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`IN THE 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
`
`Title: CONCOMITANT ADMINISTRATION OF GLUCOCORTICOID
`RECEPTOR MODULATORS AND CYP3A INHIBITORS
`_____________________
`
`DECLARATION OF DR. DAVID J. GREENBLATT, M.D.
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`TEVA1002
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`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
`
`TABLE OF CONTENTS
`
`B. 
`
`I. 
`Introduction ...................................................................................................... 1 
`II.  My background and qualifications .................................................................. 2 
`III. 
`Summary of opinions ....................................................................................... 5 
`IV.  Documents considered in formulating my opinions ........................................ 6 
`V. 
`Person of Ordinary Skill in the Art .................................................................. 8 
`VI.  State of the art before March 1, 2017 .............................................................. 9 
`A. 
`The state of the art with respect to pharmacokinetics and drug-
`drug interactions involving CYP3A inhibitors ..................................... 9 
`The state of the art with respect to the treatment of Cushing’s
`syndrome with mifepristone ................................................................ 13 
`VII.  The ’214 patent specification and claims ...................................................... 16 
`VIII.  The meaning of claim terms .......................................................................... 19 
`IX.  The basis of my obviousness analysis ........................................................... 20 
`X.  Ground 1: Claims 1-13 would have been obvious over the Korlym
`Label and Lee. ............................................................................................... 22 
`A. 
`Claim 1 would have been obvious. ..................................................... 24 
`B. 
`Claim 2 would have been obvious. ..................................................... 28 
`C. 
`Claim 3 would have been obvious. ..................................................... 29 
`D. 
`Claim 4 would have been obvious. ..................................................... 30 
`E. 
`Claim 5 would have been obvious. ..................................................... 30 
`F. 
`Claim 6 would have been obvious. ..................................................... 35 
`G. 
`Claim 7 would have been obvious. ..................................................... 36 
`H. 
`Claim 8 would have been obvious. ..................................................... 37 
`I. 
`Claim 9 would have been obvious. ..................................................... 37 
`J. 
`Claim 10 would have been obvious. ................................................... 38 
`K. 
`Claim 11 would have been obvious. ................................................... 43 
`L. 
`Claim 12 would have been obvious. ................................................... 43 
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
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`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
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`M.  Claim 13 would have been obvious. ................................................... 44 
`XI.  Ground 2: Claims 1-13 would have been obvious over the Korlym
`Label, Lee, and FDA Guidance. .................................................................... 45 
`XII.  No objective evidence supports non-obviousness of the claimed
`methods. ......................................................................................................... 49 
`A. 
`The prior art did not teach away from the claimed invention. ............ 49 
`B. 
`The claimed invention did not produce unexpected results. ............... 51 
`C. 
`There is no other evidence of objective indicia of non-
`obviousness. ........................................................................................ 55 
`XIII.  Conclusion ..................................................................................................... 55 
`Appendix I ................................................................................................................ 57
`Appendix II .............................................................................................................. 82
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`I.
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`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
`I, David J. Greenblatt, M.D., hereby declare as follows:
`
`Introduction
`1.
`
`I am over the age of eighteen (18) and competent to make this
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`declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Teva
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`Pharmaceuticals USA, Inc. for the above-captioned post-grant review (PGR). I am
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`being compensated for my time in connection with this PGR at my standard
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`consulting rate, which is $300 per hour, or $3000/day for work requiring out-of-
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`state travel.
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`3.
`
`I understand that this Declaration accompanies a petition for PGR
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`involving U.S. Patent No. 10,195,214 (“the ’214 patent”) (TEVA1001). I
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`understand that the ’214 patent resulted from U.S. Patent Application No.
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`15/627,359 (“the ’359 application”), which was filed on June 19, 2017. I also
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`understand that the ’214 patent is currently assigned to Corcept Therapeutics, Inc.
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`The ’214 patents states that it is a continuation of provisional application No.
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`62/465,772, which has a filing date of March 1, 2017. I understand that that is the
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`earliest date that Corcept can assert as a priority date. I refer to this date throughout
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`this declaration and have performed my analysis based on this date.
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`4.
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`In preparing this Declaration, I have reviewed the ’214 patent and
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`each of the documents cited in my declaration, in light of general knowledge in the
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
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`art before March 1, 2017. In formulating my opinions, I have relied upon my
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`experience, education, and knowledge in the relevant art. In formulating my
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`opinions, I have also considered the viewpoint of a person of ordinary skill in the
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`art (“POSA”) (i.e., a person of ordinary skill in the field, as defined further below
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`in Section V) prior to March 1, 2017.
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`II. My background and qualifications
`5.
`I am a physician, licensed to practice medicine in the Commonwealth
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`of Massachusetts. I received a B.A. degree in mathematics from Amherst College
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`in 1966, a M.D. from Harvard Medical School in 1970, and I completed
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`postdoctoral fellowship training at Harvard Medical School and Massachusetts
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`General Hospital in 1974.
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`6.
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`I am board-certified by the American Board of Clinical Pharmacology
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`and am one of the charter members of that board. I am currently the Louis Lasagna
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`Endowed Professor in the Department of Immunology (formerly the Department of
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`Pharmacology and Experimental Therapeutics) at Tufts University School of
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`Medicine, and I am a senior faculty member in the Graduate Program in
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`Pharmacology & Experimental Therapeutics at the Sackler School of Graduate
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`Biomedical Sciences at Tufts University. I also hold appointments as Professor of
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`Psychiatry, Medicine, and Anesthesia, Tufts University School of Medicine.
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
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`7.
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`I am the Editor-in-Chief of Clinical Pharmacology in Drug
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`Development and Co-Editor-in-Chief of the Journal of Clinical
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`Psychopharmacology.
`
`8.
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`I am the author of more than 780 original research publications in the
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`area of clinical pharmacology, psychopharmacology, pharmacokinetics, drug
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`metabolism, and drug interactions. I have more than 50 years of research
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`experience in this field, with a focus on the mechanisms and consequences of drug-
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`drug interactions involving the CYP3A group of metabolic enzymes. I have
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`received a number of awards, such as the 2005 Research Achievement Award in
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`Clinical Sciences from the American Association of Pharmaceutical Sciences; an
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`Outstanding Speaker Award from the American Association for Clinical Chemistry
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`in 2013; the Distinguished Faculty Award from Tufts University School of
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`Medicine in 2015; and the 2016 Award in Excellence in Clinical Pharmacology
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`from the Pharmaceutical Research and Manufacturers of America Foundation
`
`(PhRMA).
`
`9.
`
`I have served in other roles in my professional career. For example, I
`
`have been a member of the American Society for Clinical Pharmacology and
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`Therapeutics since the 1970s, and I received the Rawls-Palmer Award from that
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`organization in 1980. I have been a member of the American College of Clinical
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
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`Pharmacology (ACCP) since the 1970s, and I served as President of the ACCP
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`from 1996 to 1998. I have received several awards from that organization: the
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`McKeen-Cattell Award in 1985, the Distinguished Service Award in 2001, and the
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`Distinguished Investigator Award in 2002.
`
`10.
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`I have spent decades on staff at Tufts Medical Center and worked
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`closely with practicing clinicians during that time, providing input and advice on
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`pharmacological issues.
`
`11.
`
`In addition to my educational training and professional and research
`
`experiences described above, I have kept abreast of new developments relating to
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`my fields of expertise by reading scientific literature, conferring with colleagues in
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`the field, attending and presenting at scientific conferences, and presenting at
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`invited lectures. Further information regarding my qualifications and credentials is
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`set forth in my curriculum vitae, provided as TEVA1003.
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`12. Accordingly, I am an expert in clinical pharmacology,
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`pharmacokinetics, drug metabolism, and drug interactions—particularly those
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`involving CYP3A inhibitors—and have been since prior to March 1, 2017. For that
`
`reason, I am qualified to provide an opinion as to what a POSA would have
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`understood, known, or concluded before March 1, 2017.
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
`13.
`
`I understand from my review of the ’214 patent’s prosecution history
`
`(TEVA1035) that Corcept referenced my scholarship on drug-drug interactions
`
`involving CYP3A inhibitors and used that scholarship to argue that the claimed
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`method is entitled to a patent. Recognizing my extensive contributions to this field,
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`Corcept referred to the interaction between a CYP3A inhibitor and a CYP3A
`
`substrate as “the Greenblatt effect.” Corcept’s interpretation of my work, however,
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`is flawed in several respects. The discussion below identifies the correct
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`articulation of the relevant scientific principles and explains the errors in the
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`arguments Corcept advanced during prosecution.
`
`III. Summary of opinions
`14. Claims 1-13 of the ’214 patent are generally directed to methods of
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`treating Cushing’s syndrome in a patient who is receiving 900 to 1200 mg per day
`
`mifepristone by (i) lowering the daily dose of mifepristone to 600 mg and (ii) co-
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`administering a strong CYP3A inhibitor.
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`15.
`
`It is my opinion that all claims of the ’214 patent would have been
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`obvious to a POSA in view of the Korlym Label (TEVA1004) in combination with
`
`Lee (TEVA1005). See infra Section X.
`
`16.
`
`It is also my opinion that all claims of the ’214 patent would have
`
`been obvious to a POSA in view of the Korlym Label in combination with Lee and
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`FDA Guidance (TEVA1041). See infra Section XI. I have also concluded that
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
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`none of the documents I have reviewed provides any objective evidence of non-
`
`obviousness of claims 1-13 of the ’214 patent. See infra Section XII.
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`IV. Documents considered in formulating my opinions
`17.
`In formulating my opinions, I have considered all the references and
`
`documents cited herein, including those listed below.
`
`Teva
`Exhibit #
`1001
`
`1003
`1004
`1005
`
`1006
`
`1007
`
`1015
`
`1022
`
`1023
`
`Description
`
`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)
`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)
`Sitruk-Ware, R. and Spitz, I.M., “Pharmacological properties of
`mifepristone: toxicology and safety in animal and human studies,”
`Contraception 68: 409–420 (2003)
`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)
`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)
`
`
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`
`
`
`
`
`
`1024
`
`1025
`
`1026
`
`1027
`
`1034
`
`1035
`1037
`
`1040
`
`1041
`
`1046
`
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
`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)
`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
`Kaesar, B., et al., “Drug-Drug Interaction Study of Ketoconazole
`and Ritonavir-Boosted Saquinavir,” Antimicrobial Agents and
`Chemotherapy 53(2): 609–614 (2009)
`“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)
`Greenblatt, D.J, et al., “Ketoconazole inhibition of triazolam and
`alprazolam clearance: Differential kinetic and dynamic
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`V.
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
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`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
`1057
`
`1058
`
`1059
`
`consequences,” Clin. Pharmacol. Ther. 64(3):237-247 (1998)
`Greenblatt, D.J. and Koch-Weser, J., “Clinical Pharmacokinetics,”
` NEJM 293:702-705 (1975)
`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)
`
`Person of Ordinary Skill in the Art
`18.
`
`I understand that a POSA is a hypothetical person who is presumed to
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`be aware of all pertinent art, thinks along conventional wisdom in the art, and is a
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`person of ordinary creativity. Typically, a POSA in the field of the ’214 patent
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`would have had an M.D., a Pharm. D., and/or a Ph.D. in pharmacology or a related
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`discipline, with at least four years of experience in treating patients with
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`mifepristone and/or CYP3A inhibitors, or, alternatively, studying drug-drug
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`interactions involving CYP3A inhibitors. A POSA would have had knowledge of
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`the scientific literature and skills in those fields before March 15, 2017. A POSA
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`would have also had knowledge of laboratory techniques and strategies used in
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`investigating drug-drug interactions. Also, a POSA may have worked as part of a
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`multidisciplinary team and drawn upon not only his or her own skills, but also
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`taken advantage of certain specialized skills of others on the team, e.g., to solve a
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`given problem.
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
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`19.
`
`I am at least a person of ordinary skill in the art under this definition,
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`and I would have been at least a POSA in March 2017.
`
`VI. State of the art before March 1, 2017
`20.
`I have been asked to provide a summary of the state of the art as it
`
`pertains to the ’214 patent. In particular, the below presents a summary of the
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`knowledge of the art before March 1, 2017 with regard to (i) pharmacokinetics and
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`drug-drug interactions involving CYP3A inhibitors and (ii) the use of mifepristone
`
`to treat Cushing’s syndrome.
`
`A. The state of the art with respect to pharmacokinetics and drug-
`drug interactions involving CYP3A inhibitors
`21. Pharmacokinetics is the study of drug concentrations in body fluids
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`and how those concentrations change over time in relation to drug dosage and drug
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`elimination, or clearance. TEVA1057, 1.
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`22. Clearance is the process of drug removal from the body. Drug
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`metabolism or biotransformation is one of the principal mechanisms of clearance.
`
`Metabolism is accomplished by enzymes (proteins) which catalyze a molecular
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`change in structure of the drug. The most important group of such enzymes in
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`humans is termed the CYP3A subfamily. These enzymes are present in large
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`quantities in the human liver (termed hepatic CYP3A), and also in the lining of the
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`gastrointestinal tract (termed enteric CYP3A). TEVA1026, 354-355.
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
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`23. For the majority of drugs used in clinical medicine, the effect of the
`
`drug on the body is related to the amount of drug in the circulating blood. The
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`concentration of drug in blood can be termed the exposure. TEVA1059, 2227. The
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`integrated net exposure to the drug over a period of time is often measured as the
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`area under the concentration curve (AUC), which is the numeric area under a plot
`
`of blood or plasma concentration versus time. TEVA1058, 1193. Another standard
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`measurement commonly used in pharmacokinetics is “Cmax,” which refers to the
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`maximum serum concentration that a drug achieves in the body after it has been
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`administered. Id., 1187.
`
`24. The objective of clinical therapeutics is to adjust the drug exposure to
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`a range where the drug has the desired therapeutic effect. If exposure is too high,
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`there is toxicity; if exposure is too low, there is ineffectiveness. TEVA1059, 2227.
`
`25. Exposure—measured either by Cmax or AUC—is directly proportional
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`to the drug dosing rate (for example, in milligrams per day), and inversely
`
`proportional to the drug’s clearance. TEVA1057, 702; TEVA1058, 1184-1188;
`
`TEVA1059, 2227. If an intervening factor, such as a drug interaction, reduces the
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`clearance of a drug, then the exposure will increase, raising a concern about
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`possible drug toxicity. TEVA1058, 1193.
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
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`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
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`26. The relationship between exposure, dosing rate, and clearance is given
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`by the following equation: Exposure = (Dosing rate) / Clearance. TEVA1058, 6;
`
`TEVA1059, 2227.
`
`27. Clearance of the drug mifepristone is determined almost exclusively
`
`by the action of CYP3A. TEVA1022, 758-759. Thus, any co-administered drug
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`that reduces the enzymatic activity of CYP3A will reduce the clearance and
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`increase the exposure to mifepristone, unless the dosing rate is adjusted downward.
`
`28. For example, if a co-administered drug reduces clearance of
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`mifepristone to half of its original value, exposure will increase to twice its original
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`value. If dosing rate is then reduced in half, the exposure will be brought back to
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`the original intended value. The end result is that neither clinical efficacy nor the
`
`possibility of toxicity is changed.
`
`29. The strongest of known inhibitors of the CYP3A enzyme are
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`ketoconazole (used to treat fungus infections) and ritonavir (used in the treatment
`
`of HIV and hepatitis). These two drugs, along with some others, are among those
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`designated by the Food and Drug Administration as strong CYP3A inhibitors.
`
`TEVA1041, 22, Table 5.
`
`30. For a drug such as mifepristone that is metabolized mainly by CYP3A
`
`enzymes, there is high probability that coadministration of a strong CYP3A
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
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`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
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`inhibitor will cause a reduction in clearance and increase in exposure to
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`mifepristone.
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`31. What cannot be predicted or anticipated is the quantitative extent to
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`which clearance and exposure are modified by the inhibitor. The state of the art
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`does not allow us to predict these values a priori, or even based on in vitro studies.
`
`(Or, as I titled my 2014 article on this topic: “In Vitro Prediction of Clinical Drug
`
`Interactions With CYP3A Substrates: We Are Not There Yet.” TEVA1023.) The
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`actual quantitative modifications can only be determined by an actual clinical
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`study, termed a drug-drug interaction (DDI) study.
`
`32. Even for two substrate drugs that are nearly identical in structure and
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`are metabolized mainly by CYP3A enzymes, the effect of the strong inhibitors
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`ketoconazole and ritonavir on clearance and exposure can be very different
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`between the drugs. For some CYP3A substrates, coadministration with a CYP3A
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`inhibitor increases drug concentrations significantly, and so substantial dose
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`adjustments may be required. See, e.g., TEVA1007, 465 (co-administration of
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`ketoconazole and midazolam increased AUC of midazolam concentration five- to
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`16-fold, depending on route of administration); TEVA1026, 367 (co-
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`administration of ketoconazole and triazolam increased triazolam exposure by 13.7
`
`times). For other CYP3A substrates, coadministration with a CYP3A inhibitor
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`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
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`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
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`increases drug concentrations only minimally, meaning substantial dose
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`adjustments are unlikely to be required. See, e.g., TEVA1037, 613
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`(coadministration of ketoconazole and saquinavir increased saquinavir
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`concentrations by only 37%). A 2007 study by Ohno et al. demonstrates the greatly
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`differing effects of ketoconazole on the exposure to 14 different drugs metabolized
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`by CYP3A, based on human DDI studies. TEVA1027.
`
`33. This unpredictability arises from the large number of variables at play.
`
`The extent of a CYP3A inhibitor-CYP3A substrate DDI effect depends on multiple
`
`factors, including (i) whether the substrate is also metabolized by other enzymes;
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`(ii) the route of administration; (iii) the hepatic clearance of the substrate; (iv) the
`
`half-life of the substrate; (v) the extent to which the substrate is metabolized in the
`
`intestine. TEVA1046, 238; TEVA1027, 682-83. Indeed, “even under standardized
`
`in vitro study conditions,” there are significant “variations among [CYP3A]
`
`substrates in the quantitative potency of ketoconazole inhibition.” TEVA1024,
`
`220. The bottom line is that one simply does not know the precise extent or clinical
`
`significance of a specific DDI until the interaction is clinically tested.
`
`B.
`
`The state of the art with respect to the treatment of Cushing’s
`syndrome with mifepristone
`34. Based on my review of the materials listed supra Section IV, I
`
`understand that, by March 2017, it was known that mifepristone could be
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`

`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
`
`administered at doses of 300-1200 mg per day to treat the signs and symptoms of
`
`Cushing’s syndrome. TEVA1004. Specifically, in 2012, the FDA approved
`
`Corcept’s drug Korlym (mifepristone 300 mg tablets) 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.” TEVA1004, 3. The FDA-approved label
`
`recommends a 300-mg-daily starting dose and instructs that “[t]he daily dose of
`
`Korlym may be increased in 300 mg increments. The dose of Korlym may be
`
`increased to a maximum of 1200 mg once daily but should not exceed 20 mg/kg
`
`per day.” TEVA1004, 3. The label further instructs that “[d]ecisions about dose
`
`increases should be based on a clinical assessment of tolerability and degree of
`
`improvement in Cushing’s syndrome manifestations.” TEVA1004, 3.
`
`35. The Korlym Label also states that “Korlym should be used with
`
`extreme caution in patients taking ketoconazole and other strong inhibitors of
`
`CYP3A. . . . The benefit of concomitant use of these agents should be carefully
`
`weighed against the potential risks. Mifepristone should be used in combination
`
`with strong CYP3A inhibitors only when necessary, and in such cases the dose
`
`should be limited to 300 mg per day.” TEVA1004, 6. Elsewhere, the label instructs
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`- 14 -
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`

`

`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
`
`that “[m]edications that inhibit CYP3A could increase plasma mifepristone
`
`concentrations and dose reduction of Korlym may be required.” TEVA1004, 9.
`
`36.
`
`I have reviewed several of the documents that were included in the
`
`FDA Approval Package for Korlym, including the addendum to the Office of
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`Clinical Pharmacology Review Memorandum dated January 20, 2012 (“Lee”)
`
`(TEVA1005) and the FDA’s approval letter for Korlym (“FDA Approval Letter”)
`
`(TEVA1006). These documents disclose that the FDA required Corcept to perform
`
`a DDI study with mifepristone and ketoconazole as a post-marketing requirement.
`
`TEVA1005, 2. According to Lee, “[t]he goal of this study [was] to get a
`
`quantitative estimate of the change in exposure of mifepristone following co-
`
`administration with ketoconazole.” TEVA1005, 2. The results of the study would
`
`“help provide more therapeutic options available to Cushing’s patients and
`
`appropriate labeling of mifepristone when co-administered with CYP3A
`
`inhibitors.” TEVA1005, 2.
`
`37. The FDA’s post-marketing requirement was consistent with
`
`established scientific practice at the time. As explained above, mifepristone is a
`
`CYP3A substrate, so there is a potential for increase in a patient’s exposure to
`
`mifepristone when it is co-administered with a strong CYP3A inhibitor. The FDA
`
`has recommended that, when an investigational new drug is a CYP3A substrate,
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`- 15 -
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`

`

`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
`
`the sponsor should conduct a drug-drug interaction study with an index CYP3A
`
`inhibitor (such as ketoconazole) to determine “whether the interaction is
`
`sufficiently large to necessitate a dosage adjustment of the drug itself or the drugs
`
`with which it might be used, or whether the interaction would require additional
`
`therapeutic monitoring.” TEVA1041, 3, 10. Corcept, however, had not performed
`
`such a study on mifepristone, so the extent of the interaction and its clinical
`
`significance (or lack thereof) was unknown. TEVA1005, 31/100-32/100. And, as
`
`explained above, drug interactions involving CYP3A inhibitors and CYP3A
`
`substrates are not quantifiable in advance, and the only way to determine the
`
`precise extent of the interaction for a given substrate is to perform a clinical study.
`
`38. A POSA would have understood based on these materials that the
`
`FDA had limited the recommended dose of mifepristone to 300 mg when co-
`
`administered with strong CYP3A inhibitors out of an abundance of caution
`
`pending the results of the mifepristone-ketoconazole drug-drug-interaction study.
`
`Indeed, as disclosed in Lee, the FDA explicitly contemplated amending the
`
`labeling to adjust the dosage once the study was completed. TEVA1005, 2.
`
`VII. The ’214 patent specification and claims
`39. The ’214 patent is generally directed to methods of treating Cushing’s
`
`syndrome in a patient by co-administering mifepristone and a strong CYP3A
`
`inhibitor.
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`- 16 -
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`

`

`
`
`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
`40. According to the specification, the patentee made the “surprising[]”
`
`discovery that “concomitant administration of ketoconazole and mifepristone . . .
`
`does not increase the risk of toxicity in the patient, and is believed to be safe for
`
`the patient.” TEVA1001, 13:67-14:3.
`
`41. The specification discloses the results of the mifepristone-
`
`ketoconazole DDI study that the FDA required Corcept to perform (“Nguyen-
`
`Mizne study”). In that study, co-administration of mifepristone and ketoconazole
`
`was found to increase a patient’s mifepristone exposure by approximately one-
`
`third relative to administration of mifepristone alone. TEVA1001, 56:65-60:23.
`
`“[T]he resulting exposure was similar to that of a dose 2 to 3 times greater,” which
`
`was “believed to be due to a lack of dose-proportional kinetics for mifepristone.”
`
`TEVA1001, 59:52-56. The patentee purported to find this result “surprising[],”
`
`stating that a much “large[r] increase[] . . . would have been expected for such
`
`concomitant administration.” TEVA1001, 12:21-25.
`
`42. The ’214 patent has three independent claims. Independent claim 1 is
`
`reproduced below:
`
`1. A method of treating Cushing’s syndrome in a
`patient who is taking an original once-daily dose of 1200
`mg or 900 mg per day of mifepristone, comprising the
`steps of:
`
`
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`- 17 -
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`

`
`
`
`
`
`
`Petition for Post-Grant Review
`U.S. Patent No. 10,195,214
`
`TEVA1002 – Declaration of Dr. David J. Greenblatt, M.D.
`
`reducing the original once-daily dose to an adjusted
`once-daily dose of 600 mg mifepristone,
`administering the adjusted once-daily dose of 600 mg
`mifepristone and a strong CYP3A inhibitor to the
`patient,
`wherein said strong CYP3A inhibitor is selected from
`the group consisting of ketoconazole, itraconazole,
`nefazodone,
`ritonavir,
`nelfmavir,
`indinavir,
`boceprevir, clarithromycin, conivaptan, lopinavir,
`posaconazole, saquinavir, telaprevir, cobicistat,
`troleandomycin,
`tipranivir,
`paritaprevir
`and
`voriconazole.
`
`TEVA1001, 68:2-16.
`
`43.
`
`Independent claim 5 is identical to independent claim 1 with the
`
`exception that the method recited in the preamble of claim 5 is “treating symptoms
`
`associated with elevated cortisol levels,” instead of “treating Cushing’s syndrome,”
`
`as recited in claim 1. TEVA1001, 68:23-38.
`
`44.
`
`Independent claim 10 is identical to independent claim 1 with the
`
`exception that the method recited in the preamble of claim 10 is “controlling
`
`hyperglycemia secondary to hypercortisolism in a patient with endogenous
`
`Cushing’s syndrome,” instead of “treating Cushi