`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`MYLAN PHARMACEUTICALS INC., ACTAVIS
`LABORATORIES FL, INC., AMNEAL PHARMACEUTICALS LLC,
`AMNEAL PHARMACEUTICALS OF NEW YORK, LLC, DR. REDDY'S
`LABORATORIES, INC., DR. REDDY'S LABORATORIES, LTD.,
`SUN PHARMACEUTICALS INDUSTRIES, LTD.,
`SUN PHARMACEUTICALS INDUSTRIES, INC.,
`TEVA PHARMACEUTICALS USA, INC., WEST-WARD
`PHARMACEUTICAL CORP., and HIKMA PHARMACEUTICALS, LLC,
`Petitioner
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`
`Patent Owner
`
`Case IPR2016-013321
`Patent 8,822,438 B2
`
`
`
`
`
`REPLY DECLARATION OF JOHN BANTLE, M.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 8,822,438
`
`
`
`
`1 Case IPR2017-00853 has been joined with this proceeding.
`
`MYLAN PHARMS. INC. EXHIBIT 1097 PAGE 1
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`TABLE OF CONTENTS
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`Page
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`I.
`
`
`Qualifications and Background .................................................................... 4
`A.
`Education and Experience .................................................................. 4
`B.
`Bases for Opinions ............................................................................... 5
`C. Retention and Compensation ............................................................. 6
`Summary of Opinions ................................................................................... 6
`II.
`III. Legal Standards ............................................................................................. 8
`IV. Person of Ordinary Skill in the Art ............................................................. 9
`V.
`Background ..................................................................................................10
`A.
`The Three Major Steroid Pathways: Androgen,
`Glucocorticoid, and Mineralocorticoid ...........................................10
`Adrenal Steroid Synthesis Inhibitors ..............................................12
`B.
`C. Adrenal Insufficiency and Mineralocorticoid Excess ....................18
`VI. Opinions ........................................................................................................25
`A. A POSA Would Have Been Motivated to Administer
`Prednisone With AA With A Reasonable Expectation of
`Success ................................................................................................25
`1.
`A POSA would have been motivated to administer
`prednisone with abiraterone acetate because
`ketoconazole, another CYP17 inhibitor, was known to
`cause adrenal insufficiency and was therefore
`administered with a glucocorticoid ...........................................25
`O’Donnell would have motivated a POSA to administer
`prednisone with abiraterone acetate to protect against
`adrenal insufficiency or compromised adrenal reserve ............29
`A POSA would have been motivated to administer
`prednisone with abiraterone acetate to prevent
`mineralocorticoid excess ...........................................................33
`For all three conditions (adrenal insufficiency, low
`adrenal reserve, and mineralocorticoid excess), a POSA
`would have reasonably expected administration of
`prednisone to resolve patient symptoms ...................................38
`
`2.
`
`3.
`
`4.
`
`2
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`TABLE OF CONTENTS
`(continued)
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`Page
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`2.
`
`3.
`
`B.
`
`E.
`
`Dr. Auchus’s Criticisms of O’Donnell Do Not Refute
`Motivation ..........................................................................................39
`1.
`The other information reported in O’Donnell would not
`have diminished the Synacthen results. ....................................40
`Dr. Auchus’s criticisms fail to undermine O’Donnell’s
`Synacthen test results ................................................................44
`O’Donnell’s contemporaneous conclusions contradict Dr.
`Auchus’ opinions ......................................................................50
`C. Dr. Auchus’s Criticisms of the ’213 Patent Do Not Refute
`Motivation ..........................................................................................51
`D. Dr. Auchus’s Analogies to Genetic CYP17 Deficiencies Do
`Not Teach Away From Co-Administration of Abiraterone
`Acetate With Prednisone ..................................................................53
`A POSA in 2006 Would Have Administered Glucocorticoid
`Replacement Therapy Over Other Options ...................................57
`
`
`
`
`
`3
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`MYLAN PHARMS. INC. EXHIBIT 1097 PAGE 3
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`I.
`
`Qualifications and Background
`1. My name is John Bantle, M.D. I have been retained by Petitioner in
`
`the matter of the Inter Partes Review (IPR) of U.S. Patent No. 8,822,438 (the
`
`“’438 Patent”), as set forth in the above caption.
`
`A. Education and Experience
`
`2.
`
`I am a medical endocrinologist and Professor Emeritus of Medicine in
`
`the Division of Diabetes, Endocrinology, and Metabolism, Department of
`
`Medicine, at the University of Minnesota. I have substantial experience in clinical
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`research, treatment of patients, and academic publication in the field of
`
`endocrinology.
`
`3.
`
`I received a Bachelor of Science degree in 1970 from the University
`
`of Minnesota and a Doctor of Medicine degree in 1972 from the University of
`
`Minnesota Medical School. I completed an internship at Cleveland Metropolitan
`
`General Hospital in 1973; residencies in internal medicine at the Mayo Clinic in
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`Minnesota and Dunedin Public Hospital in Dunedin, New Zealand in 1975 and
`
`1976, respectively; and a fellowship in endocrinology and metabolism at the
`
`University of Minnesota in 1978.
`
`4.
`
`In addition to my teaching positions, I have held multiple clinical
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`research positions throughout my career. I was the Associate Director of the
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`General Clinical Research Center at the University of Minnesota Medical School
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`from 1983–2009, the Medical Staff Clinical Service Chief for Internal Medicine at
`
`4
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`Fairview-University Medical Center from 2001–2007, and the Clinical Research
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`Implementation Services Leader of the Clinical and Translational Science Institute
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`at the University of Minnesota from 2011–2013. In addition, I have participated in
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`numerous clinical trials, both as principal investigator and co-investigator. I have
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`authored approximately 150 publications, book chapters, and presentations on the
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`topics of endocrinology and metabolism.
`
`5.
`
`I have received numerous honors and awards for teaching, clinical
`
`excellence, and treatment of patients. For example, I was named by the Best
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`Doctors Organization as one of the Best Doctors in America for twenty
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`consecutive years from 1996–2015; I was named a Top Doctor by Minneapolis/St.
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`Paul Magazine in 1992, 1994, 1996, 1999–2002, 2004, and 2006–2017; and I
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`received the University of Minnesota Department of Medicine Clinical Excellence
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`Award in 2002, 2004, and 2011.
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`6. My curriculum vitae is attached as Exhibit A to this declaration.
`
`7.
`
`Based upon my education, training and experience, as summarized
`
`above, I believe I am qualified to provide opinion testimony as an expert in
`
`endocrinology.
`
`B.
`
`8.
`
`Bases for Opinions
`
`The opinions to which I testify are based on the education, experience,
`
`training and skill that I have accumulated in the course of my career as a practicing
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`5
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`medical endocrinologist and researcher, as well as the materials I have reviewed in
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`connection with this case.
`
`9.
`
`The list of materials I considered in forming the opinions set forth in
`
`this declaration is attached as Exhibit B to this declaration. I have also considered
`
`all materials cited in Dr. Auchus’s Declaration (Ex. 2040) not otherwise identified.
`
`C. Retention and Compensation
`
`10.
`
`In the past four years, I have not provided expert testimony in either
`
`deposition or trial. I previously submitted a declaration in Pack Pharm. v. Alva
`
`Corp., IPR2014-00868. I am being compensated at an hourly rate of $400/hour
`
`and am available to appear live for testimony in support of my opinions. My
`
`compensation in no way depends on the outcome of this proceeding. I have no
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`current or past affiliation with Janssen Oncology, Inc. or the inventor of the patent
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`at issue.
`
`II.
`
`Summary of Opinions
`11. As of August 2006, a person of ordinary skill in the art (“POSA”)
`
`would have been motivated to administer prednisone with abiraterone acetate. A
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`POSA would also have held a reasonable expectation of success in administering
`
`prednisone with abiraterone acetate.
`
`12. A POSA would have been motivated to administer prednisone with
`
`abiraterone acetate for three primary reasons. First, a POSA would have known
`
`that adrenal androgen inhibitors such as ketoconazole, a commonly known
`
`6
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`pharmaceutical agent in the same drug class as abiraterone acetate (CYP17
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`inhibitors), could cause adrenal insufficiency in patients. To prevent adrenal
`
`insufficiency, ketoconazole was administered with a glucocorticoid such as
`
`
`
`prednisone.
`
`13.
`
`Second, a POSA would have recognized that the prior art teachings
`
`and data regarding patients administered abiraterone acetate were consistent with
`
`these patients suffering from adrenal insufficiency, or, at minimum, low adrenal
`
`reserve. Low adrenal reserve was known to potentially be fatal during physiologic
`
`stress episodes such as illness or surgery. Prior art taught that administration of a
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`glucocorticoid like prednisone would remedy low adrenal reserve in addition to
`
`adrenal insufficiency.
`
`14. Third, a POSA would have understood from the prior art that
`
`abiraterone acetate inhibits the androgen and cortisol pathways in steroid
`
`biosynthesis. Inhibition of the androgen and cortisol pathways was known to cause
`
`overstimulation of
`
`the mineralocorticoid pathway, resulting
`
`in dangerous
`
`mineralocorticoid excess. Administration of a glucocorticoid was known to correct
`
`this imbalance.
`
`15. Based on all three considerations, a POSA would have administered
`
`prednisone in combination with abiraterone acetate with a reasonable expectation
`
`of success. The prior art taught that only a glucocorticoid therapy like prednisone
`
`7
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`could remedy adrenal insufficiency, low adrenal reserve, and mineralocorticoid
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`excess caused by cortisol inhibition. A POSA would have further considered
`
`administration of glucocorticoids on an as-needed basis highly risky because
`
`dangerous episodes can arise quickly, patients must be aware of the danger as it is
`
`beginning, and metastatic castration-resistant prostate cancer (“mCRPC”) patients
`
`are already under significant stress (and are thus particularly susceptible to life-
`
`threatening complications of abiraterone acetate therapy). A POSA would
`
`therefore have been motivated to administer prednisone in combination with
`
`abiraterone acetate to prevent life-threatening side effects of abiraterone acetate
`
`with reasonable expectation of success.
`
`16. None of Dr. Auchus’s criticisms or alternate interpretations of the
`
`prior art alter my conclusions. I respond to Dr. Auchus’s arguments individually
`
`below.
`
`III. Legal Standards
`I understand that my opinions regarding unpatentability are to be from
`17.
`
`the viewpoint of a person having ordinary skill in the field of technology of the
`
`patent at the patent’s priority date.
`
`18.
`
`I understand that the obviousness inquiry is a question of law based on
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`four factual predicates: (1) “the scope and content of the prior art,” (2) the
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`“differences between the prior art and the claims at issue,” (3) “the level of
`
`8
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`ordinary skill in the pertinent art,” and (4) “secondary considerations” such as
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`commercial success, long-felt but unsolved needs, failure of others, and
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`unexpected results.
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`19.
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`I also understand that when there is some recognized reason to solve a
`
`problem, and there are a finite number of identified, predictable and known
`
`solutions, a person of ordinary skill in the art has good reason to pursue the known
`
`options within his or her technical grasp. If such an approach leads to the expected
`
`success, it is likely not the product of innovation but of ordinary skill and common
`
`sense. In such a circumstance, when a patent simply arranges old elements with
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`each performing its known function and yields no more than what one would
`
`expect from such an arrangement, the combination is obvious.
`
`IV. Person of Ordinary Skill in the Art
`I have accepted and applied the definition of the person of ordinary
`20.
`
`skill in the art offered by Dr. Garnick: A person of ordinary skill in the art at the
`
`time of filing of this patent is someone who is a physician specializing in urology,
`
`endocrinology or oncology, or holds a Ph.D. in pharmacology, biochemistry or a
`
`related discipline. A related discipline may include, for example, pharmaceutical
`
`sciences. Additional experience could substitute for the advanced degree. To the
`
`extent necessary, a person of ordinary skill in the art may collaborate with one or
`
`more other persons of skill in the art for one or more aspects in which the other
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`9
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`person may have expertise, experience and/or knowledge that was obtained
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`through his or her education, industrial or academic experiences. A person of
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`ordinary skill in the art may consult with an endocrinologist, oncologist or medical
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`biochemist and thus may rely on the opinions of such specialists in evaluating the
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`claims. I have also reviewed Patent Owner’s definition of the person of ordinary
`
`skill in the art. My opinions are the same regardless of which definition is applied.
`
`V. Background
`A. The Three Major Steroid Pathways: Androgen, Glucocorticoid,
`and Mineralocorticoid
`
`21. The endocrine system is a collection of glands that regulate bodily
`
`functions as diverse as metabolism, stress response, mood, and sleep. One member
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`of the endocrine system, the adrenal glands, produces steroids that are crucial to
`
`many of these functions.
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`22. Adrenal steroids are classified into three major types: androgen,
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`glucocorticoid, and mineralocorticoid steroids. Ex. 1025 (Harrison’s 2005) at 21.
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`These steroids are produced via three major biosynthetic pathways, also named the
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`androgen, glucocorticoid, and mineralocorticoid pathways. Each pathway leads to
`
`the production of the major steroid in each class: testosterone in men (androgen),
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`cortisol (glucocorticoid), and aldosterone (mineralocorticoid).
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` Along each
`
`pathway, interaction with particular enzymes converts cholesterol into each steroid.
`
`10
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`Figure A below is a chart depicting the three adrenal steroid pathways, along with
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`the enzymes catalyzing each step.
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`
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`
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`Figure A: The Three Major Pathways of Adrenal Steroid Production
`
`See Ex. 1025 (Harrison’s 2005) at 22 (Figure 321-2); Ex. 1023 (Attard 2005)
`
`at 3 (Fig. 1). A full-size version of Figure A is attached as Exhibit C.
`
`23. As can be seen in Figure A, different enzymes are critical to each
`
`pathway. For example, for the androgen and glucocorticoid pathways, CYP450c17
`
`(“CYP17”) is a crucial link. CYP17 has two functions, the 17α-hydroxylase and
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`the 17,20-lyase functions. As Figure A depicts, the 17α-hydroxylase CYP17
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`11
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`function
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`converts
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`pregnenolone
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`to
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`17OH-pregnenolone
`
`(17α-
`
`hydroxypregnenolone)
`
`and
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`progesterone
`
`to
`
`17OH-progesterone
`
`(17α-
`
`hydroxyprogesterone) along the glucocorticoid pathway. The 17,20-lyase CYP17
`
`function converts 17OH-pregnenolone to DHEA (dehydroepiandrosterone) and
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`17OH-progesterone to androstenedione along the androgen pathway.
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`B. Adrenal Steroid Synthesis Inhibitors
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`24. Some molecules are known to inhibit adrenal steroid synthesis.
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`Adrenal steroid synthesis inhibitors act by inhibiting enzymes necessary for steroid
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`biosynthesis, impeding the links along one or more steroid pathways. Ex. 1003
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`(O’Donnell 2004) at 2.
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`25. One class of adrenal steroid synthesis inhibitors is CYP17 inhibitors.
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`CYP17 inhibitors, as their name indicates, inhibit the CYP17 enzyme. Known
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`CYP17 inhibitors as of 2006 included ketoconazole and abiraterone acetate. Ex.
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`1003 (O’Donnell 2004) at 2. Abiraterone acetate in particular was known to be
`
`selective to CYP17, inhibiting both its 17α-hydroxylase and 17,20-lyase functions.
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`Attard 2005, a publication from shortly before the priority date, summarized
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`knowledge of abiraterone acetate’s effect on steroid biosynthesis in the following
`
`figure.
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`12
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`Figure B: Figure 1 from Attard 2005 (Ex. 1023 at 3)
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`26. As Figure B shows, abiraterone acetate inhibits 17α-hydroxylase and
`
`17,20-lyase. Consequently, key links in the glucocorticoid and androgen pathways
`
`are affected, resulting in decreased production of cortisol and testosterone (as
`
`shown by the blue arrows). In contrast, as the diagram states, “[s]uppression of
`
`cortisol and its precursors causing a compensatory rise in ACTH and excess
`
`synthesis of aldosterone and its precursors is predicted (blue arrows).” Ex. 1023
`
`(Attard 2005) at 3. In other words, due to natural feedback mechanisms described
`
`in more detail in the next section below, low cortisol production results in
`
`increased ACTH production, which causes release of cholesterol. Id. However,
`
`13
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`because the glucocorticoid and androgen pathways are substantially inhibited
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`(depicted in Figure B by the red “X”s), most of the released cholesterol cannot be
`
`synthesized into glucocorticoids and androgens (as shown by the blue “down”
`
`arrows along the middle and lower pathways in Figure B). Instead, the cholesterol
`
`follows
`
`the mineralocorticoid pathway and
`
`is synthesized
`
`into active
`
`mineralocorticoids such as aldosterone (as shown by the blue “up” arrows along
`
`the upper pathway in Figure B). Id. The result is much higher mineralocorticoid
`
`levels. Id.
`
`27.
`
`In its Patent Owner response, Patent Owner created its own diagram
`
`of the pathways shown in Figure B. Patent Owner’s diagram is reproduced below
`
`as Figure C.
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`14
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`Figure C: Patent Owner Response Figure 1 (Paper No. 35, Patent Owner
`Response, at 14)
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`28. Comparison to Figure B reveals that Patent Owner’s figure (Figure C)
`
`is both factually inaccurate and highly misleading. Patent Owner omits that 17α-
`
`hydroxylase catalyzes synthesis of progesterone to 17OH-progesterone and that
`
`17,20-lyase catalyzes synthesis of 17OH-progesterone to androstenedione. These
`
`are important omissions, particularly as to 17α-hydroxylase. Figure C suggests
`
`that a major uninhibited path to produce cortisol exists (ACTH  cholesterol 
`
`pregnenolone  progesterone  17OH-progesterone  11-deoxycortisol 
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`cortisol). This is incorrect. As shown in Figure B, 17α-hydroxylase catalyzes
`
`synthesis of progesterone to 17OH-progesterone. With that synthesis inhibited,
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`15
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`primary links along the glucocorticoid pathway are disrupted. Ex. 1023 (Attard
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`2005) at 3. Figure B accordingly places blue “down” arrows along the
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`glucocorticoid pathway, illustrating the reduction in cortisol production caused by
`
`abiraterone acetate. Id.
`
`29. Moreover, Figure C is misleading. Patent Owner placed a large “X”
`
`over 17,20-lyase and a much smaller “X” over 17α-hydroxylase without
`
`justification. As I discuss in full infra ¶ 86, 90-92, the prior art data suggests that
`
`abiraterone acetate is a potent inhibitor of both 17α-hydroxylase and 17,20-lyase.
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`Indeed, the only similar contemporaneously-made diagram, Figure B, places
`
`identically-sized “X”s over both 17α-hydroxylase and 17,20-lyase. Ex. 1023
`
`(Attard 2005) at 3. While Patent Owner attempts to suggest otherwise in its figure,
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`Figure B notes that abiraterone acetate substantially suppresses cortisol production.
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`Id.
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`30. Patent Owner commits similar errors in Figure 2 of its Patent Owner
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`Response (reproduced below as Figure D).
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`16
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`Figure D: Patent Owner Response Figure 2 (Paper No. 35, Patent Owner
`Response, at 14)
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`31. Patent Owner again fails to include that 17α-hydroxylase catalyzes
`
`synthesis of progesterone to 17OH-progesterone and that 17,20-lyase catalyzes
`
`synthesis of 17OH-progesterone to androstenedione. Figure D also represents the
`
`degree of ketoconazole’s inhibition of various enzyme functions using red “X”s of
`
`differential size. However, Patent Owner presents no data supporting its
`
`suggestion that ketoconazole inhibits desmolase and 11β-hydroxylase substantially
`
`more than 17α-hydroxylase or 17,20-lyase, or that any such differential inhibition
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`has clinical significance.
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`17
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`C. Adrenal Insufficiency and Mineralocorticoid Excess
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`32. Two conditions caused by adrenal dysfunction include adrenal
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`insufficiency and mineralocorticoid excess. In a normally-functioning adrenal
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`system,
`
`feedback mechanisms maintain a balance between androgen,
`
`glucocorticoid, and mineralocorticoid steroids. In particular, the pituitary gland
`
`regulates production of adrenal steroids by producing more or
`
`less
`
`adrenocorticotropic hormone (ACTH), shown in Figure A. Ex. 1025 (Harrison’s
`
`2005) at 24, 27; Ex. 2052 (Grinspoon 1994) at 923.2 When cortisol levels are low,
`
`the pituitary gland produces more ACTH, which restores normal cortisol levels by
`
`increasing the production of precursors and directing their conversion into
`
`cortisol. Id.
`
`33. However, when enzymes necessary for steroid synthesis are inhibited
`
`(or ACTH production is impaired), the body’s natural feedback mechanisms
`
`cannot maintain proper steroid balance. Adrenal insufficiency is a condition in
`
`which the body cannot produce sufficient steroids, and cortisol in particular. Ex.
`
`1025 (Harrison’s 2005) at 35. Common clinical symptoms of primary adrenal
`
`include weakness,
`insufficiency
`
`2 Because exhibits submitted by Patent Owner (all 2000-numbered exhibits) were
`
`loss, nausea, vomiting,
`
`fatigue, weight
`
`not labelled with page numbers, I have cited to the internal page numbers for these
`
`exhibits.
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`18
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`hypotension, and hyperpigmentation.3 Ex. 1025 (Harrison’s 2005) at 36, 37; Ex.
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`1098 (Arlt 2003) at 1, 5. Early symptoms may be mild or even subclinical. Ex.
`
`1025 (Harrison’s 2005) at 36, 37; Ex. 1098 (Arlt 2003) at 1, 4-5; Ex. 2051 (Dorin
`
`2003) at 196. And “[b]ecause weakness and fatigue are common, diagnosis of
`
`early adrenocortical insufficiency may be difficult.” Ex. 1025 (Harrison’s 2005) at
`
`37; see also Ex. 2051 (Dorin 2003) at 194 (“The presentation of adrenal
`
`insufficiency may be insidious and thus difficult to recognize.”), 196 (“One
`
`difficulty in the diagnosis of primary adrenal insufficiency is the nonspecific nature
`
`of presentation and the resultant lack of clinical suspicion for the disorder.”).
`
`Indeed, “[t]he most common problem in diagnosing primary adrenal insufficiency
`
`is lack of clinical suspicion because the condition is rare and the signs and
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`symptoms are non-specific.” Ex. 2051 (Dorin 2003) at 200. However, “[a]drenal
`
`insufficiency . . . is life threatening when overlooked.” Ex. 1098 (Arlt 2003) at 1;
`
`see also Ex. 2051 (Dorin 2003) at 194 (“It is important to diagnose adrenal
`
`insufficiency because the disorder may be fatal if left unrecognized or untreated.”);
`
`Ex. 1099 (Oelkers 1996) at 1. Therefore, physicians must be cautious when
`
`adrenal insufficiency is a possible side effect of a medical intervention.
`
`3 Primary adrenal insufficiency, at issue here, is typically related to failure of the
`
`adrenal system. Secondary adrenal insufficiency is caused by dysfunction of the
`
`pituitary gland or hypothalamus.
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`19
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`34.
`
`In 2006, the Synacthen test (also called the cosyntropin, Cortrosyn, or
`
`ACTH stimulation test) was considered the standard of care for uncovering adrenal
`
`dysfunction. Ex. 1025 (Harrison’s 2005) at 36 (“The diagnosis of adrenal
`
`insufficiency should be made only with ACTH stimulation testing to assess adrenal
`
`reserve capacity for steroid production.”), 37 (“When doubt exists, measurement of
`
`ACTH levels and testing of adrenal reserve with the infusion of ACTH provide
`
`clear-cut differentiation.”); Ex. 2052 (Grinspoon 1994) at 923, 924, 927, 928, 930;
`
`Ex. 2051 (Dorin 2003) at 194, 199, 200 (“The cosyntropin simulation test has
`
`therefore emerged as the initial test used to evaluate patients for both primary and
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`secondary adrenal insufficiency.”); Ex. 1098 (Arlt 2003) at 5, 6. In the Synacthen
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`test, the patient is administered 250 µg of synthetic ACTH, and the patient’s
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`cortisol response is measured. Ex. 1025 (Harrison’s 2005) at 36; Ex. 2052
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`(Grinspoon 1994) at 927; Ex. 1098 (Arlt 2003) at 5. Historically, the change in
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`cortisol level from baseline was considered important, but as of 2006, it was more
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`typical to measure the peak cortisol level. Ex. 2052 (Grinspoon 1994) at 927. If
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`the patient’s cortisol response to Synacthen was abnormally low, the patient very
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`likely suffered from adrenal insufficiency, or at least low adrenal reserve (high
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`baseline ACTH production, causing an inability to substantially increase cortisol
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`production when needed because production is already near maximal). Ex. 1025
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`(Harrison’s 2005) at 36-38; Ex. 2051 (Dorin 2003) at 195-96, 199; Ex. 2052
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`(Grinspoon 1994) at 923, 927, 928, 930.
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`35. The Synacthen test is especially useful for identifying early cases of
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`adrenal insufficiency. “In the early phase of gradual adrenal destruction, there may
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`be no demonstrable abnormalities in the routine laboratory parameters, but adrenal
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`reserve is decreased—that is, while basal steroid output may be normal, a
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`subnormal increase occurs after stress. Adrenal stimulation with ACTH uncovers
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`abnormalities in this stage of the disease, eliciting a subnormal increase of cortisol
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`levels or no increase at all.” Ex. 1025 (Harrison’s 2005) at 36.
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`36. Other options in 2006 for physicians to monitor patients at risk for
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`developing adrenal insufficiency included measuring serum cortisol levels and
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`looking for clinical symptoms. Both options were considered inferior to the
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`Synacthen test, particularly in patients at early stages of adrenal insufficiency. Ex.
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`1025 (Harrison’s 2005) at 36-37; Ex. 1098 (Arlt 2003) at 5; Ex. 2052 (Grinspoon
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`1994) at 923, 924, 926, 930; Ex. 2051 (Dorin 2003) at 195-96. Serum cortisol
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`levels change throughout the day, and there is a wide normal range. Ex. 1098 (Arlt
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`2003) at 5; Ex. 2052 (Grinspoon 1994) at 923, 924, 926-27. While extremely low
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`serum cortisol levels indicate adrenal insufficiency, many patients with adrenal
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`insufficiency test within the low-normal serum cortisol range. Ex. 2052
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`(Grinspoon 1994) at 923, 924, 926, 930. Normal serum cortisol levels are
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`especially prevalent in newly-developing cases. Id.
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`37. Similarly, it was known in 2006 that clinical symptoms may be slow
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`to develop. Ex. 1025 (Harrison’s 2005) at 36-37; Ex. 1098 (Arlt 2003) at 4-5; Ex.
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`2051 (Dorin 2003) at 194, 196, 200. Because the most common early symptoms of
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`adrenal insufficiency—weakness and fatigue—occur frequently in people without
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`adrenal insufficiency, a physician in 2006 would have known that early diagnosis
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`of adrenal insufficiency required physicians to be on guard for abnormal test
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`results, even in the absence of serious clinical symptoms. Ex. 1025 (Harrison’s
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`2005) at 36-37; Ex. 1098 (Arlt 2003) at 1, 4-5; Ex. 2051 (Dorin 2003) at 194-96,
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`200.
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`38. A physician in 2006 would have also been aware of the risks faced by
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`patients with low adrenal reserve. Ex. 1025 (Harrison’s 2005) at 36-38; Ex. 1099
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`(Oelkers 1996) at 1; Ex. 1098 (Arlt 2003) at 7. Low adrenal reserve can be
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`considered a milder form of adrenal insufficiency. Ex. 1025 (Harrison’s 2005) at
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`36, 38. Patients with low adrenal reserve may consistently exhibit basal
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`(unstimulated) serum cortisol levels within the normal range, but they have
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`impaired ability to increase cortisol production when needed. Ex. 2052 (Grinspoon
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`1994) at 923, 924, 926, 927, 930. Specifically, in these patients, abnormally high
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`ACTH levels are required to maintain standard amounts of cortisol. This is
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`problematic because a well-functioning adrenal system must be able to rapidly
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`increase glucocorticoid production in response to certain physiologic stressors like
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`surgery, illness, or even exercise. Ex. 1025 (Harrison’s 2005) at 38; Ex. 1098 (Arlt
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`2003) at 7. But a patient with low adrenal reserve cannot increase cortisol
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`production as in normal stress response because her adrenal system is already at
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`near-peak ACTH production—and thus near-peak cortisol production—in the
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`baseline state.
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`39. A POSA in 2006 would have known that, in particularly tasking
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`situations (such as severe illness like late-stage prostate cancer), an inability to
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`rapidly increase glucocorticoid production can cause an adrenal crisis, which can
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`be fatal. Ex. 1025 (Harrison’s 2005) at 38; Ex. 1099 (Oelkers 1996) at 1; Ex. 1098
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`(Arlt 2003) at 7, 9. Therefore, while patients with low adrenal reserve may present
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`without clinical symptoms or abnormal serum cortisol levels, such patients may
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`quickly be in life-threatening danger if they encounter significant physiologic
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`stress. Ex. 1025 (Harrison’s 2005) at 38; Ex. 1099 (Oelkers 1996) at 1.
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`40.
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`“All patients with adrenal insufficiency should receive specific
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`hormone replacement.” Ex. 1025 (Harrison’s 2005) at 37. A POSA in 2006 would
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`have understood that, to remedy glucocorticoid deficiency in patients with adrenal
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`insufficiency or low adrenal reserve, glucocorticoid replacement therapy, such as
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`prednisone, is needed. Id. at 37-38; Ex. 2051 (Dorin 2003) at 196.
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`41. Another known issue in adrenal dysfunction is mineralocorticoid
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`excess (often due to hypermineralocorticoidism or aldosteronism). As the name
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`suggests, patients with mineralocorticoid excess present with abnormally high
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`accumulation of mineralocorticoids. The symptoms of mineralocorticoid excess
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`and adrenal insufficiency tend to oppose each other. Common symptoms of
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`mineralocorticoid excess include hypertension (high blood pressure), hypokalemia
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`(low potassium), and hypernatremia (high sodium). Ex. 1025 (Harrison’s 2005) at
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`32-33, 40.
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` If one of
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`these symptoms becomes sufficiently extreme,
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`mineralocorticoid excess can be fatal. Mineralocorticoid excess can occur “due to
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`a defect in cortisol biosynthesis, specifically 11- or 17-hydroxylation. ACTH
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`levels are increased, with a resultant increase in the production of the
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`mineralocorticoid 11-deoxycorticosterone.” Id. at 40.
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`42. A POSA in 2006 would have known that, when caused by selective
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`inhibition of cortisol synthesis, symptoms of mineralocorticoid excess like
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`“[h]ypertension and hypokalemia can be corrected by glucocorticoid
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`administration.” Id. Glucocorticoids cause a natural negative feedback to the
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`pituitary gland to produce less ACTH. Lower ACTH levels result in less
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`stimulation of the mineralocorticoid pathway, and thus less mineralocorticoid
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`accumulation.
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`24
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`VI. Opinions
`A. A POSA Would Have Been Motivated to Administer Prednisone
`With AA With A Reasonable Expectation of Success
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`43. Based on prior art knowledge of abiraterone acetate and similar drugs,
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`a POSA would have anticipated three major possible side effects with abiraterone
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`acetate therapy, each of which would have potentially been fatal: a