`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________
`
`MYLAN PHARMACEUTICALS INC.
`Petitioners,
`
`v.
`
`JANSSEN ONCOLOGY, INC.
`Patent Owner.
`
`_______________________
`
`Case IPR2016-01332
`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
`Mylan v. Janssen IPR2016-01332
`
`

`

`
`
`TABLE OF CONTENTS
`
`I.
`
`Introduction ...................................................................................................... 1
`
`A.
`
`B.
`
`C.
`
`Engagement ........................................................................................... 1
`
`Background and Qualifications ............................................................. 1
`
`Compensation and Prior Testimony ...................................................... 4
`
`D. Materials Considered ............................................................................. 4
`
`II.
`
`Legal Standards Regarding Patentability ........................................................ 5
`
`III. 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.
`
`Prevalence, Diagnosis, and Early Stage Treatment .................. 20
`
`First Line Hormonal Therapy for Metastatic Prostate Cancer . 22
`
`3. 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
`
`

`

`
`
`B.
`
`The Barrie patent (Exhibit 1005) ........................................................ 37
`
`C. 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.
`
`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 ............. 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.
`
`b.
`
`O’Donnell teaches that abiraterone acetate did not
`have any significant effect upon cortisol levels in
`patients ........................................................................... 46
`
`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
`
`B.
`
`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
`
`

`

`
`
`Syndrome or Symptoms of Hypertension, Hypokalemia, or
`Fluid Retention .......................................................................... 61
`
`2.
`
`3.
`
`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.
`
`2.
`
`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 ’438 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
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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 Mylan Pharmaceuticals, Inc. (hereinafter “Mylan”) in
`
`Case No. IPR2016-01332.
`
`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.
`
`
`
`1
`
`

`

`
`
`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
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`

`

`
`
`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 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.
`
`
`
`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
`
`

`

`
`
`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. 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).
`
`
`
`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. 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:
`
`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. 1003 (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.
`
`1003 (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.
`
`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.
`
`
`
`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 Mylan’s expert, Dr. Garnick, contains a diagram
`
`entitled “Major Pathways in Steroid Biosynthesis”. (Ex. 1002 (Garnick Dec.) at
`
`¶37). The steroid synthesis diagram set forth in ¶ 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
`
`

`

`
`
`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
`
`17α-hydroxylase and 17,20-lyase activities of CYP17. This is another important
`
`omission because as of August 2006, abiraterone acetate was known to
`
`differentially affect CYP17’s 17α-hydroxylase and 17,20-lyase activities: the prior
`
`art showed that abiraterone acetate is a more potent inhibitor of the 17,20-lyase
`
`activity than 17α-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
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`conditions in the body. Interference with steroid synthesis can lead to clinical
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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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`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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`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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`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. 1025 (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. 1025 (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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`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 mineralocorticoids. (Ex. 2066
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`(Mantero) at 81; Ex. 2087 (Princip. Endocr. Ch. 73) at 717). Symptoms of
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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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`mineralocorticoid excess syndrome include hypertension (i.e., high blood
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`pressure), hypokalemia (i.e., low potassium levels), and fluid retention. (Ex. 2066
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`(Mantero) at 82; Ex. 2087 (Princip. Endocr. Ch. 73) at 717). As of August 2006, it
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`was known that symptoms of mineralocorticoid excess could be managed without
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`glucocorticoid replacement, for example, by the use of drugs that block the activity
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`of mineralocorticoids. (See generally Ex. 2066 (Mantero)). Indeed, this was the
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`preferred method of treatment.
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`49. While certain treatments and disease states may be associated with
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`changes in adrenal steroid levels, these changes may not be associated with clinical
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`manifestations. Before glucocorticoid replacement is even considered, an essential
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`first question that must be answered is whether the patient has a clinical disorder
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`that is serious enough to warrant glucocorticoid replacement. This is because
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`glucocorticoid therapy is not only associated with side effects and complications,
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`but can also further reduce the body’s ability to produce steroids. (I discuss these
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`side effects and complications in detail infra in ¶¶ 131-142). This was well known
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`as of August 2006, and remains true today. (See, e.g., Ex. 2068 (Swartz) at 239
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`(“Before instituting corticosteroid therapy, it is necessary to carefully consider the
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`gains that can be reasonably expected versus the potentially undesirable metabolic
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`actions of large doses of corticosteroids. The increased incidence of hypertension,
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`chronic infectious disease, osteoporosis and impaired glucose tolerance…must be
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`carefully considered before embarking on a programme of steroid administration”).
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`Therefore, as of August 2006, a POSA would have been motivated to avoid
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`administering glucocorticoid replacement therapy if a clinical condition could be
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`managed without it.
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`50.
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`Indeed, laboratory abnormalities showing over-production or under-
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`production of steroid hormones in the absence of clinical manifestations were
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`unders