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 TY CARROLL, M.D.
`
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`V.
`VI.
`
`TABLE OF CONTENTS
`INTRODUCTION ...........................................................................................1
`I.
`EXPERIENCE AND QUALIFICATIONS.....................................................2
`II.
`SUMMARY OF OPINIONS...........................................................................3
`III.
`IV. BACKGROUND .............................................................................................4
`A.
`Cushing’s syndrome..............................................................................4
`B.
`Korlym®.................................................................................................5
`C.
`Drug-Drug Interactions .........................................................................7
`D. My Practices for Treatment of Cushing’s Syndrome............................9
`LEGAL STANDARDS .................................................................................10
`THE CLAIMS OF THE ’214 PATENT WOULD NOT HAVE BEEN
`OBVIOUS......................................................................................................12
`A.
`The POSA............................................................................................12
`B.
`Dr. Greenblatt’s Cited References ......................................................14
`1.
`The Korlym® Label...................................................................14
`2.
`Lee.............................................................................................18
`3.
`FDA Guidance ..........................................................................21
`A POSA Would Not Have Reasonably Expected To Be Able To
`Safely And Effectively Administer A Daily Dose Of 600 mg Of
`Mifepristone In Combination With A Strong CYP3A Inhibitor ........22
`1.
`A POSA Would Not Have Prescribed More Than 300 mg
`Mifepristone In Combination With A Strong CYP3A Inhibitor
`...................................................................................................23
`I Disagree With Dr. Greenblatt’s Opinions Regarding How A
`POSA Would Have Understood The Korlym Label And Lee,
`With Or Without The FDA Guidance.......................................31
`VII. CONCLUSION..............................................................................................42
`
`C.
`
`2.
`
`i
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`I, Ty Carroll, 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.
`
`In this report, I have been asked to respond to certain opinions 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,
`
`as well as 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 $500 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 expressed
`
`herein, as well as the bases for my opinions, in response to additional expert
`
`declarations submitted by Teva, or any additional discovery or other information
`
`provided in this matter.
`
`1
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`II.
`
`EXPERIENCE AND QUALIFICATIONS
`
`4.
`
`I have been a practicing endocrinologist for over 11 years. As a
`
`practicing endocrinologist, I spend the vast majority of my time seeing patients,
`
`including individuals with Cushing’s syndrome. I have treated patients with
`
`Cushing’s syndrome with mifepristone for at least the last four years.
`
`5.
`
`I am also an assistant clinical professor in the Endocrinology Center
`
`and Clinics at the Medical College of Wisconsin. I am currently teaching the
`
`second year medical student adrenal disease physiology course.
`
`6.
`
`I received a B.S. in Biochemistry from the University of Wisconsin in
`
`1998. I then obtained my M.D. from the Medical College of Wisconsin in 2002.
`
`Following that, I did my residency in Internal Medicine at the Medical College of
`
`Wisconsin and Affiliated Hospitals from 2002-2005. I then completed a
`
`fellowship in Endocrinology, Metabolism, and Clinical Nutrition at the Medical
`
`College of Wisconsin and Affiliated Hospitals from 2006-2008. I am Board
`
`certified by the American Board of Internal Medicine in Endocrinology.
`
`7.
`
`During my career I have received numerous honors and awards,
`
`including M-Magazine Top Doctors-Endocrinology (2012-2020), “Best Doctors”
`
`in America (2013-2018), and the Medical Student Teacher Award (2009).
`
`8.
`
`I have served as a reviewer for a number of peer reviewed journals,
`
`including European Journal of Endocrinology, Postgraduate Medical Journal,
`
`2
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`Clinical Endocrinology, Endocrine Practice, Journal of the American Board of
`
`Family Medicine, Endocrinology, and Journal of Clinical Endocrinology and
`
`Metabolism.
`
`9.
`
`A copy of my curriculum vitae, including a list of publications I have
`
`authored, is attached to this declaration as Appendix A.
`
`III.
`
`SUMMARY OF OPINIONS
`
`10.
`
`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
`
`date of invention for the ʼ214 patent claims. It is my opinion that Dr. Greenblatt
`
`has failed to establish that any claim of the ’214 patent would have been obvious
`
`over the cited references and/or general knowledge in the field, at the time of the
`
`’214 patent’s invention.
`
`11.
`
`Specifically, it is my opinion that as of March 2017, a person of
`
`ordinary skill in the art (“POSA”) would not have had a reasonable expectation of
`
`being able to successfully perform the methods claimed in the ’214 patent. A
`
`POSA would not have reasonably expected that 600 mg of mifepristone daily
`
`could be co-administered with a strong CYP3A inhibitor safely and effectively to
`
`patients with Cushing’s syndrome. Instead, at that time the POSA would have
`
`expected that it would not be safe to administer more than 300 mg of daily
`
`3
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`mifepristone in combination with a strong CYP3A inhibitor to patients with
`
`Cushing’s syndrome.
`
`12. An identification of the material I have considered or relied on is set
`
`forth in Appendix B thereto.
`
`IV. BACKGROUND
`
`A.
`
`Cushing’s syndrome
`
`13. Cortisol is a hormone that exists in all people. It is essential 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.
`
`14. Cushing’s syndrome is a serious and potentially life-threatening
`
`endocrine disorder caused by elevated cortisol levels (hypercortisolism). These
`
`elevated cortisol levels are the result of cortisol-producing tumors that most often
`
`arise from the pituitary or adrenal glands. It is well recognized that Cushing’s
`
`syndrome is a complex condition with serious sequelae. Ex. 1029 at 8. Due to its
`
`complexity, Cushing’s syndrome is one of the most challenging endocrine
`
`pathologies in terms of both diagnosis and treatment. Ex. 2012 at 11. Cushing’s
`
`syndrome is associated with serious clinical manifestations including obesity,
`
`diabetes, hypertension, osteoporosis, gonadal dysfunction, and neuropsychiatric
`
`and neurocognitive disorders. If inadequately treated, patients with Cushing’s
`
`4
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`syndrome experience 5-fold higher mortality rates than the general population. Ex.
`
`2035 at 510.
`
`15.
`
`The medical therapy options for patients with Cushing’s syndrome are
`
`limited. To date there are only two medications approved by the U.S. Food and
`
`Drug Administration (FDA) for treatment of manifestations of Cushing’s
`
`syndrome: mifepristone and pasireotide.
`
`B.
`
`Korlym®
`
`16. Mifepristone was approved by the FDA for treatment of patients with
`
`Cushing’s syndrome under the name Korlym® in February 2012.1 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.
`
`17. Mifepristone works in Cushing’s syndrome as a competitive inhibitor
`
`of cortisol, blocking (or “antagonizing”) cortisol’s action at its receptors (known as
`
`“glucocorticoid receptors”). Ex. 1004 at 3, 12. Thus, without actually lowering
`
`cortisol levels, Korlym® decreases the physiologic effects of excess cortisol.2
`
`Because mifepristone does not lower cortisol levels, however, it is difficult to dose
`
`
`1 Mifepristone was previously approved by the FDA as an abortifacient in
`
`2000.
`
`2 Cortisol levels can actually rise during treatment with Korlym. Ex. 1004
`
`at 12.
`
`5
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`titrate and measure effectiveness. Ex. 1032 at 1345. As far as I am aware,
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`Korlym® is the only glucocorticoid receptor antagonist approved in the United
`
`States for the treatment of the manifestations of Cushing’s syndrome.
`
`18. Mifepristone undergoes extensive first-pass metabolism. Ex. 2050 at
`
`113. Mifepristone is metabolized almost exclusively by the CYP3A enzyme. Ex.
`
`1022 at 760. Mifepristone is metabolized by CYP3A into three active
`
`metabolites: a monomethylated, a didemethylated, and a monohydroxylated
`
`metabolite. See Ex. 1004 at 13. Like mifepristone, the three active metabolites
`
`have greater affinity for the glucocorticoid receptor than cortisol itself. Ex. 1004 at
`
`12. “[T]he combined pool of mifepristone—plus its metabolites—seems to be
`
`responsible for the biological actions of mifepristone.” Ex. 1017 at Abstract.
`
`19.
`
`Like any drug, Korlym® has the potential to cause side effects. The
`
`most serious side effects associated with Korlym® include adrenal insufficiency
`
`and hypokalemia, both of which can be potentially life-threatening. Ex. 1004 at 5,
`
`20; see also Ex. 1021 at 1007; Ex. 1032 at 1345. The potential for these side
`
`effects increases in instances of over-exposure to mifepristone. I have significant
`
`experience managing both adrenal insufficiency and hypokalemia in my patients.
`
`20. While too much cortisol causes Cushing’s syndrome, too little cortisol
`
`activity can cause adrenal insufficiency. Adrenal insufficiency is a life-threatening
`
`disorder caused by deficient production or activity of glucocorticoids, including
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`cortisol. See Ex. 2020 at 1. Symptoms of adrenal insufficiency include low blood
`
`pressure (hypotension) and low blood sugar (hypoglycemia). Ex. 1004 at 5, 20.
`
`As adrenal insufficiency is potentially life-threatening, the symptoms of possible
`
`adrenal insufficiency need to be investigated promptly. If there is a strong
`
`suspicion of adrenal insufficiency, Korlym® therapy should be suspended, and if
`
`necessary, steroid therapy should be administered without delay. Ex. 1004 at 5.
`
`21. Hypokalemia is a disorder associated with insufficient levels of
`
`potassium. Severe hypokalemia “can lead to life-threatening cardiac conduction
`
`disturbances and neuromuscular dysfunction.” Ex. 2021 at 1. Due to the
`
`mechanism of action of Korlym®, cortisol levels may increase leading to increased
`
`potassium wasting by the kidneys. The largest study of Korlym® showed that
`
`hypokalemia was one of the most common side effects occurring in 44% of
`
`patients. Ex. 1004 at 5.
`
`C.
`
`Drug-Drug Interactions
`
`22. When two or more medications are administered concomitantly, there
`
`is a risk that the drugs will interact with one another. Drug-drug interactions
`
`(“DDI”) can take many forms, including pharmacokinetic interactions and
`
`pharmacodynamic interactions. Both pharmacokinetics and pharmacodynamic
`
`interactions can result in serious adverse events.
`
`7
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`23.
`
`Pharmacokinetic DDIs refer to one drug altering the blood levels of
`
`another drug. For example, pharmacokinetic DDIs occur between CYP3A
`
`inhibitors and substrates. CYP3A is an enzyme responsible for the metabolism of
`
`a significant number of drugs, including Korlym®. Several drugs have been found
`
`to inhibit the CYP3A enzyme’s ability to metabolize CYP3A substrates. In
`
`particular, the FDA has identified ketoconazole, itraconazole, and clarithromycin,
`
`among others, as strong CYP3A inhibitors because they increase the AUC of
`
`sensitive CYP3A substrates by more than 5-fold. See Ex. 2046at 8-9. Unplanned
`
`increases in exposure to a drug can have significant safety consequences.
`
`24.
`
`Pharmacodynamic DDIs, on the other hand, refer to the effects of one
`
`drug altering the effects of the second drug without altering pharmacokinetics. For
`
`example, two drugs with different mechanisms of action can independently affect
`
`the same biological pathway and have synergistic effects. Such effects can be
`
`beneficial when intended by a treating physician, but can also be dangerous when
`
`unplanned.
`
`25.
`
`POSAs have long been aware that DDIs can result in serious side
`
`effects, including death. For example, the CYP3A substrate terfenadine, which
`
`was approved by the FDA in 1985 and marketed under the name Seldane, was
`
`found to cause potentially fatal heart problems, including cardiac arrhythmias due
`
`to QT prolongation, when given in combination with the CYP3A inhibitors
`
`8
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`ketoconazole and erythromycin. The combination of terfenadine and strong
`
`CYP3A inhibitors has been blamed for hundreds of deaths. Similarly, even a
`
`substance as seemingly benign as grapefruit juice has been found to be a CYP3A
`
`inhibitor and can cause serious adverse effects when co-administered with certain
`
`CYP3A substrates. Ex. 2064.
`
`D. My Practices for Treatment of Cushing’s Syndrome
`
`26.
`
`I have treated individuals with endogenous Cushing’s syndrome for
`
`over 11 years. I would estimate that during my 11 years of practice, I have treated
`
`at least 75 individuals with Cushing’s syndrome.
`
`27.
`
`I do not have a set treatment regimen that I use with every patient.
`
`Rather, I make treatment determinations based upon both the current state of the
`
`art and the circumstances of each individual patient. The first-line treatment for
`
`endogenous Cushing’s syndrome is surgery to attempt to remove the causative
`
`tumor. Surgery, however, is not always successful and is not an option in all
`
`patients, either because the tumor is not operable or because the patient is too ill
`
`for surgery. In patients who have failed surgery or for whom surgery is not an
`
`option, treatments other than surgery are necessary, including pharmacotherapy.
`
`28. Over the years, I have prescribed a number of different medications to
`
`individuals with Cushing’s syndrome including ketoconazole, mitotane,
`
`metyrapone, pasireotide, etomidate, and mifepristone (Korlym®). I determine
`
`9
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`which medication—or combination of medications—to use based upon my
`
`knowledge of available drugs and the individual circumstances of each patient.
`
`Every patient is unique, and I must take the unique circumstances of my patients
`
`into account because every drug carries its own set of risks and benefits. Those
`
`risks and benefits will be different depending upon the individual patient.
`
`29.
`
`The medications that my patients are taking for other conditions also
`
`impact my thought process when deciding which medication(s) to use to treat their
`
`Cushing’s syndrome. It is rare to encounter a patient whose only medical
`
`condition is endogenous Cushing’s syndrome. Unfortunately, individuals with
`
`Cushing’s syndrome often present with multiple comorbidities. The comorbidities
`
`that I most often see in my patients with Cushing’s syndrome include: depression,
`
`cardiovascular disease, hypertension, insulin resistance, hyperglycemia (diabetes),
`
`obesity, and infectious diseases. The patients I see are often taking multiple
`
`medications to treat one or more of these common comorbid conditions. Because
`
`drugs have the potential to interact with one another if taken concomitantly, it is
`
`the responsibility of any prescriber to be knowledgeable about both known and
`
`potential DDIs and to adjust their prescribing practices if necessary.
`
`V.
`
`LEGAL STANDARDS
`
`30.
`
`I am not an attorney and, consequently, I offer no opinion on the law
`
`itself. My understanding of the pertinent law is outlined in this section and is the
`
`10
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`result of explanations provided by counsel. I have applied this understanding in
`
`my analysis.
`
`31.
`
`I understand that a patent is presumed valid. I understand that a patent
`
`claim is invalid if it is obvious in view of the prior art. I further understand that the
`
`frame of reference for determining whether a patent is obvious is from the
`
`perspective of a POSA at the time the invention was made (in this case, the priority
`
`date of March 1, 2017).
`
`32.
`
`In analyzing 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).
`
`33.
`
`I understand that a patent claim is obvious over multiple, combined
`
`references only if the prior art as a whole taught or suggested the 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.
`
`34.
`
`I also understand that the use of hindsight must be avoided 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
`
`11
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`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.
`
`VI. THE CLAIMS OF THE ’214 PATENT WOULD NOT HAVE BEEN
`OBVIOUS
`
`35. 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 Dr. Jee Eun Lee, Ph.D and Dr. 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.”
`
`36. Dr. Greenblatt opines 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.
`
`As explained below, Dr. Greenblatt’s opinions are based on a lack of
`
`understanding of how doctors were prescribing mifepristone as of the priority date
`
`and of the safety concerns that doctors had related to potential co-administration of
`
`mifepristone and a strong CYP3A inhibitor.
`
`A.
`
`37.
`
`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
`
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`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.
`
`38. 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 DDIs involving
`
`CYP3A inhibitors.” Ex. 1002 at ¶ 18.
`
`39.
`
`I disagree with Dr. Greenblatt’s definition of a POSA to the extent
`
`that it includes individuals without any experience treating Cushing’s syndrome
`
`patients with mifepristone and who are not part of a team that includes a person
`
`with such experience. A person without any experience prescribing mifepristone
`
`would not have understood the serious concerns present in the art among
`
`mifepristone prescribers at the time of the invention, even if they had experience
`
`treating patients with CYP3A inhibitors or studying DDIs involving CYP3A
`
`inhibitors.
`
`40.
`
`For example, as explained above, treatment of Cushing’s syndrome
`
`with mifepristone is associated with serious side effects, including adrenal
`
`insufficiency. Because mifepristone does not lower cortisol levels, prescribers
`
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`must rely on other indicators of efficacy in patients with Cushing’s syndrome, such
`
`as lower blood pressure and blood sugar. These indicators of efficacy, however,
`
`are also indicators of adrenal insufficiency. This makes safely administering
`
`mifepristone difficult even for endocrinologists who have treated many patients
`
`with Cushing’s syndrome, let alone practitioners without that training and
`
`experience.
`
`41.
`
`Thus, in my opinion, a POSA for purposes of the ’214 patent would
`
`have been an M.D. or related medical professional with at least four years of
`
`experience treating patients with Cushing’s syndrome with mifepristone either
`
`individually or have been on a team with such a person.
`
`42.
`
`I am a POSA under both Dr. Greenblatt’s and my own definitions. I
`
`have been asked by counsel to analyze the claims from the perspective of Dr.
`
`Greenblatt’s POSA.
`
`B.
`
`Dr. Greenblatt’s Cited References
`
`1.
`
`The Korlym® Label
`
`43.
`
`The Korlym® label is the FDA-approved prescribing information for
`
`Korlym®. It is directed primarily to prescribers and reflects the FDA’s views on
`
`how best to balance safety and efficacy for the labeled product. Among other
`
`things, the Korlym® label provides instructions to prescribers on how to safely and
`
`effectively prescribe Korlym®, including the approved indication, dose, and dosing
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`regimen. The Korlym® label also discloses contraindications and provides
`
`warnings about potential side effects and dangers resulting from co-administration
`
`with other drugs.
`
`44.
`
`The Korlym® label discloses that “[t]he recommended starting dose is
`
`300 mg orally once daily.” Ex. 1004 at 3. The Korlym® label also 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 instructions apply to the
`
`administration of Korlym® to patients without the complicating factors addressed
`
`in other portions of the Korlym® label.
`
`45.
`
`The first page of the Korlym® label also discloses that Korlym®
`
`should not be given in combination with a strong CYP3A inhibitor unless it is
`
`medically necessary:
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`Ex. 1004 at 1 (annotated). In the event of medical necessity, the Korlym® label
`
`instructs prescribers not to administer more than 300 mg mifepristone per day with
`
`a strong CYP3A inhibitor like ketoconazole. Id.
`
`46.
`
`The Korlym® label provides additional information regarding the
`
`dangers of co-administering of Korlym® and strong CYP3A inhibitors. For
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`example, the label explains that “[k]etoconazole and other strong inhibitors of
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`CYP3A . . . may increase exposure to mifepristone significantly.” Id. at 9.
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`Therefore, the label warns, “extreme caution should be used when these drugs are
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`prescribed in combination with Korlym®. The benefit of concomitant use of these
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`agents should be carefully weighed against the potential risks. The dose of
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`Korlym® should be limited to 300 mg and used only when necessary:”
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`Id. at 9-10.
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`47.
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`The first page of the label also clearly states that “Caution should be
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`used when Korlym® is used with strong CYP3A inhibitors. Limit mifepristone
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`dose to 300 mg per day when used with strong CYP3A inhibitors”:
`
`Id. at 1 (annotated).
`
`48.
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`In addition, the “Warnings and Precautions” section of the label states
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`that “Korlym should be used with extreme caution in patients taking ketoconazole
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`and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir,
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`nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, boceprevir,
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`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
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`concomitant use of these agents should be carefully weighed against the potential
`
`risks. Mifepristone should be used in combination with strong CYP3A inhibitors
`
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`only when necessary, and in such cases the dose should be limited to 300 mg per
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`day”:
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`Id. at 6.
`
`2.
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`Lee
`
`49.
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`Lee is a compilation of reviews of the Korlym® NDA that is part of
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`the Korlym® approval package. Lee includes the 6/14/2011 Biopharmaceutics
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`Filing Review (pages 116-119); the 6/17/2011 Clinical Pharmacology New Drug
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`Application Filing and Review Form (pages 108-115); the 1/13/2012 Clinical
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`Pharmacology Review of the Korlym NDA (pages 7-107); the 1/20/2012
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`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
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`Review of the Korlym NDA (pages 2-3). The Clinical Pharmacology Review of
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`the Korlym NDA was conducted by Jee Eun Lee, Ph.D. (Reviewer) and
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`Jayabharathi Vaidyanathan, Ph.D. (Team Leader (Acting)).
`
`50.
`
`Lee states that “there is a high potential of [ketoconazole’s]
`
`concomitant use with mifepristone” and “[t]he degree of change in exposure of
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`mifepristone when co-administered with strong CYP3A inhibitors is unknown.”
`
`Ex. 1005 at 4.
`
`51.
`
`Lee also discloses that “increase[s] in the exposure of mifepristone
`
`and/or its metabolites are expected with concomitant use of moderate and strong
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`CYP3A4 inhibitors.” Id. at 37 (emphasis added). Based on this expectation, the
`
`“[u]se of strong CYP3A4 inhibitors [was] proposed to be contraindicated by the
`
`sponsor.” Id. Lee discloses that the reviewer in the Office of Clinical
`
`Pharmacology agreed with the sponsor’s proposal to contraindicate the co-
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`administration of mifepristone and strong CYP3A inhibitors and recommended an
`
`even more conservative approach—avoiding the concomitant administration of
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`moderate CYP3A4 inhibitors:
`
`Id. at 37-38.
`
`52. Another portion of the Korlym® NDA approval package confirms this
`
`recommendation. The report of the cross discipline team leader states that “based
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`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 at 8. These recommendations are directly contrary to Dr. Greenblatt’s
`
`opinion that a POSA would have had a reasonable expectation that 600 mg of
`
`mifepristone per day could be safely co-administered with a strong CYP3A
`
`inhibitor.
`
`53.
`
`In conjunction with the recommendation to contraindicate co-
`
`administration with strong CYP3A inhibitors and avoid co-administration with
`
`moderate CYP3A inhibitors, Lee recommended that the sponsor perform a DDI
`
`study with ketoconazole as a Post Marketing Requirement (PMR). Ex. 1005 at 5.
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`Acknowledging that a DDI study with ketoconazole may not permit co-
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`administration of any dose of mifepristone with strong CYP3A inhibitors, Lee
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`stated that “[b]ased on the results of this study, the effect of moderate CYP3A
`
`inhibitors on mifepristone pharmacokinetics may need to be addressed.” Id.
`
`54.
`
`Lee also discloses clinical evidence that the interaction between
`
`mifepristone and strong CYP3A inhibitors would not be safe and would instead
`
`lead to serious consequences. In particular, Lee discloses that the average
`
`mifepristone blood serum concentration of patients with Cushing’s syndrome
`
`treated with the drug is approximately 2000 ng/mL. See id. at 38. Lee further
`
`reports that in a patient concomitantly treated with 600 mg mifepristone and
`
`ketoconazole in a Phase III clinical trial, the patient’s serum “concentrations were
`
`8,520 and 8,770 ng/mL (75 minutes apart between the two samples), which were
`
`more than 4 times higher than average trough concentrations.” Id. Dunnigan et
`
`al., which reports on the same patient, discloses that the patient described in Lee
`
`developed “clinical adrenal insufficiency [that] was likely exacerbated by the P450
`
`(CYP3A4)-inhibiting properties of ketoconazole, which led to unexpectedly high
`
`levels of mifepristone and its metabolites.” Ex. 2036 at 3. As a result of these
`
`adverse events, the patient was forced to stop taking mifepristone. Id.
`
`3.
`
`FDA Guidance
`
`55.
`
`FDA Guidance is a September 2006 “draft guidance” document
`
`distributed by the FDA “for comment purposes only.” See Ex. 1041 at 1. In my
`
`opinion, practicing medical doctors rarely rely on FDA Guidances. FDA Guidance
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`is silent on mifepristone and provides only “recommendations for sponsors of new
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`drug applications . . . who are performing in vitro and in vivo drug metabolism,
`
`drug transport, and drug-drug interaction studies.” Id. at 4. The document
`
`explicitly states that its recommendations are not intended to “bind FDA or the
`
`public.” Id. Drug sponsors are expressly told that they may use “an alternative
`
`approach” to the non-binding recommendations in the Guidance when carrying out
`
`any DDI study. See id.
`
`C.
`
`A POSA Would Not Have Reasonably Ex