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

`

`Table of Contents
`
`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`
`Page
`
`I. 
`
`II. 
`
`INTRODUCTION ........................................................................................... 1 
`
`BACKGROUND ............................................................................................. 7 
`
`A. 
`
`B. 
`
`Cushing Syndrome Is A Serious Endocrine Disorder ........................... 7 
`
`Korlym® Treats The Symptoms of Cushing’s Syndrome ..................... 7 
`
`C.  Mifepristone, the Active Ingredient in Korlym®, Can Cause
`Serious Side Effects............................................................................... 8 
`
`D.  Mifepristone Is A CYP3A Substrate ................................................... 10 
`
`E. 
`
`Drugs That Are Strong CYP3A Inhibitors Can Dangerously
`Increase CYP3A Substrate Blood Levels When Co-
`Administered ....................................................................................... 11 
`
`F.  Mifepristone Exhibits Complex Pharmacokinetics ............................. 12 
`
`G. 
`
`Prior to the Claimed Inventions, A POSA Would Not Have
`Administered More Than 300 mg of Mifepristone in
`Combination With a Strong CYP3A Inhibitor .................................... 13 
`
`1. 
`
`2. 
`
`3. 
`
`The Prior Art Taught Strong CYP3A Inhibitors Would
`Significantly Increase Mifepristone Exposure .......................... 13 
`
`Due to the Potential for an Unsafe Drug Interaction, the
`Prior Art Warned Against Co-Administration of Strong
`CYP3A Inhibitors With Greater Than 300 mg
`Mifepristone .............................................................................. 14 
`
`The Only Case Report in the Prior Art of the Co-
`Administration of a Strong CYP3A Inhibitor With 600
`mg Mifepristone Disclosed Unacceptably High
`Mifepristone Levels And Serious Adverse Events ................... 15 
`
`4. 
`
`POSAs Heeded The Warnings In The Prior Art ....................... 16 
`
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`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`
`Patent Owner Unexpectedly Discovered That 600 mg of
`Mifepristone Could Be Safely and Effectively Administered in
`Combination With A Strong CYP3A Inhibitor ................................... 17 
`
`H. 
`
`III. 
`
`PERSON OF ORDINARY SKILL IN THE ART ........................................ 20 
`
`IV.  PETITIONER’S ASSERTED REFERENCES ............................................. 22 
`
`A. 
`
`B. 
`
`C. 
`
`The 2012 Korlym Label ...................................................................... 22 
`
`Lee ....................................................................................................... 24 
`
`2006 FDA Guidance ............................................................................ 28 
`
`V. 
`
`PETITIONER HAS FAILED TO PROVE BY A
`PREPONDERANCE OF EVIDENCE THAT THE ’214 PATENT
`CLAIMS WOULD HAVE BEEN OBVIOUS .............................................. 29 
`
`A. 
`
`Petitioner Has Failed to Show That a POSA Would Have Had a
`Reasonable Expectation of Success Based on Ground One or
`Two ...................................................................................................... 29 
`
`1. 
`
`2. 
`
`Petitioner’s Declarant Confirmed that a POSA Would
`Not Have Had a Reasonable Expectation of Success ............... 30 
`
`Instead, a POSA Would Have Affirmatively Expected
`That The Claimed Inventions Would Not Be Successful ......... 34 
`
`(a) 
`
`POSAs Who Treat Cushing’s Syndrome Patients
`Did Not Expect The Claimed Inventions To Work ........ 36 
`
`(b)  Based On Pharmacokinetics Alone, A POSA
`Would Have Expected Clinically Significant
`Interactions Between Mifepristone And Strong
`CYP3A Inhibitors ........................................................... 41 
`
`(i) 
`
`Dr. Greenblatt’s Five Part Test Indicated There
`Would Be A Clinically Significant Interactions
`Between Mifepristone And Strong CYP3A
`Inhibitors .............................................................. 42 
`
`
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`- ii -
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`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`
`(ii)  The Mathematical Test For DDI Indicated There
`Would Be A Clinically Significant Interactions
`Between Mifepristone And Strong CYP3A
`Inhibitors .............................................................. 46 
`
`(iii)  Petitioner Fails To Account For Ketoconazole’s
`Metabolism ........................................................... 48 
`
`(c)  A POSA Would Also Have Expected A
`Pharmacodynamic Interaction Between
`Mifepristone And Certain Strong CYP3A
`Inhibitors, Including Ketoconazole ................................ 49 
`
`(d) 
`
`Petitioner’s Only Evidence To The Contrary Is
`Based On A Misreading Of The Lee Reference ............. 52 
`
`B. 
`
`Routine Optimization Would Not Have Led to The Claimed
`Inventions ............................................................................................ 56 
`
`1. 
`
`2. 
`
`3. 
`
`It Would Not Have Been “Routine” For a POSA To Use
`The Dosing Section of the Korlym Label To Arrive At
`The Claimed Dose ..................................................................... 58 
`
`A POSA Would Not Have Arrived at the Claimed
`Inventions Via a “Routine” DDI Study .................................... 60 
`
`Petitioner’s Routine Optimization Case Law Is
`Inapposite .................................................................................. 65 
`
`C. 
`
`Secondary Considerations Support the Nonobviousness of the
`Claims of the ’214 Patent .................................................................... 69 
`
`1. 
`
`2. 
`
`The Prior Art Teaches Away from the Claimed
`Inventions .................................................................................. 69 
`
`The Claimed Inventions Produced Unexpected Results ........... 72 
`
`VI.  CONCLUSION .............................................................................................. 77 
`
`
`
`
`
`
`
`- iii -
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`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`
`TABLE OF AUTHORITIES
`
`Page
`
`Cases
`Amerigen Pharm. Ltd. v. UCB Pharma GmBH,
`913 F.3d 1076 (Fed. Cir. 2019)............................................................................ 65
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent
`Litig.,
`676 F.3d 1063 (Fed. Cir. 2012)............................................................................ 66
`E.I. Dupont de Nemours & Co. v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018).............................................................................. 65
`Endo Pharm. Inc. v. Actavis LLC,
`922 F.3d 1365 (Fed. Cir. 2019)...................................................................... 65-66
`Grunenthal GMBH v. Alkem Labs. Ltd.,
`919 F.3d 1333 (Fed. Cir. 2019)...................................................................... 68-69
`Hoffmann-La Roche Inc. v. Cobalt Pharm. Inc.,
`No. 07-4539, 2010 WL 4687839 (D.N.J. Nov. 10, 2010) ................................... 34
`Honeywell Int’l Inc. v. Mexichem Amanco Holding S.A.,
`865 F.3d 1348 (Fed. Cir. 2017)...................................................................... 60-61
`Hospira, Inc. v. Genentech, Inc.,
`IPR2017-00804, Paper 83 (PTAB Oct. 3, 2018) .......................................... 57, 62
`InSite Vision Inc. v. Sandoz Inc.,
`No. 11-3080, 2013 WL 5975015 (D.N.J. Oct. 4, 2013) ...................................... 34
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013)...................................................................... 29-30
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016)............................................................................ 29
`Janssen Pharm., Inc. v. Watson Labs., Inc.,
`No. 08-5103, 2012 WL 3990221 (D.N.J. Sept. 11, 2012) ............................. 34-35
`Leo Pharm. Prods. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013)............................................................................ 57
`Luye Pharma v. Alkermes Pharma Ltd.,
` IPR2016-01096, Paper 74 (PTAB Nov. 28, 2017) ............................................. 69
`
`
`
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`

`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`
`Millennium Pharm., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017)............................................................................ 61
`Mylan Pharmaceuticals Inc. v. Biogen MA Inc.,
`IPR2018-01403, Paper 98 (PTAB Feb. 05, 2020) ............................................... 22
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988).............................................................................. 65
`Otsuka Pharm. Co., Ltd. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012)............................................................................ 61
`Par Pharm., Inc., v. Jazz Pharm. Ireland Ltd.,
` IPR2016-00002, Paper 12 (PTAB Apr. 12, 2016) ........................................... 61-62
`Pfizer Inc. v. Sandoz Inc.,
`No. 13-1110, 2016 WL 1611377 (D. Del. Apr. 20, 2016) .................................. 69
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007).................................................................. 6, 67-68
`Sandoz, Inc. v. AbbVie Biotech. Ltd.,
`IPR2017–01823, Paper 16 (PTAB Feb. 9, 2018) ................................................ 34
`In re Stepan Co.,
`868 F.3d 1342 (Fed. Cir. 2017)............................................................................ 57
`Valeant Pharm. Int’l, Inc. v. Mylan Pharm., Inc.,
`No. 15-8180, 2018 WL 2023537 (D.N.J. May 1, 2018) ................................ 66-67
`Vanda Pharm. Inc. v. Roxane Labs,
`203 F. Supp. 3d 412 (D. Del. 2016) ..................................................................... 66
`
`
`Statutory Authorities
`35 U.S.C. § 103 ........................................................................................................ 60
`
`
`
`
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`- v -
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`

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

`PGR2019-00048
`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)
`2024
`Incivek (telaprevir) Full Prescribing Information (October 2013)
`2025 VFEND (voriconazole) Full Prescribing Information (February 2015)
`2026 Victrelis (boceprevir) Full Prescribing Information (January 2017)
`2027 Tybost (cobicistat) Full Prescribing Information (June 2016)
`2028 Vaprisol (conivaptan hydrochloride) Full Prescribing Information (October
`2016)
`2029 Crixivan (indinavir sulfate) Full Prescribing Information (September 2016)
`2030 Kaletra (lopinavir and ritonavir) Full Prescribing Information (November
`2016)
`2031 Viracept (nelfinavir mesylate) Full Prescribing Information (September
`2016)
`
`
`
`- vii -
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`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`
`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)
`2041
`“The Hazards of Seldane,” N.Y. TIMES (January 17, 1997)
`2042 European Medicines Agency, “European Medicines Agency recommends
`suspension of marketing authorisations for oral ketoconazole,” July 26,
`2013
`2043 M. Tran & J. Grillo, “Translation of Drug Interaction Knowledge to
`Actionable Labeling,” Clin. Pharmacol. & Therapeutics, 105(6):1292-95
`(2019)
`2044 M. Fleseriu et al., “Changes in Plasma ACTH Levels and Corticotroph
`Tumor Size in Patients With Cushing’s Disease During Long-term
`Treatment With the Glucocorticoid Receptor Antagonist Mifepristone,” J.
`Clin. Endocrinol. Metab., 99(10):3718-27 (2014)
`“Treatment for Aspergillosis,” Centers for Disease Control and Prevention
`(Jan. 2, 2019), https://www.cdc.gov/fungal/diseases/aspergillosis/
`treatment.html
`“Drug Development and Drug Interactions: Table of Substrates, Inhibitors
`and Inducers,” U.S. Food and Drug Administration (Nov. 14, 2017),
`https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-
`and-drug-interactions-table-substrates-inhibitors-and-inducers
`
`2045
`
`2046
`
`
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`PGR2019-00048
`U.S. Patent No. 10,195,214
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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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`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`
`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)
`
`
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`

`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`I.
`
`INTRODUCTION
`
`The ’214 patent claims methods of treating Cushing’s syndrome and its
`
`clinical manifestations. The claims concern the surprising discovery that up to 600
`
`mg/day of mifepristone can be safely and effectively co-administered with a strong
`
`CYP3A inhibitor to patients with Cushing’s syndrome. Petitioner has failed to
`
`prove by a preponderance of the evidence that any of the claims of the ’214 patent
`
`would have been obvious.
`
`In particular, Petitioner has not shown that a POSA would have had a
`
`reasonable expectation that concomitant administration of 600 mg of mifepristone
`
`and a strong CYP3A inhibitor would be safe and effective or that that the claimed
`
`methods could have been achieved through routine optimization. To the contrary,
`
`Petitioner’s expert admitted at his deposition that he did not “believe that there
`
`would be any expectation” that the claimed methods would be safe and effective.
`
`Ex. 2059 at 161:16-24. Instead, he explained, “there are pretty much an infinite
`
`number of possibilities of what could happen” when co-administering mifepristone
`
`with a strong CYP3A inhibitor. Id. at 165:10-22. Under these circumstances,
`
`without an expectation of success, Petitioner cannot be found to have met its
`
`burden of proving obviousness.
`
`To the contrary, the record reveals that a POSA would have affirmatively
`
`expected that the claimed methods would not be safe and effective. As the Board
`
`
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`1
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`PGR2019-00048
`U.S. Patent No. 10,195,214
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`acknowledged in its Institution Decision, this case turns “in large part” on whether
`
`a POSA would have heeded the repeated instructions in the art not to exceed 300
`
`mg of mifepristone (as Patent Owner asserts) or whether a POSA would have
`
`ignored these instructions in the art (as Petitioner claims). See Institution Decision
`
`at 17. In support of this Response, Patent Owner submits the declarations of three
`
`experts: Laurence Katznelson, M.D., Ty Carroll, M.D., and F. Peter Guengerich,
`
`Ph.D. Dr. Katznelson has treated individuals with Cushing’s syndrome for over 30
`
`years, and he is currently the Medical Director of the Pituitary Center at Stanford
`
`University and the Associate Dean of Graduate Medical Education at the Stanford
`
`School of Medicine. Ex. 2058 at ¶¶ 4-16. Dr. Carroll has been a practicing
`
`endocrinologist for 11 years and currently serves an assistant clinical professor in
`
`the Endocrinology Center and Clinics at the Medical College of Wisconsin. Ex.
`
`2057 at ¶¶ 4-8. Dr. Guengerich is a Professor of Biochemistry at the Vanderbilt
`
`University School of Medicine and has studied human liver cytochrome P450
`
`proteins since 1973. Under his direction, his laboratory developed the technology
`
`used to purify several P450 proteins, including CYP3A4. Ex. 2056 at ¶¶ 2-12.
`
`Drs. Katznelson and Carroll explain that prior to the ’214 patent, the art
`
`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
`
`
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`2
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`PGR2019-00048
`U.S. Patent No. 10,195,214
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`to no more than 300 mg. Ex. 2057 at ¶¶ 11, 58-73; Ex. 2058 at ¶¶ 18, 68-78. Drs.
`
`Katznelson, Carroll, and Guengerich further explain that, based upon known
`
`principles of pharmacokinetics and pharmacodynamics, POSAs would have
`
`expected the combination of strong CYP3A inhibitors and more than 300 mg of
`
`mifepristone to produce a dangerous and clinically significant drug-drug
`
`interaction (“DDI”). Ex. 2056 at ¶¶ 55-62; Ex. 2057 at ¶ 88; Ex. 2058 at ¶ 72.
`
`On the limited record at the institution stage, the Board found that a POSA,
`
`through routine experimentation, would have had a reasonable expectation that 600
`
`mg mifepristone—twice the limit taught in the art—would be safe and effective
`
`based on a combination of three references: Lee, the 2012 Korlym Label, and the
`
`2006 FDA Guidance. Lee recommends contraindicating the co-administration of
`
`mifepristone and strong CYP3A inhibitors. The Korlym Label repeatedly warns
`
`against the dangers of such a combination and teaches that only if medically
`
`necessary should a maximum of 300 mg mifepristone be administered in
`
`combination with strong CYP3A inhibitors. The 2006 FDA Guidance is silent on
`
`mifepristone altogether, but teaches that drug interactions can cause “large changes
`
`in exposure [that] can alter the safety and efficacy profile of a drug … in important
`
`ways.” Ex. 1041 at 6. As discussed in more detail below, the Board’s analysis
`
`cannot stand with a more complete record.
`
`
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`3
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`PGR2019-00048
`U.S. Patent No. 10,195,214
`
`First, the Board reasoned that the “current record, which does not include
`
`testimonial evidence from Patent Owner, tends to support Petitioner’s position that
`
`a POSA would have known that the 300 mg limitation was put on the [Korlym]
`
`label as a precautionary measure … not because there was any evidence that higher
`
`doses would be unsafe.” Institution Decision at 18-19 (quotations omitted); see
`
`also id. at 23 (reasoning that, “[o]n the current record,” certain teachings in the art
`
`“appear to be based on the absence of data.”). The Declarations of Drs. Carroll
`
`and Katznelson demonstrate that not only was there evidence underlying the
`
`warnings in the label, but also that POSAs would have heeded the warnings in the
`
`label and not prescribed greater than 300 mg mifepristone in combination with a
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`strong CYP3A inhibitor prior to March 2017.
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`Second, the Board credited Petitioner’s expert Dr. Greenblatt’s conclusion
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`that “based on the teaching that doses as high as 1200 mg/day can be
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`tolerated . . . ‘it was reasonably likely that 600 mg would be well tolerated and
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`therapeutically effective when coadministered with a strong CYP3A inhibitor.’”
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`Institution Decision at 21 (quoting Ex. 1002 at ¶ 69). Dr. Greenblatt, however, has
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`never prescribed mifepristone, never studied mifepristone, and was not
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`“comfortable” or “prepared” to discuss its main side effects. Ex. 2059 at 155:17-
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`156:5; 91:11-92:7. He is not an endocrinologist, he is not “comfortable”
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`discussing “the particulars of Cushing’s syndrome,” nor has he ever attempted to
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`treat any individual with Cushing’s syndrome. Id. at 155:7-16, 106:12-23. This
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`stands in stark contrast to Drs. Carroll’s and Katznelson’s decades of combined
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`experience treating Cushing’s syndrome. They explain that, prior to the claimed
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`inventions, the art taught POSAs about the dangers of co-administering
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`mifepristone and strong CYP3A inhibitors, and as a result, even considering the
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`1200 mg maximum monotherapy dose, POSAs would not have expected that
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`greater than 300 mg mifepristone could be used safely and effectively in
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`combination with strong CYP3A inhibitors. Ex. 2057 at ¶¶ 44, 91-93; Ex. 2058 at
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`¶¶ 82, 97-99. They also explain that they did not, in fact, prescribe greater than
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`300 mg mifepristone in combination with strong CYP3A inhibitors. Ex. 2057 at
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`¶¶ 58-73; Ex. 2058 at ¶¶ 68-78.
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`Third, the Board held that the “current record, which does not include
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`testimonial evidence from the Patent Owner, tends to support Petitioner’s position
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`that it would have been routine for a POSA to conduct a DDI study to optimize
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`dosages for concomitant administration of mifepristone and ketoconazole.”
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`Institution Decision at 26-27. Petitioner cannot fill the gaps in its obviousness
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`argument by invoking “routine optimization,” however, at least because
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`Petitioner’s expert readily admitted that the drug-drug interaction studies that led to
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`the claimed inventions could have resulted in an “infinite” number of outcomes,
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`none of which could have been predicted in advance. Ex. 2059 at 165:10-22. The
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`Federal Circuit has made clear that this is not obviousness.
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`Fourth, relying on Pfizer v. Apotex, 480 F.3d 1348 (Fed. Cir. 2007), the
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`Board held that “the inability to predict exact appropriate dosing absent
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`experimentation does not, by itself, render the claimed dosage non-obvious.”
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`Institution Decision at 20. The Board continued, “it cannot be the case that any
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`new dosage of co-administered mifepristone is patentable simply because one must
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`test to quantify the extent of a recognized drug-drug interaction….” Id. at 21.
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`Patent Owner does not so argue. Instead, when the prior art unwaveringly teaches
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`that no more than 300 mg of a drug can be administered to patients under certain
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`conditions (and that there was an expectation of dire consequences from exceeding
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`that limit), and a patent applicant discovers, against the uniform teachings of the
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`prior art, a method of safely and effectively administering double the previously
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`taught limit under the same conditions, that discovery is entitled to patent
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`protection.
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`For at least these reasons, and as discussed further herein, the Board should
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`find no challenged claims unpatentable.
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`II. BACKGROUND
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`A. Cushing Syndrome Is A Serious Endocrine Disorder
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`Cushing’s syndrome is an endocrine disorder caused by elevated cortisol
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`levels. Ex 1001 at 1:31-32; see also Ex. 2057 at ¶ 14; Ex. 2058 at ¶ 19. These
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`elevated cortisol levels are often the result of tumors that afflict the pituitary or
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`adrenal glands. Ex. 1030 at Abstract; see also Ex. 2006 at 385-86; Ex. 2057 at ¶
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`14; Ex. 2058 at ¶ 19. The mortality rate in patients with Cushing’s syndrome is
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`high. Ex. 2035 at 510; Ex. 2057 at ¶ 14; Ex. 2058 at ¶ 21. Cushing’s syndrome is
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`considered one of the most difficult endocrine disorders to diagnose and treat. Ex.
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`2012 at 323; Ex. 2057 at ¶¶ 14-15; Ex. 2058 at ¶ 19-21.
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`B. Korlym® Treats The Symptoms of Cushing’s Syndrome
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`In 2012, Patent Owner received FDA approval for its commercial
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`mifepristone product, Korlym®. Ex. 1006; Ex. 2057 at ¶ 16; Ex. 2058 at ¶ 23.
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`Korlym® was approved as an orphan drug to control hyperglycemia in patients
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`with Cushing’s syndrome who are not surgical candidates or have not achieved
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`remission from surgery. See Ex. 1030 at Abstract; Ex. 1004 at 1; Ex. 2057 at ¶ 16;
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`Ex. 2058 at ¶ 23. Korlym® provides “rapid control of the systemic effects of
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`cortisol excess in patients with [Cushing’s syndrome].” Ex. 2011 at 6; Ex. 2057 at
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`¶ 17; Ex. 2058 at ¶ 24.
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`Korlym® controls the effects of excess cortisol by competitively blocking
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`the receptors to which cortisol binds (known as glucocorticoid receptors), “thereby
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`decreasing the physiologic effects of hypercortisolemia.” Ex. 1030 at 323; see also
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`Ex. 2012 at 314; Ex. 2057 at ¶ 17; Ex. 2058 at ¶ 24. Korlym® is the first and only
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`glucocorticoid receptor antagonist approved for the treatment of the manifestations
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`of Cushing’s syndrome. Ex. 2006 at 455.
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`C. Mifepristone, the Active Ingredient in
`Korlym®, Can Cause Serious Side Effects
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`While mifepristone can be extremely beneficial to patients with Cushing’s
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`syndrome, it is also associated with potentially fatal side-effects. Ex. 1004 at 5,
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`20; see also Ex. 1021 at 1007; Ex. 1032 at 1345; Ex. 2057 at ¶¶ 19-21; Ex. 2058 at
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`¶¶ 27-29. The art disclosed, for instance, that mifepristone therapy was associated
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`with several serious conditions, such as adrenal insufficiency and hypokalemia.
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`See, e.g., Ex. 1004 at 1; see also Ex. 1021 at 1007 (teaching that the “two main
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`challenges in the treatment of patients with [Cushing’s syndrome] with
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`mifepristone [are] hypokalemia and adrenal insufficiency”); Ex. 1032 at 1345.
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`“Adrenal insufficiency is a life-threatening disorder” caused by insufficient
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`cortisol levels or activity. See Ex. 2020 at 1; Ex. 2057 at ¶ 20; Ex. 2058 at ¶ 28;
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`see also Ex. 2006 at 458 (describing adrenal insufficiency as an “important adverse
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`event” of mifepristone treatment). Adrenal insufficiency can be extremely difficult
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`to diagnose, as “[a] life-threatening adrenal crisis can be the first presentation of
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`adrenal insufficiency.” See Ex. 2020 at 7; see also Ex. 2057 at ¶ 20. Low blood
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`pressure (hypotension) and low blood sugar (hypoglycemia) are also important
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`indications of adrenal insufficiency. Ex. 2057 at ¶ 20; Ex. 2058 at ¶ 28; Ex. 1004
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`at 5, 20.
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`Hypokalemia is an electrolyte disorder associated with abnormal losses of
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`potassium in the body. Ex. 2021 at Abstract; see also Ex. 2007 at 467 (describing
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`mifepristone-induced hypokalemia as a “pitfall” of mifepristone). Severe
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`hypokalemia “can lead to life-threatening cardiac conduction disturbances and
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`neuromuscular dysfunction.” Ex. 2021 at Abstract; see also Ex. 2057 at ¶ 21; Ex.
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`2058 at ¶ 29.
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`Over-exposure to mifepristone carries higher risks of mifepristone-related
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`side effects. As Petitioner’s own prior art states, it is “very difficult to dose titrate
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`[mifepristone],” and overexposure to mifepristone causes side effects like adrenal
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`insufficiency and hypokalemia. Ex. 1032 at 1345 (emphasis added); Ex. 1014 at
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`188. To that end, the prior art reports higher risks of serious adverse events in
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`patients exposed to higher concentrations of the drug. See, e.g., Ex. 1006 at 3
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`(“increased exposure to mifepristone is associated with serious risks for severe
`
`hypokalemia and adrenal insufficiency”); see also Ex. 2057 at ¶ 86. Drs.
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`Katznelson and Carrol report that this is consistent wi