`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN PHARMACEUTICALS INC., ACTAVIS
`LABORATORIES FL, INC., AMNEAL PHARMACEUTICALS LLC,
`AMNEAL PHARMACEUTICALS OF NEW YORK, LLC, DR. REDDY'S
`LABORATORIES, INC., DR. REDDY'S LABORATORIES, LTD.,
`SUN PHARMACEUTICALS INDUSTRIES, LTD.,
`SUN PHARMACEUTICALS INDUSTRIES, INC.,
`TEVA PHARMACEUTICALS USA, INC., WEST-WARD
`PHARMACEUTICAL CORP., and HIKMA PHARMACEUTICALS, LLC,
`
`Petitioners
`v.
`
`JANSSEN ONCOLOGY, INC.,
`
`Patent Owner
`
`Case IPR2016-013321
`Patent 8,822,438 B2
`
`
`
`
`
`REPLY DECLARATION OF IVAN T. HOFMANN
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1
`
` Case IPR2017-00853 has been joined with this proceeding.
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`TABLE OF CONTENTS
`
`I.
`
`Introduction ...................................................................................................... 3
`
`II. Qualifications, Case Background, and Definitions of Commercial Success
`and Nexus Relative to Objective Indicia of Nonobviousness ......................... 5
`
`III. Lack of Objective Indicia of Nonobviousness ................................................ 5
`
`IV. The Performance of Zytiga Does Not Provide Objective Indicia of
`Nonobviousness of the Asserted Claims of the ’438 Patent ......................... 10
`
`2.
`
`3.
`
`The Performance of Zytiga is Attributable to Features that I
`Understand Were Known in the Prior Art ........................................... 10
`1.
`The Performance of Zytiga is Driven by the Abiraterone
`Acetate Compound Which I Understand was Known in the
`Prior Art .................................................................................... 11
`The Co-administration of Prednisone with Zytiga is Motivated
`by the Use of a Glucocorticoid as Replacement Therapy Which
`I Understand was Known in the Prior Art ................................ 13
`The Vellturo Declaration Does Not Address the Impact of the
`Oral Dosage Form on Sales of Zytiga ...................................... 15
`The Analysis of Nexus within the Vellturo Declaration is
`Incomplete and Misleading ................................................................. 16
`1.
`The Fact that the ’438 Patent Allegedly Covers the Only FDA-
`Approved Indication of Zytiga Does Not Contribute to Zytiga’s
`Purported Marketplace Success ................................................ 17
`The Vellturo Declaration Fails to Demonstrate that Zytiga’s
`Purported Marketplace Success is Due to the Alleged Novelty
`of the ’438 Patent ...................................................................... 18
`The Vellturo Declaration’s Discussion of Promotional
`Expenditures and Pricing is Incomplete and Misleading ......... 21
`The Vellturo Declaration Fails to Defend the Adequacy of the
`Data Submitted During the Prosecution of the ’438 Patent ................ 24
`
`
`
`
` 2
`
`2.
`
`3.
`
`A.
`
`B.
`
`C.
`
`
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`I, Ivan T. Hofmann, hereby declare as follows.
`
`I.
`
`Introduction
`
`1.
`
`I am over the age of eighteen and otherwise competent to make this
`
`declaration.
`
`2.
`
`I have been retained as an independent expert on behalf of Petitioners
`
`for the above-captioned inter partes review (“IPR”). I previously prepared and
`
`issued the Declaration of Ivan T. Hofmann, CPA/CFF, CLP dated June 30, 2016
`
`(the “Hofmann Declaration”). Ex. 1017 (Hofmann Decl.). I submitted a
`
`substantially similar declaration in IPR2017-00853.
`
`3.
`
`I have been asked to prepare this declaration (the “Hofmann Reply
`
`Declaration”) in response to the declaration of Christopher A. Vellturo, Ph.D.
`
`dated March 8, 2017 (the “Vellturo Declaration” (Ex. 2044)), relating to the
`
`alleged commercial success of Zytiga (abiraterone acetate) and U.S. Patent No.
`
`8,822,438 (the “’438 Patent”) on behalf of Janssen Oncology, Inc. (“Janssen” or
`
`“Patent Owner”). I understand that the sole independent claim of the ’438 Patent
`
`claims “[a] method for the treatment of a prostate cancer in a human comprising
`
`administering to said human a therapeutically effective amount of abiraterone
`
`
`
` 3
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`acetate2 or a pharmaceutically acceptable salt thereof and a therapeutically
`
`effective amount of prednisone.” Ex. 1002 (Garnick Decl.) at ¶ 34; Ex. 1001 (’438
`
`Patent).
`
`4.
`
`In formulating my opinions, I have considered the documents cited in
`
`the Hofmann Declaration and the additional documents listed in Attachment A-1
`
`cited within this Hofmann Reply Declaration. In formulating my opinions
`
`expressed in this declaration, I have relied upon my education, experience, and
`
`knowledge of the subjects discussed.
`
`5.
`
`This declaration summarizes my current opinions, which are subject
`
`to change depending upon additional information and/or analysis. I reserve the
`
`right to supplement this declaration in response to any opinions of experts on
`
`behalf of the Patent Owner and/or as additional information becomes available.
`
`
`
` 2
`
` I understand that from a technical perspective, abiraterone acetate and abiraterone
`
`are distinct compounds. I also understand that abiraterone acetate metabolizes into
`
`abiraterone in the body and abiraterone is the active pharmaceutical ingredient.
`
`See, e.g., Ex. 1097 (Bantle Reply Decl.) at p. 51, footnote 11. For the purposes of
`
`this declaration, I treat the references to abiraterone acetate and abiraterone as
`
`
`
` 4
`
`interchangeable.
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`II. Qualifications, Case Background, and Definitions of Commercial
`Success and Nexus Relative to Objective Indicia of Nonobviousness
`
`6. My qualifications are generally described in Section II of the
`
`Hofmann Declaration.
`
` Ex. 1017 (Hofmann Decl.).
`
` I incorporate those
`
`qualifications by reference here. I have also provided an updated curriculum vitae
`
`in Attachment A-2 to this declaration, which contains additional details on my
`
`background, experience, and prior testimony.
`
`7. My understanding of certain topics related to the background of this
`
`matter and the definitions of commercial success and nexus are generally described
`
`in in Sections III and IV of the Hofmann Declaration, respectively. Ex. 1017
`
`(Hofmann Decl.). I incorporate those qualifications by reference here.
`
`III. Lack of Objective Indicia of Nonobviousness
`
`8.
`
`In my opinion, the performance of Zytiga fails to provide objective
`
`indicia of nonobviousness of the asserted claims of the ’438 Patent, because no
`
`other company had the ability to commercialize a product containing abiraterone
`
`acetate in the U.S. as a result of the “blocking” nature of U.S. Patent No. 5,604,213
`
`(the “’213 Patent” (Ex. 1005)).
`
`9.
`
`As discussed in the Hofmann Declaration, I understand that the ’213
`
`Patent claims both the abiraterone acetate compound and methods for treating an
`
`
`
` 5
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`androgen-dependent or estrogen-dependent disorder using abiraterone acetate. Ex.
`
`1017 (Hofmann Decl.) at ¶ 25. The ’213 Patent issued on February 18, 1997,
`
`expired on December 13, 2016, and was assigned to British Technology Group
`
`(“BTG”). Ex. 1005 (’213 Patent); Ex. 1047 (FDA Orange Book Listing for
`
`Zytiga).
`
`10.
`
`I understand that the manufacture, marketing, or commercial use of
`
`abiraterone acetate (or a method of therapy involving abiraterone acetate as a
`
`monotherapy or in conjunction with another product) in the U.S. during the life of
`
`the ’213 Patent would infringe the ’213 Patent. Ex. 1135.3 I further understand
`
`that the earliest claimed priority date (March 31, 1992), the application date
`
`(September 30, 1994), and the issuance date (February 18, 1997) of the ’213 Patent
`
`predate the earliest claimed priority date (August 25, 2006) of the ’438 Patent. Ex.
`
`1001 (’438 Patent); Ex. 1005 (’213 Patent).
`
`
`
` 3
`
` Rettig Deposition dated March 31, 2017 at 71:12-15 (testifying that abiraterone
`
`acetate is one of the specifically claimed compounds in the ’213 Patent).
`
`
`
` 6
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`11.
`
`I also understand that in April 2004, BTG (the patent owner) and
`
`Cougar Biotechnology (“Cougar”)4 entered into a license agreement that conveyed
`
`to Cougar “worldwide exclusive rights to develop and commercialize abiraterone
`
`acetate.” Ex. 1088 (BTG Press Release, April 20, 2004). Indeed, Dr. Vellturo
`
`acknowledged the exclusive nature of this worldwide license. Ex. 1136.5
`
`12. Cougar had the exclusive rights to develop and commercialize
`
`abiraterone acetate for nearly two and a half years prior to the August 25, 2006
`
`claimed priority date of the ’438 Patent. Ex. 1088 (BTG Press Release, April 20,
`
`2004); Ex. 1001 (’438 Patent). As such, due to the existence of the ’213 Patent
`
`(and the exclusive rights controlled by Cougar) at the time of the alleged invention
`
`of the ’438 Patent, no other company had the ability to commercialize abiraterone
`
`acetate products or methods of using abiraterone acetate products, including the
`
`methods described in the claims of the ’438 Patent.
`
`13. The blocking nature of the ’213 Patent (and the exclusive rights
`
`controlled by Cougar/Janssen) created an economic disincentive for potential
`
`
`
` 4
`
` I understand that Johnson & Johnson (“J&J”), Janssen’s parent company, agreed
`
`to acquire Cougar in May 2009. Ex. 2101 (J&J Press Release, May 21, 2009).
`
`5 Vellturo Deposition dated April 5, 2017, pp. 18:15-19 and 19:16-22.
`
`
`
` 7
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`competitors to commercialize abiraterone acetate products or methods of use,
`
`including the methods described in the claims of the ’438 Patent, at least until
`
`December 13, 2016. From an economic perspective, the existence of a blocking
`
`patent and
`
`the conveyance of exclusive
`
`rights prevented others
`
`from
`
`commercializing an abiraterone acetate product and limited or eliminated the
`
`economic incentives to develop the invention claimed in the ’438 Patent. Indeed,
`
`as of the ’438 Patent priority date, other parties would have understood that the
`
`’213 Patent covered the abiraterone acetate compound and would block them from
`
`bringing an abiraterone acetate product to market.
`
`14. The Vellturo Declaration asserts that opportunities arose that provided
`
`access to the ’213 Patent and argues that these opportunities indicate that the ’213
`
`Patent did not serve as a disincentive towards the development of the invention
`
`claimed by the ’438 Patent. Ex. 2044 (Vellturo Decl.) at ¶ 28.
`
`15. The Vellturo Declaration focuses on time periods nearly two and a
`
`half years before the claimed priority date of the ’438 Patent, and mischaracterizes
`
`such time periods as “immediately preceding the priority date for the ’438 patent.”
`
`Ex. 2044 (Vellturo Decl.) at ¶ 33; Ex. 1136.6 Furthermore, the Vellturo
`
`
`
` 6
`
` Vellturo Deposition dated April 5, 2017, pp. 27:11-28:13.
`
`
`
` 8
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`Declaration does not appropriately address the agreement between BTG (the patent
`
`owner) and Cougar that provided “worldwide exclusive rights to develop and
`
`commercialize abiraterone acetate” beginning in April 2004. Ex. 1088 (BTG Press
`
`Release, April 20, 2004); Ex. 1136.7 The failure of the Vellturo Declaration to
`
`address the exclusive period between April 2004 (license between Cougar and
`
`BTG) and August 25, 2006 (the claimed priority date of the ’438 Patent) renders
`
`the analysis unreliable and incomplete.
`
`16. From an economic perspective, the ’213 Patent created economic
`
`disincentives for the commercialization of abiraterone acetate by a party that did
`
`not own or control the rights to the ’213 Patent. Furthermore, once the ’213 Patent
`
`was controlled by Cougar/Janssen, the ’213 Patent provided significant economic
`
`disincentives to research, develop, and commercialize the alleged invention
`
`claimed in the ’438 Patent.
`
`17. Because
`
`economic
`
`disincentives
`
`existed
`
`to
`
`develop
`
`and
`
`commercialize the alleged invention of the ’438 Patent due to the existence of the
`
`blocking nature of the ’213 Patent, an objective market construct for abiraterone
`
`acetate upon which
`
`to potentially find objective economic evidence of
`
`
`
` 7
`
` Vellturo Deposition dated April 5, 2017, pp. 18:7-19:22.
`
`
`
` 9
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`nonobviousness in the form of commercial success of the asserted claims of the
`
`’438 Patent does not exist. As a result, from an economic perspective, the
`
`marketplace performance of Zytiga fails
`
`to provide objective
`
`indicia of
`
`nonobviousness of the asserted claims of the ’438 Patent.
`
`IV. The Performance of Zytiga Does Not Provide Objective Indicia of
`Nonobviousness of the Asserted Claims of the ’438 Patent
`
`18. Although the marketplace performance of Zytiga fails to provide
`
`objective evidence of nonobviousness from an economic perspective due to the
`
`blocking nature of the ’213 Patent, I have also considered the opinions set forth in
`
`the Vellturo Declaration regarding marketplace performance and nexus. Ex. 2044
`
`(Vellturo Decl.) at ¶¶ 35-43. As discussed in the Hofmann Declaration, and further
`
`supported below, the performance of Zytiga can be attributed to factors that I
`
`understand are not claimed by the ’438 Patent and/or were known in the prior art.
`
`A. The Performance of Zytiga is Attributable to Features that I
`Understand Were Known in the Prior Art
`19. The Vellturo Declaration contends that the nexus analysis in the
`
`Hofmann Declaration is incomplete and relies upon the testimony of Dr. Matthew
`
`Rettig. Ex. 2044 (Vellturo Decl.) at ¶¶ 35-38. Specifically, the Vellturo
`
`Declaration attributes the marketplace performance of Zytiga to the claims of the
`
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`’438 Patent without addressing whether the features driving performance were
`
`known in the prior art.
`
`20. As previously discussed, if purported commercial success is due to an
`
`element in the prior art, then no nexus exists. In essence, if the feature or features
`
`that create the purported success were known in the prior art, such success (if any)
`
`is not pertinent.
`
`The Performance of Zytiga is Driven by the Abiraterone
`Acetate Compound Which I Understand was Known in the
`Prior Art
`21. For example,
`
`(and
`
`the Vellturo Declaration
`
`1.
`
`I understand
`
`acknowledges) that the compound abiraterone acetate is covered by the ’213 Patent
`
`and was known in the prior art. Ex. 1002 (Garnick Decl.) at ¶¶ 46, 55; Ex. 2044
`
`(Vellturo Decl.) at ¶ 26. The discussion in the Vellturo Declaration fails to address
`
`the role of the efficacy of abiraterone acetate itself in the marketplace performance
`
`of Zytiga.
`
`22.
`
`I understand the efficacy of Zytiga is attributable to the inherent
`
`qualities or characteristics of abiraterone acetate, and not to the co-administration
`
`with prednisone claimed in the ’438 Patent. Ex. 1104 (Garnick Reply Decl.) at
`
`¶¶ 10, 14, 89-111. Specifically, I understand that “[a]biraterone acetate was known
`
`to be a more efficacious anti-cancer agent in the treatment of prostate cancer,
`
`
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`including metastatic hormone-refractory prostate cancer, than prior art CYP17
`
`inhibitors such as ketoconazole.” Ex. 1002 (Garnick Decl.) at ¶ 46.
`
`23. The Vellturo Declaration acknowledges that the efficacy of a drug is a
`
`fundamental factor and specifically states that “the effective treatment of a given
`
`condition or disorder is a fundamental factor affecting prescribing decisions.” Ex.
`
`2044 (Vellturo Decl.) at ¶ 15. However, Dr. Vellturo acknowledged that he did not
`
`apportion the amount of demand for Zytiga that is due to the abiraterone acetate’s
`
`anti-tumor benefits or specifically to the ’213 Patent. Ex. 1136;8 Ex. 1137.9
`
`Furthermore, Dr. Vellturo acknowledged that the ’213 Patent was not irrelevant to
`
`the Zytiga product. Ex. 1137.10
`
`24. From an economic perspective, since I understand the efficacy of
`
`Zytiga is attributable to the inherent qualities or characteristics of abiraterone
`
`acetate, and not to the co-administration with prednisone claimed in the ’438
`
`Patent, the marketplace performance associated with this efficacy does not provide
`
`
`
` 8
`
` Vellturo Deposition dated April 5, 2017, p. 69:10-18.
`
`9 Vellturo Deposition dated December 20, 2016, p. 73:20-24.
`
`10 Vellturo Deposition dated December 20, 2016, p. 74:8-11.
`
`
`12
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`a nexus between the marketplace performance of Zytiga and the claims of the ’438
`
`Patent.
`
`2. The Co-administration of Prednisone with Zytiga is Motivated by
`the Use of a Glucocorticoid as Replacement Therapy Which I
`Understand was Known in the Prior Art
`
`25. As discussed in the Hofmann Declaration, I understand that it is
`
`common to treat cancer patients with combinations of drugs, including drug
`
`combinations with a glucocorticoid. Ex. 1017 (Hofmann Decl.) at ¶ 32.
`
`Specifically, I discussed the use of ketoconazole (another CYP17 inhibitor) in
`
`combination with either prednisone or hydrocortisone as well as the FDA-
`
`approved indication of Jevtana (cabazitaxel) in combination with prednisone. Ex.
`
`1017 (Hofmann Decl.) at ¶ 32; Ex. 1138 (Jevtana Label). In addition to the above
`
`mentioned examples, Dr. Garnick testified that the use of Taxotere (docetaxel) and
`
`prednisone as a chemotherapy treatment for patients with metastatic prostate
`
`cancer was known in the art. Ex. 1104 (Garnick Reply Decl.) at ¶ 113; Ex. 1129
`
`(Taxotere approval letter); Ex. 1140 (Taxotere Label (May 2004)). Furthermore,
`
`Dr. Bantle notes a reference describing prednisone as “the glucocorticoid
`
`predominantly used in cancer chemotherapy” and states “[p]rednisone in particular
`
`is used widely by mCRPC patients due to its palliative effects.” Ex. 1097 (Bantle
`
`
`13
`
`Reply Decl.) at ¶ 96.
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`26.
`
`Indeed, I understand that on May 19, 2004 (over two years prior to the
`
`August 26, 2006 claimed priority date of the ’438 Patent), the FDA approved an
`
`indication for Taxotere in combination with prednisone for the treatment of
`
`patients with androgen independent (hormone refractory) metastatic prostate
`
`cancer. Ex. 1129 (Taxotere approval letter); Ex. 1140 (Taxotere Label (May
`
`2004)).
`
`27. As discussed in the Hofmann Declaration, I understand it was
`
`standard practice to co-administer hydrocortisone or prednisone with ketoconazole
`
`to address common side effects like hypertension, hypokalemia, and fluid
`
`retention. Ex. 1017 (Hofmann Decl.) at ¶ 32. I further understand that the role of
`
`glucocorticoid replacement therapy was known in the prior art as of the earliest
`
`priority date of the alleged invention claimed in the ’438 Patent. Ex. 1097 (Bantle
`
`Reply Decl.) at ¶¶ 12-15, 40-45, 62-66. Based on an understanding obtained from
`
`Dr. Rettig, the Vellturo Declaration asserts that the “prior practice of administering
`
`a glucocorticoid as part of combination therapy for the treatment of cancer is not
`
`relevant to an evaluation of the present invention.” Ex. 2044 (Vellturo Decl.) at ¶
`
`36.
`
`28. Specifically, the Vellturo Declaration dismisses the prior art reference
`
`of the administration of ketoconazole with prednisone because Dr. Rettig believes
`
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`14
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`the prior art purportedly did not teach that ketoconazole was safe and effective for
`
`the treatment of mCRPC and that the prior art did not provide a scientific or
`
`clinical basis for believing that prednisone would be effective for treating cancer.
`
`Ex. 2044 (Vellturo Decl.) at ¶ 36. However, Dr. Rettig testified that when he has
`
`prescribed ketoconazole he has always done so in conjunction with a steroid. Ex.
`
`1135.11
`
`29. Furthermore, the Vellturo Declaration cites a conversation with Dr.
`
`Rettig indicating that “the therapeutic effects of the two drugs in combination
`
`reflects more than the simple additive effects of each drug individually.” Ex. 2044
`
`(Vellturo Decl.) at ¶ 61. As previously discussed, I understand that the individual
`
`efficacy of abiraterone acetate and prednisone was known in the prior art. Ex.
`
`1097 (Bantle Reply Decl.) at ¶ 12-15, 40-45, 62-66.
`
`3. The Vellturo Declaration Does Not Address the Impact of the
`Oral Dosage Form on Sales of Zytiga
`
`30.
`
`I understand that the dosage form of Zytiga is a tablet for oral
`
`administration, while other competing products (such as Jevtana) require
`
`intravenous infusion. Indeed, Dr. Vellturo acknowledged that oral administration
`
`
`
`11 Rettig Deposition dated March 31, 2017, pp. 26:15-28-15.
`
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`15
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`is generally preferable to injections and testified “I recognize the fact there are
`
`benefits to oral drugs.” Ex. 1136.12 The Vellturo Declaration “didn’t explicitly
`
`isolate that contributory value” to the convenience of oral dosing and to the
`
`marketplace performance of Zytiga. Ex. 1136.13
`
`31.
`
`I understand that the benefits of oral administration are unrelated to
`
`the claimed invention of the ’438 Patent. See Ex. 1001 (’438 Patent). The failure
`
`of the Vellturo Declaration to address the impact of oral dosing on the marketplace
`
`performance of Zytiga renders the analysis unreliable and incomplete.
`
`B.
`
`The Analysis of Nexus within the Vellturo Declaration is
`Incomplete and Misleading
`32. The Vellturo Declaration argues that Zytiga’s claimed commercial
`
`success is due in significant part to the claims of the ’438 Patent for the following
`
`purported reasons:
`
`
`
`
`
`The ’438 Patent covers the only FDA-approved use of Zytiga;
`
`The majority of Zytiga use is in combination with prednisone;
`
`
`
`12 Vellturo Deposition dated April 5, 2017, p. 70:11-22.
`
`13 Vellturo Deposition dated April 5, 2017, p. 70:14-22.
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`
`
`
`
`Physicians value
`
`the combination of abiraterone acetate and
`
`prednisone for its anti-tumor benefits, and;
`
`Zytiga’s claimed commercial success is purportedly not attributable to
`
`excessive promotional expenditures or aggressively low pricing.
`
`Ex. 2044 (Vellturo Decl.) at ¶ 9.
`
`1.
`
`The Fact that the ’438 Patent Allegedly Covers the Only
`FDA-Approved Indication of Zytiga Does Not Contribute to
`Zytiga’s Purported Marketplace Success
`33. The Vellturo Declaration’s assertion that the ’438 Patent covers the
`
`only FDA-approved use of Zytiga is not sufficient to establish nexus. Ex. 2044
`
`(Vellturo Decl.) at ¶ 56. However, in order to establish nexus, I understand that
`
`there must be a direct and demonstrable connection between the purported
`
`innovative aspects of the alleged invention and what is driving sales of Zytiga, as
`
`opposed to other extrinsic factors, including what is known in the prior art. As
`
`described in Section VI of the Hofmann Declaration and throughout this
`
`declaration, it is my opinion that no nexus exists between the alleged invention of
`
`the ’438 Patent and the performance of Zytiga.
`
`34. The ’438 Patent describes and acknowledges the potential use of
`
`numerous glucocorticoid steroid agents in combination with abiraterone acetate,
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`however, only administration with prednisone appears in the claims of the ’438
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`Patent. Ex. 1001 (’438 Patent). Notably, the Patent Owner sought and received
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`approval outside the U.S. for abiraterone acetate co-administered with either
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`prednisone or prednisolone (separately described as a suitable glucocorticoid
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`according to the specification of the ’438 Patent). Ex. 1001 (’438 Patent); Ex. 1141
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`(J&J Press Release, January 11, 2013).
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`2.
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`The Vellturo Declaration Fails to Demonstrate that Zytiga’s
`Purported Marketplace Success is Due to the Alleged
`Novelty of the ’438 Patent
`35. The Vellturo Declaration asserts that physicians “overwhelmingly”
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`prescribe the combination of abiraterone acetate and prednisone. Ex. 2044
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`(Vellturo Decl.) at ¶ 57. In an attempt to support this notion, the Vellturo
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`Declaration references IBM Explorys EHR data as well as a report from Truven
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`Health Analytics (provided by Janssen). Ex. 2044 (Vellturo Decl.) at ¶¶ 57-59; Ex.
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`2135 (Truven Commercial and Medicare Data).
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`36. Even if patients on Zytiga also regularly take prednisone, an important
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`inquiry for purposes of demonstrating potential nexus is whether the sales are due
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`specifically to the alleged novelty of the ’438 Patent, rather than what is known in
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`the prior art. The Patent Owner claims the alleged novelty is the purported
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`unexpected maximizing of the anti-cancer effect of abiraterone acetate in treating
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`prostate cancer when abiraterone acetate and prednisone are co-administered. Ex.
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`2038 (Rettig Decl.) at ¶ 196; Paper No. 35 at 1-2, 54-55. However, I understand
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`that the mere existence of abiraterone acetate use with prednisone does not
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`demonstrate that additional anti-cancer effects purportedly derive from the
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`combination. Ex. 1104 (Garnick Reply Decl.) at ¶¶ 89-111, 119-122; Ex. 1091
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`(McKeague Reply Decl.) at ¶¶ 16, 40-43, 53-55.
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`37.
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`In fact, I understand from Dr. Garnick that when abiraterone acetate
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`and prednisone are prescribed, the prescriptions are written based on Zytiga
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`prescribing information which indicates that abiraterone acetate and prednisone
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`perform according to their individual known properties and prednisone is utilized to
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`mitigate the side effects of abiraterone. Ex. 2126.14 Indeed, Dr. Vellturo
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`acknowledged that within promotional materials for Zytiga, the only role of
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`prednisone which is described is the reduction in the occurrence and severity of side
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`effects. Ex. 1136.15
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`38. Furthermore, the Vellturo Declaration fails to address evidence which
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`indicates that Zytiga’s marketplace performance is driven by extrinsic factors other
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`
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`14 Garnick Deposition dated February 16, 2017, p. 143:6-17.
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`15 Vellturo Deposition dated April 5, 2017, pp. 62:15-63:5.
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`than co-administration with prednisone. Specifically, several factors indicate that
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`the impact of the co-administration with prednisone on sales is limited:
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`a.
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`As previously discussed, I understand that the efficacy of Zytiga is an
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`inherent property of the abiraterone acetate compound. Ex. 1104
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`(Garnick Reply Decl.) at ¶¶ 10, 14; see also id. at ¶¶ 89-124. As such,
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`the marketplace performance attributable to the efficacy of Zytiga does
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`not have nexus to the claims of the ’438 Patent.
`
`b.
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`The ’438 Patent specification describes co-administration with a
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`number of glucocorticoids other than prednisone. Ex. 1001 (’438
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`Patent).16
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`c.
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`Zytiga is approved in the EU for co-administration with prednisone or
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`prednisolone. Ex. 1141 (J&J Press Release, January 11, 2013).
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`d.
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`Abiraterone acetate can be prescribed with prednisolone (separately
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`identified in the ’438 Patent specification as another glucocorticoid
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`
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`16 Indeed, Dr. Vellturo acknowledged that the ’438 Patent identifies several
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`glucocorticoids, not just prednisone. Ex. 1137 (Vellturo Deposition dated
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`December 20, 2016), p. 51:18-25.
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`suitable for administration with abiraterone acetate). Ex. 1001 (’438
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`Patent) at 10:25-50.
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`3.
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`The Vellturo Declaration’s Discussion of Promotional
`Expenditures and Pricing is Incomplete and Misleading
`39. The Vellturo Declaration asserts that Zytiga’s commercial success is
`
`not due to excessive levels of marketing spend. Ex. 2044 (Vellturo Decl.) at ¶ 65.
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`However, the analysis in the Vellturo Declaration is incomplete and misleading.
`
`40. The Vellturo Declaration discusses the promotion-to-sales ratio of
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`Jevtana, Zytiga, and Xtandi. Ex. 2044 (Vellturo Decl.) at ¶¶ 64-65, Appendix E. In
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`Appendix E-1, the Vellturo Declaration claims that the promotion-to-sales ratio of
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`Zytiga is below Xtandi and consistent with Jevtana. Ex. 2044 (Vellturo Decl.) at ¶¶
`
`64-65, Appendix E-1. However, the Vellturo Declaration fails to discuss the level
`
`of marketing spend in terms of dollars relative to the select mCRPC drugs in the
`
`IMS data.17
`
`
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`17 Furthermore, the Vellturo Declaration does not address the actual absolute total
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`promotional expenditures on Zytiga by Janssen and acknowledges that “it is widely
`
`recognized that IMS marketing spend data commonly capture only a portion of the
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`total actual spend.” Ex. 2044 (Vellturo Decl.) at footnote 17.
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`41. For the period from 2010 through the first half of 2016, the total
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`marketing spend of Zytiga is actually higher than both Xtandi and Jevtana and
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`represents over 50 percent of the total promotional spend for these three products
`
`during this period. Ex. 2044 (Vellturo Decl.) at Appendix E-2. In addition, I am
`
`not aware of any marketing materials that discuss the incremental anti-tumor
`
`benefits of the combination of abiraterone acetate and prednisone, and the Vellturo
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`Declaration does not offer any evidence of such materials, indicating further lack of
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`nexus to the claimed subject matter. Indeed, Dr. Vellturo acknowledged that
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`Janssen is not allowed by the FDA to tell consumers that prednisone has anti-tumor
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`effects when taken with Zytiga. Ex. 1136.18
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`42. Furthermore, the Vellturo Declaration’s reference to the relative
`
`comparison of the promotion of Zytiga to “pharmaceutical drugs more generally”
`
`fails to discuss the fact that the markets for various pharmaceutical products
`
`includes broad categories of products treating various conditions (many of which
`
`are more consumer driven and utilize different marketing efforts than those used for
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`Zytiga). Ex. 2044 (Vellturo Decl.) at ¶ 64. The unsupported and unexplained
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`
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`18 Vellturo Deposition dated April 5, 2017, p. 64:13-17.
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`references to general marketing levels of other pharmaceutical products in the
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`
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`Vellturo Declaration are not meaningful.
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`43.
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`
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`
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`44. The Vellturo Declaration fails to address items such as discounts,
`
`rebates, chargebacks, and returns (among others) which affect the actual net price of
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`drugs. Indeed, Dr. Vellturo acknowledged that his opinions are not based on data
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`of Zytiga’s actual price. Ex. 1136.19 Thus, meaningful conclusions cannot be
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`drawn from this analysis since the Vellturo Declaration presents no evidence that
`
`the overall price or patient cost of Zytiga (including the cost of prednisone) was
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`actually higher than other drugs used to treat mCRPC, rendering the analysis
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`misleading and incomplete.
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`
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`19 Vellturo Deposition dated April 5, 2017, p. 124:13-18.
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`C. The Vellturo Declaration Fails to Defend the Adequacy of the
`Data Submitted During the Prosecution of the ’438 Patent
`45. The ’438 Patent was allowed to issue because, according to the
`
`Examiner, “[t]he unexpected commercial success of the launch of [Zytiga] obviates
`
`the rejection under 35 USC 103(a).” Ex. 1013 (Notice of Allowance, July 3, 2013)
`
`at 7. However, as Dr. Vellturo conceded during his depositio