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
`_______________________
`
`DECLARATION OF LAURENCE KATZNELSON, M.D.
`
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`V.
`VI.
`
`TABLE OF CONTENTS
`INTRODUCTION ...........................................................................................1
`I.
`EXPERIENCE AND QUALIFICATIONS.....................................................2
`II.
`SUMMARY OF OPINIONS...........................................................................4
`III.
`IV. BACKGROUND .............................................................................................5
`A.
`Cushing’s Syndrome .............................................................................5
`B.
`Korlym®.................................................................................................6
`C.
`Drug-Drug Interactions .........................................................................8
`D. My Practices for Treatment of Cushing’s Syndrome..........................10
`LEGAL STANDARDS .................................................................................11
`THE ’214 PATENT CLAIMS WOULD NOT HAVE BEEN OBVIOUS...12
`A.
`The POSA............................................................................................13
`B.
`Dr. Greenblatt’s Cited References ......................................................15
`1.
`The 2012 Korlym® Label ..........................................................15
`2.
`Lee.............................................................................................19
`3.
`FDA Guidance ..........................................................................22
`As Of The Critical Date, A POSA Would Not Have Had A
`Reasonable Expectation That 600 mg Of Mifepristone Could Be
`Safely And Effectively Used With A Strong CYP3A Inhibitor .........23
`1.
`A POSA Would Not Have Used More Than 300 mg/day of
`Mifepristone With A Strong CYP3A Inhibitor.........................24
`(a)
`POSAs Followed The Instructions in the 2012 Korlym®
`Label Because of Safety Concerns.................................25
`(i)
`Pharmacokinetic Drug Interactions......................25
`(ii)
`Pharmacodynamic Drug Interactions...................26
`(iii) Difficulty in Identifying Adrenal Insufficiency...27
`POSAs Followed The Teachings In The Art..................27
`Lee Taught Not To Co-Administer Mifepristone With
`Strong Or Moderate CYP3A Inhibitors..........................29
`Dr. Greenblatt’s Arguments Do Not Provide A Reasonable
`Expectation That 600 mg/day of Mifepristone Could Be Safely
`Administered With A Strong CYP3A Inhibitor .......................30
`
`C.
`
`(b)
`(c)
`
`2.
`
`i
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`(a)
`
`Dr. Greenblatt’s Argument That The Interaction Had
`“Not Been Studied” ........................................................30
`(b) Dr. Greenblatt’s Argument That The Label Permits
`“Doses Up To 1200 mg Per Day” ..................................31
`Dr. Greenblatt’s “Abundance of Caution” Argument....32
`(c)
`(d) Dr. Greenblatt’s Argument That Lee “Explicitly
`Contemplated Amending the Labeling”.........................33
`Dr. Greenblatt’s Argument That “Some Dose” Would Be
`Safe and Effective...........................................................35
`Dr. Greenblatt’s “Routine Optimization” Argument .....38
`(f)
`VII. CONCLUSION..............................................................................................41
`
`(e)
`
`ii
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`I, Laurence Katznelson, hereby declare and state as follows:
`
`I submit this declaration on behalf of Corcept Therapeutics, Inc. (“Corcept”),
`
`the owner of U.S. Patent No. 10,195,214, (“the ’214 patent”) in connection with
`
`the Petition for Post-Grant Review filed by Teva Pharmaceuticals USA, Inc.
`
`(“Teva” or “Petitioner”).
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been asked to respond to certain opinions set forth in the
`
`Declaration of Dr. David J. Greenblatt, M.D. (“Greenblatt Declaration”) regarding
`
`the alleged invalidity of the ’214 patent that was submitted on behalf of Petitioner.
`
`I have also been asked to provide my own understanding of the state of the relevant
`
`art at the time of the invention claimed in the ’214 patent.
`
`2.
`
`I am being compensated for my time at my usual rate of $800 per
`
`hour. My compensation does not depend in any way on the substance of my
`
`testimony or the outcome of this or any other case.
`
`3.
`
`I expressly reserve the right to supplement the opinions I express
`
`herein, as well as the bases for my opinions, in response to additional expert
`
`declarations submitted by Teva, or any additional discovery or information
`
`provided in this matter.
`
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`II.
`
`EXPERIENCE AND QUALIFICATIONS
`
`4.
`
`I am a medical doctor specializing in the pathophysiology and
`
`treatment of pituitary diseases, including Cushing’s syndrome. I am certified by
`
`the American Board of Internal Medicine in the field of Endocrinology, Diabetes
`
`and Metabolism. I have treated individuals with endogenous Cushing’s syndrome
`
`for over 30 years.
`
`5.
`
`I received my undergraduate degree (B.S., Genetics) from the
`
`University of California Berkley in 1981.
`
`6.
`
`I received by medical degree from the University of California Los
`
`Angeles in 1985.
`
`7.
`
`Following medical school, from 1986 to 1989, I completed a
`
`residency program in Internal Medicine at the Hospital of the University of
`
`Pennsylvania.
`
`8.
`
`I then pursued a Fellowship in Endocrinology and Metabolism at
`
`Massachusetts General Hospital. While pursuing my Fellowship, in 1991, I
`
`became Board Certified in Endocrinology, Diabetes and Metabolism. I completed
`
`my Fellowship in 1992.
`
`9.
`
`Between 1992 and 2004, I was an Instructor and then Assistant
`
`Professor of Medicine at Harvard Medical School, with a clinical and research
`
`focus on pituitary disorders.
`
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`10.
`
`Since 2004, I have worked as the Medical Director of the Pituitary
`
`Center at Stanford University. In that capacity, I lead a team that includes experts
`
`from a variety of disciplines, including neurologists, otolaryngologists, and
`
`neuroradiologists. We offer comprehensive, multidisciplinary, and streamlined
`
`care for the evaluation and treatment of pituitary tumors and other neuroendocrine
`
`disorders, including: acromegaly, prolactinomas, Cushing’s syndrome,
`
`nonfunctioning pituitary tumors, craniopharygiomas and disorders of the pituitary
`
`and hypothalamic region that lead to growth hormone deficiency or adrenal,
`
`thyroid, ovarian, or testicular deficiency.
`
`11.
`
`I am also currently the Associate Dean of Graduate Medical
`
`Education at the Stanford School of Medicine. I have held this position since
`
`2014.
`
`12.
`
`From 2005 to 2014, I was the Director of the Endocrinology
`
`Fellowship Training Program at Stanford. In that capacity, I trained young doctors
`
`on how to most effectively and safely treat endocrine disorders, including
`
`Cushing’s syndrome.
`
`13.
`
`In 2015, the American Association of Clinical Endocrinologists
`
`awarded me the H. Jack Baskin, M.D. Endocrine Teaching Award, which is
`
`presented annually to an endocrinologist who has made a profound impact in
`
`teaching and is actively involved in teaching in academic centers.
`
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`14.
`
`In 2017, the Endocrine Society awarded me the Laureate Award for
`
`Educator of the Year. The Endocrine Society’s Laureate Awards “celebrate the
`
`most remarkable endocrinologists in the world, whose transformative research,
`
`mentorship, public service, and translation of science to practice has earned them a
`
`place in endocrine history.”
`
`15. Over the course of my career, I have authored approximately 130
`
`articles that have been published in the peer-reviewed literature, book chapters and
`
`clinical reviews.
`
`16. A copy of my curriculum vitae, including a list of all publications I
`
`have authored, is attached to this declaration as Appendix A. In the past four
`
`years, I have been deposed one or two times in medical malpractice actions. A list
`
`of the materials I have considered or relied on in preparing my opinions is attached
`
`to this declaration as Appendix B.
`
`III.
`
`SUMMARY OF OPINIONS
`
`17.
`
`I have reviewed the ’214 patent, the Greenblatt Declaration, and other
`
`materials cited herein. I have been asked by counsel to use March 1, 2017 as the
`
`critical date for the inventions set forth in the ʼ214 patent claims.
`
`18. Based on my review of Dr. Greenblatt’s declaration and the materials
`
`he relies upon, it is my opinion that Dr. Greenblatt has failed to establish that any
`
`claim of the ’214 patent would have been obvious as of the March 2017 critical
`
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`date. Specifically, a person of ordinary skill in the art (“POSA”) would not have
`
`expected that 600 mg of daily mifepristone could be safely and effectively co-
`
`administered with a strong CYP3A inhibitor to patients with Cushing’s syndrome
`
`as set forth in the claims of the ’214 patent. Instead, at that time the POSA would
`
`have had the opposite expectation – that it would not be safe to administer more
`
`than 300 mg of daily mifepristone in combination with a strong CYP3A inhibitor
`
`to patients with Cushing’s syndrome.
`
`IV. BACKGROUND
`
`A.
`
`Cushing’s Syndrome
`
`19. Cushing’s syndrome is a serious and potentially life-threatening
`
`endocrine disorder caused by elevated cortisol levels (hypercortisolism) resulting
`
`from tumors that most often are located on the pituitary or adrenal glands.
`
`20. Cortisol is a steroid hormone produced by the adrenal glands that is
`
`necessary for many biological activities, including maintenance of cardiovascular
`
`function and the regulation of insulin. Like many hormones, there is a delicate
`
`balance between too much and too little cortisol.
`
`21.
`
`The diagnosis and treatment of Cushing’s syndrome is one of the most
`
`challenging endocrine pathologies. (Ex. 2012 (Fleseriu 2013) at 11.) Cushing’s
`
`syndrome is associated with obesity, diabetes, hypertension, osteoporosis, gonadal
`
`dysfunction, clotting, and neuropsychiatric and neurocognitive disorders. Patients
`
`5
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`with Cushing’s syndrome have a 61% increase in mortality risk. (Ex. 2067
`
`(Clayton) at 572.)
`
`22.
`
`There are currently only two medications approved by the U.S. Food
`
`and Drug Administration (FDA) for treatment of manifestations of Cushing’s
`
`syndrome: Korlym® (mifepristone) and Signifor® (pasireotide).
`
`B.
`
`Korlym®
`
`23. When the FDA approved Korlym® in 2012, it was the first--and it
`
`remains the only--glucocorticoid receptor antagonist approved in the United States
`
`for the treatment of the manifestations of Cushing’s syndrome. Specifically,
`
`Korlym® 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. (Ex. 1004 (Label) at 1.)
`
`24. Mifepristone treats patients with Cushing’s syndrome by blocking
`
`cortisol receptors. (Ex. 1004 (Label) at 3, 12.) Thus, Korlym® decreases the
`
`physiologic effects of excess cortisol without actually lowering cortisol levels.
`
`Indeed, cortisol levels can actually rise during treatment with Korlym®. (Ex. 1004
`
`(Label) at 12.) Because mifepristone does not lower cortisol levels, it is difficult to
`
`dose titrate and measure effectiveness. (Ex. 1032 (Dang) at 1345.)
`
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`25.
`
`The inability to measure cortisol blood levels to assess efficacy makes
`
`many doctors uncomfortable with prescribing Korlym® to patients with Cushing’s
`
`syndrome and increases the potential for adverse events when mifepristone is
`
`administered with other drugs. In the absence of an easily measurable end-point,
`
`clinicians use surrogate markers to assess the efficacy (and safety) of mifepristone.
`
`26. Mifepristone undergoes extensive first-pass metabolism in the liver
`
`(Ex. 2050 (Sarkar) at 113), where it is metabolized almost exclusively by the
`
`CYP3A enzyme. (Ex. 1022 (Jang) at 760.)
`
`27.
`
`There are serious side effects associated with the use of Korlym®
`
`including adrenal insufficiency, uterine or vaginal bleeding, hypokalemia, and QT
`
`prolongation, all of which can be potentially life-threatening. (Ex. 1004 (Label) at
`
`5, 20; see also Ex. 1021 (Castinetti) at 1007; Ex. 1032 (Dang) at 1345.) The
`
`potential for these side effects increases with over-exposure to mifepristone. I
`
`have significant experience managing these side effects in my patients.
`
`28.
`
`Too little cortisol activity can cause adrenal insufficiency. Adrenal
`
`insufficiency is a disorder caused by deficient production or activity of
`
`glucocorticoids, including cortisol, and can be life-threatening. (Ex. 2020
`
`(Charmandari) at 1.) The symptoms of adrenal insufficiency include low blood
`
`pressure (hypotension) and low blood sugar (hypoglycemia). (Ex. 1004 (Label) at
`
`5, 20.) I do not take symptoms of adrenal insufficiency in my patients lightly. I
`
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`closely monitor patients for signs of adrenal insufficiency. In some cases, I have
`
`needed to administer supplemental glucocorticoids to patients with adrenal
`
`insufficiency to ensure that they have sufficient cortisol activity.
`
`29. Hypokalemia is another common side effect of mifepristone therapy.
`
`Severe hypokalemia “can lead to life-threatening cardiac conduction disturbances
`
`and neuromuscular dysfunction.” (Ex. 2021 (Viera) at 1.) By blocking the cortisol
`
`receptor, mifepristone causes the body to make more cortisol. The increased
`
`cortisol can interact with mineralocorticoid receptors in the kidneys and cause the
`
`body to excrete potassium. This causes hypokalemia. Hypokalemia is one of the
`
`most common side effects of mifepristone treatment occurring in 44% of patients.
`
`(Ex. 1004 (Label) at 5.)
`
`C.
`
`Drug-Drug Interactions
`
`30. Concomitant administration of two or more medications imposes a
`
`risk that the drugs will interact with one another in a drug-drug interaction. Drug-
`
`drug interactions can take many forms, including pharmacokinetic interactions and
`
`pharmacodynamic interactions. Both pharmacokinetics and pharmacodynamic
`
`interactions can result in serious adverse events.
`
`31.
`
`Pharmacokinetic drug-drug interactions occur when one drug alters
`
`the blood levels of another drug, as with CYP3A inhibitors and substrates. The
`
`CYP3A enzyme is responsible for the metabolism of many drugs, including
`
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`Korlym®. (Ex. 1004 (Label) at 13.) Several drugs are known to inhibit CYP3A’s
`
`metabolism of CYP3A substrates. Ketoconazole, itraconazole, and clarithromycin
`
`(and others) are considered to be strong CYP3A inhibitors. In my opinion,
`
`unplanned or uncontrolled increases in exposure to a drug can have significant
`
`safety consequences.
`
`32.
`
`Pharmacodynamic drug-drug interactions are synergistic effects of
`
`two or more drugs that are not dependent on a change in blood levels. Specifically,
`
`drugs with different mechanisms of action can independently affect the same
`
`biological pathway. Such effects can be intentional by a treating physician, but can
`
`also be dangerous when unplanned.
`
`33.
`
`POSAs have long known that the co-administration of CYP3A
`
`substrates and strong CYP3A inhibitors can result in serious side effects (including
`
`death). For example, the CYP3A substrate terfenadine, approved in 1985 and
`
`marketed under the name Seldane®, caused potentially fatal heart problems,
`
`including cardiac arrhythmias due to QT prolongation, when given in combination
`
`with the CYP3A inhibitors ketoconazole and erythromycin. The combination of
`
`terfenadine and strong CYP3A inhibitors has been blamed for a number of deaths.
`
`9
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`D. My Practices for Treatment of Cushing’s Syndrome
`
`34.
`
`Including my residency and fellowship, I have treated individuals with
`
`endogenous Cushing’s syndrome for over 30 years. I would estimate that I have
`
`treated at least 300 individuals with Cushing’s syndrome.
`
`35. Different Cushing’s syndrome patients require different treatment
`
`regimens based on their individual circumstances. The first-line treatment for
`
`endogenous Cushing’s syndrome is surgery to attempt to remove the tumor that is
`
`causing the disorder. If removal of the tumor is not an option or is not entirely
`
`successful, other treatments are necessary, including pharmacotherapy.
`
`36.
`
`I have treated patients with Cushing’s syndrome with a number of
`
`different medications including ketoconazole, mitotane, metyrapone, pasireotide,
`
`etomidate, and mifepristone. I determine the treatment regimen based on the
`
`individual circumstances of each patient. Every patient is unique, and I must take
`
`the unique circumstances of my patients into account because every patient is
`
`different and every drug carries its own set of risks and benefits.
`
`37.
`
`Treatment of Cushing’s syndrome is further complicated because it is
`
`also associated with many other comorbidities such as cardiovascular disease,
`
`depression, diabetes, hypertension, infection, myopathy, obesity, osteoporosis, and
`
`sepsis. I deeply consider which other medications my patients are taking for other
`
`conditions when deciding which medication(s) to prescribe for their Cushing’s
`
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`syndrome. Given the high potential for interaction, it is the prescriber’s
`
`responsibility to be knowledgeable about both known and potential drug-drug
`
`interactions, and to adjust his or her prescribing practices accordingly.
`
`V.
`
`LEGAL STANDARDS
`
`38.
`
`I am not an attorney and offer no opinion on the law. This section
`
`outlines my understanding of the relevant law and comes from explanations
`
`received from counsel. I have applied this understanding in my analysis.
`
`39.
`
`I understand that a patent claim is invalid if it is obvious in view of
`
`the prior art. I further understand that the perspective of a POSA at the time the
`
`invention was made is used to determine whether a patent is obvious. In this case,
`
`I have been asked to use March 1, 2017 as the critical date. In other words, in
`
`reaching my opinions, I put myself back in time to before the critical date in assess
`
`how a POSA would have understood the relevant art.
`
`40.
`
`To analyze obviousness in light of the prior art, I understand that it is
`
`important to understand the scope of the claims, the level of skill in the relevant
`
`art, the scope and content of the prior art, the differences between the prior art and
`
`the claimed invention, and any objective indicia of non-obviousness (also called
`
`secondary considerations of non-obviousness).
`
`41. Counsel has informed me that a patent claim is obvious over multiple,
`
`combined references only if the prior art as a whole taught or suggested the
`
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`invention, if there was a motivation or reason to combine the teachings of the prior
`
`art references to achieve the claimed invention, and if a POSA would have had a
`
`reasonable expectation of success in doing so.
`
`42.
`
`I also understand that one must avoid the use of hindsight in
`
`determining whether an invention would have been obvious because the
`
`obviousness of an invention is evaluated from the perspective of a POSA at the
`
`time the invention was conceived. In other words, it is improper to use the
`
`invention itself as a blueprint to assemble the prior art into the claimed inventions.
`
`To assess the understanding of the POSA, I understand that I must look at the
`
`relevant art as it existed before the critical date and without the benefit of the ’214
`
`patent.
`
`VI. THE ’214 PATENT CLAIMS WOULD NOT HAVE BEEN OBVIOUS
`
`43.
`
`In his arguments that the ’214 patent claims would have been obvious
`
`before the March 2017 critical date, Dr. Greenblatt relies on three primary
`
`references: the Korlym® label, Lee, and an FDA Guidance. The Korlym® label is
`
`the FDA-approved prescribing information for Korlym® from 2012. Lee is a
`
`compilation of reviews of the Korlym® NDA by Jee Eun Lee, Ph.D and
`
`Jayabharathi Vaidyanathan, Ph.D. at the FDA’s Office of Clinical Pharmacology
`
`and Biopharmaceutics. The FDA Guidance is a September 2006 “draft guidance”
`
`document distributed by the FDA “for comment purposes only.”
`
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`44. Dr. Greenblatt provides the opinion that all of the claims of the ’214
`
`patent would have been obvious to a POSA in view of (1) the Korlym® Label and
`
`Lee and (2) the Korlym® Label in combination with Lee and the FDA Guidance. I
`
`disagree. Dr. Greenblatt’s opinions are not based on a proper understanding of
`
`how doctors were prescribing mifepristone at the critical date or of the safety
`
`concerns posed by potential co-administration of mifepristone and a strong CYP3A
`
`inhibitor.
`
`A.
`
`45.
`
`The POSA
`
`I understand from counsel that the POSA is based on the expertise
`
`relevant to the patented inventions. I further understand from counsel that the
`
`POSA does not need to be an actual person and that it can be a team of
`
`hypothetical persons with different experiences or expertise. I have been asked by
`
`counsel to comment on Dr. Greenblatt’s definition of the POSA for the ’214 patent
`
`claims.
`
`46. Dr. Greenblatt opines that “a POSA in the field of the ’214 patent
`
`would have had an M.D., a Pharm. D., and/or a Ph.D. in pharmacology or a related
`
`discipline, with at least four years of experience in treating patients with
`
`mifepristone and/or CYP3A inhibitors, or, alternatively, studying drug-drug
`
`interactions involving CYP3A inhibitors.” (Ex. 1002 (Greenblatt Decl.) at ¶ 18.)
`
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`47.
`
`In my opinion, the POSA needs to have experience treating Cushing’s
`
`syndrome patients with mifepristone, or such a person needs to be part of the team
`
`that makes up the POSA. A person without experience prescribing mifepristone
`
`would not have understood the serious concerns present in the art among
`
`mifepristone prescribers at the time of the invention. Dr. Greenblatt’s alternative
`
`experience – generally treating patients with CYP3A inhibitors or studying drug-
`
`drug interactions involving CYP3A inhibitors – is not sufficient by itself.
`
`48.
`
`The ’214 patent claims are methods of treating Cushing’s syndrome
`
`and its symptoms or comorbidities with mifepristone. (Ex. 1001 (’214 patent) at
`
`68:2-69:2.) To understand the expectations and motivations of the individuals
`
`treating Cushing’s syndrome with mifepristone – i.e., endocrinologists – the POSA
`
`must have experience actually treating Cushing’s syndrome with mifepristone.
`
`49.
`
`For example, as explained above, treatment of Cushing’s syndrome
`
`with mifepristone is associated with serious side effects, such as adrenal
`
`insufficiency. Because mifepristone does not lower cortisol levels, prescribers rely
`
`on other indicators of efficacy in Cushing’s syndrome, such as lower blood
`
`pressure or blood sugar. These indicators of efficacy, however, often overlap with
`
`the indicators of adrenal insufficiency. The inability to use of serum cortisol levels
`
`as a therapeutic target and the challenges of differentiating clinical therapeutic
`
`benefit from adrenal insufficiency makes safe administration of mifepristone
`
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`difficult even for endocrinologists, let alone people without that training and
`
`experience.
`
`50.
`
`It is my opinion that a POSA for purposes of the ’214 patent would
`
`have included an M.D. or related medical professional with at least four years of
`
`experience treating patients with Cushing’s syndrome with mifepristone as at least
`
`a member of the team that makes up the POSA.
`
`51.
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`I am a POSA under Dr. Greenblatt’s as well as my own definition. I
`
`have been asked to analyze the claims from the perspective of Dr. Greenblatt’s
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`POSA.
`
`B.
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`Dr. Greenblatt’s Cited References
`
`1.
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`The 2012 Korlym® Label
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`52.
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`The Korlym® label is the FDA-approved prescribing information for
`
`Korlym®. I understand that the specific Korlym® label that Dr. Greenblatt relies
`
`upon is the original label from the 2012 approval of Korlym®.
`
`53.
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`The Korlym® label provides instructions to prescribers on how to
`
`safely and effectively prescribe Korlym®, including the approved indication, dose,
`
`and dosing regimen. The Korlym® label also discloses contraindications and
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`provides warnings about potential side effects and dangers resulting from co-
`
`administration with other drugs.
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`54.
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`The Korlym® label discloses that “[t]he recommended starting dose is
`
`300 mg orally once daily.” (Ex. 1004 (Label) at 3.) In addition, the Korlym® label
`
`discloses that “[t]he daily dose of Korlym may be increased in 300 mg increments”
`
`and “may be increased to a maximum of 1200 mg once daily but should not exceed
`
`20 mg/kg per day.” Id. A POSA would understand that these are the default
`
`instructions for the administration of Korlym® – in other words, these are the
`
`instructions for when none of the exceptions apply (e.g., administering without
`
`anything that could cause a pharmacokinetic or pharmacodynamic interaction).
`
`55.
`
`The Korlym® label discloses that—unless medically necessary1—
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`Korlym® should not be given in combination with a strong CYP3A inhibitor:
`
`
`1 In March 2017, a POSA would have understood the term “necessary” in
`the Korlym® label to mean medically necessary, i.e. that the patient had no other
`treatment options.
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`(Ex. 1004 (Label) at 1 (highlighted).) If medically necessary, the Korlym® label
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`instructs prescribers not to administer more than 300 mg of mifepristone per day
`
`with a strong CYP3A inhibitor such as ketoconazole. Id.
`
`56.
`
`The Korlym® label also explains that “[k]etoconazole and other strong
`
`inhibitors of CYP3A . . . may increase exposure to mifepristone significantly,” and,
`
`therefore, “extreme caution should be used when these drugs are prescribed in
`
`combination with Korlym. The benefit of concomitant use of these agents should
`
`be carefully weighed against the potential risks. The dose of Korlym should be
`
`limited to 300 mg and used only when necessary.” Id. at 9.
`
`57.
`
`The label also instructs that “Caution should be used when Korlym is
`
`used with strong CYP3A inhibitors. Limit mifepristone dose to 300 mg per day
`
`when used with strong CYP3A inhibitors”:
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`(Ex. 1004 (Label) at 1 (highlighted).)
`
`58.
`
`Finally, under the “Warnings and Precautions” header, the label states
`
`that “Korlym should be used with extreme caution in patients taking ketoconazole
`
`and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir,
`
`nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, boceprevir,
`
`clarithromycin, conivaptan, lopinavir, nefazodone, posaconazole, ritonavir,
`
`saquinavir, telaprevir, telithromycin, or voriconazole, as these could substantially
`
`increase the concentration of mifepristone in the blood. 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”:
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`(Id. at 6.)
`
`2.
`
`Lee
`
`59.
`
`Lee is a part of the Korlym® NDA approval package and is a
`
`compilation of reviews of the Korlym® NDA. Lee includes the 6/14/2011
`
`Biopharmaceutics Filing Review (pages 116-119); the 6/17/2011 Clinical
`
`Pharmacology New Drug Application Filing and Review Form (pages 108-115);
`
`the 1/13/2012 Clinical Pharmacology Review of the Korlym® NDA (pages 7-107);
`
`the 1/20/2012 Addendum to the 1/13/2012 Clinical Pharmacology Review of the
`
`Korlym® NDA (pages 4-6); and the 1/23/2013 Addendum to the 1/13/2012
`
`Clinical Pharmacology Review of the Korlym® NDA (pages 2-3). The Clinical
`
`Pharmacology Review of the Korlym® NDA was conducted by Jee Eun Lee, Ph.D.
`
`(Reviewer) and Jayabharathi Vaidyanathan, Ph.D. (Team Leader (Acting)). (Ex.
`
`1005 (Lee).)
`
`60.
`
`Lee states “there is a high potential of [ketoconazole’s] concomitant
`
`use with mifepristone” and “[t]he degree of change in exposure of mifepristone
`
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`when co-administered with strong CYP3A inhibitors is unknown.” (Ex. 1005
`
`(Lee) at 4.)
`
`61.
`
`In addition, Lee discloses that “increase in the exposure of
`
`mifepristone and/or its metabolites are expected with concomitant use of moderate
`
`and strong CYP3A4 inhibitors.” (Id. at 37 (emphasis added).) Thus, the “[u]se of
`
`strong CYP3A4 inhibitors [was] proposed to be contraindicated by the sponsor.”
`
`(Id.) Lee discloses that the Office of Clinical Pharmacology agreed with the
`
`sponsor’s proposal to contraindicate the co-administration of mifepristone and
`
`strong CYP3A inhibitors and recommended an even more conservative approach,
`
`avoiding the concomitant administration of moderate CYP3A4 inhibitors:
`
`(Id. at 37-38 (highlighted).)
`
`62.
`
`The report of the Cross Discipline Team Leader confirms the
`
`recommendation of the Clinical Pharmacology Review, stating that “based on the
`
`known metabolism of mifepristone,” the clinical pharmacology reviewer
`
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`recommended that “concomitant use of strong CYP3A inhibitors is
`
`contraindicated” and “use of moderate inhibitors of CYP3A should be avoided”:
`
`(Ex. 2055 (Roman) at 8 (highlighted).) These recommendations directly contradict
`
`Dr. Greenblatt’s opinion that a POSA would have reasonably expected that 600 mg
`
`of mifepristone per day could be safely co-administered with a strong CYP3A
`
`inhibitor.
`
`63.
`
`In conjunction with the recommendation to contraindicate co-
`
`administration with strong CYP3A inhibitors and avoid co-administration with
`
`moderate CYP3A inhibitors, Lee also recommended that the Korlym® NDA
`
`sponsor perform a drug-drug interaction study with ketoconazole as a Post
`
`Marketing Requirement (PMR). (Ex. 1005 (Lee) at 5.) Lee stated that “[b]ased on
`
`the results of this study, the effect moderate CYP3A inhibitors on mifepristone
`
`pharmacokinetics may need to be addressed” (id.), thereby acknowledging that a
`
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`drug-drug interaction study with ketoconazole may not permit co-administration of
`
`any dose of mifepriston