`Wockhardt Bio AG v. Janssen Oncology, Inc.
`IPR2016-01582
`
`1
`
`
`
`TABLE OF CONTENTS
`
`Introduction .................................................................................................... .. 1
`
`A.
`
`B.
`
`C.
`
`Engagement ......................................................................................... ..1
`
`Background and Qualifications .......................................................... 1
`
`Compensation and Prior Testimony .................................................... ..4
`
`D. Materials Considered ........................................................................... ..4
`
`II.
`
`III.
`
`Legal Standards Regarding Patentability ...................................................... ..5
`
`Technical Background ................................................................................... ..7
`
`A.
`
`Control of Prostate Growth and Function by Androgens ................... ..7
`
`1.
`
`2.
`
`3.
`
`Prostate growth and function .................................................... ..7
`
`Androgen Synthesis .................................................................. ..9
`
`Clinical Disorders Associated with Under—Production or Over-
`
`Production of Steroids and Their Treatment ........................... ..15
`
`B.
`
`Prostate Cancer and Its Treatment as of August 2006 ...................... ..20
`
`1.
`
`2.
`
`3.
`
`Prevalence, Diagnosis, and Early Stage Treatment ................ ..20
`
`First Line Hormonal Therapy for Metastatic Prostate Cancer .22
`
`Metastatic Castration Resistant Prostate Cancer .................... ..22
`
`C.
`
`Endpoints for Evaluating Response to Prostate Cancer Treatment ....26
`
`IV.
`
`The ‘438 Patent and its claims ..................................................................... ..29
`
`V.
`
`Claim Construction ............
`
`........................................................................ ..33
`
`VI.
`
`Person of Ordinary Skill in the Art .............................................................. ..33
`
`VII.
`
`The Prior Art Relied On by Petitioners ....................................................... ..34
`
`A.
`
`Gerber (Exhibit 1004) ....................................................................... ..34
`
`i
`
`2
`
`
`
`B.
`
`C.
`
`The Barrie patent (Exhibit 1005) ...................................................... ..37
`
`O’Donnell (Exhibit 1003) ................................................................. ..38
`
`VIII. Rebuttal to Dr. Garnick’s Opinions Concerning Obviousness ................... ..39
`
`A.
`
`There Was No Scientific Basis in the Prior Art to Add Prednisone to
`
`Abiraterone Acetate for Purposes of Glucocorticoid Replacement....40
`
`1.
`
`As of August 2006, a POSA Would Understand that
`Abiraterone Acetate’s Mechanism of Action and Hormonal
`
`Side Effects Were Very Different from Ketoconazole ........... ..40
`
`As of August 2006, a POSA Would Understand that
`Abiraterone Acetate Did Not Cause Clinical Symptoms
`Associated with Adrenal Suppression and Maintained Normal
`Cortisol Levels ........................................................................ ..46
`
`a.
`
`O’Donnell teaches that abiraterone acetate did not
`
`have any significant effect upon cortisol levels in
`patients ......................................................................... ..46
`
`b.
`
`A POSA Would Have Concluded from the Prior Art
`
`as a Whole that Abiraterone Acetate did not Cause
`
`Any Clinical Symptoms Requiring Glucocorticoid
`Replacement ................................................................ ..51
`
`As of August 2006, a POSA Would Understand that Gerber’s
`Use of “Glucocorticoid Replacement” with Ketoconazole Did
`Not Apply to Abiraterone Acetate .......................................... ..55
`
`As of August 2006, a POSA Would Not Have Given
`Glucocorticoids to Prostate Cancer Patients Unless There Was a
`
`Clear Clinical Need Because of Their Known Severe Side
`
`Effects and their Potential to Fuel the Cancer ........................ ..56
`
`There Was No Scientific or Clinical Basis in the Prior Art to Add
`
`Prednisone to Abiraterone Acetate to Address Mineralocorticoid
`
`Excess ................................................................................................ ..61
`
`1.
`
`As of August 2006, a POSA Would Understand that
`Ketoconazole Did Not Cause Mineralocorticoid Excess
`
`ii
`
`3
`
`
`
`Syndrome or Symptoms of Hypertension, Hypokalemia, or
`Fluid Retention ........................................................................ ..61
`
`As of August 2006, Nothing in the Prior Art Would Have
`Suggested to a POSA that Abiraterone Acetate Would Cause
`Mineralocorticoid Excess ........................................................ ..66
`
`Even if Mineralocorticoid Excess Was Observed, As of August
`2006, a POSA Would Understand that It Could Be Managed
`Without Glucocorticoid Replacement .................................... ..70
`
`C.
`
`There Was No Scientific or Clinical Basis for Believing that the
`Combination of Abiraterone Acetate and Prednisone Could Be
`
`Successful in Achieving the Inventions Claimed in the ‘438 Patent ..71
`
`1.
`
`As of August 2006, the Prior Art Did Not Teach that
`Ketoconazole was “Safe and Effective” for the Treatment of
`
`mCRPC ................................................................................... ..71
`
`The Prior Art Did Not Provide a Scientific or Clinical Basis for
`Believing that Prednisone Would be Effective for Treating
`Cancer ..................................................................................... .. 83
`
`IX.
`
`Real World Facts Or “Objective Indicia of Non-Obviousness” Support the
`Non-Obviousness of the 1438 Patent Invention ........................................... .. 85
`
`A.
`
`B.
`
`C.
`
`D.
`
`The Invention Claimed in the ‘438 Patent Resulted in Unexpected
`Clinical Efficacy ................................................................................ ..85
`
`The Invention Claimed in the ‘438 Patent is Embodied in ZYTIGA®
`Therapy and Contributes Significantly to the Success of ZYTIGA® 93
`
`Long Felt But Unsolved Need ........................................................... ..96
`
`Skepticism and Failure of Others ...................................................... ..96
`
`1.
`
`2.
`
`The O’Donnell Studies ........................................................... ..97
`
`Other Failed Phase III Clinical Trials ..................................... ..98
`
`iii
`
`4
`
`
`
`I, Matthew B. Rettig, M.D., hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`A.
`
`Engagement
`
`1.
`
`I have been retained by counsel for Patent Owner Janssen Oncology
`
`Inc. (“Janssen”) to provide expert and testimony as background for the panel of
`
`Administrative Patent Judges of the Patent Trial and Appeal Board of the United
`
`States Patent and Trademark Office (“Panel”) as it considers issues relating to the
`
`patentability of U.S. Patent No. 8,822,438 (the “438 Patent) (Ex. 1001) in an inter
`
`partes review requested by Mylan Pharmaceuticals, Inc. (hereinafter “Mylan”) in
`
`Case No.1PR2016—01332.
`
`B.
`
`2.
`
`Background and Qualifications
`
`I am Medical Director of the Prostate Cancer Program of the Institute
`
`of Urologic Oncology at the David Geffen School of Medicine at the University of
`
`California, Los Angeles (“UCLA School of Medicine”). I am also Professor in the
`
`Department of Medicine and the Department of Urology at the UCLA School of
`
`Medicine. I am also Chief of the Division of Hematology-Oncology for the
`
`Veteran’s Administration (VA) Greater Los Angeles Healthcare System in West
`
`Lost Angeles. In addition, I serve as the Director of the Operation Mend Project to
`
`Enhance Cancer Care for Veterans, a collaboration between UCLA and the VA
`
`Greater Los Angeles Healthcare System to enhance cancer care for veterans.
`
`5
`
`
`
`3.
`
`I received my Bachelor’s degree in Chemistry from Wesleyan
`
`University in 1986, and my MD. from the Duke University School of Medicine in
`
`1990.
`
`l have been in active medical practice since 1991, including an internship in
`
`internal medicine at the University of Southern California, Los Angeles, a
`
`residency in internal medicine at the University of Washington, Seattle, and a
`
`fellowship in hematology/oncology at the UCLA School of Medicine. I was Board
`
`Certified in internal medicine in 1991 and have been Board Certified in oncology
`
`since 1998.
`
`4.
`
`I have both clinical and laboratory research programs. As the director
`
`of the clinical trials program in prostate cancer at UCLA, 1 conduct multiple
`
`prostate cancer clinical trials that span the spectrum of the states of the disease,
`
`from neoadjuvant therapies to post-chemotherapy, castration-resistant disease. My
`
`laboratory research program, which includes programs funded by the NIH, Prostate
`
`Cancer Foundation, American Cancer Society, Department of Defense, and the
`
`Department of Veterans Affairs, is focused on identifying biochemical targets for
`
`drug development in castration-resistant prostate cancer and kidney cancer.
`
`I have
`
`been the recipient of fifty research grants and fellowships, including nineteen that
`
`are currently active, most relate to prostate cancer.
`
`5.
`
`In addition to my medical practice, I serve on a number of advisory
`
`committees relating to oncology and urology. For example, I am a full-time
`
`6
`
`
`
`member of the VA Merit Review Oncology A Study Section (Genitourinary
`
`Prostate Cancer Section), a Director for the Multidisciplinary Tumor Board for
`
`VA—West LA, a grant reviewer for the Prostate Cancer Foundation and the Tower
`
`Cancer Research Foundation, and Chairman of the Board of Directors for the
`
`Brentwood Biomedical Research Institute (a non—profit grant—making organization
`
`at VA). I am also co-Chairman of the steering committee of the Prostate Cancer
`
`Foundation (“PCF”)—VA Strategic Partnership (known as the Precision Oncology
`
`Program Cancer of the Prostate (“POPCAP”) which is part of Vice President
`
`Joseph Biden’s National Cancer Moonshot effort, overseeing $50 million in
`
`research funding over the next five years.
`
`6.
`
`I am a recipient of multiple awards, including Creativity Award from
`
`the Prostate Cancer Foundation (2010, 2011), a Challenge Award, Prostate Cancer
`
`Foundation (2012), STOP Cancer AWard, Jerry Janger Memorial Seed Grant
`
`(2015), and a VALOR Award also from the Prostate Cancer Foundation.
`
`7.
`
`I am an author on over fifty peer-reviewed papers that have been
`
`published or accepted for publication, many relating to treatment of prostate
`
`cancer. A full list of my publications, positions, research grants, and other
`
`qualifications is contained in my curriculum vitae, Exhibit 2039.
`
`7
`
`
`
`C.
`
`8.
`
`Compensation and Prior Testimony
`
`I am being compensated at my customary rate of $900/hour for work
`
`in connection with this proceeding, such as my study of the ’438 patent and the
`
`cited prior art. If I travel for more than three hours for this proceeding (and am not
`
`otherwise billing time), I am being compensated $2,500 per day.
`
`I am also being
`
`reimbursed for reasonable and customary expenses associated with my work in this
`
`proceeding. My compensation is in no way contingent upon the outcome of this
`
`proceeding or the specifics of my testimony.
`
`D. Materials Considered
`
`9.
`
`My opinions are based on my approximately thirty years of education,
`
`research, and medical practice and experience in the fields of internal medicine and
`
`oncology, including my specific experience studying and treating prostate cancer,
`
`as well as my investigation and study of the relevant materials. In forming my
`
`opinions, I have considered the materials referred to herein and listed in Appendix
`
`A.
`
`10.
`
`I reserve the right to revise, supplement, and/or amend my opinions
`
`based on any new information that I receive and on my continuing analysis of the
`
`materials referred to herein and listed in Appendix A. I may also consider
`
`additional information in forming my opinions, including documents thatI may not
`
`yet have reviewed and that have not yet been provided to me.
`
`8
`
`
`
`II.
`
`LEGAL STANDARDS REGARDING PATENTABlLlTY
`
`11.
`
`In expressing my opinions and considering the subject matter of the
`
`claims of the ’438 Patent, I have relied on certain basic legal principles that
`
`counsel have explained to me.
`
`12.
`
`I understand that for an invention claimed in a patent to be valid and
`
`patentable, it must be, among other things, new and not obvious in light of what
`
`was known and came before it. That which was known and came before the
`
`claimed invention is generally referred to as “prior art.”
`
`13.
`
`I understand that in this proceeding the burden of proving that the
`
`’438 Patent is unpatentable falls on the Petitioners, here Mylan, and must be shown
`
`by “preponderance of the evidence.” I understand “preponderance of the
`
`evidence” to mean evidence sufficient to show that a fact is more likely true than
`
`not.
`
`14.
`
`I understand that a claimed invention is obvious when the differences
`
`between the subject matter patented and the prior art are such that the subject
`
`matter as a whole would have been obvious at the time the invention was made to a
`
`person of ordinary skill in the art (“POSA”) to which the subject matter pertains.
`
`I
`
`understand that a POSA is a hypothetical person who has the characteristics of an
`
`ordinary practitioner, including ordinary creativity.
`
`9
`
`
`
`15.
`
`I understand that in order to find a patent claim obvious, certain
`
`findings regarding the claimed invention and the prior art are required. In
`
`particular, I understand that evaluating obviousness requires consideration of four
`
`factors: (a) the scope and content of the prior art; (b) the differences between the
`
`prior art and the claims at issue; (c) the knowledge of a person of ordinary skill in
`
`the pertinent art; and ((1) whether objective factors (which may arise later in time
`
`from when the invention was made) indicating obviousness or non-obviousness are
`
`present in the particular case.
`
`16.
`
`I understand objective factors bearing on the question of obviousness
`
`or non—obviousness may include: (a) commercial success of products covered by
`
`the patent claims; (b) a long-felt need for the invention; (c) skepticism or failed
`
`attempts by others to make the invention or solve the problem solved by the
`
`invention; (d) copying of the invention by others working in the field; (e)
`
`unexpected results achieved by the invention; and (f) the fact that the patentee
`
`proceeded contrary to the accepted wisdom of the prior art. For the objective
`
`factors to be relevant, I understand that the evidence relating to these factors must
`
`have a connection or causal nexus to the subject matter as claimed.
`
`17.
`
`I understand that an invention may be considered non-obvious if one
`
`or more prior art references discourage or lead away from the subject matter of the
`
`invention. I understand that teaching away requires some clear discouragement of
`
`10
`
`10
`
`
`
`the claimed combination in the prior art.
`
`I further understand that the obviousness
`
`inquiry should not be performed with the benefit of hindsight. Instead, the inquiry
`
`must be performed based on knowledge at the time of the invention.
`
`18.
`
`For purposes of this declaration, I have been asked to use August 25,
`
`2006, the earliest effective filing date of the “438 patent, as the relevant date for my
`
`analysis. Unless I state otherwise, my opinions in this declaration are made from
`
`the perspective of a POSA as of August 25, 2006.
`
`III.
`
`TECHNICAL BACKGROUND
`
`A.
`
`Control of Prostate Growth and Function by Androgens
`
`1.
`
`Prostate growth and function
`
`19.
`
`The prostate is a gland of the male reproductive system. The prostate
`
`secretes part (~30%) of the seminal fluid that mixes with sperm to become semen.
`
`The development and maintenance of the prostate is under the control of male sex
`
`steroid hormones known as androgens. Other types of sex steroid hormones
`
`include estrogens and progestins. Non-sex steroids include (among others)
`
`glucocorticoids and mineralocorticoids, both of which are produced in the adrenal
`
`glands. (Ex. 2058 (Seifier) at 540—47; Ex. 2086 (Princip. Endoc. Ch. 72) at 705).
`
`20.
`
`The principal androgen in men is testosterone. Testosterone is
`
`derived from cholesterol, the physiologic substrate of all steroids. Besides
`
`testosterone, the other principal androgens are dehydroepiandrosterone (DHEA)
`
`and androstenedione, which have weak androgenic activity. DHEA and
`
`11
`
`11
`
`
`
`androstenedione are converted into testosterone in peripheral tissues such as
`
`prostate tissue. (Ex. 2086 (Princip. Endoc. Ch. 72) at 710-11; see also EX. 1003
`
`(O’Donnell) at 2317).
`
`21.
`
`In the normal prostate, chronic stimulation with androgens, including
`
`testosterone and its potent metabolite, dihydrotestosterone (“DHT”), is required for
`
`maintenance of tissue homeostasis and secretory function. (Ex. 1023 (Attard
`
`(2005)) at 1241). Androgen deprivation induces programmed cell death (apoptosis)
`
`in the prostate cells and results in involution (i.e., shrinkage) of the prostate gland.
`
`22.
`
`The major source of androgens in the prostate is the testosterone
`
`supplied by the testes through blood circulation (90%). Approximately 10% of
`
`androgens originate from the adrenal glands.
`
`23.
`
`Testosterone production is regulated by the hypothalamus and anterior
`
`pituitary gland. The hypothalamus produces luteinizing hormone—releasing
`
`hormone (LHRH), which stimulates the pituitary to synthesize and secrete
`
`luteinizing hormone (LH). In the testes, LH induces production of testosterone,
`
`which is synthesized from cholesterol. Testosterone acts through a negative
`
`feedback loop to decrease LHRH and, in turn, LH production and secretion,
`
`thereby maintaining serum testosterone at physiological levels. (EX. 2058 (Seifter)
`
`at 608, Fig. 37.3).
`
`12
`
`12
`
`
`
`24.
`
`Testosterone and DHT exert their biological effects by binding to the
`
`androgen receptor (AR), an intracellular protein that plays a critical role in
`
`regulating gene expression. Binding of an androgen to the AR initiates a cascade
`
`of events that results in regulation of transcription of androgen-responsive genes,
`
`which mediate cell growth and differentiation in prostate cells.
`
`(Ex. 1023 (Attard
`
`(2005)) at 1241). In particular, activation of the AR is critical at least initially for
`
`the survival and growth of prostate cancer cells. Figure 1 summarizes the
`
`production of testosterone and its action on the prostate:
`
`
`
`50.
`
`'
`
`I
`
`I
`
`III R
`“‘7
`
`3/ (ilarfloslnrol
`
`i
`
`
`testes-tunnel Ren‘flawl
`"‘ androgens
`
`)
`x
`Nucleus
`{
`_
`2
`(Wing W new .
`
` Hoslatu
`
`I?
`
`‘
`
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`
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`
`Testis“ —'
`
`Admnal qland
`
`2.
`
`Androgen Synthesis
`
`25.
`
`Steroid hormones perform different functions in the body and these
`
`functions are based on the steroid receptor to which they bind. Steroids can be
`
`13
`
`13
`
`
`
`broadly classified as mineralocorticoids (e.g., aldosterone), glucocorticoids (e.g.,
`
`cortisol and corticosterone), and sex steroids (e.g., estrogens, androgens, and
`
`progestins). (Ex. 2086 (Princip. Endocr. Ch. 72) at 705). However, the
`
`classification of steroids in a particular class is not absolute; for example, some
`
`mineralocorticoids can function as weak androgens.
`
`26.
`
`All steroid hormones, including androgens and non-androgen steroids,
`
`are derivatives of cholesterol. (Ex. 2058 (Seifier) at 551). The gonads (testes in
`
`men) produce only sex steroids, whereas the adrenal glands can produce sex
`
`steroids, glucocorticoids, and mineralocorticoids.
`
`(Id. at 551, 608). The testes are
`
`the only organs in men that produce testosterone. Importantly, the adrenal glands
`
`produce sex steroids such as DHEA and androstcnedione, but do not have the
`
`enzymatic capability to produce testosterone and DHT.1 (EX. 1003 (O’Donnell) at
`
`23 17).
`
`27.
`
`Figure 2 below describes the steroid synthesis pathwayzz
`
`1 DHT is derived from testosterone in peripheral tissues (including the testes,
`
`adrenal glands, and prostate).
`
`2 The steroid synthesis pathway was well known as of August 2006.
`
`(See e.g., Ex.
`
`1003 (O’Donnell); Ex. 2086 (Princip. Endocr. Ch. 72) at 707).
`
`10
`
`14
`
`14
`
`
`
`Figure 2
`
`M fnerlloaofllcalda
`(2|. carbons)
`
`H
`
`
`
`
`
`
` _ Dehydroepl-
`
`
`1‘:
`androsterona
`
`.\
`
`'
`
`I
`
`v -
`
`v
`
`M —
`
`-
`
`W
`
`‘
`
`7 77777
`i
`I
`
`A
`
`H
`
`“a.
`
`iiydn
`
`Ii
`
` at}suafimpw
`
`01' enzyme:
`
`Glllulurlocauon
`seems».-
`.‘..
`H
`M
`
`_
`
`
`
`i _
`75
`ID
`
`28.
`
`In Figure 2, steroid hormones are identified by their names and
`
`chemical structures. The steroid synthesis pathway includes dozens of different
`
`steroids and their intermediates. (Ex. 2086 (Princip. Endocr. Ch. 72) at 707; Ex.
`
`1003 (O’Donnell) at 2318 Fig. 1). Production of the steroids and intermediates is
`
`carefully regulated in response to changing requirements and/or to maintain
`
`homeostasis.
`
`ll
`
`15
`
`15
`
`
`
`29.
`
`As can be seen, the steroid synthesis pathway is very complex.
`
`Enzymes operate at various steps in the biochemical pathways to regulate the step-
`
`by-step biosynthesis of steroids. Figure 2 shows numerous different enzymes,
`
`inhibition of which will affect the production of downstream reaction products.
`
`While the major reactants and products of each enzymatic reaction are understood,
`
`the action of each enzyme can be affected by other enzymes and components of
`
`these pathways.
`
`30.
`
`In addition, these pathways can be affected by the individual
`
`expression and activity of these enzymes, which may vary in individuals without
`
`resulting in a disease state. The effects of enzyme inhibition can also be impacted
`
`by individual specific factors including other genes that may modify the actions of
`
`other enzymes as well as environmental factors. As a consequence, there may be
`
`significant variability in the effects of enzyme inhibition.
`
`31.
`
`In addition, a number of the steroids have overlapping functions. For
`
`example, cortisol has some weak mineralocorticoid activity and, conversely,
`
`corticosterone (a weak mineralocorticoid) has some glucocorticoid activity. (EX.
`
`2058 (Seifter) at 543); EX. 2086 (Princip. Endocr. Ch. 72) at 710. Thus, these
`
`steroids can provide some compensatory function for each other when one is in
`
`short supply. An example of this compensatory activity is rescue of cortisol
`
`deficiency by corticosterone.
`
`12
`
`16
`
`16
`
`
`
`32.
`
`As a result of differential enzyme expression and regulation, and the
`
`compensatory functions of the steroids, it is not possible to predict in advance
`
`whether changes in the levels of steroid synthesis will result in medical symptoms
`
`requiring clinical intervention.
`
`33.
`
`Figure 2 shows the steps in the production of testosterone and other
`
`male hormones from the initial starting point of cholesterol. The first step in this
`
`pathway is the production of pregnenolone from cholesterol, which is catalyzed by
`
`the enzyme desmolase (also known as side chain cleavage enzyme). (Ex. 2058
`
`(Seifter) at 545, 546). This first step is required for the production of all classes of
`
`steroids produced in the adrenal gland or testes.
`
`34.
`
`Figure 2 also shows the enzyme Cytochrome P450 17 a-
`
`hydroxylase/17,20-lyase (“CYP17”), which is a single protein that catalyzes two
`
`distinct activities, l7a—hydroxylase and 17,20-lyase. CYP17’s l7d-hydroxylase
`
`activity converts (i) pregnenolone —>l7a-hydroxy pregnenolone and (ii)
`
`progesterone —> 17u-hydroxy progesterone. CYP17’s 17,20 lyase activity converts
`
`17d-hydroxy pregnenolone —> DHEA and (ii) l7u-hydroxy progesterone -—>
`
`androstenedione.
`
`(See, e.g., Ex. 2086 (Princip. Endocr. Ch. 72) at 707).
`
`35. Aldosterone is the primary mineralocorticoid in humans. (Ex. 2086
`
`(Princip. Endocr. Ch. 72) at 710). Aldosterone is produced from pregnenolone via
`
`13
`
`17
`
`17
`
`
`
`the following pathway: pregnenolone —> progesterone —> deoxycorticosterone —)
`
`corticosterone —> aldosterone.
`
`36.
`
`Cortisol is the major glucocorticoid in humans. (Ex. 2086 (Princip.
`
`Endocr. Ch. 72) at 709). Cortisol is produced from pregnenolone and progesterone,
`
`via for example: (a) pregnenolone —>17d-hydroxy pregnelenone —> l7u—hydroxy
`
`progesterone —> 1 1-deoxycortisol —> cortisol; or (b) pregnenolone —> progesterone
`
`—>17d-hydroxy progesterone —>1 l-deoxycortisol —> cortisol.
`
`37. Androgens are formed from pregnenolone and progesterone via, for
`
`example: (a) pregnenolone —>17u -hydroxy pregnenolone —> DHEA pathway; or
`
`(b) pregnenolone —-—> progesterone —> 170L-hydroxy-progesterone —>
`
`androstenedione pathway. (As I explained above, DHEA and androstenedione are
`
`adrenal androgens which can be converted into testosterone in the prostate. (EX.
`
`2086 (Princip. Endocr. Ch. 72) at 710).
`
`38.
`
`The declaration of Mylan’s expert, Dr. Garnick, contains a diagram
`
`entitled “Major Pathways in Steroid Biosynthesis”.
`
`(Ex. 1002 (Garnick Dec.) at
`
`1137). The steroid synthesis diagram set forth in 11 37 of Dr. Garnick’s declaration
`
`contains significant omissions. For example, the diagram does not identify
`
`desmolase, the enzyme that converts cholesterol to pregenenolone, which is the
`
`first step of steroid synthesis. This first step is very important because
`
`14
`
`18
`
`18
`
`
`
`pregnelonone is the precursor for all steroid hormones. Production of all steroids
`
`is suppressed if desmolase activity is inhibited.
`
`39.
`
`In addition, Dr. Garnick’s diagram does not clearly describe the dual
`
`17a-hydroxylase and 17,20-1yase activities of CYPl7. This is another important
`
`omission because as of August 2006, abiraterone acetate was known to
`
`differentially affect CYP17’s 17cc-hydroxylase and 17,20—1yase activities: the prior
`
`art showed that abiraterone acetate is a more potent inhibitor of the 17,20-1yase
`
`activity than l7d-hydroxylase inhibitory activity.
`
`(See, e. g, Ex. 1003 (O’Donnell)
`
`at 2322); Ex. 1005 (Barrie) at col. 22:60-66).
`
`3.
`
`Clinical Disorders Associated with Under-Production or
`
`Over-Production of Steroids and Their Treatment
`
`40.
`
`Levels of steroid hormones normally vary in response to changing
`
`conditions in the body. Interference with steroid synthesis can lead to clinical
`
`disorders that interfere with the body’s normal response to stimuli. These
`
`disorders are classified as those that cause under-production or over-production of
`
`steroids. (Ex. 2058 (Seifter) at 545).
`
`lrregularities in steroid synthesis can occur
`
`due to many factors, for example, damage to the adrenal cortex, defects in the
`
`functioning of the hypothalamus or pituitary gland, or the actions of drugs that
`
`effect steroid hormone production.
`
`41.
`
`Cortisol is the major glucocorticoid in humans. (Ex. 2086 (Princip.
`
`Endocr. Ch. 72) at 709). Cortisol has multiple functions in the body. The main
`
`15
`
`19
`
`19
`
`
`
`function of cortisol is to control cellular metabolism and glucose levels in the
`
`blood. Cortisol secretion is also necessary for the body to respond to stress (e.g.,
`
`surgery, trauma, pain, infection, hypoglycemia, and hemorrhage).
`
`(See, e. g., Ex.
`
`2058 (Seifter) at 543-44).
`
`42.
`
`Cortisol levels vary during the day, with peak values in the morning
`
`and low levels in the evening. (Id. at 548). The synthesis and Secretion of cortisol
`
`is regulated by the central nervous system. In response to signals from the
`
`hypothalamus following neural stimuli, the anterior pituitary stimulates the release
`
`of adrenocorticotrophic hormone (“ACTH”). (1d. at 542.) ACTH acts on the
`
`adrenal cortex to increase synthesis of cortisol from cholesterol and its release by
`
`the adrenal cortex. As shown in Figure 3 below, cortisol production is tightly
`
`regulated to maintain its concentration in a physiologic range. This occurs not
`
`only through stimulation and secretion of cortisol by ACTH, but also through the
`
`negative feedback action of cortisol on the hypothalamus and pituitary to suppress
`
`secretion of ACTH.
`
`(See generally Ex. 2058 (Seifter) at 541-42; Ex. 2086
`
`(Princip. Endocr. Ch. 72) at 710)).
`
`16
`
`20
`
`20
`
`
`
`Figure 3
`
`Hypothalnmus
`
`
`
`43.
`
`The primary mineralocorticoid in humans is aldosterone. (Ex. 2086
`
`(Princip. Endocr. Ch. 72) at 710). Aldosterone controls water and salt retention by
`
`increasing sodium reabsorption and potassium excretion. Aldosterone production
`
`is regulated not only by ACTH, but also by the renin—angiotensin—aldosterone
`
`system. (Ex. 2058 (Seifter) at 543)
`
`44. Adrenal insufficiency is a clinical disorder that is typically
`
`characterized by the under—produetion of cortisol (a glucocorticoid) and
`
`aldosterone (a mineralocorticoid). Adrenal insufficiency can be “primary” (caused
`
`by impairment of the adrenal gland) or “secondary” (caused by impairment of the
`
`pituitary). (Ex. 2058 (Seifier) at 548-549).
`
`45.
`
`Symptoms of primary adrenal insufficiency include, but are not
`
`limited to, severe fatigue, low blood pressure, low blood sugar, dizziness,
`
`I7
`
`21
`
`21
`
`
`
`weakness, loss of appetite, weight loss, and increased skin pigmentation. (Ex.
`
`2058 (Seifter) at 549; Ex. 1025 (Harrison’s) at 2142).3
`
`46.
`
`As of August 2006, treatment of adrenal insufficiency involved
`
`replacing or substituting the hormones (118., glucocorticoids and
`
`mineralocorticoids) that the adrenal glands are not or are insufficiently making by
`
`administering physiologic or replacement doses of the under-produced hormones.
`
`47.
`
`The most commonly employed hormone for glucocorticoid
`
`replacement therapy was hydrocortisone (the synthetic form of cortisol), which has
`
`both glucocorticoid and mineralocorticoid activity. (Ex. 1025 (Harrison’s) at
`
`2147). The synthetic glucocorticoid prednisone, which has slight to moderate
`
`mineralocorticoid activity, was also used for replacement therapy for patients with
`
`adrenal insufficiency. (Id) The use of synthetic glucocorticoid dexamethasone,
`
`which has more potent glucocorticoid activity than hydrocortisone and prednisone
`
`is less common because it has less mineralocorticoid activity. (Id)
`
`48. Mineralocorticoid excess syndrome is a clinical disorder that is
`
`characteriZed by the excessive production of mineralocorticoids.
`
`(EX. 2066
`
`(Mantero) at 81; EX. 2087 (Princip. Endocr. Ch. 73) at 717). Symptoms of
`
`3 Deficiency of sex steroids is not a manifestation of adrenal insufficiency because
`
`they are produced predominantly by the gonads.
`
`18
`
`22
`
`22
`
`
`
`mineralocorticoid excess syndrome include hypertension (ta, high blood
`
`pressure), hypokalemia (i.e., low potassium levels), and fluid retention.
`
`(EX. 2066
`
`(Mantero) at 82; Ex. 2087 (Princip. Endocr. Ch. 73) at 717). As of August 2006, it
`
`was known that symptoms of mineralocorticoid excess could be managed without
`
`glucocorticoid replacement, for example, by the use of drugs that block the activity
`
`of mineralocorticoids. (See generally EX. 2066 (Mantero)). Indeed, this was the
`
`preferred method of treatment.
`
`49. While certain treatments and disease states may be associated with
`
`changes in adrenal steroid levels, these changes may not be associated with clinical
`
`manifestations. Before glucocorticoid replacement is even considered, an essential
`
`first question that must be answered is whether the patient has a clinical disorder
`
`that is serious enough to warrant glucocorticoid replacement. This is because
`
`glucocorticoid therapy is not only associated with side effects and complications,
`
`but can also further reduce the body’s ability to produce steroids. (I discuss these
`
`side effects and complications in detail infra in M 131-142). This was well known
`
`as of August 2006, and remains true today. (See, e.g., EX. 2068 (Swartz) at 239
`
`(“Before instituting corticosteroid therapy, it is necessary to carefully consider the
`
`gains that can be reasonably expected versus the potentially undesirable metabolic
`
`actions of large doses of corticosteroids. The increased incidence of hypertension,
`
`chronic infectious disease, osteoporosis and impaired glucose tolerance. . .must be
`
`19
`
`23
`
`23
`
`
`
`carefully considered before embarking on a programme of steroid administration”).
`
`Therefore, as of August 2006, a POSA would have been motivated to avoid
`
`administering glucocorticoid replacement therapy if a clinical condition could be
`
`managed without it.
`
`50.
`
`Indeed, laboratory abnormalities showing over-production or under-
`
`production of steroid hormones in the absence of clinical manifestations were
`
`understood by a POSA to not require clinical intervention. In fact, laboratory
`
`evidence of corticosteroid deficiency in the absence of symptoms attributable to
`
`the deficiency would not have even been detected in routine clinical practice
`
`because the evaluation for corticosteroid deficiency would not be triggered in the
`
`absence of clinical symptoms. (Ex. 1025 (Harrison’s) at 2142-43) (describing
`
`clinical signs and symptoms of adrenal insufficiency, which are to be confirmed by
`
`laboratory findings).
`
`B.
`
`Prostate Cancer and Its Treatment as of August 2006
`
`1.
`
`Prevalence, Diagnosis, and Early Stage Treatment
`
`51.
`
`Globally, prostate cancer is the second most common cause of cancer
`
`other than non-melanomatous skin-cancer an