Filed on behalf of: Corcept Therapeutics, Inc.
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`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 SUR-REPLY
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`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 SUR-REPLY
`
`
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`TABLE OF CONTENTS
`
`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`
`Page
`
`
`
`I.
`
`II.
`
`Introduction ...................................................................................................... 1
`
`Teva’s Reply Confirms That It Cannot Show the Required Reasonable
`Expectation of Success .................................................................................... 2
`
`A.
`
`The Reasonable Expectation of Success Argument Advanced in
`Teva’s Petition Has Been Fully Discredited ......................................... 2
`
`B.
`
`Teva’s Attempt to Change Its Definition of a POSA Fails ................... 7
`
`III. Teva’s Focus on the Alleged “Routine” Nature of the Clinical Trials
`that Led to the Claimed Methods Is Legally and Factually Deficient .......... 10
`
`A.
`
`Routine Experimentation Cannot Compensate for a Lack of
`Reasonable Expectation of Success .................................................... 10
`
`B.
`
`Corcept’s DDI Studies Were Not “Routine” ...................................... 15
`
`IV. Teva’s Remaining Arguments Fail to Revive its Obviousness Case ............ 18
`
`A.
`
`B.
`
`C.
`
`D.
`
`Lee Recommended Contraindicating Mifepristone and Strong
`CYP3A Inhibitors ................................................................................ 18
`
`The Dunnigan Case Report Reinforced the Prior Art Teachings
`that the Combination of Greater Than 300 mg Mifepristone and
`Strong CYP3A Inhibitors Would Not Be Safe for Patients ................ 19
`
`Alleged “Motivation” to Perform a DDI Study Does not
`Compel a Finding of Obviousness ...................................................... 21
`
`The Federal Circuit’s Decision in the Valeant Case Does Not
`Compel a Finding of Obviousness ...................................................... 23
`
`Conclusion ..................................................................................................... 25
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`V.
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`PGR2019-00048
`U.S. Patent No. 10,195,214
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`
`TABLE OF AUTHORITIES
`
`Cases
`
`Page
`
`Apotex Inc. v. Celgene Corp.,
`IPR2018-00685, Paper 8 (P.T.A.B. Sept. 27, 2018) ............................................20
`Apple Inc. v. Qualcomm,
`IPR2018-01252, Paper 28 (P.T.A.B. Jan. 22, 2020) ...........................................19
`Eli Lilly & Co. v. Teva Pharm. Int’l.,
`IPR2018-01710, Paper 69 (P.T.A.B. Mar. 31, 2020) .................................. 11, 14
`Honeywell Int’l Inc. v. Mexichem Amanco Holding,
`865 F.3d 1348 (Fed. Cir. 2017) ..................................................................... 11, 21
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) ...........................................................................20
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ...........................................................................16
`Ralph Lauren Corp. v. Lexos Media IP,
`IPR2018-01749, Paper 21 (P.T.A.B. Apr. 3, 2020) .............................................15
`In re Stepan Co.,
`868 F.3d 1342 (Fed. Cir. 2017) .......................................................................7, 11
`Tietex Int’l, Ltd. v. Precision Fabrics Grp., Inc.,
`IPR2014-01248, Paper 39 (P.T.A.B. Feb. 27, 2016) ...........................................14
`Valeant Pharm. Int’l, Inc. v. Mylan Pharm. Inc.,
`955 F.3d 25 (Fed. Cir. 2020).......................................................................... 23-25
`Wasica Fin. GmbH v. Cont’l Auto. Sys., Inc.,
`853 F.3d 1272 (Fed. Cir. 2017) .................................................................... 10, 15
`Statutory Authorities
`35 U.S.C. §103 .........................................................................................................15
`Rules and Regulations
`MPEP 2144.05 .........................................................................................................11
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`PGR2019-00048
`U.S. Patent No. 10,195,214
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`
`Table of Abbreviations
`
`Patent Owner, Corcept Therapeutics, Inc.
`
`Drug-Drug Interaction
`
`The United States Food & Drug Administration
`
`Institution Decision
`
`Post Grant Review
`
`Patent Owner Preliminary Response
`
`Patent Owner Response
`
`Person of Skill in the Art
`
`Corcept
`
`DDI
`
`FDA
`
`ID
`
`PGR
`
`POPR
`
`POR
`
`POSA
`
`Teva
`
`Petitioner, Teva Pharmaceuticals USA, Inc.
`
`* Unless otherwise noted, all emphasis added throughout brief.
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`PGR2019-00048
`U.S. Patent No. 10,195,214
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`
`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
`January 16, 2019 Email from U. Everett to Counsel
`2003
`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
`
`
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`- iv -
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`U.S. Patent No. 10,195,214
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`
`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)
`2020 E. Charmandari et al., “Adrenal Insufficiency,” Lancet, 383(9935):2152-
`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)
`Incivek (telaprevir) Full Prescribing Information (October 2013)
`2024
`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)
`
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`U.S. Patent No. 10,195,214
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`2033
`
`2032 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)
`2035 T. Carroll & J.W. Findling, “The Use of Mifepristone in the Treatment of
`Cushing’s Syndrome,” Drugs of Today, 48(8):509-18 (2012)
`2036 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)
`“The Hazards of Seldane,” N.Y. TIMES (January 17, 1997)
`2041
`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
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`2046
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`2047 September 06, 2019 Email from D. Sterling to Counsel
`2048 Declaration of Nicholas A. LoCastro
`2049 D.J. Greenblatt & L. Von Moltke, “Clinical studies of drug-drug
`interactions: design and interpretation,” Chapter 24 in ENZYME- AND
`TRANSPORTER-BASED DRUG-DRUG INTERACTIONS: PROGRESS AND FUTURE
`CHALLENGES (2010)
`2050 N.N. Sarkar, “Mifepristone: bioavailability, pharmacokinetics and use-
`effectiveness,” Eur. J. Obstetrics & Gynecol & Reproductive Biol.,
`101(2):113-20 (2002)
`2051 D.J. Greenblatt, “Drug-Drug Noninteractions,” Cardiovascular
`Therapeutics, 27:226-29 (2009)
`2052 H.K. Greenblatt & D.J. Greenblatt, “Liver Injury Associated with
`Ketoconazole: Review of the Published Evidence,” J. Clin. Pharmacol.,
`54(12):1321-29 (2014)
`2053 L. Von Moltke et al., “In Vitro Approaches to Predicting Drug Interactions
`in Vivo,” Biochem. Pharmacol., 55:113-22 (1998)
`2054 D.J. Greenblatt et al., “Kinetic and dynamic interaction study of zolpidem
`with ketoconazole, itraconazole, and fluconazole,” Clin. Pharmacol. &
`Therapeutics, 64:661-71 (1998)
`2055 D. Roman, Cross Discipline Team Leader Review, NDA 202107 (2012)
`2056 Declaration of F. Peter Guengerich, Ph.D.
`2057 Declaration of Ty Carroll, M.D.
`2058 Declaration of Laurence Katznelson, M.D.
`2059 Deposition Transcript of Dr. Greenblatt
`2060 O. Heikinheimo et al., “Antiprogesterone RU 486 – A Drug for Non-
`Surgical Abortion,” Annals of Medicine, 22:75-84 (1990)
`2061 Y. Shi et al., “Pharmacokinetic study of RU 486 and its metabolites after
`oral administration of single doses to pregnant and non-pregnant women,”
`Contraception, 48:133-149 (1993)
`2062 Y. Huang et al., “Pharmacokinetics and Dose Proportionality of
`Ketoconazole in Normal Volunteers,” Antimicrobial Agents &
`Chemotherapy, 30(2):206-10 (1986)
`
`
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`2063
`
`“FDA advises against using oral ketoconazole in drug interaction studies
`due to serious potential side effects,” Oct. 18, 2013. Internet Archive,
`https://web.archive.org/web/20131018234822/http://www.fda.gov/Drugs/
`DrugSafety/ucm371017.htm
`2064 D.G. Bailey et al., “Grapefruit–medication interactions: Forbidden fruit or
`avoidable consequences?” CMAJ, 185(4):309-16 (2013)
`2065 A. Im & L.J. Appleman, “Mifepristone: pharmacology and clinical impact
`in reproductive medicine, endocrinology and oncology,” Expert Opin.
`Pharmacother., 11(3):481-88 (2010)
`2066 L.L. Von Moltke et al., “Metabolism of Drugs by Cytochrome P450 3A
`Isoforms: Impligbecations for Drug Interactions in Psychopharmacology,”
`Clin. Pharmacokinetics, 29(Suppl. 1):33-44 (1995)
`2067 R. Clayton, “Mortality in patients with Cushing’s disease more than 10
`years after remission: a multicentre, multinational, retrospective cohort
`study,” Lancet Diabetes-Endocrinol., 4:569-76 (2016)
`2068 Declaration of Daniel C. Wiesner
`2069 M. Zemskova, Medical Review(s), NDA 202107 (2012)
`2070 Second Deposition Transcript of Dr. Greenblatt
`2071 Deposition Transcript of Dr. Dobs
`
`
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`PGR2019-00048
`U.S. Patent No. 10,195,214
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`I.
`
`Introduction
`
`This PGR’s outcome turns on whether Teva has met its burden of showing
`
`that a POSA would have had a reasonable expectation of success. Teva’s Reply
`
`confirms that both the law and the evidence, including the testimony of all five
`
`expert declarants, show that the answer is resoundingly “no.”
`
`First, in its Petition for PGR, Teva correctly identified the threshold
`
`question:
`
`the question is whether a skilled artisan would have had a
`reasonable expectation of success in treating a patient
`having Cushing’s syndrome by administering a once-daily
`dose of 600 mg mifepristone concomitantly with a strong
`CYP3A inhibitor.
`
`Petition, 58. As the Board explained, the answer to Teva’s question “turns, in
`
`large part, on how the POSA would have interpreted” the Korlym Label. ID, 17.
`
`In its Response, Corcept addressed this question through expert POSA testimony;
`
`contemporaneous peer-reviewed POSA articles; and guidance from a published
`
`case report, all of which uniformly show that a POSA would not have reasonably
`
`expected to safely treat Cushing’s syndrome with any dose above 300 mg
`
`mifepristone—let alone the specifically claimed 600 mg dose—in combination
`
`with a strong CYP3A inhibitor.
`
`In Reply, Teva fails to substantively respond to this dispositive issue
`
`(because it has no response). Instead, Teva does an about-face and argues that:
`
`
`
`1
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`PGR2019-00048
`U.S. Patent No. 10,195,214
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`Corcept’s responses are largely beside the point because
`they focus on the wrong question. Corcept contends that
`a clinician following the 2012 Korlym Label would not
`have deviated from the label’s instruction to limit
`mifepristone to 300 mg per day when co-administered
`with strong CYP3A inhibitors.
`
`Reply, 1. Of course, the “wrong question” is the exact question set forth in the
`
`Petition and the exact question that the Board addressed in the ID. ID, 17. Teva
`
`cannot now run away from the threshold question. The lack of a reasonable
`
`expectation of success is dispositive of the obviousness challenge.
`
`Second, realizing it cannot meet the proper standard (which it set forth in the
`
`Petition), in Reply, Teva now argues that it need only show “a POSA would have
`
`reasonably expected success in optimizing the dose” by conducting a routine DDI
`
`study. Reply, 8. Teva’s attempt at replacing the reasonable expectation of success
`
`inquiry with “routine optimization” is legally improper. Even if it were proper,
`
`Teva’s own declarants confirmed that the clinical DDI studies such as those carried
`
`out by Corcept would not have been routine to a POSA as of the priority date.
`
`Accordingly, Teva’s obviousness challenge fails.
`
`II. Teva’s Reply Confirms That It Cannot Show the Required Reasonable
`Expectation of Success
`
`A. The Reasonable Expectation of Success Argument Advanced in
`Teva’s Petition Has Been Fully Discredited
`
`Teva begins its Reply by contending Corcept’s arguments regarding how
`
`POSAs would have interpreted the 2012 Korlym Label focus on the “wrong
`
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`2
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`PGR2019-00048
`U.S. Patent No. 10,195,214
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`question” and are “non sequiturs.” Reply, 1, 6. This makes little sense—not only
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`did Teva itself put this question at issue in the Petition, but “how the POSA would
`
`have interpreted … the Korlym Label” is the question on which the ID turned. ID,
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`17. It is not surprising, however, that Teva now seeks to shift focus away from this
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`question, given that the evidence turned out to be overwhelmingly one-sided.
`
`The obviousness argument advanced in the Petition was two-pronged. First,
`
`the Petition posited that based on the 2012 Korlym Label (EX1004), “a skilled
`
`artisan would have had a reasonable expectation that 600 mg could be
`
`administered safely, even in combination with a strong CYP3A inhibitor.” See,
`
`e.g., Petition, 33; EX1002, ¶¶69, 86, 105. Second, the Petition contended that
`
`based on Lee (EX1005), “a skilled artisan would have known exactly how to test
`
`that expectation: run a clinical study to determine the extent and significance of the
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`drug-drug interaction.” Petition, 34; EX1002, ¶¶70, 87, 106.
`
`The Board explained that the ID “turn[ed], in large part, on how the POSA
`
`would have interpreted” the “300 mg limitation” in the 2012 Korlym Label. ID,
`
`17. In the absence of testimonial evidence from Corcept, the Board credited the
`
`interpretation of the Label offered by Teva and Dr. Greenblatt—namely, that a
`
`POSA would have given little weight to the 300 mg limitation (ID, 18-19), and
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`instead would have reasonably expected doses above 300 mg mifepristone could
`
`be safely co-administered with strong CYP3A inhibitors based on the Label’s
`
`
`
`3
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`PGR2019-00048
`U.S. Patent No. 10,195,214
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`teaching that mifepristone monotherapy “doses as high as 1200 mg/day can be
`
`tolerated.” Id., 21. The Board expressly stated it “consider[ed]” each of the
`
`arguments raised in Corcept’s POPR with Dr. Greenblatt’s “interpretation of the
`
`300 mg limitation in mind.” Id., 19.
`
`In the POR, Corcept presented several lines of evidence that independently
`
`establish that Dr. Greenblatt’s interpretation of the Korlym Label does not reflect
`
`what a POSA would have understood or expected at the time of invention,
`
`including:
`
` Dr. Greenblatt’s admission that he did not “believe that there
`would be any expectation” as of the priority date that the
`claimed methods would be safe and effective. POR, 30-34.
`
` Dr. Greenblatt’s admissions that he has never prescribed
`mifepristone, never studied mifepristone, and was not
`“comfortable” or “prepared” to discuss its main side effects, nor
`“the particulars of Cushing’s syndrome.” POR, 4-5.
`
` Testimony from respected endocrinologists with over forty
`years of combined experience treating Cushing’s syndrome
`(Drs. Katznelson and Carroll) that prior to the ’214 patent, the
`art as a whole—including peer-reviewed journal articles by
`endocrinologists and a published case report of forced
`discontinuation of co-administration of 600 mg mifepristone
`with ketoconazole—uniformly taught POSAs that, due to safety
`concerns, mifepristone should never be co-administered with
`strong CYP3A inhibitors unless medically necessary, and under
`those extreme circumstances, the maximum dose of
`mifepristone was limited to no more than 300 mg. POR, 5; 14-
`16, 36-41. Thus, they each testified that a POSA would not
`have reasonably expected doses above 300 mg mifepristone to
`be safe when co-administered with a strong CYP3A inhibitor.
`Id.
`
`
`
`4
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` Testimony from a pharmacologist who has studied cytochrome P450
`proteins since 1973, including interactions with other drugs (Dr.
`Guengerich), that based upon known principles of pharmacokinetics
`and pharmacodynamics—including a five-factor test that Dr.
`Greenblatt set forth in his first declaration but did not himself
`conduct—POSAs would have expected that the combination of a
`strong CYP3A inhibitor and more than 300 mg of mifepristone would
`be “highly probable” to result in a dangerous and clinically significant
`DDI. POR, 41-52.
`
`The above-cited evidence conclusively demonstrates that a POSA would not have
`
`expected that more than 300 mg of mifepristone could be safely administered in
`
`combination with a strong CYP3A inhibitor prior to the claimed inventions.
`
`In its Reply, Teva does not attempt to defend its prior argument regarding
`
`the expectation of a POSA concerning the co-administration of strong CYP3A
`
`inhibitors and greater than 300 mg mifepristone. Indeed, Teva neither disputes nor
`
`attempts to walk back any of Dr. Greenblatt’s admissions, despite submitting a
`
`second declaration from Dr. Greenblatt. To the contrary, Dr. Greenblatt confirmed
`
`that a POSA:
`
`would not be able to say, one way or another, whether co-
`administration of 600 mg mifepristone and a strong
`CYP3A inhibitor was likely to be safe or unsafe.
`
`EX1067, ¶23. This stands in stark contrast to his earlier opinion, upon which the
`
`Board based institution, that:
`
`it was reasonably likely that 600 mg would be well
`tolerated
`and
`therapeutically
`effective when
`coadministered with a strong CYP3A inhibitor.
`
`
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`5
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`ID, 21 (quoting EX1002, ¶69). Thus, Dr. Greenblatt himself no longer stands by
`
`his prior opinion.
`
`Teva also does not dispute—or even question—the above-referenced
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`prescribing experience of Drs. Carroll and Katznelson. In fact, despite submitting
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`the opinion of an endocrinologist for the first time in Reply, Teva’s endocrinologist
`
`(Dr. Dobs) did not testify that a POSA would have reasonably expected doses
`
`above 300 mg could be safely co-administered with strong CYP3A inhibitors.
`
`EX2071, 152:21-153:6. It is telling that Teva was unable to locate a single
`
`endocrinologist to substantiate its position in the Petition that a POSA would have
`
`expected greater than 300 mg of mifepristone could be safely co-administered with
`
`a strong CYP3A inhibitor.
`
`Further, Drs. Greenblatt and Dobs improperly failed to consider, let alone
`
`address, the peer-reviewed literature identified in the POR and discussed in the
`
`declarations of Drs. Carroll and Katznelson that teaches away from the claimed
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`inventions. EX2071, 17:8-12; 19:6-12; 55:22-56:5; 147:10-14; 152:17-20;
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`EX2070, 14:3-7.
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`Moreover, neither Teva nor its experts dispute Dr. Guengerich’s analysis of
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`Dr. Greenblatt’s five-factor test, which would have led a POSA to expect a
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`clinically significant and potentially dangerous DDI when mifepristone is co-
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`administered with a strong CYP3A inhibitor with a low Ki, such as ketoconazole.
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`POR, 42-48. Dr. Greenblatt admitted that his five-factor test can be used as a
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`“guide” to “determining whether a drug interaction is unlikely, possible, probable,
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`[or] highly probable,” and that a POSA could use those factors to develop a
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`qualitative expectation of the likelihood of a DDI. EX2070, 43:2-14. Yet, Dr.
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`Greenblatt did not analyze any of the five-factors in either of his declarations; only
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`Dr. Guengerich has. Compare EX2056, ¶¶55-63, with EX1002, ¶33. And Dr.
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`Guengerich’s unrebutted analysis indicates that a POSA would have had a
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`qualitative expectation that the combination of more than 300 mg mifepristone
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`with a strong CYP3A inhibitor would be highly probable to cause a clinically
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`significant DDI.
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`Teva’s failure to rebut any of the record evidence demonstrating that a
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`POSA would not have had a reasonable expectation of success is dispositive of the
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`obviousness challenge presented by the Petition. See, e.g., In re Stepan Co., 868
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`F.3d 1342, 1347 (Fed. Cir. 2017). On this basis alone, the Board should uphold the
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`patentability of the challenged claims.
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`B.
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`Teva’s Attempt to Change Its Definition of a POSA Fails
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`Unable to rebut the opinions of Corcept’s experts on the dispositive question
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`presented by the Petition, Teva instead spends almost five pages of its Reply
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`arguing against the definition of a POSA that Teva itself proposed in the Petition.
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`Specifically, Teva now suggests that the Board should “accord the opinions of Drs.
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`Carroll and Katznelson—and Corcept’s arguments based on those opinions—no
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`weight because they approach the obviousness inquiry exclusively from the
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`perspective of a practicing clinician.” Reply, 7.
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`Under Teva’s own definition, however, the POSA could be either a clinician
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`with experience using mifepristone, such as Drs. Carroll or Katznelson, or
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`someone experienced in studying CYP3A-mediated drug-drug interactions.
`
`Petition, 22 (explaining the POSA “would have had at least four years of
`
`experience either treating patients with mifepristone and/or CYP3A inhibitors or,
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`alternatively, studying drug-drug interactions involving CYP3A inhibitors.”).
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`Indeed, the reasonable expectation of success argument in the Petition hinged on
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`Teva’s attempt to have Dr. Greenblatt opine from the perspective of a clinician.
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`See, e.g., EX1002, ¶130 (opining on what “any physician reading the label’s
`
`instructions … would have understood”). Dr. Greenblatt admitted at deposition,
`
`however, that he lacks the requisite experience as a clinician, and his testimony
`
`from this perspective was thoroughly rebutted by Drs. Carroll and Katznelson,
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`actual clinicians with experience treating patients with mifepristone. EX2057, ¶¶4-
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`9; EX2058, ¶¶4-16.
`
`The Petition’s inclusion of clinicians in the definition of a POSA was
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`consistent with the purpose of the patent and the claims, which are directed to
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`safely treating Cushing’s syndrome—not any specific pharmacokinetic outcome.
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`EX1001, 68:1-69:2; EX2071, 33:5-12 (Teva’s expert confirming that the claims of
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`the ’214 patent are “directed to people doing the prescribing or involved in the
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`prescribing of the drug mifepristone in clinical practice”); 28:20-29:21. Indeed,
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`given the complexity of treating Cushing’s syndrome with mifepristone, the POR
`
`noted that the inclusion of a person with relevant clinical experience in the POSA
`
`definition should be mandatory, rather than optional.1 POR, 20-22. Notably, a
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`practicing clinician is uniquely qualified to speak to the main issue identified by
`
`the Board—how a POSA would have interpreted the 300 mg limitation in the 2012
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`Korlym Label. ID, 17; cf. EX2059, 155:7-156:5; 91:11-92:7; 106:12-23. Teva has
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`1 Teva claims it is “incredibl[e]” that Dr. Greenblatt is not a POSA under
`
`Corcept’s definition because Corcept relied on certain articles by Dr. Greenblatt
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`during prosecution. Reply, 4. Teva omits, however, that Dr. Greenblatt’s articles
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`were presented to the examiner in affidavits by two experienced clinicians, who
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`were discussing their understanding of the art. EX1035, 552-553, 584-585. And
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`Dr. Greenblatt failed to consult with any clinicians in formulating his opinions.
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`Corcept is not suggesting that the POSA’s analysis should “exclusively” be that of
`
`a clinician, but Teva’s analysis fails because it seeks to completely cut out the
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`clinician’s view, despite expressly acknowledging that view would be part of the
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`POSA definition.
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`no basis to now exclude clinicians such as Drs. Carroll and Katznelson from the
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`POSA. Wasica Fin. GmbH v. Cont'l Auto. Sys., Inc., 853 F.3d 1272, 1286 (Fed.
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`Cir. 2017) (“Shifting arguments in this fashion is foreclosed by statute, [Federal
`
`Circuit] precedent, and Board guidelines.”). Accordingly, Teva cannot show a
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`reasonable expectation of success, thus its obviousness challenge fails.
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`III. Teva’s Focus on the Alleged “Routine” Nature of the Clinical Trials
`that Led to the Claimed Methods Is Legally and Factually Deficient
`
`Realizing the evidence does not support the expectation of success alleged in
`
`the Petition, Teva now turns its efforts to arguing that the alleged “routine” nature
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`of the testing that led to the claimed methods renders the inventions obvious. See
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`Reply, §III. First, even if the nature of the testing were “routine,” such a showing
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`cannot meet Teva’s burden to show a reasonable expectation of success. Second,
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`Teva is wrong as a factual matter: the evidence shows, and Teva’s experts agree,
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`that the testing that led to the claimed inventions was not “routine.”
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`A. Routine Experimentation Cannot Compensate for a Lack of
`Reasonable Expectation of Success
`
`Rather than address the pivotal question of “how the POSA would have
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`interpreted … the Korlym Label,” Teva in Reply attempts to recast the issue as a
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`“dose-optimization problem.” Teva now argues that the relevant question is “what
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`a POSA instructed to optimize the dose would have done,” contending a “POSA
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`would have reasonably expected that co-administration of the two drugs at some
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`dose could treat Cushing’s syndrome” and it was simply a matter of designing a
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`“routine” clinical trial to “identify the optimal mifepristone dose.” Reply, 1, 7, 14.
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`Teva’s argument fails on all counts.
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`As an initial matter, Teva’s reinterpretation of the reasonable expectation of
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`success inquiry is legally incorrect. Teva cannot meet its burden of showing a
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`reasonable expectation that doses above 300 mg/day mifepristone could be safely
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`co-administered with strong CYP3A inhibitors merely by arguing that a POSA
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`would have reasonably expected to be able to perform a “routine” series of drug-
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`drug interaction trials to identify “some” optimized dose of mifepristone. See, e.g.,
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`Stepan, 868 F.3d at 1345-46 (reversing PTAB finding of obviousness, noting the
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`Board did not “articulate why a person of ordinary skill in the art would have had a
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`reasonable expectation of success” before carrying out the allegedly routine tests
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`that led to the claimed inventions).
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`Indeed, the Board recently explained that where the art demonstrates “the
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`skilled artisan would no more have expected failure …. than would have expected
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`success,” it is legal error for the Board to “gloss[] over that finding with a ‘routine
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`testing’ rationale.” Eli Lilly & Co. v. Teva Pharm. Int’l., IPR2018-01710, Paper 69
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`at 137-38 (PTAB Mar. 31, 2020) (quoting Honeywell Int’l Inc. v. Mexichem
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`Amanco Holding, 865 F.3d 1348 (Fed. Cir. 2017)); see also MPEP 2144.05
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`(stating that a rejection based on routine optimization “must include an explanation
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`of why it would have been routine optimization to arrive at the claimed invention
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`and why a person of ordinary skill in the art would have had a reasonable
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`expectation of success”). Yet this is precisely what Teva asks the Board to do
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`here—Teva seeks to use the mantra of “routine testing” to gloss over the fact that it
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`has presented no evidence that a POSA would have expected any doses above 300
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`mg/day mifepristone—including the claimed 600 mg/day dose—could be safely
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`co-administered with strong CYP3A inhibitors to treat Cushing’s syndrome. On
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`this basis alone, Teva’s routine experimentation argument fails.
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`Moreover, contrary to Teva’s assertion, FDA did not instruct Corcept to
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`“optimize the dose” by running a DDI study. Instead, FDA expressed concern that
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`“increased exposure to mifepristone is associated with serious risks for severe
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`hypokalemia and adrenal insufficiency,” and determined that a DDI study was
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`needed to “to characterize the effect of co-administration of strong CYP3A4
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`inhibitors on increasing mif
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