`
`UNITED STATES PATENT AND TRADEMARK OFFICE
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`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________
`
`WOCKHARDT BIO AG
`Petitioner
`
`
`
`JANSSEN ONCOLOGY, INC.
`Patent Owner
`
`_______________________
`
`Case IPR2016-01582
`Patent 8,822,438 B2
`
`_______________________
`
`
`DECLARATION OF MATTHEW B. RETTIG, M.D.
`IN SUPPORT OF JANSSEN ONCOLOGY, INC.’S
`PATENT OWNER RESPONSE
`
`1
`
`
`
`
`
`
`
`JANSSEN EXHIBIT 2038
`Wockhardt v. Janssen IPR2016-01582
`
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`Introduction ..........................................................................................................................1
`
`A.
`
`B.
`
`C.
`
`D.
`
`Engagement..............................................................................................................1
`
`Background and Qualifications ................................................................................1
`
`Compensation and Prior Testimony .........................................................................4
`
`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 ...........................................21
`
`1.
`
`2.
`
`3.
`
`Prevalence, Diagnosis, and Early Stage Treatment ...................................21
`
`First Line Hormonal Therapy for Metastatic Prostate Cancer ...................22
`
`Metastatic Castration Resistant Prostate Cancer ........................................23
`
`C.
`
`Endpoints for Evaluating Response to Prostate Cancer Treatment .......................26
`
`The ‘438 Patent and its claims ...........................................................................................29
`
`Claim Construction ............................................................................................................33
`
`Person of Ordinary Skill in the Art ....................................................................................34
`
`IV.
`
`V.
`
`VI.
`
`VII. The Prior Art Relied On by Petitioners ..............................................................................35
`
`A.
`
`B.
`
`C.
`
`Gerber (Exhibit 1004) ............................................................................................35
`
`O’Donnell (Exhibit 1005) ......................................................................................37
`
`Sartor (Ex. 1006) ....................................................................................................39
`
`
`
`i
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`
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`
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`VIII. Rebuttal to Dr. Godley’s Opinions Concerning Obviousness ...........................................41
`
`A.
`
`There Was No Scientific Basis in the Prior Art to Add Prednisone to Abiraterone
`Acetate for Purposes of Glucocorticoid Replacement ...........................................41
`
`1.
`
`2.
`
`3.
`
`4.
`
`As of August 2006, a POSA Would Understand that Abiraterone Acetate’s
`Mechanism of Action and Hormonal Side Effects Were Very Different
`from Ketoconazole .....................................................................................41
`
`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 ....................................................47
`
`a.
`
`b.
`
`O’Donnell teaches that abiraterone acetate did not have any
`significant effect upon cortisol levels in patients .......................47
`
`A POSA Would Have Concluded from the Prior Art as a
`Whole that Abiraterone Acetate did not Cause Any Clinical
`Symptoms Requiring Glucocorticoid Replacement ..................52
`
`As of August 2006, a POSA Would Understand that Gerber’s Use of
`“Glucocorticoid Replacement” with Ketoconazole Did Not Apply to
`Abiraterone Acetate ...................................................................................56
`
`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 Cancer57
`
`B.
`
`There Was No Scientific or Clinical Basis in the Prior Art to Add Prednisone to
`Abiraterone Acetate to Address Mineralocorticoid Excess ...................................63
`
`1.
`
`2.
`
`3.
`
`As of August 2006, a POSA Would Understand that Ketoconazole Did
`Not Cause Mineralocorticoid Excess Syndrome or Symptoms of
`Hypertension, Hypokalemia, or Fluid Retention .......................................63
`
`As of August 2006, Nothing in the Prior Art Would Have Suggested to a
`POSA that Abiraterone Acetate Would Cause Mineralocorticoid Excess 68
`
`Even if Mineralocorticoid Excess Was Observed, As of August 2006, a
`POSA Would Understand that It Could Be Managed Without
`Glucocorticoid Replacement ......................................................................71
`
`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 Based on Gerber and/or Ketoconazole .....73
`
`1.
`
`As of August 2006, the Prior Art Did Not Teach that Ketoconazole was
`“Safe and Effective” for the Treatment of mCRPC ...................................73
`
`
`
`ii
`
`
`
`
`
`D.
`
`The Prior Art Did Not Provide a Scientific or Clinical Basis for Believing that
`Prednisone Would be Effective for Treating Cancer Based on Sartor and/or the
`State of the Art .......................................................................................................85
`
`1.
`
`2.
`
`Sartor Did Not Establish that Prednisone “Treats Prostate Cancer ...........86
`
`No Other Prior Art Cited by Wockhardt Established that Glucocorticoids,
`Including Prednisone, Were Effective for Treating Prostate Cancer .........90
`
`a.
`
`b.
`
`c.
`
`Prior Art Describing Single-Agent Use of Glucocorticoids,
`Such as Prednisone, Did Not Demonstrate Prednisone Was an
`Effective Treatment for Prostate Cancer ..................................91
`
`Prior Art Describing Use of Prednisone with Ketoconazole as
`Glucocorticoid Replacement Does Not Demonstrate
`Prednisone Was an Effective Treatment for Prostate Cancer .98
`
`Glucocorticoids, including prednisone, were used with
`chemotherapy agents for managing side effects that would not
`occur with abiraterone acetate, not for “treating” prostate
`cancer ............................................................................................99
`
`IX.
`
`Real World Facts Or “Objective Indicia of Non-Obviousness” Support the Non-
`Obviousness of the ’438 Patent Invention .......................................................................104
`
`A.
`
`B.
`
`C.
`
`D.
`
`The Invention Claimed in the ‘438 Patent Resulted in Unexpected Clinical
`Efficacy ................................................................................................................104
`
`The Invention Claimed in the ‘438 Patent is Embodied in ZYTIGA® Therapy and
`Contributes Significantly to the Success of ZYTIGA® ......................................114
`
`Long Felt But Unsolved Need .............................................................................118
`
`Skepticism and Failure of Others .........................................................................118
`
`1.
`
`2.
`
`The O’Donnell Studies ............................................................................119
`
`Other Failed Phase III Clinical Trials ......................................................120
`
`
`
`
`
`iii
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`
`
`I.
`
`I, Matthew B. Rettig, M.D., hereby declare as follows:
`
`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 Wockhardt Bio AG (hereinafter “Wockhardt”) in Case
`
`No. IPR2016-01582.
`
`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.
`
`
`
`1
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`
`
`
`
`3.
`
`I received my Bachelor’s degree in Chemistry from Wesleyan
`
`University in 1986, and my M.D. from the Duke University School of Medicine in
`
`1990. I 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, I 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
`
`
`
`2
`
`
`
`
`
`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.
`
`
`
`3
`
`
`
`
`
`C. Compensation and Prior Testimony
`8.
`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 that I may not
`
`yet have reviewed and that have not yet been provided to me.
`
`
`
`4
`
`
`
`
`
`II. LEGAL STANDARDS REGARDING PATENTABILITY
`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 Wockhardt, 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.
`
`
`
`5
`
`
`
`
`
`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 (d) 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
`
`
`
`6
`
`
`
`
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`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 (Seifter) 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
`
`
`
`7
`
`
`
`
`
`androstenedione are converted into testosterone in peripheral tissues such as
`
`prostate tissue. (Ex. 2086 (Princip. Endoc. Ch. 72) at 710-11; see also Ex. 1005
`
`(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. 1008 (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).
`
`
`
`8
`
`
`
`
`
`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. 1008 (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:
`
`Figure 1
`
`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
`
`
`
`
`
`9
`
`
`
`
`
`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 (Seifter) 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 androstenedione, but do not have the
`
`enzymatic capability to produce testosterone and DHT.1 (Ex. 1005 (O’Donnell) at
`
`2317).
`
`27. Figure 2 below describes the steroid synthesis pathway2:
`
`
`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.
`
`1005 (O’Donnell); Ex. 2086 (Princip. Endocr. Ch. 72) at 707).
`
`
`
`10
`
`
`
`
`
`Figure 2
`
`
`
`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.
`
`1005 (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.
`
`
`
`11
`
`
`
`
`
`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
`
`
`
`
`
`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 α-
`
`hydroxylase/17,20-lyase (“CYP17”), which is a single protein that catalyzes two
`
`distinct activities, 17α-hydroxylase and 17,20-lyase. CYP17’s 17α-hydroxylase
`
`activity converts (i) pregnenolone →17α-hydroxy pregnenolone and (ii)
`
`progesterone → 17α-hydroxy progesterone. CYP17’s 17,20 lyase activity converts
`
`17α-hydroxy pregnenolone → DHEA and (ii) 17α-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
`
`
`
`
`
`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 →17α-hydroxy pregnelenone → 17α-hydroxy
`
`progesterone → 11-deoxycortisol → cortisol; or (b) pregnenolone → progesterone
`
`→17α-hydroxy progesterone →11-deoxycortisol → cortisol.
`
`37. Androgens are formed from pregnenolone and progesterone via, for
`
`example: (a) pregnenolone →17α -hydroxy pregnenolone → DHEA pathway; or
`
`(b) pregnenolone → progesterone → 17α-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 Wockhardt’s expert, Dr. Godley, contains a
`
`diagram entitled “Pathways of adrenal steroid hormone synthesis.” (Ex. 1002
`
`(Godley Dec.) at ¶32). The steroid synthesis diagram set forth in ¶32 of Dr.
`
`Godley declaration contains several oversimplifications. For example, the diagram
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`includes headings – mineralocorticoid pathway, glucocorticoid pathway, and
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`androgen pathway – above three columns of the diagram representing enzymatic
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`reactions. The headings are misleading insofar as they do not show that many of
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`14
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`the adrenal hormones depicted in the diagram have multiple functions. For
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`example, cortisol, a glucocorticoid, has some weak mineralocorticoid activity. In
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`addition, corticosterone has glucocorticoid activity. Further, in 2006, studies had
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`shown that glucocorticoids could have some androgenic activity. (Ex. 2024
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`(Krishnan) at Abstract, 1891-94, 1897-99; Ex. 1036 (Fakih) at 554, 560-61). And,
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`in fact, the inventors of the ‘438 patent hypothesized and demonstrated that
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`precursor adrenal steroids could also have androgenic activity in advanced prostate
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`cancer. (See, e.g., Ex. 1079 (Attard 2008) at 4565). As a result, these categorical
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`headings oversimplify the complex nature of the adrenal steroid synthesis
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`pathways and the multifaceted role steroid hormones plays in human physiology.
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`39.
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` Dr. Godley’s diagram does, however, clearly describe the dual 17α-
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`hydroxylase and 17,20-lyase activities of CYP17. This is important because as of
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`August 2006, abiraterone acetate was known to differentially affect CYP17’s 17α-
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`hydroxylase and 17,20-lyase activities: the prior art showed that abiraterone
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`acetate is a more potent inhibitor of the 17,20-lyase activity than 17α-hydroxylase
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`inhibitory activity. (See, e.g., Ex. 1005 (O’Donnell) at 2322); Ex. 1030 (Barrie) at
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`col. 22:60-66).
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`3.
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`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
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`conditions in the body. Interference with steroid synthesis can lead to clinical
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`15
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`disorders that interfere with the body’s normal response to stimuli. These
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`disorders are classified as those that cause under-production or over-production of
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`steroids. (Ex. 2058 (Seifter) at 545). Irregularities in steroid synthesis can occur
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`due to many factors, for example, damage to the adrenal cortex, defects in the
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`functioning of the hypothalamus or pituitary gland, or the actions of drugs that
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`effect steroid hormone production.
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`41. Cortisol is the major glucocorticoid in humans. (Ex. 2086 (Princip.
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`Endocr. Ch. 72) at 709). Cortisol has multiple functions in the body. The main
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`function of cortisol is to control cellular metabolism and glucose levels in the
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`blood. Cortisol secretion is also necessary for the body to respond to stress (e.g.,
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`surgery, trauma, pain, infection, hypoglycemia, and hemorrhage). (See, e.g., Ex.
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`2058 (Seifter) at 543-44).
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`42. Cortisol levels vary during the day, with peak values in the morning
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`and low levels in the evening. (Id. at 548). The synthesis and secretion of cortisol
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`is regulated by the central nervous system. In response to signals from the
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`hypothalamus following neural stimuli, the anterior pituitary stimulates the release
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`of adrenocorticotrophic hormone (“ACTH”). (Id. at 542.) ACTH acts on the
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`adrenal cortex to increase synthesis of cortisol from cholesterol and its release by
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`the adrenal cortex. As shown in Figure 3 below, cortisol production is tightly
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`regulated to maintain its concentration in a physiologic range. This occurs not
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`16
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`only through stimulation and secretion of cortisol by ACTH, but also through the
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`negative feedback action of cortisol on the hypothalamus and pituitary to suppress
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`secretion of ACTH. (See generally Ex. 2058 (Seifter) at 541-42; Ex. 2086
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`(Princip. Endocr. Ch. 72) at 710)).
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`Figure 3
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`
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`43. The primary mineralocorticoid in humans is aldosterone. (Ex. 2086
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`(Princip. Endocr. Ch. 72) at 710). Aldosterone controls water and salt retention by
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`increasing sodium reabsorption and potassium excretion. Aldosterone production
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`is regulated not only by ACTH, but also by the renin-angiotensin-aldosterone
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`system. (Ex. 2058 (Seifter) at 543)
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`44. Adrenal insufficiency is a clinical disorder that is typically
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`characterized by the under-production of cortisol (a glucocorticoid) and
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`aldosterone (a mineralocorticoid). Adrenal insufficiency can be “primary” (caused
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`17
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`by impairment of the adrenal gland) or “secondary” (caused by impairment of the
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`pituitary). (Ex. 2058 (Seifter) at 548-549).
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`45. Symptoms of primary adrenal insufficiency include, but are not
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`limited to, severe fatigue, low blood pressure, low blood sugar, dizziness,
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`weakness, loss of appetite, weight loss, and increased skin pigmentation. (Ex.
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`2058 (Seifter) at 549; Ex. 1009 (Harrison’s) at 2142).3
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`46. As of August 2006, treatment of adrenal insufficiency involved
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`replacing or substituting the hormones (i.e., glucocorticoids and
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`mineralocorticoids) that the adrenal glands are not or are insufficiently making by
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`administering physiologic or replacement doses of the under-produced hormones.
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`47. The most commonly employed hormone for glucocorticoid
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`replacement therapy was hydrocortisone (the synthetic form of cortisol), which has
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`both glucocorticoid and mineralocorticoid activity. (Ex. 1009 (Harrison’s) at
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`2147). The synthetic glucocorticoid prednisone, which has slight to moderate
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`mineralocorticoid activity, was also used for replacement therapy for patients with
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`adrenal insufficiency. (Id.) The use of synthetic glucocorticoid dexamethasone,
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`3 Deficiency of sex steroids is not a manifestation of adrenal insufficiency because
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`they are produced predominantly by the gonads.
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`18
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`which has more potent glucocorticoid activity than hydrocortisone and prednisone
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`is less common because it has less mineralocorticoid activity. (Id.)
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`48. Mineralocorticoid excess syndrome is a clinical disorder that is
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`characterized by the excessive production of mineralo