J$N20}l)
`EXHIBIT NO._
`1. l l, · l 1 W1C
`
`IN THE UNITED ST ATES PATENT AND TRADEMARK OFFICE
`BEFORE THE PA TENT TRIAL AND APPEAL BOARD
`In the Inter Partes Review (IPR) of
`U.S. Patent Nos. 8,822,438
`
`DECLARATION OF DR. SCOTT R. SERELS, M.D.
`
`I, Scott R. Serels, M.D., do hereby declare:
`
`1.
`
`I am making this declaration at the request of Amerigen
`
`Pharmaceuticals, Ltd., in the matter of the Inter Partes Review (IPR) of U.S. Patent
`
`No. 8,822,438 (the '"438 Patent"), as set forth in the above caption.
`
`2.
`
`I am being compensated for my work in this matter at the rate of
`
`$500.00 per hour. My compensation in no way depends on the outcome of this
`
`proceeding. The opinions I set forth herein are my own, and are based on the
`
`education, experience, training and skill that I have accumulated in the course of
`
`my career as a practicing urologist and researcher, as well as the materials I have
`
`reviewed in connection with this case.
`
`A.
`
`Education and Professional Background
`
`3.
`
`I currently practice medicine at the Bladder Control Center of
`
`Norwalk, where I am the director of daily operations involving urodynamics,
`
`female urology and neurourology. I was board certified in urology in 2001, and
`
`American Board of Urology recertified in 2009.
`
`I became board certified in
`
`female pelvic medicine and reconstructive surgery in 2013.
`
`AMERIGEN 1002
`
`JANSSEN EXHIBIT 2010
`Mylan v. Janssen IPR2016-01332
`
`
`EXHIBIT NO._
`1. l l, · l 1 W1C
`
`IN THE UNITED ST ATES PATENT AND TRADEMARK OFFICE
`BEFORE THE PA TENT TRIAL AND APPEAL BOARD
`In the Inter Partes Review (IPR) of
`U.S. Patent Nos. 8,822,438
`
`DECLARATION OF DR. SCOTT R. SERELS, M.D.
`
`I, Scott R. Serels, M.D., do hereby declare:
`
`1.
`
`I am making this declaration at the request of Amerigen
`
`Pharmaceuticals, Ltd., in the matter of the Inter Partes Review (IPR) of U.S. Patent
`
`No. 8,822,438 (the '"438 Patent"), as set forth in the above caption.
`
`2.
`
`I am being compensated for my work in this matter at the rate of
`
`$500.00 per hour. My compensation in no way depends on the outcome of this
`
`proceeding. The opinions I set forth herein are my own, and are based on the
`
`education, experience, training and skill that I have accumulated in the course of
`
`my career as a practicing urologist and researcher, as well as the materials I have
`
`reviewed in connection with this case.
`
`A.
`
`Education and Professional Background
`
`3.
`
`I currently practice medicine at the Bladder Control Center of
`
`Norwalk, where I am the director of daily operations involving urodynamics,
`
`female urology and neurourology. I was board certified in urology in 2001, and
`
`American Board of Urology recertified in 2009.
`
`I became board certified in
`
`female pelvic medicine and reconstructive surgery in 2013.
`
`AMERIGEN 1002
`
`JANSSEN EXHIBIT 2010
`Mylan v. Janssen IPR2016-01332
`
`
`
`4.
`
`I received my bachelor of arts degrees in biology and economics
`
`magna cum laude from Brandeis University in 1988.
`
`I received my medical
`
`degree from New York University School of Medicine in 1992. I then completed
`
`two years of surgical residency, and four years of urologic residency at the Albert
`
`Einstein College of Medicine and Montefiore Medical Center. During my urologic
`
`residency, I completed rotations in urologic oncology and female urology at
`
`Memorial Sloan Kettering and UCLA, respectively. I then went to the Cleveland
`
`Clinic Foundation to serve as a clinical associate specializing in female urology,
`
`urodynamics and neurourology.
`
`5.
`
`I am Associate Professor of Urology at the University of Vermont
`
`School of Medicine and a clinical faculty member at the Frank H. Netter School of
`
`Medicine at Quinnipiac University, where I also serve as a member of the faculty
`
`counsel. I am also the Urogynecology Section Head at Norwalk Hospital in
`
`Norwalk, Connecticut.
`
`I have authored approximately 100 peer reviewed
`
`publications, presentations and abstracts in the fields of urology and
`
`urogynecology.
`
`6.
`
`Attached as Exhibit 1 is my curriculum vitae providing the details of
`
`my education, experience and training in medicine, including in the field of
`
`urology.
`
`Page 2
`
`
`
`B. Materials Considered
`
`7.
`
`The list of materials I considered in forming the opinions set forth in
`
`this declaration includes the following:
`
`Description
`Exhibit
`AMO 1001 U.S. Patent No. 8,822,438 to Auerbach and Belldegrum, "Methods
`and Compositions for Treating Cancer" ("the '438 patent")
`AMO 1003 O'Donnell, A. et al., "Hormonal impact of the 17a-hydroxylase/C17_
`20-lyase inhibitor abiraterone acetate (CB7630) in patients with
`prostate cancer," British Journal of Cancer, (90):2317-2325 (2004)
`("O'Donnell")
`
`AMO 1004 Gerber, G.S. et al., "Prostate specific antigen for assessing response
`to ketoconazole and prednisone in patients with hormone refractory
`metastatic cancer," The Journal of Urology, 144(5):1177-9 (1990)
`("Gerber")
`AMO 1005 U.S. Patent No. 5,604,213, Barrie S.E. et al., "17-Substituted
`Steroids Useful In Cancer Treatment" ("the '213 patent")
`AMO 1006 Tannock, I. et al., "Chemotherapy with Mitoxantrone Plus
`Prednisone or Prednisone Alone for Symptomatic Hormone-
`Resistant Prostate Cancer," Journal of Clin. Oncology, 14(6): 1756-
`1764 (1996)
`AMO 1009 Ryan, C.J., et. al., "Abiraterone in Metastatic Prostate Cancer
`without Previous Chemotherapy," New Engl. J Med., 368: 138-148
`(2012)
`AMO 1011 March 4, 2013 Response (excerpt from prosecution history of '438
`patent)
`
`Page 3
`
`
`
`AMG 1012 June 4, 2013 Response (excerpt from prosecution history of '438
`patent)
`
`AMG 1018 Zytiga® Prescribing Information (2011)
`
`AMG 1019 Zytiga® Prescribing Information and Co-administration Brochure
`(2015)
`
`AMG 1020 Harris, K.A. et al., "Low dose ketoconazole with replacement doses
`of hydrocortisone in patients with progressive androgen independent
`prostate cancer," J Ural., 168(2):542-5 (2002)
`AMG 1021 William Oh, "Secondary hormonal therapies in the treatment of
`prostate cancer," Urology, volume 60:87-93 (Supplement 3A)
`(2002)
`AMG 1022 Tannock, I. et al., "Docetaxel plus Prednisone or Mitoxantrone plus
`Prednisone for Advanced Prostate Cancer," N Eng. J Med.,
`351:1502-12 (2004)
`
`AMG 1023 Attard, G. et al., "Selective blockade of androgenic steroid synthesis
`by novel lyase inhibitors as a therapeutic strategy for treating
`metastatic prostate cancer," Br. J Ural. 96(9): 1241-1246 (2005)
`AMG 1024 Hellerstedt et al., "The Current State of Hormonal Therapy for
`Prostate Cancer," CA Cancer J Clin., 52: 154-179 (2002)
`AMG 1025 Kasper, D.L. et al. (Eds.), Harrison's Principles of Internal
`Medicine, 16th Edition (2005), p. 549
`AMG 1026 Auchus, R.J. "The genetics, pathophysiology, and management of
`human deficiencies of P450cl 7," Endocrinol. Metab. Clin. North
`Am. (30)1:101-119 (2001)
`
`Page 4
`
`
`
`AMG 1027 Costa-Santos, M. et al., "Two Prevalent CYPl 7 Mutations and
`Genotype-Phenotype Correlations in 24 Brazilian Patients with 17-
`Hydroxylase Deficiency," J Clin. Endocrin. & Metabol. (89)1 :49-
`60 (2004)
`AMG 1028 Jubelirer, S.J., et al., "High dose ketoconazole for the treatment of
`hormone refractory metastatic prostate carcinoma," J Urol.,
`142(1):89-901 (1989)
`AMG 1029 U.S. Patent 5,688,977, Sisti, N.J. et al., "Method for Docetaxel
`Synthesis"
`AMG 1030 U.S. Food and Drug Administration ("FDA") FDA News Release
`dated May 19, 2004, "FDA Approves New Indication for Taxotere-
`Prostate Cancer"
`AMG 1031 Tannock, I. et al., "Treatment of metastatic prostatic cancer with
`low-dose prednisone: evaluation of pain and quality of life as
`pragmatic indices of response," Journal ofClin. Oncology, 7:590-7
`(1989)
`AMG 1032 Taxotere® Prescribing Information (2004)
`AMG 1033 Scher, H.I. et al., "Increased survival with Enzalutamide in Prostate
`Cancer after Chemotherapy," New Eng. J Med., 367:1187-97
`(2012)
`AMG 1034 de Bono, J.S. et al., "Abiraterone and Increased Survival Ill
`Metastatic Prostate Cancer," New Engl. J Med., 364:1995-2005
`(2011)
`AMG 1035 Orange Book listing for Zytiga®
`
`C.
`
`8.
`
`Lega1Standards
`
`In my opinion, given the disclosure of the '438 Patent, I consider a
`
`Page 5
`
`
`
`person of ordinary skill in the art at the time of filing of this patent to be someone
`
`who is a physician specializing in urology or oncology, or holds a Ph.D. in
`
`pharmacology, biochemistry or a related discipline.' Additional experience could
`
`substitute for the advanced degree.
`
`9.
`
`I understand that, to the extent necessary, a person of ordinary skill in
`
`the art may collaborate with one or more other persons of skill in the art for one or
`
`more aspects with which the other person may have expertise, experience and/or
`
`knowledge that was obtained through his or her education, industrial or academic
`
`experiences.
`
`10.
`
`I understand that a person of ordinary skill in the art may consult with
`
`an enzymologist and/or molecular biologist and thus may rely on the opinions of
`
`such specialists in evaluating the claims.
`
`11.
`
`I have been told that the obviousness mquiry 1s a question of law
`
`based on four factual predicates: (1) "the scope and content of the prior art," (2)
`
`the "differences between the prior art and the claims at issue," (3) "the level of
`
`ordinary skill in the pertinent art," and ( 4) "secondary considerations" such as
`
`commercial success, long-felt but unsolved needs, failure of others, and unexpected
`
`results. I have been told that the combination of familiar elements according to
`
`known methods is likely to be obvious when it does no more than yield
`
`1 A related discipline may include, for example, pharmaceutical sciences.
`
`Page 6
`
`
`
`predictable results. I have also been told that the motivation to combine may be
`
`found in many different places and forms. Thus, for example, a challenger is not
`
`limited to the same motivation that the patentee had.
`
`12.
`
`I have been informed that secondary considerations of non(cid:173)
`
`obviousness include commercial success, satisfaction of a long-felt unmet need,
`
`unexpected results, prior failure of others, industry praise, licensing, and copying.
`
`I understand that evidence of such secondary considerations is only relevant to the
`
`obviousness analysis if the patentee can show a direct link, or nexus, between the
`
`secondary consideration and the claims of the patent, and that the evidence must be
`
`commensurate in scope with the asserted claims. I also understand that for results
`
`to be considered unexpected for these purposes, there must be a substantial
`
`difference from the prior art. In other words, a difference of kind, and not merely
`
`of degree.
`
`D. Background and the '438 Patent
`
`13. The prostate gland is part of the human male reproductive system and
`
`is involved in the synthesis and storage of seminal fluid. Prostate cancer is an
`
`androgen-dependent disease, and is the most common cancer among men and the
`
`second-most most common form of death from cancer among men in the United
`
`States. (AMG Ex. 1001, ('483 patent) col. 1, 11. 20-34; AMG Ex. 1022, (Tannock)
`
`p. 1501).
`
`Page 7
`
`
`
`14.
`
`The activation of androgen receptors ("AR") on prostate cells
`
`regulates the transcriptional activation of a wide variety of genes involved in
`
`controlling the growth of the normal prostate gland and m promoting the
`
`progression and proliferation of prostate cancer. (AMO Ex. 1023, (Attard) page
`
`1241; AMO Ex. 1003, (O'Donnell) p. 2317). The two most important androgens
`
`responsible for activating the AR are testosterone and its derivative
`
`dihydrotestosterone or DHT. Testosterone is synthesized primarily in the testes
`
`and the adrenals. (AMO Ex. 1003, (O'Donnell) p. 2317). In non-castrate men, the
`
`testes are responsible for producing the vast majority of circulating testosterone.
`
`(AMO Ex. 1003, (O'Donnell) p. 2317). The production of testosterone is regulated
`
`by endocrine feedback loops that respond to varying levels of hormones involved
`
`in the testosterone synthetic pathway, including hormonal precursors to
`
`testosterone and testosterone itself.
`
`15.
`
`The treatment options for treating prostate cancer depend to a great
`
`extent on whether the prostate cancer is confined or localized to the prostate or
`
`whether it has spread to other organs (i.e., metastasized) from the prostate. The
`
`goal of treating primary prostate cancer (i.e., prostate cancer localized to the
`
`prostate) is to interfere with the proliferation of prostate cancer cells by interrupting
`
`production of testosterone and DHT in the testes, or interfere with their function.
`
`(AMO Ex. 1003, (O'Donnell) p. 2317; AMO Ex. 1024, (Hellerstedt) p. 154).
`
`Page 8
`
`
`
`16. As of 2006, the most common course of treatment for localized
`
`prostate cancer would have been surgical removal of the prostate (prostatectomy)
`
`or radiation therapy of the prostate. (AMG Ex. 1001, ('438 patent) col. 1, 11. 25-34;
`
`AMG Ex. 1023, (Attard) p. 1241).
`
`1 7.
`
`In addition, a significant number of patients either progress after
`
`localized therapy or present with metastatic/non-localized prostate cancer. (AMG
`
`Ex. 1023, (Attard) p. 1241). Metastatic prostate cancer is cancer that has spread
`
`beyond the primary tumor in the prostate to other parts of the body. Prostate
`
`cancer metastasizes most often to pelvic lymph nodes and to the bone, and the most
`
`significant symptom is pain. (AMG Ex. 1025, (Harrison's) p. 549; AMG Ex. 1006,
`
`(Tannock) p. 1756). Non-localized disease and/or metastatic disease is usually
`
`treated with reduction of testosterone production by either hormonal manipulation
`
`or orchiectomy.
`
`18. The treatment of metastatic prostate cancer requires systemic therapy.
`
`It was known that as much as ten percent of baseline circulating testosterone
`
`remains in prostate cancer patients who have undergone localized androgen
`
`ablation through surgical or medical castration. (AMG Ex. 1003 (O'Donnell), p.
`
`2317). The adrenal glands were known to be responsible for the production of a
`
`substantial amount of this extratesticular source of testosterone, which was known
`
`to be an important alternative source of AR stimulation.
`
`(AMG Ex. 1003,
`
`Page 9
`
`
`
`(O'Donnell) p. 2317). The first-line treatment for metastatic prostate cancer
`
`patients smce at least the 1980's has involved systemic suppression of
`
`extratesticular testosterone production by the peripheral organs, including the
`
`adrenal glands, and is commonly referred to as hormone therapy. (AMG Ex. 1024,
`
`(Hellerstedt) p. 154). Hormone therapy involves systemic administration of
`
`luteinizing hormone-releasing hormone agonists ("LHRH agonists"), such as
`
`leuprorelin (marketed under the brand name Lupron®). (See, e.g., AMG Ex. 1024,
`
`(Hellerstedt) p. 154). LHRH agonists like Lupron® work by triggering a negative
`
`feedback mechanism in the adrenal system that eventually results in a decrease in
`
`production of testosterone and DHT by the adrenal glands.
`
`19. As the diagram below shows, approximately 90% of the testosterone
`
`is produced in the testes and 10% in the adrenals. (AMG Ex. 1024, (Hellerstedt),
`
`p. 159). The diagram also shows that LHRH is produced in the hypothalamus, a
`
`small gland in the brain. LHRH is normally released by the hypothalamus in
`
`pulses. (AMG Ex. 1024, (Hellerstedt), p. 157). This leads to the pulsative release
`
`of LH from the anterior pituitary. LH then acts on receptors on the Leydig cells of
`
`the testes, leading to production of testosterone. LHRH agonists such as Lupron®
`
`bind to LHRH receptors in the hypothalamus and stimulate the increased
`
`production and release of LH by the pituitary. Initially, this surge in LH triggers a
`
`flare in testosterone production. (See, e.g., AMG Ex. 1024, (Hellerstedt) p. 157,
`
`Page 10
`
`
`
`Fig. 2 at p. 159).
`
`StratogM>S for Androoan Oopnvation
`
`Hypotha.larnus
`Estrogen=~+==
`
`I LHRH
`=~,;====== LHRH Analogs (leuprolide, goserelin)
`====== LHRH Antagonists (abarelix)
`1.
`
`Anterior Pituitary f,
`
`r:e:al Gland
`
`Testicles
`
`
`~ 90% T 10% T --- Conversion
`
`Steroids
`f
`
`Surgical Castration \ )
`T
`T
`Rnasteride prevents
`Sa.R
`Nonsteroidal antiandrogeos
`T conversion to active metabolite
`block binding of T and DHT ~ dihydrotestosterone.
`to the androgen receptor.
`(flutamide, bicalutamide,
`AR
`DHT
`nilutamide)
`'--DNA--- Cell Proliferation
`
`Prostate Cancer Cell
`
`L.ri RH - l...u1CW'UZJnQ honnonc-"'6Dcm1ng honnooc.
`LH - l.utoinizng hon-none.
`T - T-toatcrone.
`OHT - Dihvdrot.on1o.tOf"Of'IO.
`
`20. The testosterone flare is followed by a decrease in testosterone
`
`production as the adrenal endocrine system responds to the overproduction of
`
`LHRH by feedback inhibition of the hypothalamic-pituitary-adrenal axis.
`
`In
`
`particular, the LHRH surge triggers downregulation of LHRH receptors in the
`
`pituitary, inhibiting further production and release of LH, and causmg a
`
`corresponding decrease m the production of testosterone.
`
`(AMG Ex. 1024,
`
`(Hellerstedt), p. 157).
`
`In addition to the use of LHRH agonists to interrupt
`
`production of testosterone m the adrenal glands, the first-line treatment of
`
`metastatic prostate cancer usually also includes systemic anti-androgen therapy
`
`Page 11
`
`
`
`using drugs such as bicalutamide. (AMO Ex. 1024, (Hellerstedt), p. 158). Anti(cid:173)
`
`androgens work by interfering with or antagonizing the binding of testosterone and
`
`DHT to the androgen receptors ("AR") on prostate cancer cells. (AMO Ex. 1024,
`
`(Hellerstedt), p. 158). The objective of anti-androgens is to prevent testosterone
`
`from binding to AR on prostate cancer cells.
`
`21.
`
`In almost all cases, patients with metastatic prostate cancer develop
`
`what is referred to as refractory or castration-resistant prostate cancer ("CRPC"),
`
`i.e., prostate cancer that does not respond to a reduction in testosterone levels by
`
`surgical or chemical means and resumes growth. (AMO Ex. 1024, (Hellerstedt), p.
`
`154). It was known that in these patients, the sensitivity of the AR is greatly
`
`increased, so that activation of the AR is enhanced at lower levels of testosterone.
`
`(AMO Ex. 1003, (O'Donnell) p. 2317; AMO Ex. 1023, (Attard) p. 1241).
`
`22.
`
`It was also known that the prognosis for these patients as of 2006 was
`
`poor and almost invariably resulted in incurable progression of the disease. (AMO
`
`Ex. 1021, (Oh) Abstract; AMO Ex. 1022, (Tannock 2004) p. 1503; AMO Ex. 1023,
`
`(Attard) p. 1241). The treatment of metastatic refractory prostate cancer usually
`
`also comprised the use of secondary hormone therapy, usually in combination with
`
`anti-androgen therapy. (AMO Ex. 1021, (Oh) Abstract; AMO Ex. 1023, (Attard)
`
`pp. 1241-1242).
`
`j Ketoconazole, a non-specific inhibitor of 17-a hydroxylase, an
`
`Page 12
`
`
`
`enzyme critical to steroid synthesis, also was commonly used off-label in
`
`combination with prednisone to treat metastatic refractory prostate cancer. (AMG
`
`Ex. 1021, (Oh) Abstract; AMG Ex. 1020, (Harris) Abstract; AMG Ex. 1025,
`
`(Harrison's) p. 548).
`
`24. The '438 Patent is directed to a method for treating a prostate cancer in
`
`a human, the method including administration of a therapeutically effective amount
`
`of abiraterone acetate and a therapeutically effective amount of prednisone. The
`
`'438 Patent includes one independent claim and 19 dependent claims. Claim 1, the
`
`only independent claim, recites as follows:
`
`1. A method for the treatment of a prostate cancer in a human
`comprising administering to said human a therapeutically effective
`amount of abiraterone acetate or a pharmaceutically acceptable salt
`thereof and a therapeutically effective amount of prednisone. (AMG
`Ex. 1001, ('438 patent) claim 1).
`
`25. The dependent claims of the '438 Patent further specify the amount of
`
`abiraterone acetate and/or prednisone administered to a human patient, the type of
`
`prostate cancer including refractory prostate cancer to be treated in such patient,
`
`and r, ar anti-cancer agents administered previously to such patient.
`
`/~ Abiraterone acetate is a 17a-hydroxylase/C17,20-lyase inhibitor. (AMG
`
`Ex. 1003, (O'Donnell) pp. 2318, 2322).
`
`l Zu-hydroxylase/Ci-js-Iyase inhibitors
`
`(also referred to as "CYPl 7 inhibitors") were known in the art to be useful in the
`
`treatment of androgen-dependent cancers, includi~state cancer, by
`
`Page 13
`
`
`
`contributing to suppression of peripheral androgen production. (AMO Ex. 1003,
`
`(O'Donnell) p. 2318). As I explained before, the two sites thought to produce most
`
`of the androgenic steroids in human males are the testes and the adrenal cortex.
`
`(AMO Ex. 1023, (Attard) p. 1242-1243). It was known in the art that plasma
`
`testosterone is not completely suppressed by castration, in part because of
`
`peripheral conversion of adrenal androgenic steroids to testosterone by l 7a(cid:173)
`
`hydroxylase/Ci-js-lyase. (AMO Ex. 1003, (O'Donnell) p. 2317; AMO Ex. 1023,
`
`(Attard) pp. 1242-1243). It was also known that AR on the prostate cancer cells of
`
`patients with refractory metastatic prostate cancer was "hypersensitive" to
`
`androgenic steroid stimulation. (AMO Ex. 1003, (O'Donnell) p. 2317; AMO Ex.
`
`1023, (Attard) p. 1241).
`
`27. CYPl 7 inhibitors were known to inhibit l 7a-hydroxylase/C17,20-lyase
`
`("CYP 1 7"), an enzyme that is critical to androgen synthesis in both the testes and
`
`the adrenal cortex.
`
`(AMO Ex. 1003, (O'Donnell) p. 2318; AMO Ex. 1023,
`
`(Attard) p. 1242). The following diagram explains how CYPl 7 inhibitors work to
`
`inhibit production of testosterone"
`
`2 The diagram shows CYPl 7 at the reaction in which it adds a hydroxyl (-OH)
`
`group to pregnenolone and removes the side chain from 1 7-hydroxypregnenolone.
`
`Similarly, CYPl 7 is used in the reaction to add a hydroxyl (-OH) group to
`
`progesterone and remove the side chain from 17-hydroxy progesterone, although
`
`Page 14
`
`
`
`Major Pathways in Steroid Biosynthe.sis
`
`0
`
`CYPI? ..
`
`CYPl? .. Dehydroeplandrosterone
`.. ctS;=
`..
`~·m, &
`.CYPllOl'"UJ '
`t 17~HSD
`:f"
`
`~~
`•17,SHSD
`... CYPl!l
`Tes1ost8fone 011
`o
`
`Estrone
`
`... CYPlt
`
`"-oti
`
`HO
`
`D MffOI' pror,tateig n
`D MffOI' mlnerllooortloold
`D M., gonfldel 11trogen•
`D MffOf gl1.10ocortlcold (tPecle• vlWlltion)
`D MffOI' gonedll on(i'ogon
`
`28. The CYPl 7 enzyme has two activities in the steroidogenic pathway:
`
`not explicitly labeled as such in the diagram. The use of CYP 1 7 in these two
`
`reactions was well known as seen in, for example, AMG Ex. 1003, (O'Donnell) p.
`
`2318 which has a diagram that shows CYP 1 7 in these reactions.
`
`Page 15
`
`
`
`(1) acting as a 17a-hydroxylase, and (2) acting as a 17,20 lyase. (AMG Ex. 1003,
`
`(O'Donnell) p. 2318, Fig. 1). As a 17a-hydroxylase, CYP17 adds a hydroxyl
`
`group (-OH) to pregnenolone and progesterone at carbon 17 of the steroid D ring,
`
`converting both compounds to their 17-hydroxy forms.
`
`(AMG Ex. 1003,
`
`(O'Donnell) p. 2318, Fig. 1). As a 17,20 lyase, it acts to split the side chain off of
`
`17-hydroxyprogesterone and 17-hydroxypregnenolone.
`
`(AMG Ex.
`
`1003,
`
`(O'Donnell) p. 2318, Fig. 1). Importantly, the l 7a-hydroxylase activity of CYPl 7
`
`is essential to the synthesis of both (1) sex hormones, i.e., androgens (i.e.,
`
`testosterone) and estrogens, and (2) cortisol. Cortisol is an essential steroid that is
`
`critical to basic metabolic functions including the formation of glucose,
`
`cardiovascular function, and the activation of the anti-stress and inflammatory
`
`pathways. One of skill in the art would have expected that the administration of a
`
`CYPl 7 inhibitor would interfere with the production of both testosterone (in men)
`
`and cortisol. (AMG Ex. 1027, (Costa-Santos) Abstract, p. 49; AMG Ex. 1026,
`
`(Auchus) Abstract).
`
`29. While the CYPl 7 enzyme is essential for androgen biosynthesis, it
`
`also plays an important role in the production of cortisol, a glucocorticoid. The
`
`diagram below shows the control of cortisol production in the adrenal cortex. As
`
`more cortisol is produced, there is a negative feedback on the hypothalamus and
`
`anterior pituitary that reduces the production of ACTH, which consequently
`
`Page 16
`
`
`
`reduces the production of cortisol. It is this negative feedback mechanism that
`
`gives the pulsative production of cortisol described above.
`
`Cortisol: Negative Feedback Loop
`Releasing hormone
`
`Hypothalamus
`
`B
`
`Anterior
`plttatary
`
`H
`
`* ACTH
`* Cortisol *
`
`Negative feedback by
`cortisol
`
`CopyrlghtC 2011, 2007 by Saunders,
`an Imprint of 8sevler Inc. All rights
`reserved.
`
`29
`
`(The Human Body In Health and Illness, 4th Edition, Barbara Herlihy, Chapter 14,
`
`endocr~ system.)
`
`~ When a CYPl 7 inhibitor is administered, cortisol production is
`
`compromised (e.g., reduced), which interferes with the negative feedback
`
`mechanism that maintains cortisol levels within the normal physiological range.
`
`Specifically, the pituitary gland produces more adrenocorticotropic hormone
`
`(ACTH) to stimulate greater production of glucocorticoids, which are formed from
`
`Page 17
`
`
`
`ACTH, in part, by a reaction involving CYPl 7. However, in the presence of a
`
`CYPl 7 inhibitor, the conversion in the CYPl 7 pathway from ACTH to cortisol
`
`cannot occur. In other words, an increase in ACTH will not provide the necessary
`
`quantities of cortisol because the CYP 17 pathway from ACTH to cortisol is
`
`blocked by the CYPl 7 inhibitor. However, a different, minor pathway results in
`
`some of the ACTH being converted to cortisol, although the majority of the ACTH
`
`will be converted into mineralocorticoids.
`
`31.
`
`It was known that CYPl 7 inhibition of cortisol increased ACTH drive
`
`(i.e., increased ACTH production), which resulted in a corresponding increase in
`
`mineralocorticoids. (AMG Ex. 1027, (Costa-Santos) Abstract, p. 49; AMG Ex.
`
`1026, (Auchus) Abstract; AMG Ex. 1025, (Harrison's) p. 2145). An increase in
`
`mineralocorticoids beyond normal levels, known as "mineralocorticoid excess,"
`
`was known to have adverse effects, including hypertension, hypokalemia
`
`(decrease in circulating potassium levels), and fluid retention.
`
`(AMG Ex. 1027,
`
`(Costa-Santos) Abstract, p. 49; AMG Ex. 1025, (Harrison's) pp. 2143, 2145,
`
`2146).
`
`32.
`
`It also was known in the art to administer a glucocorticoid, such
`
`hydrocortisone or prednisone, to suppress ACTH drive by way of a negative
`
`feedback loop akin to that triggered by cortisol. (AMG Ex. 1027, (Costa-Santos)
`
`Abstract, p. 49; AMG Ex. 1025, (Harrison's) pp. 2143, 2145, 2146). By
`
`Page 18
`
`
`
`suppressing ACTH drive, fewer mineralocorticoids are produced and the adverse
`
`side effects of hypertension, hypokalemia, and fluid retention are reduced even in
`
`the presence of the CYP 1 7 inhibition.
`
`33. Ketoconazole was known to be a non-specific inhibitor of CYPl 7,
`
`was known to have a direct anti-tumor effect in vitro and was known to be
`
`effective as a second-line treatment for metastatic hormone refractory prostate
`
`cancer. (AMO Ex. 1003, (O'Donnell) p. 2318; AMO Ex. 1021, (Oh) Abstract, p .
`
`. 1020, (Harris) pp. 542-543).
`
`owever, the administration of ketoconazole to treat prostate cancer
`
`was known to reduce cortisol levels and potentially result in mineralocorticoid
`
`excess, giving rise to side effects commonly associated with mineralocorticoid
`
`excess, including hypertension, hypokalemia, and fluid retention. (AMO Ex. 1028,
`
`(Jubelirer) Abstract; AMO Ex. 1003, (O'Donnell) p. 2323; AMO Ex. 1021, (Oh)
`
`Abstract, p. 49; AMO Ex. 1020, (Harris) pp. 542-544). These side effects reduced
`
`the safety and tolerability of administering ketoconazole.
`
`(AMO Ex. 1028,
`
`(Jubelirer) Abstract; AMO Ex. 1003, (O'Donnell) p. 2323; AMO Ex. 1021, (Oh)
`
`Abstract, p. 49; AMO Ex. 1020, (Harris) pp. 542-544). To address these side
`
`effects, it was standard practice in the art to co-administer a glucocorticoid such as
`
`hydrocortisone or prednisone with ketoconazole to improve the safety and
`
`tolerability of administration of ketoconazole to treat prostate cancer in a human
`
`Page 19
`
`
`
`patient. (AMG Ex. 1003, (O'Donnell) p. 2323; AMG Ex. 1020, (Harris) Abstract,
`
`p. 542; AMG Ex. 1021, (Oh) Abstract).
`
`35. The combination of ketoconazole with prednisone, although not
`
`approved by the FDA in combination for treating prostate cancer, was reported in
`
`the literature to be safe and effective in treating patients with hormone refractory
`
`metastatic prostate cancer. (AMG Ex. 1004, (Gerber) Abstract).
`
`36. Abiraterone acetate was known to be a more efficacious anti-cancer
`
`agent in the treatment of prostate cancer, including metastatic hormone refractory
`
`prostate cancer, than prior art CYPl 7 inhibitors such as ketoconazole. (AMG Ex.
`
`1003, (O'Donnell) pp. 2318, 2322, 2323, 2325). In particular, abiraterone acetate
`
`was known to be more effective in inhibiting testosterone levels in vivo in a
`
`mammal than ketoconazole. (AMG Ex. 1005, ('213 patent), col. 25, I. 13 - col. 26,
`
`I. 63; AMG Ex. 1003, (O'Donnell) p. 2318).
`
`E.
`
`Claim Construction
`
`3 7.
`
`I understand that the claims in an IPR proceeding are construed in
`
`accordance with the broadest reasonable construction consistent with the
`
`I have been told that, for purposes of this declaration, the claim terms
`
`"treating" and "treatment" should be construed as those terms are defined
`
`in the specification of the '438 Patent to mean the "eradication, removal,
`
`Page 20
`
`
`
`modification, management or control of a tumor or primary, regional, or metastatic
`
`cancer cells or tissue and the minimization or delay of the spread of cancer."
`
`(AMO Ex. 1001, ('438 Patent) col. 3, 11. 46-50). I agree with this construction
`
`because it is consistent with the broadest reasonable construction as understood by
`
`one of ordinary skill in the art.
`
`39. The term "anti-cancer agent" should be construed as defined in the
`
`specification of the '438 patent as referring to "any therapeutic agent that directly
`
`or indirectly kills cancer cells or directly or indirectly prohibits, stops or reduces
`
`the proliferation of cancer cells." (AMO Ex. 1001, ('438 Patent) col. 4, 11. 8-16). I
`
`agree with this construction because it is consistent with the broadest reasonable
`
`construction as understood by one of ordinary skill in the art.
`
`40.
`
`The term "refractory cancer" should be construed as defined in the
`
`specification of the '438 patent to mean "cancer that is not responding to an anti(cid:173)
`
`cancer treatment or cancer that is not responding sufficiently to an anti-cancer
`
`treatment." (AMO Ex. 1001, ('438 Patent) col. 4, 11. 23-27). I agree with this
`
`construction because it is consistent with the broadest reasonable construction as
`
`understood by one of ordinary skill in the art.
`
`41. The term "refractory patient" should be construed as defined in the
`
`specification of the '438 patent to mean "a patient who has refractory cancer."
`
`(AMO Ex. 1001, ('438 Patent) col. 4, 11. 28-30).
`
`I agree with this construction
`
`Page 21
`
`
`
`because it is consistent with the broadest reasonable construction as understood by
`
`one of ordinary skill in the art.
`
`42. The term "relapse cancer" should be construed as defined in the
`
`specification of the '438 patent to mean "cancer that was at one time responsive to
`
`an anti-cancer treatment but has become no longer responsive to such treatment or
`
`is no longer responding sufficiently to such treatment." (AMG Ex. 1001, ('438
`
`Patent) col. 4, 11. 31-35). I agree with this construction because it is consistent with
`
`the broadest reasonable construction as understood by one of ordinary skill in the
`
`art.
`
`43. The term "recurring cancer" should be construed as defined in the
`
`specification of the '438 patent to mean "cancer that has returned after a patient has
`
`been earlier diagnosed with cancer, under gone treatment or had been previously
`
`diagnosed as cancer-free." (AMG Ex. 1001, ('438 Patent) col. 4, 11. 36-39). I agree
`
`with this construction because it is consistent with the broadest reasonable
`
`construction as understood by one of ordinary skill in the art.
`
`F.
`
`Claim 1 is Unpatentable as Obvious over O'Donnell in view of
`
`Gerber or the '213 patent in view of Gerber
`
`44. Claim 1 is directed to a method for treating prostate cancer in a human
`
`compnsmg administration of therapeutically effective amounts of abiraterone
`
`acetate, or a pharmaceutically acceptable salt thereof, and prednisone. Because
`
`Page 22
`
`
`
`both the use of abiraterone acetate to treat prostate cancer and the co(cid:173)
`
`administration of prednisone in treatment of prostate cancer with a CYPl 7
`
`inhibitor were present in one or more of O'Donnell (AMG Ex. 1003), Gerber
`
`(AMG Ex. 1004) and the '213 patent (AMG Ex. 1005), claim 1 is obvious. Each
`
`of the limitations of claim 1 is present in these prior art documents, as explained in
`
`detail below.
`
`a. A method for the treatment of a prostate cancer in a human comprising
`administering to said human a therapeutically effective amount of
`abiraterone acetate
`
`45. Both O'Donnell and the '213 patent teach that abiraterone acetate is a
`
`selective CYPl 7 inhibitor that is more effective in suppressing testosterone levels in
`
`a mammal in vivo than ketoconazole, another CYPl 7 inhibitor known in the art.
`
`(AMG Ex. 1003, (O'Donnell) pp. 2318, 2322, 2323, 2325; AMG Ex. 1005,
`
`('213 patent) col. 25, 1. 13 - col. 26, 1. 63). O'Donnell teaches that 500-800 mg of
`
`abiraterone acetate can be useful in suppressing testosterone levels in a human
`
`patient with prostate cancer, including metastatic refractory prostate cancer. (AMG
`
`Ex. 1003, (O'Donnell) Abstract). The '213 patent discloses that abiraterone acetate
`
`may be administered in a method of treating androgen- and estrogen-dependent
`
`disorders, especially prostate cancer, as a pharmaceutical composition. (AMG Ex.
`
`1005, ('213 patent) col. 10, 11. 47-56). The '213 patent further discloses that a
`
`therapeutically effective amount of abiraterone acetate comprises 20-800 mg/patient
`
`Page 23
`
`
`
`per day. (AMG Ex. 1005, ('213 patent), col. 10, 11. 55-56).
`
`46.
`
`It would have been obvious to
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