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
`________________________
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,822,438
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`
`
`
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, Virginia 22313–1450
`
`

`

`
`
`
`
`Wockhardt
`Exhibit #
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`LIST OF EXHIBITS
`
`Description
`
`Auerbauch, A. H. & Belldegrum, A. S., U.S. Patent No. 8,822,438
`(filed Feb. 24, 2011; issued Sep. 2, 2014) (“the ’438 patent”)
`Declaration of Paul A. Godley, MD, Ph.D., MPP
`
`Dr. Paul A. Godley’s Curriculum Vitae
`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. 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).
`
`i
`
`

`

`
`
`Wockhardt
`Exhibit #
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`Description
`
`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)
`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)
`
`ii
`
`

`

`
`
`Wockhardt
`Exhibit #
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`Description
`
`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)
`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)
`
`iii
`
`

`

`
`
`Wockhardt
`Exhibit #
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`Description
`
`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)
`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)
`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., 62-83,
`1431-1462
`Ganong, W. F. (1979). Review of Medical Physiology. Los Altos,
`CA: Lange Medical Publications, 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)
`
`iv
`
`

`

`
`
`Wockhardt
`Exhibit #
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`Description
`
`Rajfer, J. et al, “Mechanism of inhibition of human testicular
`steroidogenesis by oral ketoconazole,” J Clin Endocrinol Metab,
`63:1193-1198 (1986)
`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)
`
`v
`
`

`

`
`
`Wockhardt
`Exhibit #
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`Description
`
`Mayo Clinic Website, Prostate cancer,
`http://www.mayoclinic.org/diseasesconditions/prostate-
`cancer/basics/definition/con-20029597?p=1 (accessed Aug. 8, 2016)
`Cancer.org (ACS), “What are the key statistics about prostate
`cancer?”
`http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-
`cancer-key-statistics (accessed Aug. 8, 2016)
`Cancer.net (ASCO Patient Website), Treatment of Metastatic
`Castration-Resistant Prostate Cancer,
`http://www.cancer.net/research-and-advocacy/asco-care-and-
`treatment-recommendations-patients/treatment-metastatic-
`castration-resistant-prostate-cancer (accessed Aug. 9, 2016)
`Kirby, M., C. Hirst, and E.D. Crawford (2011), “Characterising the
`Castration-Resistant Prostate Cancer Population: A Systematic
`Review,” International Journal of Clinical Practice 65(11): 1180-
`1192
`Zytiga Label (Mar. 20, 2015),
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202379s
`018lbl.pdf (accessed Aug. 9, 2016)
`Zytiga Website, How Zytiga® (abiraterone acetate) Works,
`https://www.zytiga.com/print/about-zytiga/how-zytiga-works
`(accessed Aug. 8, 2016)
`Mayo Clinic Website, Hormone Therapy for Prostate Cancer,
`http://www.mayoclinic.org/tests-procedures/hormone-therapy-for-
`prostate-cancer/home/ovc-20201738 (accessed Aug. 8, 2016).
`FDA Website, Drugs@FDA – Zytiga,
`http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fu
`seaction=Search.DrugDetails (accessed Aug. 8, 2016)
`FDA News Release, “FDA expands Zytiga’s use for late-stage
`prostate cancer,” 12/10/2012,
`http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/u
`cm331492.htm (accessed Aug. 8, 2016)
`
`vi
`
`

`

`
`
`Wockhardt
`Exhibit #
`1057
`
`1058
`
`1059
`
`1060
`
`1061
`
`1062
`
`1063
`
`1064
`
`1065
`
`1066
`
`1067
`
`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`Description
`
`Wells Fargo Securities, LLC., “Johnson & Johnson,” 6/29/2015.
`FDA Website, Orange Book, Zytiga (NDA 202379),
`http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm
`?Appl_No=202379&Product_No=001&table1=OB_Rx (accessed
`Aug. 8, 2016)
`Murphy, William J., John L. Orcutt, and Paul C. Remus (2012),
`Patent Valuation: Improving Decision Making through Analysis,
`Hoboken, NJ: Wiley
`Cowen & Company, “Quick Take – Johnson & Johnson,”
`William Blair, “Biotechnology – Zytiga Fourth-Quarter Sales Imply
`Xtandi Strength,” 1/22/2013
`Zytiga Brochure, Putting Prednisone in Perspective, 3/2015
`Jevtana Website, Dosing and Administration,
`http://www.jevtana.com/hcp/dosing/default.aspx (accessed Aug. 8,
`2016)
`FDA News Release, “FDA Approves New Treatment for Advanced
`Prostate Cancer,” 06/17/2010,
`http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/u
`cm216143.htm (accessed Aug. 8, 2016)
`Nasdaq.com, “One Drug To Rule Them All: Medivation’s Xtandi
`To Dominate Prostate Cancer Market,” available at
`http://www.nasdaq.com/article/one-drug-to-rule-them-all-
`medications-xtandi-to-dominate-prostate-cancer-market-cm376782
`(accessed Aug. 8, 2016)
`Medivation Press Release, “U.S. FDA Approves New Indication for
`the Use of XTANDI® (Enzalutamide) Capsules for Patients With
`Metastatic Castration-Resistant Prostate Cancer,” 9/10/2014,
`http://investors.medivation.com/releasedetail.cfm?ReleaseID=87026
`7 (accessed Aug. 8, 2016)
`UBS Research, “Medivation – A Look at the Growth and Share in
`Prostate Cancer,” 2/3/2014
`
`vii
`
`

`

`
`
`Wockhardt
`Exhibit #
`
`1068
`
`1069
`
`1070
`
`1071
`
`1072
`
`1073
`
`1074
`
`1075
`
`1076
`
`1077
`1078
`
`1079
`
`1080
`
`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`Description
`
`Wedbush Securities, Inc., “Medivation: Zytiga Market Share
`Decline Accelerates From Last Quarter,” 7/14/2015
`RBC Capital Markets (via Barron’s Website), “Xtandi Beats
`Casodex, Set to Top Zytiga,” 4/3/2015,
`http://www.barrons.com/articles/xtandi-beats-casodex-set-to-top-
`zytiga-1428075331 (accessed Aug. 8, 2016)
`Cowen & Company, “Biotechnology Quarterly,” 7/2/2012.
`Credit Suisse, “Prostate Cancer – Implications of Zytiga’s Pre-
`Chemo Approval,” 12/11/2012
`UBS Investment Research, “Johnson & Johnson – Zytiga Label
`Extended,” 12/10/2012
`William Blair, “Medivation, Inc. – Looking into Recent
`Weaknesses,” 7/15/2015
`Bloomberg.com, “Tesaro Rises on $85 Million J&J Cancer Drug
`Licensing Deal,” available at
`www.bloomberg.com/news/articles/2016-04-06/j-j-to-pay-85-
`million-to-license-tesaro-cancer-drug-rights (accessed Aug. 9, 2016)
`Scherer, F.M., et al., (Eds.). (1990). Industrial Market Structure and
`Economic Performance, Third Ed. Boston, MA: Houghton Mifflin
`Company.
`Investor Words, “hurdle rate,” accessed at
`http://www.investorwords.com/2362/hurdle_rate.html (accessed
`Aug. 8, 2016)
`Declaration of Robert D. Stoner, Ph.D.
`Dr. Robert D. Stoner’s Curriculum Vitae
`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)
`IMS Health Data, 2012–2015 (submitted in Amerigen Pharms. Ltd.
`v. Janssen Oncology, Inc., IPR2016-00286, Ex. 1067)
`
`viii
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`TABLE OF CONTENTS
`
`
`Introduction ..................................................................................................... 1 
`
`Grounds for standing (37 C.F.R. § 42.104(a)) ............................................... 3 
`
`
`
`I. 
`
`II. 
`
`III. 
`
`Statement of the precise relief requested and the reasons therefore .............. 3 
`
`IV.  Overview ......................................................................................................... 3 
`
`A. 
`
`B. 
`
`Person of ordinary skill in the art (“POSA”) ........................................ 3 
`
`Scope and content of the art before August 25, 2006 ........................... 4 
`
`1.  Metastatic castration-resistant prostate cancer .......................... 5 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`By August 25, 2006, PSA levels were known to be an
`indicator of prostate cancer progression and tumor
`burden ......................................................................................... 7 
`
`By August 25, 2006, prednisone was known to treat
`prostate cancer and was co-administered with other anti-
`cancer agents as part of the standard of care ............................. 8 
`
`Inhibition of CYP17 was known to affect cortisol
`production and lead to mineralocorticoid excess ....................... 9 
`
`Ketoconazole and abiraterone acetate were well-known
`inhibitors of CYP17 by August 25, 2006 ................................ 11 
`
`C. 
`
`Gerber (WCK1004) ............................................................................. 13 
`
`D.  O’Donnell (WCK1005) ....................................................................... 14 
`
`E. 
`
`F. 
`
`Sartor (WCK1006) .............................................................................. 16 
`
`Summary of the ’438 patent ................................................................ 17 
`
`1. 
`
`2. 
`
`3. 
`
`Brief description of the ’438 patent ......................................... 17 
`
`The ’438 patent claims ............................................................. 17 
`
`Prosecution background and summary of arguments .............. 18 
`
`ix
`
`

`

`
`V. 
`
`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`Claim construction ........................................................................................ 20 
`
`A. 
`
`B. 
`
`“treat,” “treating,” and “treatment” ..................................................... 20 
`
`“therapeutically effective amount of prednisone”............................... 20 
`
`VI. 
`
`Identification of challenge (37 C.F.R. § 42.104(b)) ..................................... 21 
`
`A.  Ground 1: Claims 1-20 would have been obvious over Gerber,
`O’Donnell, and Sartor ......................................................................... 23 
`
`1. 
`
`Claim 1 ..................................................................................... 25 
`
`(a)  Co-administering a CYP17 inhibitor and
`prednisone to treat prostate cancer was well-
`known in the art ............................................................. 28 
`(b)  Abiraterone acetate was well-known to be a
`potent and more specific inhibitor of CYP17
`than ketoconazole and to effectively reduce
`testosterone .................................................................... 29 
`(c)  A POSA would have had a reason and the
`know-how to combine abiraterone and
`prednisone to treat prostate cancer ................................ 30 
`(d)  A POSA would have had a reasonable
`expectation of success in practicing the method
`of claim 1 ....................................................................... 34 
`
`Claims 2 and 3 .......................................................................... 36 
`
`Claim 4 ..................................................................................... 36 
`
`Claim 5 ..................................................................................... 38 
`
`Claims 6-8 ................................................................................ 39 
`
`Claim 9 ..................................................................................... 41 
`
`Claims 10 and 11...................................................................... 41 
`
`Claims 12 and 13...................................................................... 42 
`
`Claims 14-16 ............................................................................ 43 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`6. 
`
`7. 
`
`8. 
`
`9. 
`
`x
`
`

`

`
`
`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`10.  Claim 17 ................................................................................... 44 
`
`11.  Claims 18-20 ............................................................................ 45 
`
`B. 
`
`Objective indicia of nonobviousness do not weigh in favor of
`patentability of claims 1-20 ................................................................. 46 
`
`1. 
`
`No unexpected superior results ................................................ 48 
`
`(a)  Unexpected results raised during prosecution
`do not weigh in favor of patentability ........................... 48 
`Janssen failed to provide probative evidence of
`unexpected results in the 286 POPR ............................. 49 
`
`(b) 
`
`2. 
`
`No commercial success ............................................................ 55 
`
`(a) 
`
`(b) 
`
`Patent-based and FDA-based exclusivities limit
`any economic relevance of commercial success ........... 56 
`There is no nexus between the performance of
`Zytiga® and the ’438 patent claims because any
`features of the ’438 patent driving Zytiga®’s
`sales already existed in the prior art .............................. 60 
`(c)  Xtandi® has taken Zytiga®’s market share .................... 62 
`(d)  Unexpected commercial success of Zytiga® is
`neither economically nor legally relevant, and
`the performance metrics for Zytiga® presented
`during prosecution of the ’438 patent are
`misleading and incomplete ............................................ 63 
`
`3. 
`
`4. 
`
`No long felt need and failure of others .................................... 64 
`
`Copying by generic drug makers is irrelevant ......................... 65 
`
`VII.  Conclusion .................................................................................................... 66 
`
`VIII.  Mandatory notices (37 C.F.R. § 42.8) .......................................................... 66 
`
`
`
`
`xi
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
`
`Introduction
`
`
`
`I.
`
`Pursuant to 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42, Wockhardt Bio AG
`
`submits this Petition for Inter Partes Review (“IPR”) seeking cancellation of
`
`claims 1-20 of U.S. Patent No. 8,822,438 (WCK1001) as unpatentable under 35
`
`U.S.C. § 103(a).
`
`The challenged claims are generally directed to methods of treating prostate
`
`cancer comprising administering a therapeutically effective amount of abiraterone
`
`acetate and a therapeutically effective amount of prednisone. (WCK1001, 16:16-
`
`20.) Dependent claims recite dosage amounts for the abiraterone and prednisone,
`
`as well as the type of prostate cancer to be treated. (Id., 16:21-17:14.)
`
`However, every element of the challenged claims existed in the prior art. For
`
`instance, abiraterone acetate was a well-known, potent, specific inhibitor of
`
`CYP17, an enzyme that functions to produce testosterone: a fuel for prostate
`
`cancer growth. And O’Donnell (WCK1005) demonstrates that abiraterone acetate
`
`was used to treat prostate cancer by August 25, 2006.1
`
`Further, using glucocorticoids, such as prednisone, in treating prostate
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`cancer had been known since at least the 1950’s. In fact, Sartor (WCK1006)
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`1 Petitioner does not concede that the ’438 patent is entitled to an effective filing
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`date of August 25, 2006, rather that it is not entitled to any earlier date.
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`1
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`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
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`teaches the anti-prostate cancer effect of prednisone. For example, Sartor reports
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`that administering prednisone caused a significant reduction in PSA levels, a
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`primary indicator of prostate cancer tumor burden, in patients participating in
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`clinical trials. In addition, co-administering prednisone with other anti-cancer
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`agents had long been part of the standard of care when treating prostate cancer.
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`(WCK1007, 1509; WCK1029, 8253; WCK1002, ¶¶29, 41-45.) And finally, co-
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`administering prednisone with CYP17 inhibitors, such as ketoconazole, was seen
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`as necessary to prevent unwanted side effects that can result from CYP17
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`inhibition. (WCK1005, 2323; WCK1011; 542-544; WCK1016, 1947; WCK1040,
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`814; WCK1002, ¶40, 44.)
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`This petition and the supporting Declaration of Dr. Paul A. Godley
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`(WCK1002), an expert in the diagnosis and treatment of genitourinary cancers,
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`evidence that the challenged claims merely combine the known elements of using
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`abiraterone and prednisone individually to treat prostate cancer, achieving
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`predictable results. As such, each of the challenged claims fall squarely within the
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`Supreme Court’s KSR decision and its extensive progeny as fatally obvious. KSR
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`Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Further, no publicly available
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`evidence of objective indicia of nonobviousness weighs in favor of patentability.
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`Accordingly, this Petition demonstrates that Wockhardt is reasonably likely to
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`prevail with respect to at least one challenged claim.
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`2
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`Petition for Inter Partes Review of U.S. Patent No. 8,822,438
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`II. Grounds for standing (37 C.F.R. § 42.104(a))
`Wockhardt certifies that the ’438 patent is available for IPR and Wockhardt
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`is not barred or estopped from requesting IPR of any of the challenged claims.
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`III. Statement of the precise relief requested and the reasons therefore
`The Office should institute IPR under 35 U.S.C. §§ 311-319 and 37 C.F.R.
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`§§ 42.1-.80 and 42.100-42.123, and cancel claims 1-20 of the ’438 patent as
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`unpatentable under pre-AIA 35 U.S.C. § 103(a) for the reasons explained below.
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`This petition is accompanied and supported by the declarations of Dr. Paul A.
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`Godley (WCK1002), an expert in the diagnosis and treatment of genitourinary
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`cancers, and Dr. Robert Stoner (WCK1077), an expert in industrial organization
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`and economics. Wockhardt’s detailed, full statement of the reasons for relief
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`requested is provided in § VI.
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`IV. Overview
`A.
`Person of ordinary skill in the art (“POSA”)
`A POSA is a hypothetical person who is presumed to be aware of all
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`pertinent art, thinks along conventional wisdom in the art, and is a person of
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`ordinary creativity. With respect to the ’438 patent, a POSA would be a treating
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`clinician specializing in oncology, typically holding an M.D. degree, with at least
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`five years of experience specializing in medical oncology. (WCK1002, ¶17.)
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`Alternatively, a POSA would have an M.D., with at least five years of experience
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`specializing in urology and at least two years of clinical experience. (Id.) A POSA
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`would have also typically worked as part of a multi-disciplinary team and drawn
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`upon not only his or her own skills, but also taken advantage of certain specialized
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`skills of others in the team, to solve a given problem. (Id.) For example, such a
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`team may be comprised of a biochemist (who, e.g., would have knowledge relating
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`to enzyme inhibition), an endocrinologist (who, e.g., would have knowledge
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`relating to hormone-directed treatments), and a pharmaceutical scientist (who, e.g.,
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`who have knowledge related to developing pharmaceutical dosage forms). (Id.)
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`Before August 25, 2006, a POSA would have been aware of the teachings
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`provided by the references discussed in this Petition and by Dr. Godley, who also
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`discusses prior art teachings confirming the general knowledge of a POSA.
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`See Abbott Labs. v. Andrx Pharm., Inc., 452 F.3d 1331, 1336 (Fed. Cir.
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`2006) (stating that a person of ordinary skill possesses the “understandings
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`and knowledge reflected in the prior art”); see also Randall Mfg. v. Rea, 733 F.3d
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`1355, 1362 (Fed. Cir. 2013) (“[T]he knowledge of [a person of ordinary skill in the
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`art] is part of the store of public knowledge that must be consulted when
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`considering whether a claimed invention would have been obvious”). A POSA,
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`based on then existing literature, would also have had general knowledge of the
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`methods used to treat and monitor prostate cancer. (WCK1002, ¶18.)
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`Scope and content of the art before August 25, 2006
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`B.
`Prostate cancer, an androgen-dependent disease, is the second leading cause
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`4
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`of cancer death among men in the U.S. (WCK1007, 1503; WCK1008, 1241;
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`WCK1002, ¶19.) Androgen steroids activate the androgen receptor (“AR”) on
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`prostate cells, resulting in the transcription of target genes involved in prostate cell
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`proliferation, differentiation, and apoptosis. (WCK1046, 460, Fig. 1; WCK1002,
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`¶20.) In prostate cancer patients, activation of the AR by androgen steroids also
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`results in the progression and proliferation of the cancer. (WCK1008, 1241;
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`WCK1002, ¶20.) Testosterone and its metabolite dihydrotestosterone (“DHT”) are
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`two important androgens responsible for activating the AR. (WCK1008, 1241;
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`WCK1002, ¶20.)
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`1. Metastatic castration-resistant prostate cancer
`Treatment focusing on targeting prostate cancer through surgical removal of
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`the prostate and local tumors fails in 15-33% of prostate cancer patients and results
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`in metastatic disease. (WCK1008, 1241; WCK1002, ¶¶21-23.) Prostate cancer
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`frequently metastasizes to pelvic lymph nodes and bone, with pain usually being
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`the most significant symptom. (WCK1010, 1756; WCK1002, ¶23.) The first step
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`in treating metastatic disease typically involves orchiectomy (i.e., surgical
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`castration) or administering drugs that decrease androgen production (i.e.,
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`chemical castration) (WCK1010, 1756; WCK1002, ¶¶23-26.)
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`However, it was well-known in the art that peripheral conversion of adrenal
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`steroids to testosterone resulted in as much as 10% of baseline circulating
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`androgens remaining in castrate men. (WCK1005, 2317; WCK1009, 548;
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`WCK1002, ¶31.) This extratesticular source of androgens was well-known to be an
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`important alternate source of AR stimulation that can lead to prostate cancer
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`growth despite castrate levels of testosterone. (WCK1005, 2317; WCK1002, ¶31.)
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`Indeed, almost all castrate patients will 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 despite a reduction in androgen levels from surgical or chemical
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`castration.2 (WCK1007, 1503; WCK1017, 62; WCK1002, ¶26.)
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`In addition, the art taught that, after androgen deprivation treatment, prostate
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`tumors evolve mechanisms to reactivate AR signaling and AR-responsive
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`pathways. (WCK1029, 8254; WCK1008, 1242; WCK1002, ¶27.) Preclinical
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`models suggested that low levels of androgens, equivalent to castrate levels,
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`continued to fuel prostate cancer growth. (WCK1008, 1242; WCK1002, ¶27.)
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`Further, it was well-known that the AR could acquire greater sensitivity in mCRPC
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`patients, and thus, could be activated at lower levels of testosterone (WCK1005,
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`2 mCRPC 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; WCK1002, ¶ 26 n.1.) Reference to mCRPC in this petition encompasses
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`these other alternate terms.
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`2317; WCK1008, 1242; WCK1002, ¶27.) And inhibiting androgen synthesis
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`through known inhibitors of androgen production, such as ketoconazole and
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`abiraterone acetate, was well-known. (WCK1009, 549; WCK1002, ¶¶36, 38.)
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`Ultimately, when a patient stopped responding to hormone-focused
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`treatments, cytotoxic agents were usually considered as the next line of treatment.
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`(WCK1009, 549; WCK1002, ¶29.) In 2004, co-administering docetaxel and
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`prednisone was the standard of care for patients who did not respond to androgen
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`deprivation therapy. (WCK1029, 8253; WCK1002, ¶29.) And prior to 2004, the
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`combination of mitoxantrone and prednisone had been the standard chemotherapy
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`regimen for mCRPC. (WCK1007, 1509; WCK1029, 8253; WCK1002, ¶29.) As
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`such, prednisone had been part of the standard of care for mCRPC long before
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`August 25, 2006. (WCK1002, ¶29.)
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`2.
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`By August 25, 2006, PSA levels were known to be an
`indicator of prostate cancer progression and tumor burden
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`Prostate-specific antigen (“PSA”) testing was important in the diagnosis,
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`management, and treatment of hormone refractory prostate cancer, by August 25,
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`2006. (WCK1004, 1177; WCK1009, 543-544; WCK1018, Abstract; WCK1002,
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`¶30.) Both nonmalignant and malignant epithelial cells of the prostate produce
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`PSA. (WCK1009, 544; WCK1002, ¶30.) Doctors monitored PSA levels in prostate
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`cancer patients to determine disease progression. (WCK1009, 544, 548-550;
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`WCK1002, ¶30.) A decrease in PSA levels generally correlates with a response to
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`treatment, while rising levels correlates with disease progression. (WCK1006, 252;
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`WCK1009, 544, 546-549; WCK1002, ¶30.) Additionally, PSA was a well-known
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`predictor of tumor burden, as well as recurrence and survival. (WCK1018,
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`Abstract; WCK1002, ¶30.)
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`3.
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`By August 25, 2006, prednisone was known to treat prostate
`cancer and was co-administered with other anti-cancer
`agents as part of the standard of care
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`It was also well-known that glucocort