UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`WOCKHARDT BIO AG
`Petitioner
`
`v.
`
`JANSSEN ONCOLOGY, INC.
`Patent Owner
`
`_____________________
`
`Case IPR: Unassigned
`
`U.S. Patent No. 8,822,438
`_____________________
`
`DECLARATION OF PAUL A. GODLEY, M.D., Ph.D., MPP
`
`
`WCK1002
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`

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`
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
`TABLE OF CONTENTS
`
`C. 
`
`Overview .......................................................................................................... 1 
`I. 
`II.  My background and qualifications .................................................................. 3 
`III.  List of documents considered in formulating my opinion .............................. 5 
`IV.  Person of ordinary skill in the art .................................................................. 11 
`V. 
`State of the art before August 25, 2006 ......................................................... 12 
`A. 
`The standard of care for prostate cancer, as of August 25, 2006 ........ 12 
`B. 
`PSA levels were known to be an indicator of prostate cancer
`progression and tumor burden ............................................................. 18 
`Inhibiting adrenal androgen production was a focus of treating
`hormone refractory prostate cancer ..................................................... 18 
`1. 
`Ketoconazole was a known CYP17 inhibitor ........................... 22 
`2. 
`Abiraterone acetate was known to be a potent and more
`selective than ketoconazole and to effectively reduce
`testosterone levels ..................................................................... 23 
`Inhibiting cortisol production increased
`mineralocorticoids ..................................................................... 24 
`D.  Glucocorticoids, such as prednisone, were part of the standard
`of care in treating mCRPC .................................................................. 24 
`VI.  The ’438 patent and its claims ....................................................................... 26 
`A. 
`Independent claim 1 ............................................................................ 27 
`B. 
`Dependent claims 2-20 ........................................................................ 27 
`C. 
`Claim construction .............................................................................. 29 
`1. 
`“treat,” “treating,” and “treatment” ........................................... 29 
`2. 
`“therapeutically effective amount of prednisone” .................... 29 
`
`3. 
`
`i
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
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`VII.  The basis of my analysis with respect to obviousness .................................. 30 
`A.  A POSA reading Gerber, O’Donnell, and Sartor would have
`had the reason and the know-how to arrive at the methods of
`claims 1-20 with a reasonable expectation of success ........................ 31 
`1. 
`Independent claim 1 .................................................................. 37 
`(a)  A POSA would have had reason to administer a
`CYP17 inhibitor and prednisone to treat prostate
`cancer .............................................................................. 40 
`(b)  Abiraterone acetate was well-known to be a potent
`and more specific inhibitor of CYP17 than
`ketoconazole and to effectively reduce testosterone
`levels ............................................................................... 41 
`(c)  A POSA would have had reason to administer a
`therapeutically effective amount of abiraterone
`acetate and prednisone to treat prostate cancer .............. 43 
`(d)  A POSA would have had a reasonable expectation
`of successfully practicing the method of claim 1 ........... 47 
`Dependent Claims 2-20 ............................................................. 49 
`(a)  Claims 2 and 3 ................................................................ 49 
`(b)  Claim 4 ............................................................................ 50 
`(c)  Claim 5 ............................................................................ 51 
`(d)  Claims 6 and 7 ................................................................ 52 
`(e)  Claim 8 ............................................................................ 52 
`(f) 
`Claim 9 ............................................................................ 54 
`(g)  Claims 10 and 11 ............................................................ 54 
`(h)  Claims 12 and 13 ............................................................ 57 
`(i) 
`Claims 14-17 ................................................................... 57 
`(j) 
`Claims 18-20 ................................................................... 59 
`
`2. 
`
`ii
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`B. 
`
`Objective indicia of non-obviousness ................................................. 61 
`1. 
`No unexpectedly superior results .............................................. 61 
`2. 
`No long-felt but unmet need or failure of others ...................... 67 
`The commercial success of Zytiga® is not the result of
`3. 
`unexpected results of the claimed invention ............................. 68 
`VIII.  Conclusion ..................................................................................................... 69 
`
`
`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
`iii
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`WCK1002
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`
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`I.
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
`I, Paul A. Godley, do hereby declare as follows:
`
`Overview
`1.
`
`I am over the age of 18 and otherwise competent to make this
`
`declaration. This declaration is based on my personal knowledge as an expert in
`
`the diagnosis and treatment of genitourinary cancers. I understand this declaration
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`is being submitted together with a petition for Inter Partes Review (“IPR”) of
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`claims 1-20 of U.S. Patent No. 8,822,438 (“the ’438 patent”) (WCK1001).
`
`2.
`
`I have been retained as an expert on behalf of Wockhardt Bio AG
`
`(“Wockhardt”), the Petitioner, for this IPR. I am being compensated for my time in
`
`connection with this IPR at my standard legal consultant rate of $500/hr. I have no
`
`personal or financial interest in Wockhardt or in the outcome of this proceeding.
`
`3.
`
`I understand that the ’438 patent issued on September 2, 2014, and
`
`resulted from U.S. Application No. 13/034,340, filed on February 24, 2011, which
`
`is a continuation of U.S. Application No. 11/844,440, filed on August 24, 2007,
`
`which claims the benefit of U.S. Provisional Application No. 60/921,506, filed on
`
`August 25, 2006. I also understand that the face page of the ’438 patent states that
`
`the ’438 patent is currently assigned to Janssen Oncology, Inc. (“Janssen”).
`
`4.
`
`The face page of the ’438 patent cites several related U.S. patent
`
`applications including U.S. Application No. 13/034,340, filed on February 24,
`
`2011, which is a continuation of U.S. Application No. 11/844,440, filed on August
`
`
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`1
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`WCK1002
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
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`24, 2007, which claims the benefit of U.S. Provisional Application No.
`
`60/921,506, filed on August 25, 2006. I understand that the ’438 patent is related to
`
`those applications. The earliest filing date of any of those listed applications is
`
`August 25, 2006. I understand that, based on that date, the earliest possible date to
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`which the ’438 patent may claim priority is August 25, 2006. I have been asked to
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`provide my analysis of the ’438 patent based on prior art and the knowledge in the
`
`art before August 25, 2006.
`
`5.
`
`In preparing this declaration, I have reviewed the ’438 patent
`
`(WCK1001) and considered each of the documents cited in this petition, in light of
`
`the general knowledge in the art before August 25, 2006. I have also relied upon
`
`my experience in the relevant art and considered the viewpoint of a person of
`
`ordinary skill in the art (“POSA”; defined in § IV) before August 25, 2006.
`
`6.
`
`Claim 1, the sole independent claim, of the ’438 patent is generally
`
`directed to a method of treating 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.
`
`7.
`
`Broadly, this declaration sets forth my opinion that all claims of the
`
`’438 patent would have been obvious over the prior art. First, this declaration sets
`
`forth my opinion that a POSA would have had a reason to arrive at the subject
`
`
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`2
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
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`matter recited in claims 1-20 of the ’438 patent, with a reasonable expectation of
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`success, by combining the disclosures of Gerber (WCK1004), O’Donnell
`
`(WCK1005), Sartor (WCK1006), and a POSA’s knowledge of the prior state of the
`
`art, as discussed in this declaration below.
`
`8.
`
`Second, this declaration describes how, in reaching my conclusions
`
`regarding obviousness, I have considered potential objective indicia of
`
`nonobviousness and concluded that there are none that I am aware of that would
`
`support a claim of nonobviousness.
`
`II. My background and qualifications
`9. My qualifications and credentials are fully set forth in my curriculum
`
`vitae, attached as WCK1003. I am an expert in the field of medical oncology and
`
`epidemiology. Over the past 25 years, I have accumulated significant training and
`
`experiencing in diagnosing and treating prostate cancer. Accordingly, I am
`
`knowledgeable about the experimental techniques and methods of treatment used
`
`in this field.
`
`10.
`
`I received a B.A. in Sociology from Yale University in 1979. I
`
`received my M.D. from Harvard Medical School in 1984. Also in 1984, I received
`
`a M.P.P. from Harvard University. I also received a Ph.D. in Epidemiology from
`
`the University of North Carolina (“UNC”) in 1993.
`
`
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
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`11. From 1984 to 1987, I completed a 3 year residency in internal
`
`
`
`medicine at Case Western Reserve University School of Medicine. While pursuing
`
`my Ph.D., I completed a fellowship in the Cancer Epidemiology Program at UNC.
`
`I further completed a fellowship in Hematology/Oncology at UNC from 1988 to
`
`1991.
`
`12.
`
`In 1988, I became Board Certified in Internal Medicine by the
`
`American Board of Internal Medicine. In 1991, I became Board Certified in
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`Medical Oncology by the American Board of Internal Medicine. I am licensed to
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`practice medicine in North Carolina.
`
`13. Since 1991, I have held various Instructor and Professorship positions
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`at UNC in the Division of Medical Oncology, the Department of Epidemiology,
`
`the Division of Hematology/Oncology, and the Department of Urology. Currently,
`
`I am a Rush Dickson Distinguished Professor of Prostate Cancer Research at UNC.
`
`I am also a Professor in UNC’s Department of Urology and the Division of
`
`Hematology/Oncology. I am also an Adjunct Professor in UNC’s Department of
`
`Epidemiology.
`
`14.
`
`I have been an investigator on over 100 clinical trials related to
`
`prostate cancer. I have published more than 125 papers and abstracts in peer-
`
`reviewed journals. From 1996 to 2008, I chaired the Data and Safety Monitoring
`
`Committees for the Prostate Cancer Prevention Trial (PCPT) and the SELECT
`
`
`
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`WCK1002
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
`
`PCPT funded by the Southwest Oncology Group and the National Cancer Institute.
`
`In 1997, I was a member of the American Cancer Society Prostate Cancer Data
`
`Review Workshop and the National Cancer Institute Prostate Cancer Progress
`
`Review Group. In 1999, I was a scientist reviewer for the USAMRMC Prostate
`
`Cancer Research Program. I have chaired multiple Special Emphasis Panels for the
`
`NIH Peer Review Committee. I have also been invited to give over 40 extramural
`
`presentations related to prostate cancer. I am also currently an Associate Editor of
`
`the Journal of the National Cancer Institute.
`
`15. Accordingly, I am expert in the field of medical oncology, particularly
`
`in diagnosing and treating prostate cancer, and have been since 1991. For that
`
`reason, I am qualified to provide an opinion as to what a POSA would have
`
`understood, known, or concluded as of August 25, 2006.
`
`III. List of documents considered in formulating my opinion
`16.
`In formulating my opinion, I have considered all documents cited
`
`herein, including the following:
`
`Wockhardt
`Exhibit #
`
`Description
`
`1001
`
`1003
`
`Auerbauch, A. H. & Belldegrum, A. S., U.S. Patent No. 8,822,438
`(filed Feb. 24, 2011; issued Sep. 2, 2014) (“the ’438 patent”)
`Dr. Paul A. Godley’s Curriculum Vitae
`
`
`
`5
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`WCK1002
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`
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`Wockhardt
`Exhibit #
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
`Description
`
`Gerber, G. S. & Chodak, G. W., “Prostate specific antigen for
`assessing response to ketoconazole and prednisone in patients with
`hormone refractory metastatic prostate cancer,” J. of Urology,
`144(5): 1177-9 (1990) (“Gerber”)
`O’Donnell, A. et al., “Hormonal impact of the 17α-
`hydroxylase/C17,20-lyase inhibitor abiraterone acetate (CB7630) in
`patients with prostate cancer,” British J. of Cancer, 90: 2317-2325
`(2004) (“O’Donnell)
`Sartor, O. et al., “Effect of prednisone on prostate-specific antigen
`in patients with hormone-refractory prostate cancer,” Urology, 52:
`252-6 (1998) (“Sartor”)
`Tannock, I. F. et al., “Docetaxel plus prednisone or mitoxantrone
`plus prednisone for advanced prostate cancer,” New Engl. J. Med.,
`351: 1502-1512 (2004)
`Attard, G. et al., “Selective blockade of androgenic steroid synthesis
`by novel lyase inhibitors as a therapeutic strategy for treating
`metastatic prostate cancer,” BJU Inter., 96:1241-1246 (2005)
`Kasper, D. L. et al. (Eds.). (2005). Harrison’s Principles of Internal
`Medicine , Vol. 1, 16th ed. , Ch. 81:543-550 & Ch. 321:2127-2148,
`New York City, NY: The McGraw-Hill Companies, Inc.
`Tannock, I.F. et al., “Chemotherapy with mitoxantrone plus
`prednisone or prednisone alone for symptomatic hormone-resistant
`prostate cancer: a Canadian randomized trial with palliative end
`points,” J. Clin. Oncol., 14: 1756-1764 (1996).
`Harris, K.A. et al., “Low dose ketoconazole with replacement doses
`of hydrocortisone in patients with progressive androgen independent
`prostate cancer,” J. of Urology, 168: 542-545 (2002)
`Hellerstedt, B. A. and Pienta, K. J., “The current state of hormonal
`therapy for prostate cancer,” CA Cancer J. Clin., 52:154-179 (2002)
`
`
`
`6
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`WCK1002
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`
`
`Wockhardt
`Exhibit #
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
`Description
`
`Trump, D. L. et al., “High-dose ketoconazole in advanced hormone-
`refractory prostate cancer: endocrinologic and clinical effects,” J.
`Clin. Oncol., 7:1093-1098 (1989)
`Costa-Santos, M. et al., “Two prevalent CYP17 mutations and
`geno-type-phenotype correlations in 24 Brazilian patients with 17-
`hydroxylyase deficiency,” J. of Clin. Endocrin. & Metab., 89(1):
`49-60 (2004)
`Oh, W.K., “Secondary hormonal therapies in the treatment of
`prostate cancer,” Urology, 60 (Suppl 3A): 87-93 (2002)
`Scholz, M. et al., “Long-term outcome for men with androgen
`independent prostate cancer treated with ketoconazole and
`hydrocortisone,” J. of Urology, 173: 1947-1952 (2005)
`Fosså, S. D., et al., “Flutamide versus prednisone in patients with
`prostate cancer symptomatically progressing after androgen-ablative
`therapy: a phase III study of the European Organization for
`Research and Treatment of Cancer Genitourinary Group,” J. of Clin.
`Oncol., 19(1): 62-71 (2001)
`Brassel, S. A. et al., “Prostate-specific antigen versus prostate-
`specific antigen density as predictor of tumor volume, margin status,
`pathologic stage, and biochemical recurrence of prostate cancer,”
`Urology, 66:1229-1233 (2005)
`Berry, W. et al., “Phase III study of mitoxantrone plus low dose
`prednisone versus low dose prednisone alone in patients with
`asymptomatic hormone refractory prostate cancer,” J. of Urology,
`168: 2439-2443 (2002)
`U.S. Food and Drug Administration (“FDA”) News Release dated
`May 19, 2004, “FDA Approves New Indication for Taxotere—
`Prostate Cancer,”
`http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2
`004/ucm108301.htm (last accessed 8/8/2016)
`
`
`
`7
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`Wockhardt
`Exhibit #
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`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
`Description
`
`Ryan, C. J. et al., “Phase II study of abiraterone acetate in
`chemotherapy-naïve metastatic castration-resistant prostate cancer
`displaying bone flare discordant with serologic response,” Clin.
`Cancer Res., 17:4854-4861 (2011) (“Ryan 2011”)
`Attard, F. et al., “Selective inhibition of CYP17 with abiraterone
`acetate is highly active in the treatment of castration-resistant
`prostate cancer,” J. of Clin. Oncol., 27:3742-3748 (2009) (“Attard
`2009”)
`Ryan, C. J. et al, “Abiraterone in metastatic prostate cancer without
`previous chemotherapy,” N Engl J Med, 368:138-148 (2013) (“Ryan
`2013”)
`Danila, D. C. et al., “Phase II multicenter study of abiraterone
`acetate plus prednisone therapy in patients with docetaxel-treated
`castration-resistant prostate cancer,” J. of Clin. Oncol., 28:1496-
`1501 (2010) (“Danila”)
`Kelly, W. K. et al., “Prostate-specific antigen as a measure of
`disease outcome in metastatic hormone-refractory prostate cancer,”
`J. of Clin. Oncol., 11:607-615 (1993)
`Small, E. J. et al., “Serum prostate-specific antigen decline as a
`marker of clinical outcome in hormone-refractory prostate cancer
`patients: association with progression-free survival, pain end points,
`and survival,” J. of Clin. Oncol., 19:1304-1311 (2001)
`Miller, G. M. & Hinman, Jr., F., “Cortisone treatment in advanced
`carcinoma of the prostate,” J. of Urology, 72(3): 485-496 (1954)
`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,” J. of Clin. Oncol., 7(5): 590-597
`(1989)
`
`
`
`8
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`WCK1002
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`

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`
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`Wockhardt
`Exhibit #
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
`Description
`
`Scher, H. I. & Sawyers, C. L., “Biology of progressive, castration-
`resistant prostate cancer: directed therapies targeting the androgen-
`receptor signaling axis,” J Clin Oncol, 23:8253-8261 (2005)
`Barrie, S. E. et al, U.S. Patent No. 5,604,213 (filed Sep. 30, 1994;
`issued Feb. 18, 1997) (“Barrie”)
`File History for U.S. Patent No. 8,822,438
`Gilman, A. et al. (Eds.). (1990). The Pharmacological Basis of
`Therapeutics, 8th ed. Elmsford, NY: Pergamon Press, Inc., pp.62-83,
`1431-1462
`Ganong, W. F. (1979). Review of Medical Physiology. Los Altos,
`CA: Lange Medical Publications, pp.277-300
`Taxotere Prescribing Information (2004),
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/020449s
`028lbl.pdf (last accessed 8/8/2016)
`Potter, G. A. et al, “Novel steroidal inhibitors of human cytochrome
`P45017α (17α-hydroxylase-C17,20-lyase): potential agents for the
`treatment of prostate cancer,” J. Med. Chem., 38:2463-2471 (1995)
`(“Potter”)
`Fakih, M. et al., “Glucocorticoids and Treatment of Prostate Cancer:
`A Preclinical and Clinical Reivew,” Urology, 60:553-561 (2002)
`(“Fakih”)
`MacAdams, M. R. et al, “Reduction of serum testosterone levels
`during chronic glucocorticoid therapy,” Ann Int Med, 104:648-651
`(1986)
`Rajfer, J. et al, “Mechanism of inhibition of human testicular
`steroidogenesis by oral ketoconazole,” J Clin Endocrinol Metab,
`63:1193-1198 (1986)
`
`
`
`9
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`Wockhardt
`Exhibit #
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
`Description
`
`Santen, R. J. et al, “Site of action of low dose ketoconazole on
`androgen biosynthesis in men,” J Clin Endocrinol Metab, 57:732
`(1983)
`Sonino, N., “The use of ketoconazole as an inhibitor of steroid
`production,” N Engl J of Med, 317:812-817 (1987)
`Osol, A. (Ed.). (1980). Remington’s Pharmaceutical Sciences, 16th
`ed. Easton, PA: Mack Publishing Company, Ch. 89: 1553-1584 and
`Ch. 99: 1703-1714
`Sartor, O., “Abiraterone prolongs survival in metastatic prostate
`cancer,” Nat Rev Clin Oncol, 8:515-516 (2011)
`Fisher, R. I. et al, “Comparison of a standard regimen (CHOP) with
`three intensive chemotherapy regimens for advanced non-Hodgkin’s
`lymphoma,” N Engl J Med, 328:1002-1006 (1993)
`Bearden, J. D. et al, “Combination chemotherapy using
`cyclophosphamide, vincristine, methotrexate, 5-fluoruracil, and
`prednisone in solid tumors,” Cancer, 39:21-26 (1977)
`Mauro, F. R. et al, “Fludarabine + prednisone ± α-interferon
`followed or not by α-interferon maintenance therapy for previously
`untreated patients with chronic lympocytic leukemia: long term
`results of a randomized study,” Haematologica, 88:1348-1357
`(2003)
`Scher, H. I. et al, “Targeting the androgen receptor: improving
`outcomes for castration resistant prostate cancer,” Endocrine-
`Related Cancer, 11:459-476 (2004)
`Yamamoto, M. et al, “Role of prostate-specific antigen and digital
`rectal examination in the detection of prostate cancer,” Int J Urol,
`1:74-77 (1994)
`
`
`
`10
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`WCK1002
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`

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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
`
`Description
`
`Attard,, G. et al, “Phase I clinical trial of a selective inhibitor of
`CYP17, abiraterone acetate, confirms that castration-resistant
`prostate cancer commonly remains hormone driven,” J Clin Oncol,
`26(28):4563-4571 (2008) (“Attard 2008”)
`
`
`
`Wockhardt
`Exhibit #
`
`1079
`
`
`
`IV. Person of ordinary skill in the art
`17.
`I understand that a POSA is a hypothetical person who is presumed to
`
`be aware of all the pertinent art, thinks along conventional wisdom in the art, and is
`
`a person of ordinary creativity. A POSA may work as a part of a multi-disciplinary
`
`team and draw upon not only his or her own skill, but also take advantage of
`
`certain specialized skills of others in the team, to solve a given problem. In regard
`
`to the ’438 patent, a POSA typically would have had a M.D., with at least five
`
`years of experience specializing in medical oncology. Alternatively, a POSA
`
`would have had a M.D., with at least five years of experience specializing in
`
`urology and at least two years of clinical experience. A POSA would have also
`
`typically worked as part of a multi-disciplinary team and drawn upon not only his
`
`or her own skills, but also taken advantage of certain specialized skills of others in
`
`the team, to solve a given problem. For example, such a team may be comprised of
`
`a biochemist (whom would have knowledge relating to enzyme inhibition), an
`
`endocrinologist (whom would have knowledge relating to hormone-directed
`
`
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`11
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
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`treatments), and a pharmaceutical scientist (whom who have knowledge related to
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`developing pharmaceutical dosage forms).
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`V.
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`State of the art before August 25, 2006
`18. Before August 25, 2006, the state of the art included the teachings
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`provided by the references discussed in this Declaration. Additionally, a POSA,
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`based on then-existing literature, would also have had general knowledge of the
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`diagnostic methods used to treat and monitor prostate cancer, as well as various
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`courses of treatment of prostate cancer.
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`A. The standard of care for prostate cancer, as of August 25, 2006
`19. Prostate cancer is an androgen-dependent disease. It is the most
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`common cancer among men and the second-most leading cause of cancer death
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`among men in the United States. (WCK1007, p.1503, WCK1008, p.1241).
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`20. Androgen receptors (“AR”) in the prostate are nuclear transcription
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`factors that control expression of genes involved in cell growth, differentiation,
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`homeostasis, and apoptosis. (WCK1046, p.460, Fig. 1). Androgen steroids bind to
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`and activate the AR. (WCK1008, p.1241; WCK1046, p.460, Fig. 1). Testosterone
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`and its metabolite, dihydrotestosterone (“DHT”), are two important androgens that
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`activate AR. (WCK1008, p.1241). Although the entire pathway of testosterone
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`production is present only in the testes, the adrenal glands, located above the
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
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`kidneys, release DHEA and androstenedione, which may be subsequently
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`converted into testosterone. (WCK1005, p.2317).
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`21. Treatment options for treating prostate cancer depend to a great extent
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`on whether the prostate cancer is localized (i.e., clinically confined to the prostate;
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`known as primary prostate cancer) or whether it has spread to other areas of the
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`body (i.e., metastasized) from the prostate. (WCK1009, p.546-550).
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`22. By August 25, 2006, patients with primary prostate cancer were
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`managed by radical surgery (i.e., prostatectomy), radiation therapy, or watchful
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`waiting. (WCK1009, p.546).
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`23. However, in 15-33% of patients, the cancer progressed and they
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`develop metastatic disease. (WCK1008, p.1241). “Prostate cancer metastasizes
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`most often to pelvic lymph nodes and bone,” with pain usually being the most
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`significant symptom. (WCK1010, p.1756). Metastatic disease is typically initially
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`treated by orchiectomy (i.e., surgical castration) or by drugs that decrease testicular
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`androgen (i.e., testosterone) production (i.e., chemical castration) (WCK1010,
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`p.1756). Drugs intended to lower testosterone levels through chemical castration
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`include gonadotropin-releasing hormone (GnRH) analogues (also known as
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`luteinizing hormone-releasing hormone agonists (“LHRH agonists”)), estrogens
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`and progestational agents, and the antiandrogens that bind to the androgen receptor
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`but do not signal. (WCK1009, p.548).
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
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`24. As the diagram below shows, LHRH is produced in the hypothalamus.
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`The hypothalamus normally releases LHRH in pulses, which leads to a pulsatile
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`release of follicle-stimulating hormone (“FSH”) and in luteinizing hormone
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`(“LH”). (WCK1012, p.157). “LH attaches to receptors on the Leydig cells of the
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`testes, promoting testosterone production.” (WCK1012, p.157). LHRH agonists,
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`such as leuprolide acetate and gosereline acetate, first produce a rise in LH and
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`FSH, followed by a decrease in the pituitary gland’s receptors, resulting in
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`chemical castration. (WCK1009, p.548). Initial treatment with LHRH agonists
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`corresponds to an increase in testosterone production caused by a surge of LH.
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`(WCK1012, p.157). However, “[c]onstant exposure to LHRH after treatment with
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`an LHRH agonist … eventually causes downregulation of receptors in the
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`pituitary, inhibition of FSH and LH release, and a concomitant decrease in
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`testosterone production.” (WCK1012, p.157).
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`Interr Partes Reeview of UU.S. Patent
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`No. 8,8222,438
`002)
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`DDeclarationn of Paul AA. Godley,
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`M.D., Ph..D., MPP ((Exhibit 1
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`Fig. 1. PPathways oof Androgeen Deprivaation. (WCKK1012, p.
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`225.
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`In adddition to LLHRH agonnists, antiaandrogens,
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`such as fluutamide,
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`bicalutaamide, or nnilutamide,, may be addministere
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`d to reducee the initiaal rise in
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`159).
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`testosterrone that results fromm treatmennt with LHRRH agonissts. (WCK11009, p.54
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`8).
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`Antianddrogens bloock the binnding of anndrogens too the androogen recepttor.
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`(WCK11009, p.5488).
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`226. Whille androgenn deprivatiion or supppression re
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`mains the
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`focus of
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`than 90%
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`of patientss initially
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`metastaatic prostatee cancer treatment, and greater
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
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`responded to treatment, the duration of the response is frequently short-lived.
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`(WCK1008, p.1241). Almost all patients go on to develop refractory or metastatic
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`castration-resistant prostate cancer (“mCRPC”), i.e., prostate cancer that
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`progresses even after a reduction in androgen levels despite surgical or chemical
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`castration. (WCK1007, p.1503; WCK1017, p.62).1
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`27.
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`It was recognized that progression of mCRPC despite androgen
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`deprivation was associated with an active androgen receptor-signaling pathway.
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`(WCK1029, p.8254). This was demonstrated by nearly all cases of progression
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`being accompanied by a rise in PSA levels. (WCK1029, p.8254). It was
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`hypothesized that after androgen deprivation treatment prostate tumors can evolve
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`mechanisms that reactivate AR signaling and AR-responsive pathways.
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`(WCK1008, p.1242). Preclinical models suggested that prostate cancer cells
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`actually acquire the ability to grow in the presence of low levels of androgens
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`equivalent to castrate levels. (WCK1008, p.1242). Further, it was known that the
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`sensitivity of the AR is increased in patients with mCRPC, so that the activation of
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`1mCRPC is also widely referred to in the literature as “hormone refractory,”
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`“hormone resistant,” “androgen resistant,” or “androgen refractory.” (WCK1029,
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`p.8254). My use of mCRPC encompasses these other alternate terms.
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
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`AR is enhanced at lower levels of testosterone (WCK1005, p.2317; WCK1008,
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`p.1242).
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`28. As of August 25, 2006, the prognosis for patients with mCRPC was
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`poor and treatment often focused on palliative care (WCK1007, p.1503;
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`WCK1008, p.1241). However, despite progression on first-line hormonal
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`treatments, such as LHRH agonists and antiandrogens, the majority of tumors
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`remain sensitive to second-line hormonal treatments. (WCK1009, p.549;
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`WCK1029, p.8254). Patients progressing after treatment with LHRH agonists and
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`antiandrogens may be treated with a different antiandrogen. (WCK1009, p.549).
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`Other second-line hormone therapies included estrogens, progestins, ketoconazole,
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`and glucocorticoids. (WCK1009, p.549).
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`29. Once a patient stopped responding to hormone treatments, cytotoxic
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`agents were considered as the next step in treatment. (WCK1009, p.549). In 2004,
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`the standard of care for patients who had progressed on androgen deprivation
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`therapy became the combination of docetaxel and prednisone. (WCK1029,
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`p.8253). Before then, combined treatment with mitoxantrone and prednisone had
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`been the standard chemotherapy regimen for hormone refractory prostate cancer.
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`(WCK1007, p.1509). As such, a POSA would have known that prednisone had
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`been part of the standard of care for hormone refractory prostate cancer well before
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`August 25, 2006.
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1002)
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`B.
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`PSA levels were known to be an indicator of prostate cancer
`progression and tumor burden
`30. Prostate-specific antigen (“PSA”) testing was important in the
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`diagnosis, management, and treatment of hormone refractory prostate cancer.
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`(WCK1004, p.1177; WCK1009, pp.543-544; WCK1018, Abstract). PSA is
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`produced by both healthy and cancerous epithelial cells of the prostate.
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`(WCK1009, p.544). PSA levels are monitored in patients with a prostate cancer
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`diagnosis. (WCK1009, pp.544, 548-550). This is because decreasing levels of PSA
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`correlate with a response t