`
`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: 2016-01582
`
`U.S. Patent No. 8,822,438
`_____________________
`
`DECLARATION OF PAUL A. GODLEY, M.D., Ph.D., MPP
`
`
`WCK1104
`Wockhardt Bio AG v. Janssen Oncology, Inc.
`IPR2016-01582
`
`

`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`TABLE OF CONTENTS
`
`
`
`I. 
`
`II. 
`
`E. 
`
`F. 
`
`
`Introduction ...................................................................................................... 1 
`A.  Qualifications ........................................................................................ 1 
`B. 
`Scope of work ........................................................................................ 1 
`Analysis of the Rettig Declaration................................................................... 6 
`A. 
`Claim construction ................................................................................ 6 
`B. 
`PSA levels were known in the art to be an indicator of a
`response to prostate cancer therapy ....................................................... 7 
`A POSA would not have discounted the disclosure of Gerber ............. 8 
`C. 
`D.  Abiraterone acetate was known to be a more specific CYP17
`inhibitor than ketoconazole ................................................................. 12 
`Glucocorticoids, including prednisone, have long been used to
`treat prostate cancer ............................................................................. 15 
`1. 
`Glucocorticoids, including prednisone, were generally
`well tolerated and safe .............................................................. 15 
`Prednisone was known in the art to treat prostate cancer ......... 17 
`The effects of prednisone on mutant AR are not well
`understood ................................................................................. 19 
`Dr. Rettig’s testimony about the prior art does not change my
`conclusions regarding the ’438 patent claims ..................................... 19 
`G.  Dr. Rettig’s and Dr. Auchus’ interpretations of O’Donnell do
`not conflict with my opinions .............................................................. 20 
`1. 
`A POSA would have relied on O’Donnell’s Synacthen
`test results to indicate that abiraterone acetate would
`cause a cortisol deficiency ........................................................ 21 
`A POSA would have expected abiraterone acetate to
`cause mineralocorticoid excess ................................................. 22 
`
`2. 
`3. 
`
`2. 
`
`i
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`

`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`
`III.  Objective indicia of non-obviousness ........................................................... 25 
`A.  No unexpected results ......................................................................... 25 
`B. 
`No long-felt, but unmet need ............................................................... 29 
`C. 
`No commercial success ....................................................................... 29 
`
`ii
`
`

`

`
`
`
`I.
`
`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`I, Paul A. Godley, do hereby declare as follows:
`
`Introduction
`A. Qualifications
`1. My background and qualifications are generally described in Section
`
`II of my initial declaration submitted in the proceeding on August 10, 2016
`
`(“Initial Declaration”) (WCK1002, ¶¶9-15). I incorporate those qualifications by
`
`reference here. I have also provided an updated curriculum vitae, attached as
`
`WCK1105, which contains more details on my background, experience, and
`
`publications. I am being compensated as set forth in my previous Declaration
`
`(WCK1002, ¶2), and I continue to have no personal or financial interest in
`
`Wockhardt or in the outcome of this proceeding.
`
`B.
`2.
`
`Scope of work
`
`For this declaration, I was asked to review and discuss the declaration
`
`of Dr. Matthew Rettig (“the Rettig Declaration”). (JSN2038). I have also reviewed
`
`the declaration of Dr. Richard Auchus (“the Auchus Declaraction”) (JSN2040), Dr.
`
`Rettig’s deposition transcript (WCK1097), and Janssen’s Patent Owner Response
`
`(“Janssen’s POR”) (Paper 43). This declaration is a statement of my opinions in
`
`this matter and the basis and reasons for those opinions. In forming the opinions
`
`expressed in this declaration, I have relied upon my education, experience, and
`
`
`
`1
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`

`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`
`knowledge of the subject matter discussed. I have also reviewed, considered, or
`
`relied upon documents and other materials, which are cited in the table below:
`
`Wockhardt/Janssen
`Exhibit #
`WCK1002
`
`WCK1004
`
`WCK1005
`
`WCK1006
`
`WCK1009
`
`WCK1010
`
`WCK1011
`
`Description
`
`Declaration of Paul A. Godley, M.D., Ph.D., MPP
`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”)
`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)
`
`
`
`2
`
`

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`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`WCK1016
`
`WCK1017
`
`WCK1019
`
`WCK1021
`
`WCK1022
`
`WCK1023
`
`WCK1024
`
`WCK1025
`
`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)
`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)
`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)
`
`3
`
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`WCK1026
`
`WCK1028
`
`WCK1030
`
`WCK1033
`
`WCK1034
`
`WCK1035
`
`WCK1040
`
`WCK1063
`
`WCK1079
`
`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)
`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)
`
`Barrie, S. E. et al, U.S. Patent No. 5,604,213 (filed Sep. 30,
`1994; issued Feb. 18, 1997) (“Barrie”)
`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/
`020449s028lbl.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”)
`Sonino, N., “The use of ketoconazole as an inhibitor of
`steroid production,” N Engl J of Med, 317:812-817 (1987)
`
`Jevtana Website, Dosing and Administration,
`http://www.jevtana.com/hcp/dosing/default.aspx (accessed
`Aug. 8, 2016)
`
`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”)
`
`4
`
`
`
`
`
`

`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`WCK1083
`
`WCK1090
`
`WCK1091
`
`WCK1092
`
`WCK1093
`
`WCK1094
`
`WCK1095
`
`WCK1096
`
`Nishimura, K. et al., “Low Doses of Oral Dexamethasone
`for Hormone-Refractory Prostate Carcinoma,” Cancer
`89:2570-2576 (2000)
`Auchus, R.J., “The Genetics, Pathophysiology, and
`Management of Human Deficiencies of P450c17,”
`Endocrinol. Metab. Clin. North Am., 30(1):101-119 (2001)
`Auchus, R.J. et al., “Use of Prednisone with Abiraterone
`Acetate in Metastatic Castration-Resistant Prostate
`Cancer,” Oncologist 19:1231-1240 (2014)
`Attard, G. et al., “Clinical and Biochemical Consequences
`of CYP17A1 Inhibition with Abiraterone Given with and
`without Exogenous Glucocorticoids in Castrate Men with
`Advanced Prostate Cancer,” J. Clin. Endocrinol. Metab.
`97(2):507-516 (2012)
`Akakura, K. et al., “Possible Mechanism of
`Dexamethasone Therapy for Prostate Cancer: Suppression
`of Circulating Level of Interleukin-6,” Prostate 56:106-109
`(2003)
`Attard, G., et al. “A randomized trial of abiraterone acetate
`(AA) administered with 1 of 4 glucocorticoid (GC)
`regimens in metastatic castration-resistant prostate cancer
`(mCRPC) patients (pts),” Journal of Clinical Oncology,
`34:Suppl 2, 261 (2016)
`Ryan, C.J. et al., “Phase I Clinical Trial of the CYP17
`Inhibitor Abiraterone Acetate Demonstrating Clinical
`Activity in Patients With Castration-Resistant Prostate
`Cancer Who Received Prior Ketoconazole Therapy,” J.
`Clin. Oncol. 28:1481-1488 (2010)
`Reid, A.H.M. et al., “Significant and Sustained Antitumor
`Activity in Post-Docetaxel, Castration-Resistant Prostate
`Cancer With the CYP17 Inhibitor Abiraterone Acetate,” J.
`Clin. Oncol. 28:1489-1495 (2010)
`
`WCK1097
`
`Deposition Transcript of Matthew B. Rettig, M.D.
`
`5
`
`
`
`
`
`

`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`
`
`JSN2057
`
`JSN2159
`
`JSN2161
`
`Bubley, G.J. et al., “Eligibility and Response Guidelines
`for Phase II Clinical Trials in Androgen-Independent
`Prostate Cancer: Recommendations From the Prostate-
`Specific Antigen Working Group,” J. Clin. Oncol.
`17:3461-3467 (1999)
`de Bono, J.S. et al., “Abiraterone and Increased Survival in
`Metastatic Prostate Cancer,” NEJM 364(21):1995-2005
`(2011)
`
`Deposition Transcript of Paul A. Godley, M.D., Ph.D.,
`MPP
`
`II. Analysis of the Rettig Declaration
`A. Claim construction
`3.
`Dr. Retting states that he understands the terms “treat,” “treating,” and
`
`“treatment,” as recited in the claims of the ’438 patent, to require reducing the
`
`growth or spread of the cancer itself. (JSN2038, ¶77). And Dr. Rettig has testified
`
`that he understands this to include “eradicating the primary tumor, reducing tumor
`
`burden, improving clinical outcomes such as survival.” (WCK1097, 19:20-25).1 I
`
`disagree with this understanding of the terms “treat,” “treating,” and “treatment.”
`
`
`1 I note that while Dr. Rettig indicates that reducing tumor burden falls under the
`
`Board’s construction of “treat,” “treating,” and “treatment,” Dr. Rettig does not
`
`apply this understanding to his analysis of the prior art and claims of the ’438
`
`patent throughout his declaration.
`
`
`
`6
`
`

`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`4.
`
`Instead, I understand that the Board has construed the terms “treat,”
`
`
`
`“treating,” and “treatment” to “include the eradication, removal, 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.” (Paper 43,
`
`IPR2016-01582). As such, I understand that the Board’s definition of “treatment”
`
`does not require a showing of survival benefit or reduction in the growth or spread
`
`of cancer. Thus, any prostate cancer therapy that elicits a measurable response
`
`(e.g., a PSA response), regardless of proven survival benefit or reduction in the
`
`growth or spread of cancer, would be considered “treatment.” As such, a POSA
`
`would understand that a decline in PSA level is indicative of whether a particular
`
`cancer therapy is modifying, managing, or controlling the tumor. And moreover, a
`
`POSA would understand this construction of “treatment” is not limited solely to an
`
`increased survival outcome or reduction in the growth or spread of cancer, but can
`
`encompass any modification, management, or control of the tumor.
`
`B.
`
`5.
`
`PSA levels were known in the art to be an indicator of a response
`to prostate cancer therapy
`
`I understand that during his deposition, Dr. Rettig stated that “PSA is
`
`a poor surrogate for changes in tumor burden.” (WCK1097, 23:4-11). I disagree.
`
`As I stated in my previous Declaration, it was well-known in the art that decreasing
`
`levels of PSA correlate with a response to treatment and that a PSA reduction has
`
`
`
`7
`
`

`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`
`been shown to be a predictor of tumor burden. (WCK1002, ¶30). This is because
`
`the tumor produces PSA. (WCK1009, p.544).
`
`6.
`
`And in fact, the PSA Working Group defines a “PSA response” as a
`
`PSA decline of at least 50% confirmed by a second PSA value four or more weeks
`
`later. (JSN2057, p.3464). And in fact, I note that Janssen’s own clinical trials used
`
`PSA response as the primary end point. (WCK1021, p.4856; WCK1022, p.3743).
`
`Thus, a POSA would have known that a decline in PSA levels would have
`
`suggested the modification, management, or control of the cancer by a particular
`
`therapy and the minimization or delay in the spread of cancer.
`
`C. A POSA would not have discounted the disclosure of Gerber
`7.
`I understand that Dr. Rettig claims that a POSA would not rely on the
`
`results of Gerber because Gerber does not disclose the results of a randomized
`
`clinical trial. (JSN2038, ¶¶177, 178). I disagree with this assessment.
`
`8.
`
`Gerber is a retrospective review of patient charts from patients treated
`
`with ketoconazole and prednisone. Chart reviews, such as Gerber, are commonly
`
`used by clinicians to document and communicate important observations in a
`
`clinical setting, and are useful in identifying trends in therapies. Moreover, chart
`
`reviews are especially informative in the field of cancer treatment where carrying
`
`out placebo controlled studies can be difficult due to the possible terminal nature of
`
`the disease. Additionally, randomized trials are typically very expensive, so
`
`
`
`8
`
`

`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`
`clinicians typically seek prior evidence of a therapy's efficacy before moving
`
`forward with a randomized trial. Chart reviews are important lower level studies
`
`that provide such data and support for a future clinical trial. Moreover, I am
`
`informed that Gerber is prior art for all that it discloses for purposes of determining
`
`obviousness, and that there is no requirement that its disclosure needs to be
`
`supported by randomized clinical trials, as Dr. Rettig incorrectly argues.
`
`9.
`
`Dr. Rettig also claims that Gerber does not teach a POSA that the
`
`combination of ketoconazole and prednisone is “safe and effective” for treating
`
`prostate cancer because Gerber did not perform a placebo-controlled clinical study.
`
`(JSN2038 at ¶176). I disagree.
`
`10. Prior to August 2006, many clinicians were administering
`
`ketoconazole and glucocorticoids to patients who had progressed on first- and/or
`
`second-line prostate cancer therapies. (WCK1004, p. 1177; WCK1005, p. 2323;
`
`WCK1011, p. 542; WCK1016, p. 1947)—a practice that Dr. Rettig confirmed at
`
`his deposition. (WCK1097, 24:25-26:3). Gerber published data related to the
`
`patients they had treated. And a POSA reading Gerber would have understood the
`
`potential benefits of treating prostate cancer with ketoconazole and prednisone
`
`despite the lack of a placebo-controlled clinical study.
`
`11. Gerber discloses data from 15 patients that had been treated with
`
`ketoconazole and prednisone. (WCK1004, Abstract). Using the PSA Working
`
`
`
`9
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`

`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`
`Group’s definition of “PSA response,” as discussed by Dr. Rettig (JSN2038,
`
`¶185), two of the 15 patients in Gerber had a response to treatment, i.e., they had
`
`PSA declines of greater than 50% for at least eight weeks. (WCK1004, p.1178).
`
`Again, Dr. Rettig, based on his incorrect definition of “treat,” “treating,” and
`
`“treatment,” discounts Gerber’s disclosure, by arguing that no radiologic evidence
`
`or survival data was given for the two patients who saw a greater than 50%
`
`reduction in PSA. (JSN2038, ¶187). However, as Dr. Rettig stated in his
`
`declaration, “patients who showed a greater than 50% decrease in PSA were likely
`
`to have actually experienced a clinically significant response”, with which I agree.
`
`(JSN2038, ¶67).
`
`12. Further, and more importantly, I understand that based on the Board’s
`
`construction, the claims of the ’438 patent do not require a showing of radiological
`
`evidence or increased survival. And PSA reduction as evidence of treatment
`
`response (e.g., modification, management, or control of cancer) is well understood
`
`in the art. Consequently, a POSA reading Gerber would know that at least two of
`
`the patients treated with ketoconazole and prednisone did in fact respond to
`
`treatment. (WCK1004, pp. 1178, 1179). As such, despite Dr. Rettig’s statements to
`
`the contrary, Gerber teaches the treatment of prostate cancer, as meant within the
`
`scope of the ’438 patent’s claims, using ketoconazole and prednisone. Moreover,
`
`
`
`10
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`

`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`
`also contrary to Dr. Rettig’s assertions, a POSA would not have been dissuaded
`
`from relying on Gerber’s teachings.
`
`13. Gerber also states that “[k]etoconazole was generally well tolerated.”
`
`And Gerber goes on to conclude that “there appears to be a small subgroup of
`
`patients with progressive prostate cancer despite hormonal therapy who will derive
`
`significant benefit from the combination of ketoconazole and glucocorticoid
`
`replacement therapy.” (WCK1004, p. 1179). As such, a POSA would understand
`
`from Gerber that ketoconazole and prednisone would have been a safe and
`
`effective therapy in patients with mCRPC.
`
`14. Further, physicians routinely prescribe drugs for indications that have
`
`not been approved by the FDA: this is known as “off-label use.” These off-label
`
`uses are not necessarily supported by placebo-controlled clinical trials. Rather,
`
`physicians rely on empirical evidence, such as evidence published in peer-
`
`reviewed journals like the Gerber reference. As I have stated in my previous
`
`Declaration, the off-label use of ketoconazole and a glucocorticoid for treating
`
`prostate cancer was well-known in the art. (WCK1002, ¶37, 44, 45). And in fact,
`
`Dr. Rettig himself admitted that he has treated prostate cancer patients with
`
`ketoconazole and a steroid during his deposition. (WCK1097, 24:25-25:6). These
`
`facts undermine Dr. Rettig’s insistence that a treatment regimen needs to be proven
`
`
`
`11
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`

`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`
`safe and effective with placebo-controlled randomized trials before they’re relevant
`
`to this patent. He is incorrect.
`
`D. Abiraterone acetate was known to be a more specific CYP17
`inhibitor than ketoconazole
`
`15.
`
`I understand that Dr. Rettig has testified that ketoconazole and
`
`abiraterone acetate have different mechanisms of action for reducing androgens
`
`and that a POSA would not have expected the two activities to cause similar side
`
`effects, such as a reduction in cortisol levels. (JSN2038, ¶100). Figures 4 and 5 in
`
`the Rettig Declaration attempt to convey a difference in the inhibitory effect of
`
`abiraterone acetate and ketoconazole against various enzyme activities. However,
`
`these figures mischaracterize the extent of both abiraterone acetate’s and
`
`ketoconazole’s enzyme inhibitory effects and are not supported by any actual data.
`
`And Dr. Rettig’s testimony does not change my conclusion that a POSA would
`
`have modified Gerber to replace administering ketoconazole with abiraterone
`
`acetate, as discussed in my previous Declaration and below. (WCK1002, ¶¶72-75).
`
`16. First, Dr. Rettig failed to identify CYP17’s 17α-hydroxylase
`
`mediation of the conversion of progesterone to 17-hydroxyprogesterone in both
`
`Figures 4 and 5, which is also an important pathway for the production of cortisol.
`
`Dr. Rettig has further provided no evidence and cited no literature supporting the
`
`relative inhibition potencies that he has arbitrarily marked.
`
`
`
`12
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`

`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
`
`17. As I stated in my previous Declaration, it was known that
`
`
`
`ketoconazole inhibited several cytochrome P450 enzymes, including CYP17.
`
`(WCK1002, ¶36). Also, as I previously stated, it was known that because
`
`ketoconazole inhibited the CYP17 enzyme, in particular the 17α-hydroxylase
`
`activity of the CYP17 enzyme, it would have been expected to have an inhibitory
`
`effect on cortisol production. (WCK1002, ¶37). Indeed, as Figure 4 in the Rettig
`
`Declaration demonstrates, abiraterone acetate inhibits CYP17’s 17α-hydroxylase
`
`activity, preventing both the conversion of progesterone to 17-
`
`hydroxyprogesterone and 17α-hydroxypregnenolone to 17α-hydroxyprogesterone.
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`(See also WCK1002, p.19, Fig. 2). And both of these conversions lead to cortisol
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`production. Moreover, abiraterone acetate inhibits CYP17’s 17α-hydroxylase
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`activity more potently than ketoconazole, as supported by data disclosed in the
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`Barrie patent and Potter reference. (WCK1030, compare 22:60-66 with 24:60-61;
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`WCK1035, p.2466, Table 1, compare compound 2 with ketoconazole).
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`18. As such, it was well-known by August 2006 that both ketoconazole
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`and abiraterone acetate inhibit the same CYP17 enzyme that is necessary for
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`cortisol and androgen production. Therefore, ketoconazole and abiraterone acetate
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`do not have different mechanisms of action, as Dr. Rettig suggests. Rather,
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`ketoconazole simply inhibits more enzymes than abiraterone acetate. That is the
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`relevant fact here. And a POSA would have known that abiraterone acetate
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
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`inhibited the CYP17 enzyme more potently than ketoconazole. Thus, a POSA
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`would understand that abiraterone acetate had the same mechanisms of action as
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`ketoconazole for inhibiting cortisol and androgen production, but would work
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`more effectively.
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`19. Further, Dr. Rettig implies in Figure 4 of the Rettig Declaration that
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`abiraterone acetate inhibits the 17,20-lyase activity of the CYP17 enzyme more
`
`potently than the 17α-hydroxylase activity. This is again misleading because
`
`abiraterone is actually the active moiety in vivo, not abiraterone acetate, which Dr.
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`Rettig admitted to during his deposition. (WCK1097, 31:12-24). While Dr. Rettig
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`offers no support for the assertion that abiraterone inhibits the 17,20-lyase activity
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`more potently than the 17α-hydroxylase activity, a POSA would have known that
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`the published literature does not support this. In fact, both the Barrie patent and the
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`Potter reference state that the abiraterone in vitro IC50 values are very similar for
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`CYP17’s 17α-hydroxylase and 17,2-lyase activities (4 nM vs. 2.9 nM,
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`respectively). (WCK1030, 23:23-28 at Ex. 2; WCK1035, Table 1, compound 3).
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`Therefore, a POSA would have expected abiraterone’s in vivo inhibition of the
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`17α-hydroxylase and 17,20-lyase activities to be similar in potency. And, more
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`importantly, a POSA would have sought to use abiraterone acetate in place of
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`ketoconazole to inhibit CYP17 because of its more potent activity that would have
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
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`reduced androgen production, which is a goal of prostate cancer treatment.
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`(WCK1002, ¶67).
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`20.
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`I understand that during his deposition Dr. Rettig admitted that the
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`basis for administering a glucocorticoid with ketoconazole was to replace the
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`cortisol lost due to ketoconazole’s inhibitory activity on CYP17. (WCK1097, 27:9-
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`28:5). Thus, a POSA would have also sought to do the same when administering
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`abiraterone acetate. This is because a reduction in cortisol would likewise have
`
`been predicted from abiraterone’s inhibitory effect on CYP17. (WCK1030, 23:23-
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`28 at Ex. 2; WCK1035, Table 1, compound 3).
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`E. Glucocorticoids, including prednisone, have long been used to
`treat prostate cancer
`1. Glucocorticoids, including prednisone, were generally well
`tolerated and safe
`
`21.
`
`I understand that Dr. Rettig argues that prednisone would not have
`
`been administered to prostate cancer patients unless absolutely necessary due to
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`side effects associated with glucocorticoids. (JSN2038, ¶134). I disagree. As I
`
`explained in my previous Declaration, glucocorticoids, including prednisone, have
`
`been routinely given to prostate cancer patients for many years. (WCK1002, ¶¶41-
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`45). Tannock 1989 discloses that prostate cancer patients who received 7.5 to 10
`
`mg/day of prednisone had a reduction in pain and an increase in quality of life.
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`(WCK1028, Abstract). Nishimura discloses treating prostate cancer patients with
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
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`0.5-2 mg/day of oral dexamethasone and reports that “[a]ll toxicities were mild and
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`manageable on an outpatient basis.” (WCK1083, p. 2575). Moreover, only two
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`chemotherapy drugs are approved for treating prostate cancer, docetaxel and
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`cabazitaxel, both of which are indicated for co-administration with 10 mg/day
`
`prednisone. (WCK1034, p.29; WCK1063, p.1). In the clinical trial disclosed by
`
`Attard 2008, 10 of 21 patients treated (48%) had previously received continuous
`
`dexamethasone therapy. (WCK1079, p.4565, Table 1 and p.4566). Further,
`
`prednisone is often administered in the placebo arm of placebo-controlled prostate
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`cancer clinical studies. (WCK1010, Abstract; WCK1019, Abstract; WCK1023,
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`Abstract; JSN2159, p.1997). Thus, treating prostate cancer patients with
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`glucocorticoids, including prednisone, was common and routine by August 2006
`
`and has remained so since.
`
`22. Dr. Rettig cites to Fosså (WCK1017) for examples of the side effects
`
`of prednisone treatment. (JSN2038, ¶135). Fosså discloses administering 20
`
`mg/day of prednisone to prostate cancer patients. (WCK1017, p.63). However, as I
`
`stated in my previous Declaration, a POSA would have known to adjust the dosage
`
`of prednisone from 20 mg to 10 mg or lower to minimize these side effects.
`
`(WCK1002, ¶¶93-94). And in fact, Fosså discloses that 2 patients had their
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`prednisone dosage reduced to 10 mg/day. (WCK1017, p.65). Moreover, when
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`treating a life threatening disease, such as prostate cancer, on balance the possible
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
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`side effects from daily, low-dose administration of prednisone would not have
`
`been a concern. (JSN2162, 60:1-24).
`
`Prednisone was known in the art to treat prostate cancer
`
`2.
`I understand that, as for Gerber, Dr. Rettig claims that a POSA would
`
`23.
`
`discount Sartor’s results because Sartor is a chart review that did not disclose the
`
`results of randomized clinical trials that a POSA would not rely on their results.
`
`(JSN2038, ¶ 201). As I discussed above, chart reviews are commonly used by
`
`clinicians to document and communicate important observations in a clinical
`
`setting, and are useful in identifying trends in therapies, especially in the field of
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`cancer treatment. Moreover, as I have stated above, I am informed that Sartor is
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`prior art for all that it discloses for purposes of determining obviousness, and that
`
`there is no requirement that its disclosure needs to be supported by randomized
`
`clinical trials, as Dr. Rettig incorrectly argues.
`
`24. And even though Sartor is a chart review, notably, Sartor selectively
`
`included patients that controlled for confounding variables (e.g., radiation therapy,
`
`antiandrogen withdrawal, ketoconazole treatment, suramin treatment,
`
`aminoglutethimide treatment, or chemotherapy) known to affect PSA levels.
`
`(WCK1006, p.253). A POSA reading Sartor, therefore, would rely on the data
`
`Sartor provided. And, again, the fact that Sartor is not a placebo-controlled clinical
`
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`Inter Partes Review of U.S. Patent No. 8,822,438
`Reply Declaration of Paul A. Godley, M.D., Ph.D., MPP (Exhibit 1104)
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`study does not negate the fact that its results would nevertheless provide a POSA
`
`useful data to assess the effectiveness of prednisone to treat prostate cancer.
`
`25. Sartor teaches that 34% of patients treated with prednisone had a PSA
`
`decline of greater than 50% with a duration of response of at least 4 months.
`
`(WCK1006, Abstract). Again, these patients meet the PSA Working Group’s
`
`definition of “PSA response.” Dr. Rettig tries to argue that these results were not
`
`validated by additional measurements such as a reduction in measurable tumor size
`
`or an improvement in bone scans. (JSN2038, ¶202). Again, I understand the
`
`Board’s construction does not require a measurement of tumor size, an
`
`improvement in bone scans, or a specific length of time for a treatment response.
`
`But as I explained before, a PSA decline of greater than 50% correlated with a
`
`treatment response (i.e., modification, management, or control of a tumor and
`
`minimization or delay in the spread of cancer). (WCK1025, Abstract; WCK1026,
`
`Abstract). So, a POSA reading Sartor would have understood that prednisone
`
`would treat prostate cancer (i.e., modify, manage, or control a tumor and minimize
`
`or delay the spread of cancer) because Sartor discloses that 34% of his patients had
`
`a PSA