigation, Petitioner has asserted that the claims of the ’214 patent are invalid as
`
`obvious, relying on identical arguments and references. The district court is
`
`expected to make its decision on Petitioner’s arguments several months before the
`
`Board would issue a Final Written Decision on this Petition. Thus, the Petition is
`
`merely a second attempt at invalidating the ’214 patent. The Board has previously
`
`declined to institute petitions under similar circumstances. For this reason alone,
`
`the Board should deny institution.
`
`Even if the Board reaches the merits of the Petition, however, institution
`
`should be denied because Petitioner has not demonstrated any reasonable
`
`likelihood that any challenged claim would have been obvious. Most significantly,
`
`Petitioner has not even attempted to show a reasonable expectation of success,
`
`which alone is fatal to the Petition.
`
`Mifepristone is a drug approved by the FDA to treat the clinical
`
`manifestations of Cushing’s syndrome, a debilitating endocrine disorder. The
`
`1
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`claimed inventions in the ’214 patent relate to safe and effective methods of
`
`administering mifepristone in combination with certain drugs that are strong
`
`inhibitors of the bodily enzyme known as CYP3A. The class of drugs that are
`
`strong inhibitors of the CYP3A enzyme is diverse and includes drugs that are used
`
`for a variety of purposes, and many patients with Cushing’s syndrome have
`
`medical needs that warrant taking drugs from within that class. Mifepristone,
`
`however, is primarily metabolized by the CYP3A enzyme. As a result, before the
`
`discoveries that led to the claimed methods of treatment, the prior art consistently
`
`taught that mifepristone could only be safely used in combination with a strong
`
`CYP3A inhibitor at doses of 300 mg per day or less, due to significant—and
`
`potentially life-threatening—safety concerns associated with the interaction
`
`between mifepristone and the strong CYP3A inhibitor in the body.
`
`In particular, the prior art labeling for the FDA-approved mifepristone
`
`product, Korlym®, as well as references disclosing the administration of
`
`mifepristone, disclosed that if a patient was taking either mifepristone or a strong
`
`CYP3A inhibitor and a physician wanted to add the other drug to the treatment
`
`regimen, the POSA had two only options. He/she could either discontinue the drug
`
`the patient was currently taking before starting the new drug (e.g. discontinue
`
`mifepristone before administering the strong CYP3A inhibitor), or—and only if
`
`medically necessary—administer the drugs concomitantly, but dose no more than
`
`2
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`300 mg of mifepristone. The prior art clearly and consistently presents these—and
`
`only these—two choices. A 300 mg/day dose of mifepristone, however, is
`
`insufficient to treat most patients with Cushing’s syndrome, thus leaving patients
`
`who had a need to take drugs that were strong CYP3A inhibitors without a viable
`
`treatment option for their Cushing’s syndrome.
`
`Through a series of drug-drug interaction (“DDI”) trials, however, Patent
`
`Owner surprisingly discovered methods of treatment wherein 600 mg of
`
`mifepristone could safely and effectively be administered in combination with
`
`strong CYP3A inhibitors for the treatment of Cushing’s syndrome and its
`
`manifestations. At the time of invention, a person of skill in the art (“POSA”)
`
`would not have reasonably expected this outcome. Indeed, Petitioner’s own
`
`Declarant readily concedes that a POSA could not predict the “extent or clinical
`
`significance of a specific DDI until the interaction is clinically tested” and “[t]he
`
`state of the art does not allow us to predict these values a priori . . . [t]he actual
`
`quantitative modifications can only be determined by an actual clinical study.”
`
`Ex. 1002 at ¶ 31, 33 (emphasis added). As such, a POSA would not have had a
`
`reasonable expectation of success in achieving the claimed invention, and thus the
`
`Petition should be denied.
`
`Lacking any evidence of a reasonable expectation of success in the prior art,
`
`Petitioner argues that “arriving at the specific once-daily dose of 600 mg in
`
`3
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`conjunction with strong CYP3A inhibitors would have been merely the product of
`
`routine optimization.” Pet. at 32. Petitioner’s “routine optimization” argument
`
`cannot cure the fatal deficiency in the Petition. Not only is the argument wrong—
`
`nothing about the process of determining the claimed methods was “routine”—but
`
`the Petition also cannot simply invoke the words “routine optimization” as a magic
`
`wand to establish obviousness. To the contrary, the law is clear that a reasonable
`
`expectation of success must be demonstrated, and Petitioner has not established
`
`one here. Petitioner’s “routine optimization” argument is rooted in hindsight, and
`
`ignores the significant teaching away from the claimed inventions in the prior art
`
`and the significant safety concerns that would have precluded a POSA from having
`
`a reasonable expectation of success. As such, the Petition fails to set forth a
`
`reasonable likelihood that any challenged claim would have been obvious, and
`
`should be denied.
`
`Secondary indicia of non-obviousness further support the patentability of the
`
`challenged claims. As explained herein, the prior art teaches away from the
`
`claimed invention and the claimed inventions produced unexpected results. For
`
`these additional reasons, the Board should deny institution of the Petition.
`
`Accordingly, the Board should decline to institute this Petition, which is not
`
`only unlikely to succeed on the merits, but is entirely duplicative of co-pending
`
`district court litigation.
`
`4
`
`

`

`II.
`
`PGR2019-00048
`U.S. Patent No. 10,195,214
`THE BOARD SHOULD DENY THE PETITION UNDER 35 U.S.C. §
`324(a) BECAUSE PARALLEL DISTRICT COURT LITIGATION
`RENDERS INSTITUTION INEFFICIENT
`The decision whether to institute a post-grant review is discretionary. See 35
`
`U.S.C. § 324(a). To that end, the August 2018 Update to the Office Patent Trial
`
`Practice Guide (Ex. 2001) “invites parties to address [the] factors that may bear on
`
`the Board’s discretionary decision to institute or not institute.” See NHK Spring
`
`Co., Ltd. v. Intri-Plex Techs., Inc., IPR2018-00752, Paper 8, at 20 n.4 (PTAB Sept.
`
`12, 2018). One such factor strongly counsels against institution here: inefficiency.
`
`As explained in the August 2018 Update to the Office Patent Trial Practice
`
`Guide, post grant review was “designed to establish a more efficient and
`
`streamlined patent system that will improve patent quality and limit unnecessary
`
`and counterproductive litigation costs.” Ex. 2001 at 9 (quoting H.R. Rep. No.
`
`112–98, pt. 1, at 40 (2011)). To that end, “[p]ost grant reviews were meant to be
`
`‘quick and cost effective alternatives to litigation.’” Id. (quoting 2011
`
`U.S.C.C.A.N. 67, 69) (emphasis added).
`
`The instant Petition was not filed as an alternative to litigation. Instead,
`
`Petitioner is seeking a second bite at the apple on the validity of the ’214 patent.
`
`Specifically, the ʼ214 patent is currently the subject of litigation between Petitioner
`
`and Patent Owner in the District of New Jersey, which has been ongoing since
`
`March 15, 2018. See Corcept Therapeutics, Inc. v. Teva Pharm. USA, Inc., No.
`
`5
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`18-3632 (D.N.J.) (hereafter, “the district court litigation”).1 The district court
`
`litigation concerns Petitioner’s filing of an ANDA 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. In the district court litigation, 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. For instance, Petitioner has asserted in the district court litigation that
`
`the claims of the ʼ214 patent are obvious in view of the combination of 2012
`
`Korlym Label, Lee, and FDA Guidance (the same three references it relies on in its
`
`Petition) for reasons that are repeated verbatim in its Petition. See Ex. 2002
`
`(providing examples of identical, substantive arguments made by Petitioner in
`
`PGR2019-00048 and in the district court litigation).
`
`The 30-month stay of FDA approval of Petitioner’s ANDA expires August
`
`2, 2020. The parties and district court intend for the court to issue a decision prior
`
`to that date, whether after trial or, at a minimum, after a preliminary injunction
`
`
`1 Corcept sued Teva for infringement of the ’214 patent in Civil Action No.
`
`19-5066 (D.N.J.) on February 8, 2019. That case was consolidated with Civil
`
`Action No. 18-3632 on February 21, 2019. See Corcept Therapeutics, Inc. v. Teva
`
`Pharm. USA, Inc., No. 18-3632, D.I. 59.
`
`6
`
`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`hearing. Indeed, Petitioner was unwilling to agree to any Scheduling Order in the
`
`district court litigation that “extends resolution of the asserted patents beyond the
`
`30-month stay (i.e., August 2020).” See Ex. 2003 at 1. The district court
`
`litigation is currently in fact discovery and is progressing toward (1) a Markman
`
`hearing in January 2020 and (2) a trial in the summer of 2020 in advance of the
`
`August 2020 expiration of the 30-month stay.2 Thus, by August 2020, the district
`
`court will have issued a decision on the same challenge that Petitioner is making
`
`here to the validity of the ’214 patent.
`
`Under these circumstances, institution would be an inefficient use of the
`
`Board’s resources, and should be denied. Institution would not result in a Final
`
`Written Decision until late-November 2020, several months after the district court
`
`will have issued a decision on the same references and arguments presented in this
`
`Petition. The Board has exercised its discretion to deny institution in similar
`
`instances. For instance, in NHK Spring Co., the Board declined to institute where
`
`
`2 The district court has also already expended significant resources, having
`
`ruled on several motions. See, e.g., Case No. 18-3632, D.I. 31 (Ex. 2004) (opinion
`
`denying motion to dismiss); Case No. 18-3632, D.I. 73 (Ex. 2005) (opinion
`
`denying request for inclusion of patent prosecution bars in discovery
`
`confidentiality order).
`
`7
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`PGR2019-00048
`U.S. Patent No. 10,195,214
`a district court proceeding involving the same patent was scheduled to go to trial
`
`several months before a Final Written Decision would have been due, and the
`
`petitioner relied on the same prior art references and arguments in its Petition and
`
`at the district court. See IPR2018-00752, Paper 8 at 20. Likewise in in Mylan
`
`Pharm., Inc. v. Bayer Intellectual Property GMBH, the Board denied institution
`
`where, “[g]iven the advanced stage of [a] copending district court case and the
`
`extensive overlap of the asserted prior art [and] expert testimony . . . it would be an
`
`inefficient use of Board resources to proceed with th[e] inter partes review in
`
`parallel with the district court case.” IPR2018-01143, Paper 13 at 13 (PTAB Dec.
`
`3, 2018). In E-One, Inc. v. Oshkosh Corp., the Board similarly declined to institute
`
`review where the Petition presented the same issues, arguments, and evidence as in
`
`a parallel district court case, and the district court was set to complete trial before
`
`the Board issued a Final Written Decision. See IPR2019-00161, Paper 16 at 9
`
`(PTAB May 15, 2019).
`
`Likewise here, Petitioner is relying on the same alleged prior art and
`
`arguments regarding the ’214 patent in the Petition as in the district court litigation.
`
`In addition, there will not be a Final Written Decision in this PGR until late-
`
`November 2020, months after the district court litigation will have concluded.
`
`Thus, institution here, as in NHK Spring, Mylan, and E-One would be an
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`8
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`PGR2019-00048
`U.S. Patent No. 10,195,214
`inefficient use of Board resources. The Petition should be denied on this basis
`
`alone.
`
`III. THE BOARD SHOULD DENY INSTITUTION BECAUSE
`PETITIONER DOES NOT DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT ANY CHALLENGED CLAIM WOULD HAVE
`BEEN OBVIOUS
`
`To the extent that the Board is nonetheless inclined to entertain the
`
`substance of the Petition, neither of the two alleged Grounds of obviousness
`
`demonstrates a reasonable likelihood that any challenged claim would have been
`
`obvious. On this independent basis, the Petition should be denied.
`
`A.
`
`The State of the Art and the ʼ214 Patent
`
`1.
`
`Cushing’s Syndrome is a Debilitating
`and Difficult-to-Treat Disorder
`
`Cushing’s syndrome is a “debilitating endocrine disorder” caused by
`
`elevated circulating cortisol levels, which are often the result of tumors that afflict
`
`the pituitary or adrenal glands. Ex. 1030 at Abstract; see also Ex. 2006 at 385-86.
`
`“The excess cortisol seen in Cushing’s syndrome results in hypertension,
`
`hyperglycemia, obesity, and a myriad of other problems.” Ex. 1030 at 320. These
`
`myriad other problems include “a risk of life-threatening cardiovascular, infectious
`
`and metabolic complications.” Ex. 2007 at 464. Excess cortisol can also have
`
`“major effects on the brain that can result in psychopathology and neurocognitive
`
`dysfunction.” Id. As such, Cushing’s syndrome is “associated with significant
`
`morbidity and mortality.” Ex. 2008 at 1. Some studies have estimated Cushing’s
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`PGR2019-00048
`U.S. Patent No. 10,195,214
`syndrome increases the risk of death in affected patients by as much as 4.8 times.
`
`See Ex. 2009 at 313.
`
`The first line of treatment for patients with Cushing’s syndrome is surgery,
`
`the goal of which is to remove the tumor responsible for generating excess cortisol.
`
`See Ex. 1030 at 319. Many patients are not candidates for surgery, however, often
`
`because they are too sick to survive the procedure or have tumors that cannot be
`
`located or completely removed. These patients require medical therapy. See id.
`
`At the time of invention, although several options for additional treatment existed,
`
`“few [were] readily available and all ha[d] dose-limiting adverse effects.” Id.
`
`2.
`
`Korlym® (Mifepristone) Is a First-in-Class Glucocorticoid
`Receptor Antagonist with a Complex Pharmacokinetic
`Profile
`
`Patent Owner’s commercial drug product is marketed as Korlym®
`
`(mifepristone) 300 mg Tablets. It was approved by the FDA in 2012 as an “orphan
`
`drug” to control hyperglycemia in the subset of patients with Cushing’s syndrome
`
`who are not surgical candidates or have not achieved remission from surgery.3 See
`
`
`3 Hyperglycemia (high blood sugar) is common amongst patients with
`
`Cushing’s syndrome and is caused by the hypercortisolism that characterizes the
`
`disease. See Ex. 1029 at 2046; Ex. 1030 at 320. If left untreated, hyperglycemia
`
`10
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`PGR2019-00048
`U.S. Patent No. 10,195,214
`Ex. 1030 at Abstract; Ex. 1004 at 1. The use of Korlym® has been found to result
`
`in “rapid control of the systemic effects of cortisol excess in patients with
`
`[Cushing’s syndrome].” Ex. 2011 at 6.
`
`The active ingredient in Korlym® is mifepristone. Mifepristone works
`
`through a mechanism of action distinct from other therapies for Cushing’s
`
`syndrome. Specifically, rather than lowering the elevated levels of cortisol in the
`
`body, mifepristone occupies and selectively inhibits the receptors to which cortisol
`
`seeks to bind (known as glucocorticoid receptors), “thereby decreasing the
`
`physiologic effects of hypercortisolemia.” Ex. 1030 at 323; see also Ex. 2012 at
`
`314. Mifepristone’s distinct mechanism of action renders it “rapidly effective in
`
`controlling hypercortisolism,” which allows it to play a unique “role in the
`
`management of [Cushing’s syndrome], especially when the presence of severe
`
`disease or concomitant conditions requires a rapid control of cortisol excess.” Ex.
`
`2006 at 455. Korlym® is the first and only glucocorticoid receptor antagonist
`
`approved for the treatment of the manifestations of Cushing’s syndrome. See id.
`
`Although mifepristone has the ability to rapidly control hypercortisolism, the
`
`drug is difficult to dose effectively. Since mifepristone does not lower circulating
`
`
`can become severe and lead to serious complications requiring emergency care,
`
`such as a diabetic coma. See Ex. 2010.
`
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`PGR2019-00048
`U.S. Patent No. 10,195,214
`cortisol levels but only blocks the action of cortisol by preventing its uptake at
`
`receptor sites, “it is very difficult to dose titrate [mifepristone] and judge
`
`effectiveness.” Ex. 1032 at 1345 (emphasis added). The art, and in particular
`
`Korlym®’s package insert, taught that mifepristone could be dosed from 300 to
`
`1200 mg per day for the treatment of Cushing’s syndrome, see Ex. 1004 at 3, but
`
`also that many patients did not respond to lower doses within that range. In fact, in
`
`clinical trials, only 13.3 percent of patients who responded to the drug were
`
`administered 300 mg of mifepristone , while the remaining 86.7 percent of patients
`
`who responded only did so once their doses were increased to higher levels. See
`
`Ex. 1029 at 2042.
`
`The difficulties associated with dosing Korlym® also relate to the complex
`
`and unpredictable pharmacokinetic characteristics of the drug. Mifepristone is a
`
`CYP3A substrate. In other words, it is primarily metabolized in the body by the
`
`CYP3A enzyme. Aspects of mifepristone’s metabolism, however, complicate the
`
`determination of a safe and effective dose. First, the art disclosed that mifepristone
`
`exhibits a non-linear pharmacokinetic profile. Ex. 2013 at Abstract. Following
`
`administration,