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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.
`_______________________
`PGR2019-00048
`Patent 10,195,214 B2
`_______________________
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
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`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`PGR2019-00048
`Patent 10,195,214 B2
`
`B.
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`2.
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`2.
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`3.
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`I.
`II.
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`V.
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`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1
`Corcept’s arguments regarding the definition of a POSA betray a
`misunderstanding of the obviousness inquiry. ................................................ 3
`III. A POSA would have arrived at the claimed 600-mg dose through
`routine optimization. ........................................................................................ 8
`A. A POSA would have reasonably expected success in optimizing
`the dose by conducting a drug-drug interaction study. ......................... 8
`1.
`Clinical DDI studies are routine, and Corcept’s DDI
`study was no exception. .............................................................. 8
`A POSA would have reasonably expected to identify the
`optimal dose of mifepristone through a DDI study. ................. 13
`Corcept’s contrary arguments lack merit. ........................................... 17
`1.
`FDA recommended permitting co-administration of
`strong CYP3A inhibitors and 300 mg mifepristone and
`contemplated increasing the permitted dose pending the
`results of the DDI study. ........................................................... 17
`Dunnigan would not have led a POSA to expect that co-
`administering strong CYP3A inhibitors with 600 mg
`mifepristone would be dangerous. ............................................ 19
`The unpredictability of the DDI simply reinforces the
`motivation to perform a clinical DDI study. ............................. 21
`IV. Corcept’s suggestion that obviousness requires the ability to predict
`the exact dosing without experimentation is legally incorrect. ..................... 24
`Conclusion ..................................................................................................... 26
`
`
`
`i
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`
`
`Teva
`Exhibit #
`
`PGR2019-00048
`Patent 10,195,214 B2
`
`
`
`LIST OF EXHIBITS
`
`Description
`
`1001
`
`1002
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`Belanoff, J.K., “Concomitant Administration Of Glucocorticoid
`Receptor Modulators And CYP3A Inhibitors,” U.S. Patent No.
`10,195,214 B2 (filed June 19, 2017; issued February 5, 2019)
`Declaration of David J. Greenblatt, M.D.
`Curriculum Vitae for David J. Greenblatt. M.D.
`Korlym Label (2012)
`Lee et al., Office of Clinical Pharmacology Review NDA 20687
`(Addendum, KorlymTM, Mifepristone) (2012)
`FDA Approval Letter for Korlym (mifepristone) tablets, NDA
`20217, dated February 17, 2012
`Tsunoda, S.M., et al., “Differentiation of intestinal and hepatic
`cytochrome P450 3A activity with use of midazolam as an in vivo
`probe: Effect of ketoconazole,” Clin. Pharmacol. Ther. 66(5): 461–
`471 (1999)
`Ullmann, A., et al., “Method For Treating Cushing’s Syndrome,”
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`October 13, 2008; published October 14, 2010)
`Sartor, O. and Cutler, G.B., “Mifepristone: Treatment of Cushing’s
`Syndrome,” Clinical Obstetrics and Gynecology 39(2): 506–510
`(1996)
`Pozza, C., et al., “Management Strategies for Aggressive Cushing’s
`Syndrome: From Macroadenomas to Ectopics,” J. Oncol. 109: 1–9
`(2012)
`Castinetti, F., “Medical Treatment of Cushing’s Syndrome:
`Glucocorticoid Receptor Antagonists and Mifepristone,”
`Neuroendocrinology 92(suppl. 1): 125–130 (2010)
`Nieman, L.K., “Successful Treatment of Cushing's Syndrome with
`the Glucocorticoid Antagonist RU 486*,” J. Clin. Endocrinol.
`Metab. 61(3): 536–540 (1985)
`
`ii
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`
`
`Teva
`Exhibit #
`
`
`
`
`
`PGR2019-00048
`Patent 10,195,214 B2
`
`Description
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`Brogden, R.N., et al., ” Mifepristone A Review of its
`Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic
`Potential,” Drugs 45(3): 384–409 (1993)
`Molitch. M.E., “Current approaches to the pharmacological
`management of Cushing’s disease,” Mol. Cell. Endocrinol. 408:
`185–189 (2015)
`Sitruk-Ware, R. and Spitz, I.M., “Pharmacological properties of
`mifepristone: toxicology and safety in animal and human studies,”
`Contraception 68: 409–420 (2003)
`Heikinheimo, O., “Pharmacokinetics of The Antiprogesterone RU
`486 in Women During Multiple Dose Administration,” J. Steriod.
`Biochem. 32(1A): 21–25 (1989)
`Heikinheimo, O., et al., “The pharmacokinetics of mifepristone in
`humans reveal insights into differential mechanisms of antiprogestin
`action,” Contraception 68: 421–426 (2003)
`Blasey, C.M., et al., “Efficacy and Safety of Mifepristone for the
`Treatment of Psychotic Depression,” J. Clin. Psychopharmacol.
`31:436–440 (2011)
`Belanoff, J.K., “Optimizing Mifepristone Levels in Plasma Serum
`of Patients Suffering from Mental Disorders Treatable with
`Glucocorticoid Receptor Antagonists,” U.S. Patent No. 8,921,348
`B2 (filed October 29, 2013; issued December 30, 2014)
`Belanoff, J.K., “Optimizing Mifepristone Levels in Plasma Serum
`of Patients Suffering from Mental Disorders Treatable with
`Glucocorticod Receptor Antagonists,” U.S. Patent No. 8.598,149 B2
`(filed August 27, 2008; issued December 3, 2013)
`Castinetti, F., et al., “Merits and pitfalls of mifepristone in
`Cushing’s syndrome,” Eur. J. Endocrinol.160: 1003–1010 (2009)
`Jang, G.R., et al., “Identification of CYP3A4 as the Principal
`Enzyme Catalyzing Mifepristone (RU 486) Oxidation in Human
`Liver Microsomes,” Biochem. Pharmacol. 52: 753–761 (1996)
`
`iii
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`Teva
`Exhibit #
`
`
`
`
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`PGR2019-00048
`Patent 10,195,214 B2
`
`Description
`
`1023
`
`1024
`
`1025
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`1026
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`1027
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`1028
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`1029
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`1030
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`1031
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`Greenblatt, D., “In Vitro Prediction of Clinical Drug Interactions
`With CYP3A Substrates: We Are Not There Yet,” Clin. Pharm.
`Ther. 95(2): 133–135 (2014)
`Greenblatt, D.J., et al., “Mechanism of cytochrome P450-3A
`inhibition by ketoconazole,” J. Pharm. Pharmacol. 63: 214–221
`(2011)
`Greenblatt, D.J. and von Moltke, L.L., “Clinical Studies of Drug-
`Drug Interactions: Design and Interpretation,” in Enzyme- and
`Transporter-Based Drug-Drug Interactions: Progress and Future
`Challenges. Pang, K.S. et al., ed., pp. 625–649, New York,
`Springer: (2010)
`Greenblatt, D.J., et al., “The CYP3 Family” in Cytochromes P450:
`Role in the Metabolism and Toxicity of Drugs and other
`Xenobiotics. Ionnides, C., ed., pp. 354–383, Royal Society of
`Chemistry: (2008)
`Ohno, Y., et al., “General Framework for the Quantitative
`Prediction of CYP3A4-Mediated Oral Drug Interactions Based on
`the AUC Increase by Coadministration of Standard Drugs,” Clin.
`Pharmacokinet. 46(8): 681–696 (2007)
`Archive History of NCT00936741 History of Changes for Study:
`NCT00936741 An Extension Study of CORLUX in the Treatment
`of Endogenous Cushing's Syndrome (July 9, 2009) on
`ClinicalTrials.gov
`Fleseriu, M., et al., “Mifepristone, a Glucocorticoid Receptor
`Antagonist, Produces Clinical and Metabolic Benefits in Patients
`with Cushing’s Syndrome,” J. Clin. Endocrinol. Metab.
`97(6):2039–2049 (2012)
`Morgan, F.H. and Laufgraben, M.J., “Mifepristone for Management
`of Cushing’s Syndrome,” Pharmacotherapy 33(3):319–329 (2013)
`Schteingart, D.E., “Drugs in the medical treatment of Cushing's
`syndrome,” Expert Opin. Emerging Drugs 14(4):661–671 (2009)
`
`iv
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`Teva
`Exhibit #
`
`
`
`
`
`PGR2019-00048
`Patent 10,195,214 B2
`
`Description
`
`Dang, C.N. and Trainor, P., “Pharmacological Management of
`Cushing’s Syndrome: An Update,” Arq. Bras. Endocrinol. Metab.
`51(8):1339–1348 (2007)
`Zhang, L., et al., “Predicting Drug–Drug Interactions: An FDA
`Perspective,” The AAPS Journal 11(2): 300–306 (2009)
`Nguyen, D. and Minze, S., “Effects of Ketoconazole on the
`Pharmacokinetics of Mifepristone, a Competitive Glucocorticoid
`Receptor Antagonist, in Healthy Men,” Adv. Ther. 34:2371–2385
`(2017)
`File History of U.S. Patent No. 10,195,214 B2
`Korlym Label Revised: 05/2017 (2017)
`Kaesar, B., et al., “Drug-Drug Interaction Study of Ketoconazole
`and Ritonavir-Boosted Saquinavir,” Antimicrobial Agents and
`Chemotherapy 53(2): 609–614 (2009)
`Truong, H.L.., et al., “Budget impact of pasireotide for the treatment
`of Cushing’s disease, a rare endocrine disorder associated with
`considerable comorbidities,” J. Med. Economics 17(4): 299–295
`(2014)
`Belanoff, J. and Gross, C., “Optimizing Mifepristone Levels for
`Cushing's Patients,” U.S. Patent No. 9,943,526 B2 (filed April 20,
`2016; issued April 17, 2018)
`“A Guide to Drug Safety Terms,” FDA Consumer Health
`Information / U. S. Food and Drug Administration, (2012)
`downloaded from www.tinyurl.com/y6oao2sj
`“Guidance for Industry Drug Interaction Studies — Study Design,
`Data Analysis, and Implications for Dosing and Labeling,” 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) (2006)
`File History for U.S. Patent No. 9,943,526 B2
`
`1032
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`1033
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`1034
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`1035
`1036
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`1037
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`1038
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`1039
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`1040
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`1041
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`1042
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`v
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`Teva
`Exhibit #
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`
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`PGR2019-00048
`Patent 10,195,214 B2
`
`Description
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`Corcept Therapeutics Incorporated Announces FDA Approval of
`Korlym(TM) (Mifepristone): First and Only Approved Medication
`for Cushing's Syndrome Patients,” Ex. 99 from Corcept
`Therapeutics Press Release (2012), downloaded from
`https://www.sec.gov/Archives/edgar/data/1088856/0001193125123
`47804/d357533d10q.htm
`Form 8-K, Corcept Therapeutics, Inc. (2012), downloaded from
`https://www.sec.gov/Archives/edgar/data/1088856/0001102624120
`00138/corcepttherapeutics8k.htm
`Form 10-Q, Corcept Therapeutics, Inc. (2012), downloaded from
`https://www.sec.gov/Archives/edgar/data/1088856/0001102624120
`00138/corcepttherapeuticsincorpora.htm
`Greenblatt, D.J, et al., “Ketoconazole inhibition of triazolam and
`alprazolam clearance: Differential kinetic and dynamic
`consequences,” Clin. Pharmacol. Ther. 64(3):237–247 (1998)
`Drugs@FDA: FDA Approved Drug Products, downloaded from
`https://www.accessdata.fda.gov/scripts/cder/daf/
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`korlym_toc.cfm] Internet Archive.
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`ta.fda.gov/drugsatfda_docs/nda/2012/202107Orig1s000Lbl.pdf]
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`vi
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`
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`Teva
`Exhibit #
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`
`
`
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`PGR2019-00048
`Patent 10,195,214 B2
`
`Description
`
`Center For Drug Evaluation and Research. Application Number:
`202107Orig1s000.Clinical Pharmacology and Biopharmaceuticals
`Review(s). 18 February 2017.
`[http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202107O
`rig1s000ClinPharmR.pdf] Internet Archive.
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`.pdf]
`Center For Drug Evaluation and Research. Application Number:
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`rig1s000Approv.pdf]. Internet Archive.
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`Archive.
`[https://web.archive.org/web/20061102162753/http://www.fda.gov/
`cder/guidance/6695dft.pdf]
`FDA Guidance Documents, downloaded from
`https://www.fda.gov/regulatoryinformation/guidances/
`Declaration of Atul Kaushik
`Wilkinson, G., “Pharmacokinetics The Dynamics of Drug
`Absorption, Distribution and Elimination,” in Goodman & Gilmans’
`The Pharmacological Basis of Therapeutics, Tenth Edition,
`Hardman, J., ed., pp. 3–29, McGraw-Hill, New York (2001)
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`escribinginfo.pdf]
`Greenblatt, D.J. and Koch-Weser, J., “Clinical Pharmacokinetics,”
`NEJM 293:702–705 (1975)
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`vii
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`Teva
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`
`
`
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`PGR2019-00048
`Patent 10,195,214 B2
`
`Description
`
`1058
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`1059
`1060
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`1062
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`Pharmacodynamics for Medical Students:A Proposed Course
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`Declaration of J.C. Rozendaal
`Declaration of Uma N. Everett
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`Feb. 21, 2019)
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`Feb. 7, 2019)
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`PGR2019-00048 (May 8, 2020)
`Deposition Transcript of Deposition of F. Peter Guengerich, M.D.,
`Case PGR2019-00048 (May 14, 2020)
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`viii
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`Teva
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`PGR2019-00048
`Patent 10,195,214 B2
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`Description
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`1074
`
`1075
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`1076
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`1077
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`1079
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`1080
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`Outeiro, N., et al., “No Increased Risk of Ketoconazole Toxicity in
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`26(4): 299–303 (1986)
`
`ix
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`I.
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`PGR2019-00048
`Patent 10,195,214 B2
`
`Introduction
`The ’214 patent claims a method of treating Cushing’s syndrome by co-
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`administering 600 mg mifepristone and a strong CYP3A inhibitor. The prior-art
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`2012 Korlym Label undisputedly discloses every limitation of the challenged
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`claims except the specific dose of mifepristone. And, as the Board already
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`concluded, “arriving at the claimed dosage…would have been the product of
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`routine optimization.” DI, 23. Indeed, the prior art provides an explicit roadmap for
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`that routine optimization: Lee and associated documents in Korlym’s Drug
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`Approval Package disclose that FDA instructed Corcept to run a routine drug-drug
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`interaction study to optimize the dose. It is difficult to imagine a more clear-cut
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`obviousness case. There is nothing inventive about optimizing dosing of a drug
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`where the prior art provides both the motivation and the means to do so.
`
`Corcept’s responses are largely beside the point because they focus on the
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`wrong question. Corcept contends that a clinician following the 2012 Korlym
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`Label would not have deviated from the label’s instruction to limit mifepristone to
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`300 mg per day when co-administered with strong CYP3A inhibitors. But the
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`question is not what a physician treating Cushing’s syndrome would have done
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`based on the label alone; rather, it is what a POSA instructed to optimize the dose
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`would have done in light of all prior art. The art provides a ready answer: run a
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`clinical DDI study. And the evidence shows that a POSA would have expected
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`such a study to be successful.
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`Patent 10,195,214 B2
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`Corcept’s attempts to engage with the real issues fare no better. Corcept
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`argues that the claimed invention produced unexpected results because a POSA
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`would have expected co-administration of strong CYP3A inhibitors with more than
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`300 mg mifepristone to be dangerous. The evidence does not support this theory.
`
`As Teva’s expert Dr. Greenblatt—whose scholarship formed the principal basis for
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`Corcept’s unexpected-results arguments during prosecution—has explained, DDIs
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`involving CYP3A inhibitors and CYP3A substrates are unpredictable. There is no
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`a priori expectation about the extent or clinical significance of a given DDI: as
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`Corcept’s own expert Dr. Guengerich admitted, “that’s why you do these studies.”
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`TEVA1070, 65:14–18 (emphasis added).
`
`Corcept, relying on testimony from Dr. Guengerich, also claims that clinical
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`DDI studies are not “routine” because their designs involve choices among
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`different variables, such as the identity of the CYP3A inhibitor, the patient
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`population, etc. These studies may appear complicated to Dr. Guengerich, who has
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`never designed such a study nor served as a principal investigator on one. Id.,
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`20:6–23:17. But the only expert in this proceeding who does design these studies—
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`Dr. Greenblatt—explains that clinical DDI studies are routine. TEVA1067, ¶8;
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`TEVA1002, ¶70. And the particular DDI study Corcept ran was no exception.
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`Corcept simply did what the prior art said to do and claimed the results.
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`Patent 10,195,214 B2
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`At bottom, Corcept’s patentability arguments rest on the premise that, for a
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`
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`method claim involving dosing to be obvious, a POSA must be able to predict the
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`exact optimized dose in advance. That is wrong. Obviousness does not require
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`absolute predictability. And “it cannot be the case that any new dosage of co-
`
`administered mifepristone is patentable simply because one must test to quantify
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`the extent of a recognized drug-drug interaction, especially when the prior art
`
`expressly teaches to conduct such testing.” DI, 21. Here, a POSA would have
`
`followed the prior-art instructions to perform a clinical DDI study and would have
`
`reasonably expected to arrive at the claimed 600-mg dose. The claims are obvious.
`
`II. Corcept’s arguments regarding the definition of a POSA betray a
`misunderstanding of the obviousness inquiry.
`A. A determination of the level of ordinary skill in the art depends on
`
`several factors, among them “the educational level of the inventor,” the “type of
`
`problems encountered in the art,” the sophistication of relevant technology, and the
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`educational level of those in the field. Daiichi Sankyo Co., Ltd. v. Apotex, Inc., 501
`
`F.3d 1254, 1256 (Fed. Cir. 2007). At bottom, the key inquiry is the probable skill
`
`level of one investigating “the problem the invention…was trying to solve.” Id. at
`
`1257.
`
`Here, that “problem” was determining the extent and clinical significance of
`
`the DDI between mifepristone and strong CYP3A inhibitors. TEVA1001, 3:40–57;
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`3
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`Patent 10,195,214 B2
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`TEVA1035, 339 (“[T]he present invention arose out of our investigations into the
`
`
`
`safety of co-administering mifepristone along with CYP3A inhibitors….”).
`
`Accordingly, as Dr. Greenblatt explains, TEVA1002, ¶18, a POSA could have had
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`experience with drug-drug interactions and/or DDI studies, and could—though
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`need not—have experience treating Cushing’s syndrome. Accord DI, 6. Corcept
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`itself recognized this during prosecution by relying on the scholarship of Dr.
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`Greenblatt, who is not an endocrinologist but who is a preeminent authority on
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`DDIs involving strong CYP3A inhibitors. See, e.g., TEVA1035, 542
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`(characterizing the interaction between strong CYP3A inhibitors and CYP3A
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`substrates as “the Greenblatt effect” after Dr. Greenblatt).1
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`B. Now, incredibly, Corcept asserts that Dr. Greenblatt—the centerpiece
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`of Corcept’s patentability arguments during prosecution—is not even a POSA
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`because he lacks experience treating Cushing’s syndrome. POR, 37–38. Corcept
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`and its experts contend that the POSA “requires a medical professional with
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`experience treating Cushing’s syndrome patients with mifepristone”—i.e., an
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`endocrinologist. POR, 20–21; TEVA1069, 45:21–46:3, 49:9–50:6; TEVA1071,
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`38:19–42:22.
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`1 Corcept also characterized “FDA” (which, of course, likewise does not
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`treat Cushing’s syndrome) as a POSA. TEVA1035, 340.
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`4
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`PGR2019-00048
`Patent 10,195,214 B2
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`This argument is readily refuted by the relevant art and the patent itself. The
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`
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`lead author of the paper disclosing the results of Corcept’s mifepristone-
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`ketoconazole DDI study (the basis for the patent) is a pharmacist with experience
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`managing clinical trials, not an endocrinologist. TEVA1072. Nor would the
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`patent’s inventor qualify as a POSA under Corcept’s definition. Dr. Belanoff, as
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`Corcept’s expert Dr. Carroll admitted, is a psychiatrist. TEVA1069, 54:3–4; but
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`see Daiichi, 501 F.3d at 1257 (level of skill in the art should reflect background of
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`inventor); Alza Corp. v. Andrz Pharm., LLC, 607 F. Supp. 2d 614, 637 (D. Del.
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`2009) (same).2
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`C.
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`To make matters worse, Corcept has misapplied its own definition of
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`a POSA. While Corcept purports to at least allow a pharmacologist on the team,
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`POR, 20, Corcept’s POSA in fact looks at the obviousness question exclusively
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`from the perspective of a practicing endocrinologist and need not even consider the
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`views of those (like Dr. Greenblatt) with expertise in clinical DDI studies. See
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`TEVA1069, 50:7–51:9; TEVA1071, 49:22–52:24. That cannot be correct: a
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`clinical DDI study—as FDA requested—is precisely how Corcept arrived at the
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`2 Neither Dr. Carroll nor Dr. Katznelson considered Dr. Belanoff’s
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`background in forming their definition of a POSA. TEVA1069, 54:5–15;
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`TEVA1071, 43:22–44:2.
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`5
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`PGR2019-00048
`Patent 10,195,214 B2
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`purported invention. The ’214 patent is directed to solving a drug-drug interaction
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`
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`problem. A POSA accordingly would have needed experience with DDI studies, or
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`would have sought input from someone with such experience. TEVA1002, ¶18;
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`see Daiichi, 501 F.3d at 1255–57 (concluding that POSA for a patent claiming
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`methods of treating ear infections by administering ofloxacin required experience
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`“developing pharmaceutical formulations and treatment methods for the ear” and
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`rejecting district court’s conclusion that the POSA would be merely a general
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`practitioner because “while a general practitioner could (and would) prescribe the
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`invention of the…patent to treat ear infections, he would not have the training or
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`knowledge to develop the claimed compound absent some specialty training”).
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`Many of Corcept’s patentability arguments are non sequiturs even under
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`Corcept’s definition of a POSA because they fail to appreciate this fundamental
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`point. For example, Corcept, relying on Drs. Carroll and Katznelson—
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`endocrinologists and paid Corcept speakers for the last decade, TEVA1069, 24:7–
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`24; TEVA1071, 19:7–21:5—argues that a clinician treating Cushing’s syndrome
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`would not have administered more than 300 mg mifepristone based on the 2012
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`Korlym Label. E.g., POR, 16, 36–41; EX2057; EX2058. Indeed, Corcept’s
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`clinicians go so far as to say that there could have been no “experimentation” with
`
`doses above 300 mg because here “the ‘experiment’ is the medical treatment of a
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`human being that could incur potentially life-threatening side effects.” EX2057,
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`6
`
`
`
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`¶92; EX2058, ¶99.
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`PGR2019-00048
`Patent 10,195,214 B2
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`But, regardless of whose definition of a POSA is applied, the question is not
`
`whether a clinician would have administered a patient more than 300 mg
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`mifepristone with a strong CYP3A inhibitor based on the 2012 Korlym Label. The
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`question, rather, is whether someone trying to solve the dose-optimization problem
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`would have experimented with doses of mifepristone exceeding 300 mg to
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`“provide more therapeutic options available to Cushing’s patients and appropriate
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`labeling of mifepristone when co-administered with CYP3A inhibitors.”
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`TEVA1005, 5. The “experiment” is not “medical treatment of a human being”; it is
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`a routine DDI study. The Board should accord the opinions of Drs. Carroll and
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`Katznelson—and Corcept’s arguments based on those opinions—no weight
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`because they approach the obviousness inquiry exclusively from the perspective of
`
`a practicing clinician, with no consideration of what one with experience involving
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`DDIs would have done. See TEVA1069, 60:4–61:23, 63:10–64:14, 66:4–23 (Dr.
`
`Carroll admitting that he offered his opinions “based on my definition of a POSA”
`
`and “can’t really give any opinion” from the perspective of Dr. Greenblatt’s
`
`POSA); TEVA1071, 49:22–52:24 (Dr. Katznelson admitting that he did not
`
`consider the viewpoint of one with expertise in studying DDIs).
`
`7
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`PGR2019-00048
`Patent 10,195,214 B2
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`III. A POSA would have arrived at the claimed 600-mg dose through
`routine optimization.
`Corcept does not and cannot dispute that a POSA would have been
`
`motivated to optimize the dosing of mifepristone when co-administered with
`
`strong CYP3A inhibitors. POR, 29. As the Board observed, Lee “expressly
`
`recommends conducting studies to optimize dosing,” and FDA Guidance provides
`
`“a method for” conducting such studies. DI, 25, 34. The only question, therefore, is
`
`whether a POSA would have reasonably expected success in arriving at the
`
`claimed invention.
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`The answer is yes. Corcept did exactly what the prior art instructed: it ran a
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`clinical DDI study involving mifepristone and ketoconazole. Such studies are
`
`routine in the art, and Corcept’s study was no exception. The answer Corcept’s
`
`study produced—that one could treat Cushing’s syndrome by co-administering 600
`
`mg mifepristone with a strong CYP3A inhibitor—was not predictable with
`
`absolute precision in advance, but it was well within the range of outcomes a
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`POSA would have expected. TEVA1002, ¶71.
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`A. A POSA would have reasonably expected success in optimizing
`the dose by conducting a drug-drug interaction study.
`1.
`Clinical DDI studies are routine, and Corcept’s DDI study
`was no exception.
`As Dr. Greenblatt explained and the Board agreed, clinical DDI
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`a.
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`studies were routine in the art before March 2017. DI, 26; TEVA1002, ¶70;
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`8
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`PGR2019-00048
`Patent 10,195,214 B2
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`TEVA1067, ¶8. Indeed, FDA’s Guidance for Industry on DDI studies—published
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`
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`in 2006—offers extensive instructions to POSAs concerning design and analysis of
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`clinical DDI studies. TEVA1041. Accordingly, conducting such a study would
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`have been well within a POSA’s abilities.
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`Corcept offers two rejoinders; both lack merit.
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`First, Corcept attacks FDA Guidance as “a ‘draft guidance’ document
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`distributed by FDA ‘for comment purposes only.’” POR, 28. Many FDA Guidance
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`documents are labeled “drafts,” but they still provide relevant and useful
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`information to those in the art. TEVA1067, ¶13 n.1; TEVA1068, ¶¶17–18. Indeed,
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`pharmaceutical companies developing drugs for FDA approval ignore FDA
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`Guidance documents at their peril. TEVA1067, ¶13 n.1; TEVA1068, ¶¶17–18.
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`Corcept itself relied on FDA’s draft DDI guidance during prosecution. TEVA1035,
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`362.
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`Second, Corcept, relying on Dr. Guengerich’s testimony, argues that clinical
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`DDI studies are complicated and not “routine” because they involve “numerous
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`choices”: “study design…, dosing regimen combinations…, the strong CYP3A
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`inhibitor, dose of mifepristone, dose of CYP3A inhibitor, whether the study is
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`blinded or un-blinded, and the patient population.” POR, 62; EX2056, ¶76. But,
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`within the bounds of responsible scientific practice, a POSA’s choice among the
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`variables would not be expected to influence the results of the study. TEVA1067,
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`9
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`PGR2019-00048
`Patent 10,195,214 B2
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`¶¶9–21. There may be different ways to run DDI studies, but that does not make
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`those studies complicated. Id.
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`In any event, the purported list of “variables” is a makeweight. There are far
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`fewer variables than Dr. Guengerich suggests. The prior art itself resolves many of
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`the choices. FDA itself selected ketoconazole as the strong CYP3A inhibitor for
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`Corcept’s DDI study, since there was a “high potential of [ketoconazole’s]
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`concomitant use with mifepristone.” TEVA1005, 4–5. FDA likewise chose the
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`patient population (healthy subjects). TEVA1066, 23. A POSA would have known
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`this based on the Korlym Drug Approval Package.
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`FDA Guidance provides further illumination, noting that “[s]tudies can
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`usually be open label (unblinded)” and instructing that “[t]he inhibiting/inducing
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`drugs and the substrates should be dosed so that the exposures of both drugs are
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`relevant to their clinical use.” TEVA1041, 10. Dr. Guengerich agreed with this
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`statement. TEVA1070, 104:20–105:3. As to the dose of ketoconazole, Dr.
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`Guengerich admits that ketoconazole is a “widely used” index inhibitor whose
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`inhibition is not “dose- or concentration-dependent.” EX2056, ¶84. This means
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`both that the chosen dose of ketoconazole is irrelevant and that the results of a DDI
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`study using ketoconazole would necessarily “have been applicable to other strong
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`CYP3A inhibitors.” Id. As to the mifepristone dose, it was known that 300 mg
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`could be co-administered with ketoconazole. TEVA1004, 1. Accordingly, as Dr.
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`10
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`PGR2019-00048
`Patent 10,195,214 B2
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`Katznelson admitted, since “600 mg is the next dose escalation of
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`
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`mifepristone…that would be the dose that would need to be studied.” TEVA1071,
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`81:8–11; see TEVA1067, ¶16; TEVA1068, ¶27. That is exactly what Corcept did.
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`TEVA1001, 60:43–51.
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`This leaves only study design. FDA Guidance explains that “[a] study can
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`use a randomized crossover…a one-sequence crossover…, or a parallel design.”
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`TEVA1041, 9. As Dr. Greenblatt explains, crossover designs3 (as Corcept chose,
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`TEVA1001, 60:43–56) are generally preferred for DDI studies because they allow
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`patients to serve as their own controls and therefore eliminate confounding factors
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`introduced by inter-patient variability in pharmacokinetics. TEVA1067, ¶10. But
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`parallel designs “are still perfectly adequate when the circumstances call for them.”
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`Id. The “study design” variable thus does not unduly complicate the picture either.
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`In short, Corcept’s attempt to make routine clinical DDI studies look
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`complicated fails. The purported array of variables involved may appear
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`bewildering to Dr. Guengerich, who has never designed a clinical DDI study.
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`TEVA1070, 20:6–23:17; see TEVA1069, 20:18
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