UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`MYLAN LABORATORIES LIMITED
`Petitioner,
`v.
`AVENTIS PHARMA S.A.
`Patent Owner.
`________________
`
`Case IPR2016-00712
`U.S. Patent No. 8,927,592
`________________
`
`DECLARATION OF ALTON OLIVER SARTOR, M.D.
`
`Aventis Exhibit 2001
`Mylan v. Aventis, IPR 2016-00712
`
`

`
`TABLE OF CONTENTS
`
`IPR2016-00712
`
`I.
`
`II.
`
`III.
`
`QUALIFICATIONS ............................................................................................................1
`
`SCOPE OF ASSIGNMENT AND APPROACH ................................................................4
`
`APPLICABLE STANDARDS AND CONTROLLING PRINCIPLES..............................5
`
`A.
`
`B.
`
`C.
`
`Interpreting Patent Claims .......................................................................................5
`
`Obviousness .............................................................................................................6
`
`Person of Ordinary Skill in the Art..........................................................................7
`
`IV.
`
`THE STATE OF THE ART ................................................................................................8
`
`A.
`
`B.
`
`Background Information..........................................................................................8
`
`Information Regarding Use of Cabazitaxel in Prostate Cancer
`Progressing During or After Treatment with Docetaxel........................................16
`
`V.
`
`CLAIM CONSTRUCTION...............................................................................................18
`
`A.
`
`B.
`
`A method for treating a patient ..............................................................................18
`
`A method of increasing the survival of a patient ...................................................22
`
`VI.
`
`Disclosure of Mylan’s Prior Art ........................................................................................25
`
`A.
`
`B.
`
`C.
`
`D.
`
`Attard .....................................................................................................................25
`
`Pivot .......................................................................................................................27
`
`Winquist.................................................................................................................27
`
`TROPIC Listing.....................................................................................................28
`
`VII. Dr. Seth’s Arguments Are Unsupported............................................................................29
`
`A.
`
`B.
`
`Phase II Data in Breast Cancer ..............................................................................30
`
`Phase III Protocols .................................................................................................41
`
`VIII. Declaration.........................................................................................................................43
`
`

`
`IPR2016-00712
`
`I, Alton Oliver Sartor, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I am the same Dr. Sartor who submitted a declaration under 37 C.F.R. §
`
`1.132 during the prosecution of U.S. Patent Application No. 13/457,720, which I
`
`understand issued as U.S. Patent No. 8,927,592 (the “’592 patent”). Exh. 1004 at
`
`164-222. I will refer to my previous declaration as the “Prosecution Declaration.”
`
`2.
`
`I am the Laborde Professor of Cancer Research in the Medicine and
`
`Urology Departments of Tulane University School of Medicine. I am also the
`
`Medical Director and Associate Director for Clinical Programs of the Tulane
`
`Cancer Center.
`
`3.
`
`I received my M.D. from Tulane University in 1982. I completed an
`
`internship at the University of Pennsylvania before training in internal medicine at
`
`Tulane University School of Medicine. I then completed a fellowship at the
`
`National Cancer Institute (“NCI”) in Bethesda, Maryland in 1989. From 1989-
`
`1990 I was a Senior Staff Fellow at the Laboratory of Cellular Development and
`
`Oncology, National Institutes of Dental Research before serving as a Senior
`
`Investigator at the NCI until 1993.
`
`4.
`
`In 1993 I returned to Louisiana to serve as Associate Professor of Medicine
`
`at the Louisiana State University (“LSU”) Medical School in Shreveport, L.A. and
`
`then moved to the LSU Health Sciences Center in New Orleans, L.A. in 1998 as
`
`1
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`

`
`IPR2016-00712
`the Patricia Powers Strong Professor of Oncology, Stanley S. Scott Cancer Center
`
`Director, and Hematology/Oncology Section Chief. I became the Co-Director of
`
`the Louisiana Cancer Research Consortium at its origin in 2002.
`
`5.
`
`In 2006 I left LSU and joined the Lank Center for Genitourinary Oncology
`
`at the Dana Farber Cancer Research Institute and Harvard Medical School. In
`
`2008 I joined Tulane University. Further information regarding my academic
`
`background and work experience can be found in my curriculum vitae, a copy of
`
`which is submitted separately in Exhibit 2002.
`
`6. During the course of my career, my interests have focused on treating
`
`prostate cancer, particularly in patients who have failed initial therapy. I have
`
`published more than 300 scholarly articles, including many on clinical trials of
`
`agents to treat prostate cancer. These publications have been cited more than
`
`14,000 times.
`
`7.
`
`I have been appointed to numerous scientific committees. I am currently
`
`serving as Chairman of the Tulane Cancer Center Strategic Planning Committee;
`
`Medical Chair of the Genitourinary Committee of NRG Oncology (the world’s
`
`largest radiation oncology research group); and served as an FDA Public
`
`Workshop Panelist in 2013 on Clinical Trial Design Issues - Drug & Device
`
`Development for Localized Prostate Cancer.
`
`2
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`

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`IPR2016-00712
`I have served on the editorial boards of scientific journals such as The
`
`8.
`
`Prostate, Urology, and Personalized Medicine in Oncology. I am currently Editor-
`
`in-Chief of the Clinical Genitourinary Cancer journal.
`
`9.
`
`I continue to treat patients at the Tulane Cancer Center and Urology Multi-
`
`Disciplinary Clinic. I see approximately 25-50 patients per week with urologic
`
`malignancies. Currently about 1000 patients are under my care, mostly with
`
`prostate cancer. From 2005-2016, I have been named one of the “Best Doctors in
`
`America” by Best Doctors, Inc.
`
`10. I was a principal investigator (“PI”) or co-PI on numerous prospective
`
`international clinical trials evaluating new therapies for patients with advanced
`
`prostate cancer, including five pivotal trials that have led to FDA approvals. I was
`
`a co-PI on the TROPIC phase III study comparing cabazitaxel plus prednisone to
`
`mitoxantrone plus prednisone in patients with metastatic castration-resistant
`
`prostate cancer (“mCRPC”) previously treated with a docetaxel-containing
`
`treatment, a study sponsored by Sanofi. I understand Sanofi to be a related
`
`company to Aventis Pharma S.A. I am currently a co-PI on another phase III
`
`clinical trial of cabazitaxel, also sponsored by Sanofi.
`
`11. I have significant experience in the clinical evaluation of cancer
`
`treatments, evaluation of novel treatments for patients with prostate cancer that
`
`have failed initial therapies, and treatment of patients with advanced prostate
`
`3
`
`

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`IPR2016-00712
`cancer. I have administered docetaxel therapy to my prostate cancer patients since
`
`the approval of Taxotere® in 2004.
`
`I have also administered cabazitaxel therapy to
`
`patients progressing after docetaxel therapy since the approval of Jevtana® in 2010.
`
`Therefore, I believe that I am qualified to render the opinions set forth in this
`
`declaration.
`
`II.
`
`SCOPE OF ASSIGNMENT AND APPROACH
`
`12. I have been retained as an expert on behalf of Patent Owner Aventis
`
`Pharma S.A. (“Aventis”) to provide information and opinions to the Patent Trial
`
`and Appeal Board (“the Board”) to assist in the determination of the validity of the
`
`claims of the ’592 patent for which a Petition for Inter Partes Review (“IPR”) has
`
`been filed by Mylan Laboratories Ltd. (“Mylan”). Specifically, counsel for
`
`Aventis asked me to provide opinions regarding the meaning of Claims 1 and 27 of
`
`the ’592 patent (Exh. 1001), and to respond to arguments made by Mylan’s expert
`
`Dr. Rahul Seth regarding the validity of Claims 1-5 and 7-30 in view of certain
`
`prior art references.
`
`13. I have been informed by counsel and I understand that this stage of the
`
`proceeding is to determine the sufficiency of Mylan’s Petition. To the extent I do
`
`not explicitly respond to arguments made by Mylan or Mylan’s expert, Dr. Rahul
`
`Seth, it does not mean that I agree with those arguments.
`
`4
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`

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`IPR2016-00712
`14. I have been informed by counsel and I understand that the analysis of
`
`whether a patent is obvious is performed from the perspective of a person of
`
`ordinary skill in the art at the time of the patented invention. I understand the
`
`relevant timeframe for the patented invention of the ’592 patent is October 29,
`
`2009 for Claims 1-5 and 10-20, and June 17, 2010 for Claims 7-9.
`
`15. A list of documents that I relied on in connection with the development of
`
`my opinions set forth in this declaration and in the Prosecution Declaration is
`
`attached as Appendix 1. I have also reviewed the declaration of Dr. Seth and the
`
`documents cited therein.
`
`16. I am being compensated for my time spent in connection with this matter
`
`at a rate of $500.00 per hour. My compensation does not depend on the outcome
`
`of this proceeding or the conclusions in this report.
`
`17. To the extent that I am presented with new information concerning the
`
`subject matter of this declaration or affecting any of my assumptions, I reserve the
`
`right to supplement this declaration accordingly.
`
`III. APPLICABLE STANDARDS AND CONTROLLING PRINCIPLES
`
`A.
`
`Interpreting Patent Claims
`
`18. I have been asked to provide my opinion as to the meaning of terms in
`
`Claims 1 and 27 of the ’592 patent. I have been informed and understand that I
`
`should interpret the claims from the point of view of a person of ordinary skill in
`
`5
`
`

`
`IPR2016-00712
`the art as of October 29, 2009 and that my interpretation should be consistent with
`
`the broadest reasonable construction in light of the patent.
`
`B.
`
`Obviousness
`
`19. I have been informed by counsel and I understand that an issued patent
`
`claim is invalid as obvious if it can be shown that the differences between the
`
`patented subject matter and the prior art are such that the subject matter as a whole
`
`would have been obvious, at the time the invention was made, to a person having
`
`ordinary skill in the art. I understand that for an invention that is composed of
`
`several elements, it is not enough to demonstrate that each was independently
`
`known in the art.
`
`20. I understand and have been informed by counsel that when the question is
`
`whether it would have been obvious to combine elements in the prior art, the Board
`
`will determine whether there was a reason to combine the elements in the manner
`
`claimed by the patent at issue. I also understand that it must be shown that a
`
`person of ordinary skill in the art would have had a reasonable expectation of
`
`success in combining the prior art references.
`
`21. I understand and have been informed by counsel that relevant
`
`considerations include the level of ordinary skill in the art; the scope and content of
`
`the prior art; differences between the prior art and the claims at issue; and the so-
`
`called objective secondary factors of nonobviousness. Secondary factors of
`
`6
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`IPR2016-00712
`nonobviousness may include, for example, evidence of unexpected results,
`
`commercial success, long felt but unmet needs, failure of others, and copying.
`
`22. I have been informed by counsel and I understand that, in order to evaluate
`
`the obviousness of any claim of the ’592 patent over a given prior art combination,
`
`I should analyze whether the prior art references, including collectively in
`
`combination, disclose each and every element of the allegedly invalid claim as
`
`those references are read by the person of ordinary skill in the art at the time of the
`
`invention.
`
`C.
`
`Person of Ordinary Skill in the Art
`
`23. I have been informed by counsel and I understand that the “person of
`
`ordinary skill in the art” is a hypothetical person who is presumed to be familiar
`
`with the relevant scientific field and its literature at the time of invention. This
`
`hypothetical person is also a person of ordinary creativity capable of understanding
`
`the scientific principles applicable to the pertinent field.
`
`24. It is my opinion that the person of ordinary skill in the art in the field of the
`
`’592 patent would be an oncologist with experience treating prostate cancer
`
`patients, including treating patients with metastatic prostate cancer. The skilled
`
`person would also have experience evaluating new therapies for prostate cancer.
`
`He or she would also have access to information regarding mechanisms of drug
`
`resistance and pharmacokinetics.
`
`7
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`

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`IPR2016-00712
`25. Based on my training and experience, I believe I am (and was as of
`
`October 29, 2009 and June 17, 2010) a person of greater than ordinary skill in the
`
`relevant art, which permits me to give an opinion about the qualifications of one of
`
`ordinary skill at the time of the invention.
`
`26. Dr. Seth defines the person of ordinary skill in the art differently, in that he
`
`includes specific pieces of information that such a person would have, and makes
`
`assumptions about what a person would do with cabazitaxel and a corticoid. Exh.
`
`1002 at ¶40.
`
`27. My opinions stated in this declaration would be the same if rendered from
`
`the perspective of a person of ordinary skill in the art as described by Dr. Seth.
`
`IV. THE STATE OF THE ART
`
`A.
`
`Background Information
`
`28. Cancer that has spread beyond the prostate is called “metastatic.”
`
`Metastatic prostate cancer is typically treated with hormone-based therapy to lower
`
`or block hormones that promote cancer growth. This is referred to as androgen
`
`ablation, androgen suppression, or androgen deprivation. The first hormonal
`
`therapy is typically surgical or medical castration. This results in improvement in
`
`tumor volume and symptoms, but is not curative.
`
`29. Prostate cancer that has progressed despite castrate-levels of testosterone is
`
`referred to as castration resistant prostate cancer or “CRPC.” This has also
`
`8
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`

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`IPR2016-00712
`previously been referred to in the literature as hormone refractory or androgen
`
`independent prostate cancer. See Exh. 1001 at col. 4, ll. 4-5.
`
`30. Most men with metastatic prostate cancer progress to castration resistant
`
`prostate cancer, commonly referred to as “mCRPC.” Pienta & Smith, Advances in
`
`Prostate Cancer Chemotherapy: A New Era Begins, 55 CA Cancer J. Clin. 300-18
`
`(2005) (Exh. 2083) at 300. mCRPC is an incurable condition; therefore the goals
`
`of therapy are to improve quality of life through symptom control and to prolong
`
`the life of patients.
`
`31. mCRPC is challenging because, as noted in the Prosecution Declaration,
`
`the disease is heterogeneous, both intra and interpatient. Exh. 2083 at 316;
`
`Mackinnon et al., Molecular Biology Underlying the Clinical Heterogeneity of
`
`Prostate Cancer, An Update, 133 Arch. Pathol. Lab. Med. 1033-40 (2009) (Exh.
`
`2025) at 1033. This means that within a patient there are a variety of different
`
`types of cancer cells and that there are differences between patients, making it
`
`difficult to generalize from one patient to another. See Exh. 2025 at 1033; Exh.
`
`2083 at 316; see also Cabral, Factors Determining Cellular Mechanisms of
`
`Resistance to Antimitotic Drugs, 4 Drug Resistance Updates 3-8 (2001) (“Cabral”)
`
`(Exh. 2009) at 3 (“Tumor cells from patients are frequently very heterogeneous . . .
`
`.”).
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`9
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`IPR2016-00712
`32. Furthermore, there were various proposed mechanisms by which prostate
`
`cancer became castration resistant. Exh. 2083 at 300-02; Exh. 2025 at 1034-35.
`
`33. Prior to 2004, no chemotherapy had been demonstrated to improve overall
`
`survival of mCRPC patients. Mitoxantrone in combination with a corticosteroid
`
`was shown to relieve pain and improve quality of life more than taking a
`
`corticosteroid alone, but did not prolong the life of patients. Tannock, Docetaxel
`
`plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer,
`
`351(15) N. Eng. J. Med. 1502-12 (2004) (“Tannock”) (Exh. 1013) at 1503; August
`
`2008 Novantrone® Label (Exh. 2111) at 9-12, 14.
`
`34. In 2004, docetaxel therapy was shown to statistically significantly increase
`
`overall survival of mCRPC patients, both in combination with prednisone and
`
`estramustine. Exh. 2083 at 304-07. Docetaxel was approved in combination with
`
`prednisone for the treatment of mCRPC in May 2004. May 19, 2004 FDA News
`
`Release (Exh. 2058).
`
`35. Unfortunately, even upon approval it was known that nearly all patients
`
`will progress after docetaxel therapy because of drug resistance. Rosenberg et al.,
`
`Activity of Second-Line Chemotherapy in Docetaxel-Refractory Hormone-
`
`Refractory Prostate Cancer Patients, Randomized Phase 2 Study of Ixabepilone or
`
`Mitoxantrone and Prednisone, 110(3) Cancer 556-63 (2007) (Exh. 1027) at 557.
`
`At that time, there were no options to prolong life after therapy with docetaxel.
`
`10
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`

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`IPR2016-00712
`36. Mitoxantrone became the de facto community standard for a patient that
`
`progressed during or after docetaxel because of mitoxantrone’s palliative benefits,
`
`but mitoxantrone did not prolong life. See Exh. 1027 at 557. Docetaxel
`
`retreatment was occasionally tried for patients who had responded well to
`
`docetaxel first-line. Exh. 1022 at 162. But docetaxel retreatment was not the
`
`community standard, especially for patients who progressed during or shortly after
`
`first-line docetaxel.
`
`37. Several mechanisms of docetaxel resistance had been described in the
`
`literature, including over-expression of multidrug efflux pumps such as P-
`
`glycoprotein (“PGP”), alterations in tubulin, alterations in various signaling
`
`pathways, alterations in the cell cycle, and alterations in the control of apoptosis.
`
`Galletti et al., Paclitaxel and Docetaxel Resistance: Molecular Mechanisms and
`
`Development of New Generation Taxanes, 2 Chem. Med. Chem. 920-42 (2007)
`
`(“Galletti”) (Exh. 1020) at 939; Exh. 2009 at 3.
`
`38. Dr. Seth focuses only on PGP (Exh. 1002 at ¶77), but people skilled in the
`
`art recognized that PGP had been identified by in vitro studies. Exh. 1020 at 923.
`
`It was recognized that the role of PGP in the clinical setting had not been
`
`established, and that cell cultures may not represent the clinical situation. Attard et
`
`al., Update on Tubulin-Binding Agents, 54 Pathologie Biologie 72-84 (2006)
`
`(“Attard”) (Exh. 1021) at 73; Exh. 2009 at 3; Exh. 1020 at 939.
`
`11
`
`

`
`IPR2016-00712
`39. Cabral reports that single-step selection for resistance “should be the best
`
`predictor” for clinical resistance. Exh. 2009 at 5. Based on single-step
`
`experiments, Cabral concludes that for paclitaxel and other drugs that promote
`
`microtubule assembly, “tubulin mutations should be seen most frequently.” Id. at
`
`4-5. Takeda found different mechanisms of resistance in two paclitaxel resistant
`
`hormone refractory prostate cancer cell lines. Takeda et al., The Establishment of
`
`Two Paclitaxel-Resistant Prostate Cancer Cell Lines and the Mechanisms of
`
`Paclitaxel Resistance with Two Cell Lines, 67 The Prostate 955-67 (2007)
`
`(“Takeda”) (Exh. 2091) at 960. One of the cell lines did not overexpress PGP. Id.
`
`The Takeda group found, however, that expression patterns were different than in
`
`previously studied paclitaxel resistant breast cancer cells. Id. at 965.
`
`40. Galletti reported in 2007 that the contribution of distinct resistance
`
`phenotypes and their role in the clinical setting had not been fully evaluated, but it
`
`was becoming increasingly clear that “resistance can often be mediated by more
`
`than one mechanism in a single cell at the same time.” Exh. 1020 at 939. Even
`
`today, the mechanisms of taxane resistance are not well understood. Vrignaud et
`
`al., Preclinical Antitumor Activity of Cabazitaxel, a Semisynthetic Taxane Active in
`
`Taxane-Resistant Tumors, 19(11) Clin. Cancer Res. 2973-83 (2013) (Exh. 2096) at
`
`2974.
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`12
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`IPR2016-00712
`41. On top of the complexity of castration resistance and docetaxel resistance,
`
`it was notoriously difficult to evaluate new treatments for metastatic prostate
`
`cancer because most patients do not have measureable disease, meaning it is not
`
`possible to track response by measuring tumor size. Exh. 2083 at 303. Instead
`
`most patients have metastases to the bone, which can be difficult to monitor. Id.
`
`As noted in the Prosecution Declaration, PSA was utilized to monitor response in
`
`patients with non measureable disease, but PSA reductions were of questionable
`
`value and were not surrogates for survival. Exh. 1004 at 185-87. In fact, there
`
`were no established surrogates for survival, leading to a high failure rate in phase
`
`III. Id.
`
`42. The Prosecution Declaration describes a number of agents with reported
`
`activity in phase I or II prostate cancer studies. As shown below, most of these
`
`agents had objectively measured response rates, either changes in tumor size or
`
`reductions in PSA levels, of 10% or higher.
`
`43. In a phase II CRPC trial of suramin, over 35% of patients with measurable
`
`disease had a tumor response, and nearly 34% of patients had a PSA decline of
`
`75% or more. Kaur et al., Suramin’s Development: What Did We Learn, 20
`
`Investigational New Drugs 209-19 (2002) (Exh. 2020) at 210.
`
`44. A phase II mCRPC study of satraplatin reported a 26% PSA response, and
`
`a 10% tumor response rate in patients with measurable disease. Latif et al., Phase
`
`13
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`IPR2016-00712
`II Study of Oral Bis(Aceto) Ammine Dichloro (Cyclohexamine) Platinum (IV) (JM-
`
`216, BMS-1892751) Given Daily X5 in Hormone Refractory Prostate Cancer
`
`(HRPC), 23 Investigational New Drugs 79-84 (2005) (Exh. 2110) at 79.
`
`45. A phase II mCRPC study of DN-101 in combination with docetaxel
`
`reported PSA response rates of 63% and tumor response rates of 29% in patients
`
`with measurable disease. Beer et al., Double-Blinded Randomized Study of High-
`
`Dose Calcitriol plus Docetaxel Compared with Placebo plus Docetaxel in
`
`Androgen-Independent Prostate Cancer: A Report from the ASCENT Investigators,
`
`26(6) J. Clin. Oncol. 669-74 (2007) (Exh. 2006) at 671.
`
`46. A phase II mCRPC study of GVAX reported 11% of patients with a PSA
`
`decrease of more than 25%. Small et al., Granulocyte Macrophage Colony-
`
`Stimulating Factor-Secreting Allogeneic Cellular Immunotherapy for Hormone-
`
`Refractory Prostate Cancer, 13 Clin. Cancer Res. 3883-91 (2007) (Exh. 2034) at
`
`3885.
`
`47. A phase II mCRPC post-docetaxel study of bevacizumab in combination
`
`with docetaxel reported 55% of patients with major PSA responses and that 37.5%
`
`of patients with measurable disease had tumor responses. Di Lorenzo et al.,
`
`Combination of Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-
`
`Refractory Prostate Cancer: A Phase 2 Study, 54 European Urol. 1089-96 (2008)
`
`(Exh. 2014) at 1092.
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`14
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`IPR2016-00712
`48. A phase II mCRPC post-docetaxel study of sunitinib reported 12.1% of
`
`patients with PSA declines of 50% or more and 11.1% of measurable disease
`
`patients with a tumor response. Sonpavde et al., Sunitinib Malate for Metastatic
`
`Castration-Resistant Prostate Cancer Following Docetaxel-Based Chemotherapy,
`
`21 Annals of Oncol. 319-24 (2009) (Exh. 2107) at 319.
`
`49. A phase I/II mCRPC study of ipilimumab alone or in combination with
`
`radiotherapy reported that 16% of patients had a PSA decline of at least 50%.
`
`Slovin et al., Ipilimumab Alone or in Combination with Radiotherapy in Metastatic
`
`Castration-Resistant Prostate Cancer: Results from an Open-Label, Multicenter
`
`Phase I/II Study, 24 Annals of Oncol. 1813-21 (2013) (Exh. 2033) at Table 4.
`
`50. A phase II mCRPC post-docetaxel study of custirsen in combination with
`
`docetaxel or mitoxantrone reported a 23% objective response rate in evaluable
`
`patients, PSA of declines of 90% or more in 20% of patients, and PSA declines of
`
`50% or more in 40% of patients. Saad et al., Randomized Phase II Trial of
`
`Custirsen (OGX-011) in Combination with Docetaxel or Mitoxantrone as Second-
`
`Line Therapy in Patients with Metastatic Castrate-Resistant Prostate Cancer
`
`Progressing After First-Line Docetaxel: CUOG Trial P-06c, 17(17) Clin. Cancer
`
`Res. 5765-73 (2011) (Exh. 2106) at 5765.
`
`51. A phase I/II mCRPC study of orteronel reported 80% of patients with at
`
`least a 50% PSA decline and 27% with at least a 90% PSA decline. Van Hook et
`
`15
`
`

`
`IPR2016-00712
`al., Orteronel for the Treatment of Prostate Cancer, 10(5) Future Oncol. 803-11
`
`(2014) (Exh. 2041) at 805.
`
`52. However, as noted in the Prosecution Declaration, for each of the agents
`
`discussed above in paragraphs 43-51, phase III studies were unsuccessful. Exh.
`
`1004 at 172-79.
`
`B.
`
`Information Regarding Use of Cabazitaxel in Prostate Cancer
`Progressing During or After Treatment with Docetaxel
`
`53. Prior to October 2009, the only clinical data available on the use of
`
`cabazitaxel for prostate cancer was the phase I dose ranging and pharmacokinetic
`
`study of Mita et al., Phase I and Pharmacokinetic Study of XRP6258 (RPR
`
`116258A), a Novel Taxane, Administered as a 1-Hour Infusion Every 3 Weeks in
`
`Patients with Advanced Solid Tumors, 15(2) Clin. Cancer Res. 723-30 (2009)
`
`(“Mita”) (Exh. 1012) described in paragraphs 49-56 and 72-76 of the Prosecution
`
`Declaration. Exh. 1004 at 181-82, 187-89. Mita reported a single docetaxel-
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`refractory patient with a partial response. Exh. 1012 at 727. Mita did not include a
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`corticoid.
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`54. As of 2009, it was also known that Sanofi was performing a phase III trial
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`of cabazitaxel plus prednisone versus mitoxantrone plus prednisone in patients
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`with mCRPC previously treated with docetaxel. This was disclosed in the
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`Beardsley reference that I addressed in the Prosecution Declaration. Exh. 1004 at
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`16
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`IPR2016-00712
`180-81 (discussing Beardsley & Chi, Systemic Therapy After First-Line Docetaxel
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`in Metastatic Castration-Resistant Prostate Cancer, 2 Current Opin. Supportive &
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`Palliative Care 161-66 (2008) (“Beardsley”) (Exh. 1022)).
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`55. The existence of this phase III trial was also disclosed in other references
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`that I understand were before the patent office: the National Horizon Scanning
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`Center (University of Birmingham), Cabazitaxel (XRP-6258) for Hormone
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`Refractory, Metastatic Prostate Cancer – Second Line After Docetaxel (April
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`2009) (“NHSC”) (Exh. 2078), and a listing for the TROPIC study at
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`clinicaltrials.gov last updated on December 28, 2006 (“2006 clinicaltrials.gov
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`listing”) (Exh. 2100). Exh. 1001 at 2, 3; Exh. 1004 at 123, 1891.
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`56. I understand that Mylan and Dr. Seth rely on Winquist, Open Clinical Uro-
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`Oncology Trials in Canada, 15(1) Canadian J. Urol. 3942-49 (2008) (“Winquist”)
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`(Exh. 1009), which was not before the patent office. But, the disclosure of
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`Winquist is largely the same as the disclosure of NHSC. NHSC also discloses the
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`existence of a phase III study examining 25 mg/m2 cabazitaxel in combination with
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`prednisone every three weeks compared to mitoxantrone in combination with
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`prednisone in patients with mCRPC previously treated with docetaxel-therapy.
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`Exh. 2078 at 2-3. NHSC also discloses that the primary endpoint is overall
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`survival. Id. at 3.
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`IPR2016-00712
`57. I also understand that Mylan and Dr. Seth rely on a later listing from the
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`clinicaltrials.gov website that they refer to as the “TROPIC Listing” (Exh. 1008),
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`which was not before the patent office. But this later document from the
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`clinicaltrials.gov website presents largely the same information as the 2006
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`clinicaltrials.gov listing except that the TROPIC Listing shows that the study had
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`not yet been terminated as of 2008. Both documents describe inclusion and
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`exclusion criteria. Exh. 2100 at 2; Exh. 1008 at 2.
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`58. Neither NHSC, Winquist, nor the 2006 or 2008 listings for the TROPIC
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`study on clinicaltrials.gov provide any data on the use of cabazitaxel to treat
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`prostate cancer.
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`V.
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`CLAIM CONSTRUCTION
`
`A.
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`A method for treating a patient
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`59. Based on my reading of the claims, the specification, and my knowledge in
`
`the field, a person of ordinary skill in the art would understand that the claimed
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`“method for treating a patient with prostate cancer that has progressed during or
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`after treatment with docetaxel” would be “a method that produces a therapeutic
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`effect in the patient.”
`
`60. The specification of the ’592 patent describes an unmet need for a therapy
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`to treat prostate cancer patients that have progressed during or after docetaxel
`
`therapy. Exh. 1001 at col.1, ll. 18-26, col. 2, ll.18-24. Indeed, it was recognized in
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`18
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`IPR2016-00712
`the art that a therapeutically effective treatment for patients that had progressed
`
`after docetaxel was urgently needed. Exh. 1022 at 161. The fact that the claim
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`recites a method for treating patients that have already progressed during or after
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`treatment with docetaxel indicates that the method meets this need.
`
`61. As noted in the Prosecution Declaration, people of ordinary skill were
`
`aware of numerous experimental therapies that failed to produce adequate results
`
`in clinical trials. Exh. 1004 at 172-75. Accordingly, a therapy that failed to
`
`produce therapeutic effects would not be useful to treat patients worsening during
`
`or after docetaxel therapy because it would not meet the medical need.
`
`62. The ’592 patent describes therapeutic effects as including an increase in
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`overall survival, reduction in tumor size, reduction in metastasis, complete
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`remission, partial remission, stable disease or complete response. Exh. 1001 at col.
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`3, ll. 24-29. I note that an increase in overall survival is a specific treatment
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`outcome.
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`63. Example 1 of the ’592 patent describes a phase III clinical trial in which 25
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`mg/m2 of cabazitaxel in combination with prednisone produced therapeutic effects.
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`Exh. 1001 at Table 1. The cabazitaxel arm had statistically significantly better
`
`tumor response rates and PSA response rates and statistically significantly longer
`
`overall survival and progression-free survival. Exh. 1001 at Table 1. Progression-
`
`free survival measures the time before the cancer worsens. Exh. 1001 at col. 11, ll.
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`19
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`IPR2016-00712
`21-24. An extension of progression-free survival indicates that patients
`
`experienced longer periods of stable disease before their cancer worsened.
`
`64. Dr. Seth construes this phrase to include “treatments that provide no
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`therapeutic benefit,” and “experimental treatments.” Exh. 1002 at ¶43. He does
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`not refer to anywhere in the patent that discusses experimental or palliative
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`therapies.
`
`65.
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`Instead Dr. Seth refers to the fact that “patient” is defined in the
`
`specification as including an animal. Exh. 1002 at ¶43. But, the claim recites a
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`patient with prostate cancer that has progressed during or after treatment with
`
`docetaxel. Docetaxel was not approved for use in animals, and it was known that
`
`very few species were known to develop prostate cancer spontaneously. Mubiru et
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`al., Nonhuman Primates as Models for Studies of Prostate Specific Antigen and
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`Prostatic Diseases, 68(14) Prostate 1-16 (2008) (Exh. 2109) at 2.
`
`66. Dr. Seth also points to the response rate in Example 1 as showing that less
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`than one in six patients had an objective response. Exh. 1002 at ¶44. I assume that
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`he is referring to the tumor response rate. That is misleading because only about
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`half of the patients in Example 1 had measureable disease and were evaluable for
`
`tumor response. Exh. 1001 at Table 4. PSA response is also an objectively
`
`measured response, and the PSA response rate for cabazitaxel therapy reported in
`
`Example 1 is 39.2%, far higher than one in six patients. Furthermore, the overall
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`IPR2016-00712
`survival and progression-free survival data indicate additional therapeutic effects in
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`patients.
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`67. A person of ordinary skill understands that a method produces therapeutic
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`effects where that method has been shown to produce those effects in a clinical
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`trial such as that described in Example 1.
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`68. A POSA would not select a therapy for a patient in a clinical setting
`
`without expecting the regimen to produce a therapeutic effect. Docetaxel is a
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`cytotoxic chemotherapy that is known to cause nausea, hair loss, fatigue,
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`neutropenia, and sensory neuropathy. Exh. 1013 at Table 4. A person of ordinary
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`skill would not choose another potentially toxic medication for a patient previously
`
`treated with docetaxel without knowing the medicine to be efficacious. In other
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`words,