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 No: PGR2019-00048
`U.S. Patent No. 10,195,214
`
`Title: CONCOMITANT ADMINISTRATION OF GLUCOCORTICOID
`RECEPTOR MODULATORS AND CYP3A INHIBITORS
`_______________________
`
`Petition for Post-Grant Review
`Under 35 U.S.C. §§ 321-328 and 37 C.F.R. § 42.200 et seq.
`
`
`
`
`
`
`
`
`

`

`
`
`
`I.
`
`II.
`
`III.
`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TABLE OF CONTENTS
`
`Statement of Precise Relief Requested and Reasons Therefor (37
`C.F.R. § 42.22(a)) ............................................................................................ 1
`
`Introduction ...................................................................................................... 1
`
`State of the Art Before March 1, 2017 ............................................................ 7
`
`A.
`
`B.
`
`C.
`
`1970s-2000s: Researchers develop mifepristone and test it in
`Cushing’s syndrome patients. ............................................................... 7
`2009: Corcept initiates a clinical trial to obtain FDA approval to
`market mifepristone for the treatment of Cushing’s syndrome. ........... 9
`2012: The FDA approves Korlym to control hyperglycemia
`secondary to hypercortisolism in adult patients with
`endogenous Cushing’s syndrome patients who have type 2
`diabetes mellitus or glucose intolerance and have failed surgery
`or are not candidates for surgery, but imposes a post-marketing
`requirement that Corcept conduct a drug-drug interaction study
`with mifepristone and ketoconazole. ................................................... 10
`
`IV. The ’214 Patent .............................................................................................. 14
`
`A.
`B.
`C.
`
`The ’214 patent specification .............................................................. 15
`The challenged claims ......................................................................... 17
`The prosecution history of the ’214 patent ......................................... 18
`
`V.
`
`Person of Ordinary Skill in the Art ................................................................ 22
`
`VI. Claim Construction ........................................................................................ 23
`
`VII.
`
`Identification of Challenge Under 37 C.F.R. § 42.204(b) ............................. 23
`
`A. Ground 1: Claims 1-13 Would Have Been Obvious Over The
`Korlym Label and Lee. ........................................................................ 24
`1.
`The Korlym Label and Lee were publicly available as of
`February 2012 and therefore qualify as prior art to the
`’214 patent under 35 U.S.C. § 102(a)(1). ................................. 25
`Independent claims 1, 5, and 10 would have been
`obvious over the Korlym Label and Lee. ................................. 29
`Dependent claims 2-4, 6-9, and 11-13 would have been
`obvious over the Korlym Label and Lee. ................................. 40
`
`2.
`
`3.
`
`i
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`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`B.
`
`C.
`
`D.
`
`2.
`
`Ground 2: Claims 1-13 Would Have Been Obvious Over The
`Korlym Label, Lee, and FDA Guidance. ............................................ 42
`1.
`FDA Guidance was publicly available as of September
`2006 and therefore qualify as prior art to the ’214 patent
`under 35 U.S.C. § 102(a)(1). ..................................................... 42
`Claims 1-13 would have been obvious over the Korlym
`Label, Lee and FDA Guidance ................................................. 44
`There are no objective indicia of non-obviousness supporting
`the patentability of the challenged claims. .......................................... 46
`The same or substantially the same prior art or arguments were
`not previously presented to the Office. ............................................... 61
`
`VIII. Conclusion ..................................................................................................... 64
`
`IX. Grounds For Standing (37 C.F.R. § 42.204(a)) ............................................. 64
`
`X. Mandatory Notices (37 C.F.R. §42.8(a)(1)) .................................................. 65
`
`
`
`ii
`
`

`

`
`
`
`Teva
`Exhibit #
`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`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,”
`U.S. Patent Application Publication No. 2010/0261693 A1 (filed
`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)
`
`iii
`
`

`

`
`
`Teva
`Exhibit #
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`Description
`
`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)
`
`iv
`
`

`

`
`
`Teva
`Exhibit #
`
`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`Description
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`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)
`
`v
`
`

`

`
`
`Teva
`Exhibit #
`
`1032
`
`1033
`
`1034
`
`1035
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`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
`
`vi
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`

`

`
`
`Teva
`Exhibit #
`
`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`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/
`Korlym (mifepristone) Tablets, 300 mg. 05 April 2016.[
`https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202107_
`korlym_toc.cfm] Internet Archive.
`[https://web.archive.org/web/20160405152243/https://www.accessd
`ata.fda.gov/drugsatfda_docs/nda/2012/202107_korlym_toc.cfm]
`Center For Drug Evaluation and Research. Application Number:
`202107Origls000.Labeling.
`[http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202107O
`rig1s000Lbl.pdf] Internet Archive.
`[https://web.archive.org/web/20170217054603/http://www.accessda
`ta.fda.gov/drugsatfda_docs/nda/2012/202107Orig1s000Lbl.pdf]
`
`vii
`
`

`

`
`
`Teva
`Exhibit #
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`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.
`[https://web.archive.org/web/20170218063600/http://www.accessda
`ta.fda.gov/drugsatfda_docs/nda/2012/202107Orig1s000ClinPharmR
`.pdf]
`Center For Drug Evaluation and Research. Application Number:
`202107Orig1s000. Approval Letter. 17 February 2017.
`[http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202107O
`rig1s000Approv.pdf]. Internet Archive.
`[https://web.archive.org/web/20170217191413/http://www.accessda
`ta.fda.gov/drugsatfda_docs/nda/2012/202107Orig1s000Approv.pdf]
`Guidance for Industry. Drug Interaction Studies-Study Design, Data
`Analysis, and Implications for Dosing and Labeling. 02 November
`2016. [http://www.fda.gov/cder/guidance/6695dft.pdf] Internet
`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)
`Korlym Label. 04 March 2012.[
`http://www.corcept.com/prescribinginfo.pdf] _Internet Archive_.
`[https://web.archive.org/web/20120304133653/www.corcept.com/pr
`escribinginfo.pdf]
`Greenblatt, D.J. and Koch-Weser, J., “Clinical Pharmacokinetics,”
` NEJM 293:702-705 (1975)
`
`viii
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`

`

`
`
`Teva
`Exhibit #
`
`1058
`
`1059
`
`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`Description
`
`Greenblatt, D.J. and Abourjaily, P.N., “Pharmacokinetics and
`Pharmacodynamics for Medical Students:A Proposed Course
`Outline,” J. Clin. Pharmacol. 56(10): 1180–1195 (2016)
`Friedman, H. and Greenblatt, D.J., “Rational Therapeutic Drug
`Monitoring,” JAMA 256(16): 2227-2233 (1986)
`
`ix
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`

`

`
`
`I.
`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`Statement of Precise Relief Requested and Reasons Therefor (37 C.F.R.
`§ 42.22(a))
`
`Petitioner Teva Pharmaceuticals USA, Inc. submits this Petition for Post-
`
`Grant Review seeking cancellation of claims 1-13 of U.S. Patent No. 10,195,214
`
`B2 (“the ’214 patent”; TEVA1001), issued to Corcept Therapeutics, Inc. The ’214
`
`patent claims priority to provisional application No. 62/465,772, filed on March 1,
`
`2017.1 TEVA1001, face page. All the challenged claims are thus eligible for post-
`
`grant review. See AIA § 3(n)(1).
`
`This Petition is supported by the declaration of Dr. David J. Greenblatt,
`
`M.D. (TEVA1002), an expert in clinical pharmacology, and demonstrates that
`
`claims 1-13 are unpatentable under 35 U.S.C. § 103. Teva thus respectfully
`
`requests that the Board institute this PGR.
`
`II.
`
`Introduction
`
`The ’214 patent is one of several method-of-treatment patents that Corcept
`
`has listed in the Orange Book for its drug Korlym® (mifepristone). Mifepristone is
`
`an old drug. It was developed in the early 1980s and was FDA-approved in 2000
`
`under the brand name Mifeprex® for the early termination of pregnancy.
`
`Mifepristone has been used in the treatment of various disorders—including
`
`1 Teva does not concede that the ’214 patent claims are entitled to claim
`
`priority benefit to March 1, 2017.
`
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
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`Cushing’s syndrome and various psychiatric conditions—since at least 1985. It
`
`was not until 2012, however, that Corcept obtained FDA approval for Korlym®,
`
`which is indicated to control hyperglycemia secondary to hypercortisolism in adult
`
`patients with endogenous Cushing’s syndrome who have type 2 diabetes mellitus
`
`or glucose intolerance and have failed surgery or are not candidates for surgery. At
`
`that time, Corcept had no patents on this indication to list in the Orange Book, so
`
`its market exclusivity on Korlym® was at risk. Accordingly, in the following
`
`years, Corcept prosecuted a flurry of patent applications involving the treatment of
`
`Cushing’s syndrome with mifepristone and listed the resulting patents in the
`
`Orange Book in an attempt to block competitors.
`
`The problem for Corcept is that the ’214 patent was filed long after the
`
`original FDA-approved label for Korlym® (“the Korlym Label”)2 as well as all the
`
`other materials in Korlym’s Drug Approval Package were released to the public.
`
`Those materials are thus prior art to the ’214 patent, and they disclose all the
`
`elements of claims 1-13 and render those claims unpatentable as obvious under 35
`
`U.S.C. § 103.
`
`
`2 Corcept Therapeutics, Korlym® (mifepristone) package insert, Menlo
`
`Park, CA (2012) (“Korlym Label”) (TEVA1004).
`
`2
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`

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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`The ’214 patent claims a method of treating Cushing’s syndrome in a patient
`
`who is receiving 900 to 1200 mg-per-day mifepristone by lowering the daily dose
`
`of mifepristone to 600 mg and co-administering a strong CYP3A inhibitor such as
`
`ketoconazole. But, as Corcept admitted during prosecution, the Korlym Label
`
`discloses (i) treatment of Cushing’s syndrome with 300 to 1200 mg-per-day
`
`mifepristone; (ii) co-administration of mifepristone and strong CYP3A inhibitors;
`
`and (iii) lowering the dose of mifepristone when co-administered with strong
`
`CYP3A inhibitors. The claimed method adds nothing of substance to the prior art.
`
`Corcept overcame the Korlym Label during prosecution by relying on two
`
`purported objective indicia of non-obviousness: teaching away and unexpected
`
`results. TEVA1035, 527-547. But Corcept’s arguments were legally and factually
`
`baseless, and the examiner erred in crediting them.
`
`First, Corcept argued that the prior art taught away from the claimed
`
`invention because the Korlym Label recommends reducing the mifepristone daily
`
`dose to 300 mg (rather than 600 mg) when co-administering mifepristone with a
`
`strong CYP3A inhibitor. Corcept’s theory was that the 300 mg limitation would
`
`have discouraged those in the art from trying higher doses when co-administering
`
`mifepristone and strong CYP3A inhibitors. Id., 533-537.
`
`The facts do not support this theory. When the FDA approved Korlym® in
`
`2012, it released as part of Korlym’s Drug Approval Package a Clinical
`
`3
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`

`

`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`
`Pharmacology Review Memorandum (“Lee”).3 Lee discloses that the FDA
`
`
`
`required the 300 mg limitation on the mifepristone dose when co-administered
`
`with a strong CYP3A inhibitor as a conservative precautionary measure pending
`
`the results of a drug-drug interaction (“DDI”) study that the FDA mandated as a
`
`post-marketing requirement for Korlym’s® approval. Lee notes that, because there
`
`was a “high potential” that mifepristone and ketoconazole (a strong CYP3A
`
`inhibitor) would be used together, a DDI study would “help provide more
`
`therapeutic options available to Cushing’s patients and appropriate labeling of
`
`mifepristone when co-administered with CYP3A inhibitors.” TEVA1005,1-2. In
`
`other words, the DDI study recommended in Lee would allow the FDA to
`
`determine whether the mifepristone dose could be increased above the
`
`conservative 300-mg estimate. Accordingly, the prior art would not have
`
`“discourage[d] investigation into the invention claimed,” Galderma Labs., L.P. v.
`
`Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013) (quoting DePuy Spine, Inc. v.
`
`Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)). On the
`
`contrary the prior art affirmatively encouraged testing higher doses; indeed, as
`
`
`3 Lee et al., Office of Clinical Pharmacology Review NDA 20687
`
`(Addendum, KorlymTM, Mifepristone) (2012) (TEVA1005).
`
`4
`
`

`

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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`noted above, the FDA publicly instructed Corcept to do so. TEVA1005,1-2.
`
`Corcept’s teaching-away argument thus fails as a matter of law.
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`Second, Corcept argued that a skilled artisan would have been surprised that
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`600 mg mifepristone could be co-administered with a strong CYP3A inhibitor
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`because, according to Corcept, one would have expected a strong CYP3A inhibitor
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`to cause a “dramatic spike” in a patient’s mifepristone blood levels. Corcept
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`termed this phenomenon the “Greenblatt effect” after Dr. Greenblatt, a clinical
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`pharmacologist whom Corcept recognized as the preeminent expert in drug-drug
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`interactions involving CYP3A inhibitors. TEVA1035, 542-546.
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`But, as Dr. Greenblatt himself explains in his expert declaration
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`accompanying this Petition, the premise of Corcept’s unexpected-results argument
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`is wrong. One would not have had an a priori expectation of any particular
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`increase in mifepristone blood levels when co-administered with a strong CYP3A
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`inhibitor. One would simply have run the experiment to find out the precise extent
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`of the interaction and then adjusted the dose accordingly. TEVA1002, ¶¶67-70.
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`Indeed, that is precisely what the FDA required Corcept to do, in order to ensure
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`that patients were able to take both mifepristone and strong CYP3A inhibitors at a
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`safe but effective level. TEVA1005, 1. And the answer that Corcept got—that
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`mifepristone blood levels increased about 33%—was well within the range that a
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`skilled artisan would have expected. TEVA1002, ¶71. Finally, as Dr. Greenblatt
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`further explains, there is nothing critical about the claimed reduction of the
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`mifepristone dose to 600 mg specifically. Arriving at the specific dose reduction
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`recited in the challenged claims would have been nothing more than routine
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`optimization using methods familiar to a person of skill in the art. TEVA1002, ¶69.
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`At bottom, Corcept’s unexpected-results argument reduces to an assertion
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`that, when the extent of a particular phenomenon (here, the interaction between
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`mifepristone and a strong CYP3A inhibitor) is not quantifiable in advance, any
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`outcome is an “unexpected result” that is probative of nonobviousness. That is
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`incorrect as a matter of law. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364
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`(Fed. Cir. 2007) (rejecting “a rule of law equating unpredictability to
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`patentability”).
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`In short, there were no unexpected results here that justified giving Corcept a
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`patent on a method that was disclosed by its own prior-art drug label and that was
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`the product of the routine optimization required and guided by the FDA.
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`TEVA1002, ¶¶126-145.
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`The Board should therefore institute PGR and cancel the challenged claims
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`under 35 U.S.C. § 103.
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`III. State of the Art Before March 1, 2017
`A.
`1970s-2000s: Researchers develop mifepristone and test it in
`Cushing’s syndrome patients.
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
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`Mifepristone (RU-486) was originally developed as an antiprogestin (i.e., an
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`abortifacient) in the 1980s. TEVA1009, 2; TEVA1010, 3; TEVA1011, 125.
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`However, researchers recognized in the early stages of the drug’s development that
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`it also functions as a glucocorticoid receptor antagonist (GRA). TEVA1009, 2.
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`GRAs were known to inhibit the effect of cortisol on tissues by competing with
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`cortisol for receptor sites, so some researchers hypothesized that the drug could
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`also be used to treat conditions such as Cushing’s syndrome that are characterized
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`by hypercortisolism. TEVA1012, 536; see also TEVA1013, 391.
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`In 1985, Dr. Lynette Nieman and her colleagues reported that they had
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`successfully treated a patient with Cushing’s syndrome by orally administering
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`mifepristone once daily for a nine-week period. TEVA1012, Abstract. In the
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`twenty-five years following Dr. Neiman’s initial study, other researchers
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`investigated the treatment of Cushing’s syndrome with mifepristone, reporting
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`generally positive findings. TEVA1014, 187-188; TEVA1011, 126.
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`By the early 2000s, those in the field had a comprehensive understanding of
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`the pharmacokinetic properties of mifepristone. See generally TEVA1015.
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`Researchers had known since the 1980s that mifepristone exhibited nonlinear
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`pharmacokinetics at doses above 100 mg/day. TEVA1016, 24; TEVA1017.4
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`
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`Researchers likewise knew that patients needed to maintain mifepristone plasma
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`levels of at least 1300 ng/mL or above in order to benefit from treatment with
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`mifepristone. TEVA1018, Abstract; TEVA1019, Abstract; TEVA1020, Abstract.
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`And researchers knew that mifepristone was well tolerated at doses of 1200
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`mg/day and above—meaning mifepristone plasma levels on the order of 2000-
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`3000 ng/mL did not present significant toxicity risks. TEVA1018, 436;
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`TEVA1012, 539; TEVA1021, 1006.
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`Those in the art also knew (and had known since 1996) that clearance of the
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`drug mifepristone is determined almost exclusively by the action of the enzyme
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`CYP3A—i.e., mifepristone is what is known as a “CYP3A substrate.” TEVA1022,
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`758-759; TEVA1002 ¶ 27. Accordingly, it was known that co-administration of a
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`strong CYP3A inhibitor with mifepristone would be likely to increase a patient’s
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`mifepristone exposure. TEVA1015, 415. But the state of the art did not (and still
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`4 For example, a 1993 review article on mifepristone explained that doses
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`above 100 mg/day resulted in maximum mifepristone plasma concentration levels
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`of 1.4 to 1.7 mg/L (1400 to 1700 ng/mL), whereas doses of six times that (600 mg)
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`raised plasma concentration levels only to about 2 mg/L (2000 ng/mL).
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`TEVA1013, 392; see also TEVA1015, 413-414.
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`U.S. Patent No. 10,195,214
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`does not) allow researchers to predict the exact degree of the interaction of a given
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`CYP3A inhibitor-CYP3A substrate pair using in vitro studies. TEVA1023, 135;
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`TEVA1024, 220; TEVA1025, Abstract; TEVA1026, 357, 368; TEVA1027,
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`Abstract; TEVA1002 ¶¶ 31-33. An FDA Guidance document published in 2006
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`(“FDA Guidance”) recognizes this, and accordingly recommends that those
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`investigating new drugs for FDA approval conduct both in vitro and in vivo studies
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`on drugs that are inhibitors, inducers, or substrates of CYP3A, in order to
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`determine the existence and extent of any potentially harmful drug-drug
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`interactions. TEVA1041, 2-4. However, as of 2009, no one had published a clinical
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`DDI study on mifepristone in the presence of a strong CYP3A inhibitor, so the
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`precise extent of the drug-drug interaction was unknown. TEVA1002 ¶¶ 31-33, 37.
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`B.
`
`2009: Corcept initiates a clinical trial to obtain FDA approval to
`market mifepristone for the treatment of Cushing’s syndrome.
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`In 2009, against this backdrop, Corcept initiated the first major clinical trial
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`of mifepristone in patients with Cushing’s syndrome in an effort to obtain FDA
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`approval to market the drug for the treatment of such patients. TEVA1028. The
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`results of this trial, nicknamed SEISMIC (“Study of the Efficacy and Safety of
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`Mifepristone in the Treatment of Endogenous Cushing’s Syndrome”), are
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`disclosed in a 2012 article published in the Journal of Endocrinology and
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`Metabolism. TEVA1029, 2041-2046. SEISMIC was a 24-week, open-label study
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`in which 50 participants were administered one daily dose of mifepristone. Id.,
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`2040. The starting dose was 300 mg/day, and doses could be increased in 300 mg
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`increments up to 1200 mg/day. Id. The results led the authors to conclude that
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`“[m]ifepristone produced significant clinical and metabolic improvement in
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`patients with [Cushing’s syndrome] with an acceptable risk-benefit profile during 6
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`months of treatment.” Id., 2039.
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`C.
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`2012: The FDA approves Korlym to control hyperglycemia
`secondary to hypercortisolism in adult patients with endogenous
`Cushing’s syndrome patients who have type 2 diabetes mellitus or
`glucose intolerance and have failed surgery or are not candidates
`for surgery, but imposes a post-marketing requirement that
`Corcept conduct a drug-drug interaction study with mifepristone
`and ketoconazole.
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`Based on the results of the SEISMIC study, the FDA approved Corcept’s
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`New Drug Application for Korlym® (300 mg mifepristone tablets) in February
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`2012. TEVA1006, 1. The FDA approved Korlym® for a single indication: to
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`“control hyperglycemia secondary to hypercortisolism in adult patients with
`
`endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose
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`intolerance and have failed surgery or are not candidates for surgery.” TEVA1004,
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`1; TEVA1006, 1. The FDA-approved label recommended a 300 mg-per-day
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`starting dose and instructed that the dose could be increased in 300 mg increments
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`to a maximum of 1200 mg-per-day, “based on a clinical assessment of tolerability
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`and degree of improvement in Cushing’s syndrome manifestations.” TEVA1004,
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`3; see also id. (“Careful and gradual titration of Korlym accompanied by
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`monitoring for recognized adverse reactions . . . may reduce the risk of severe
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`adverse reactions.”).
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`The FDA’s approval came with a condition, however. The FDA imposed a
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`post-marketing requirement on Corcept to conduct a “drug-drug interaction clinical
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`trial to determine a quantitative estimate of the change in exposure of mifepristone
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`following co-administration of ketoconazole (a strong CYP3A inhibitor).”
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`TEVA1006, 3. The FDA recognized that mifepristone was likely to be used in
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`conjunction with ketoconazole, since ketoconazole—which is FDA-approved to
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`treat certain fungal infections—had been previously used in patients with
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`Cushing’s syndrome. TEVA1006, 3; TEVA1005, 4/100 (“Since ketoconazole is
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`being used in the management of Cushing’s disease, there is a potential of its
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`concomitant use with mifepristone.”). Indeed, it had been known for years that
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`ketoconazole could treat Cushing’s, and moreover that clinicians might need to use
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`combination therapy involving mifepristone and ketoconazole to treat patients who
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`have the disease. TEVA1030, 326; see also TEVA1031, 663, 668; TEVA1010, 3;
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`TEVA1014, 185; TEVA1011,129; TEVA1021,160; TEVA1032, 1339. But
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`because “[t]he degree of change in exposure of mifepristone when co-administered
`
`with strong CYP3A inhibitors [was] unknown,” the FDA required Corcept to
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`perform the DDI clinical study to “help provide more therapeutic options available
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`to Cushing’s patients and appropriate labeling of mifepristone when co-
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`administered with CYP3A inhibitors.” TEVA1005, 1-2; TEVA1006, 3; see also
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`TEVA1045 (Corcept disclosing in an August 9, 201