`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________
`
`
`WEST-WARD PHARMACEUTICALS INTERNATIONAL LIMITED,
`Petitioner
`
`v.
`
`NOVARTIS PHARMACEUTICALS
`CORPORATION,
`Patent Owner
`
`__________
`
`
`
`Case IPR2018-
`
`U.S. Patent No. 8,410,131
`
`__________
`
`
`DECLARATION OF DANIEL CHANG CHO, M.D., IN SUPPORT OF THE
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,410,131
`
`
`
`
`West-Ward Exhibit 1112
`Cho Declaration
`Page 001
`
`

`

`
`
`TABLE OF CONTENTS
`
`I.
`
`
`INTRODUCTION AND QUALIFICATIONS ............................................... 1
`
`II.
`
`
`OPINIONS ....................................................................................................... 3
`
`III.
`
`
`SIGNATURE ................................................................................................... 4
`
`i
`
`West-Ward Exhibit 1112
`Cho Declaration
`Page 002
`
`

`

`
`
`I, Daniel Chang Cho, M.D., hereby declare as follows:
`
`
`I.
`
`INTRODUCTION AND QUALIFICATIONS
`
`1.
`
`I have been retained by counsel for West-Ward Pharmaceuticals
`
`International Limited (“West-Ward”) to provide my opinion concerning the
`
`validity of U.S. Patent No. 8,140,131 (Ex. 1001, “the ’131 Patent”) in support of
`
`West-Ward’s Petition for Inter Partes Review of the ’131 patent.
`
`2.
`
`I have been a licensed medical doctor since 2000 and am Board
`
`certified in Medical Oncology. I currently serve as Assistant Professor of
`
`Medicine at NYU School of Medicine and hold the position of Attending
`
`Oncologist of Hematology and Oncology at NYU Cancer Center.
`
`3.
`
`For the last 15 years, I have specialized in the diagnosis and treatment
`
`of kidney cancer, during which time I have treated thousands of patients with
`
`kidney cancer.
`
`4.
`
`I graduated from Yale University, New Haven, CT in 1996, after
`
`which I attended the medical school at Washington University, St. Louis, MO,
`
`receiving my M.D. in 2000. I completed an Internship and Residency in Internal
`
`Medicine in 2003, followed by a Fellowship in Hematology and Oncology at Beth
`
`Israel Deaconess Medical Center which was completed in 2006. I received a
`
`Master of Medical Science at Harvard University in 2007. I was a Clinical
`
`Teaching Fellow of Medicine at Harvard Medical School from 2000 to 2006
`
`1
`
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`Page 003
`
`

`

`
`
`before becoming an Instructor and then Assistant Professor of Medicine from
`
`2011-2013. I am currently an Assistant Professor of Medicine at NYU School of
`
`Medicine.
`
`5.
`
`I have held several hospital appointments over my career to date.
`
`From 2000-2006, I was a Teaching Fellow of Medicine at Beth Israel Deaconess
`
`Medical Center before beginning an Attending Oncologist position in Hematology
`
`and Oncology at Beth Israel Deaconess Medical Center.
`
`6.
`
`I have held several other professional positions and major
`
`administrative leadership positions. I have been a member of the Advisory Board
`
`for Wyeth Pharmaceuticals and Genentech Pharmaceuticals and I am a member of
`
`the Kidney Cancer Think Tank as part of the Kidney Cancer Association. I was
`
`the Course Director on the Hematology and Oncology Grand Rounds at Beth Israel
`
`Deaconess Medical Center from 2007-2013, and was Director of the Experimental
`
`Therapeutics Program at both Beth Israel Deaconess Medical Center and NYU
`
`Cancer Center. I am also currently the Director of the Translational Research
`
`Laboratory at NYU Cancer Center.
`
`7.
`
`I have conducted pre-clinical and translational research directed
`
`towards exploiting the PI3-Kinase/Akt/mTOR pathway for the treatment of
`
`patients with advanced renal cell cancer. In that regard, my research focused on
`
`identifying predictive biomarkers of response to treatment with mTOR inhibitors,
`
`2
`
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`

`

`
`
`and also on developing pre-clinical rationale for novel therapeutic strategies
`
`targeting that pathway.
`
`8.
`
`I am actively involved in the clinical trials program at NYU Cancer
`
`Center, where I serve as the Co-Chair of the Phase I/II Committee and have
`
`previously been a member on various clinical trial committees at Dana-
`
`Farber/Harvard Cancer Center and Beth Israel Deaconess Medical Center. I have
`
`also led at least twenty, and participated in over a hundred, clinical trials directed
`
`towards treatment of kidney cancer.
`
`9.
`
`I have authored more than 50 journal articles, abstracts, and other
`
`publications relating primarily to the diagnosis and treatment of kidney cancers and
`
`other advanced solid tumors.
`
`10. A copy of my curriculum vitae is attached as Exhibit 1113, providing
`
`a list of my publications, and describing my education, training and experience in
`
`greater detail.
`
`
`
` OPINIONS II.
`
`11.
`
`I have reviewed and agree with the opinions and conclusions set forth
`
`at Exhibit 1010 of this IPR (which is the declaration of Dr. Pantuck filed in
`
`Breckenridge IPR2017-0592). For convenience and expediency, I will not
`
`reiterate all of those opinions again but instead have appended Dr. Pantuck’s
`
`3
`
`West-Ward Exhibit 1112
`Cho Declaration
`Page 005
`
`

`

`West-Ward Exhibit 1112
`Cho Declaration
`Page 006
`
`

`

`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`________________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`________________________
`
`
`BRECKENRIDGE PHARMACEUTICAL, INC.
`Petitioner
`v.
`
`NOVARTIS PHARMACEUTICALS CORPORATION
`Patent Owner
`________________________
`
`
`Case IPR2017-_______
`U.S. Patent No. 8,410,131
`________________________
`
`
`DECLARATION OF ALLAN J. PANTUCK, M.D. IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,410,131
`
`
`
`
`
`Breckenridge Exhibit 1010
`Pantuck Declaration
`
`West-Ward Exhibit 1112
`Cho Declaration
`Page 007
`
`APPENDIX TO WEST-WARD EXHIBIT 1112
`
`DECLARATION OF DANIEL CHANG CHO, MD
`
`

`

`Table of Contents
`
`INTRODUCTION AND QUALIFICATIONS ................................................... 1
`I.
`II. UNDERSTANDING OF THE GOVERNING LAW ......................................... 3
`A.
`Invalidity by Anticipation ............................................................................ 3
`B.
`Invalidity by Obviousness ........................................................................... 3
`C.
`Interpreting Claims Before the Patent Office .............................................. 6
`D. Materials Relied on in Forming My Opinions ............................................. 7
`III. THE PERSON OF ORDINARY SKILL IN THE ART OF THE '131
`PATENT .............................................................................................................. 7
`IV. PERSPECTIVE APPLIED IN THIS DECLARATION ..................................... 8
`V. ALTERNATIVE NAMES FOR RAPAMYCIN AND ITS DERIVATIVES .... 9
`VI. OVERVIEW OF THE '131 PATENT ............................................................... 13
`A. Disclosure of the '131 Patent ..................................................................... 13
`B. Prosecution History of the '131 Patent ...................................................... 22
`VII. CLAIM CONSTRUCTIONS ......................................................................... 32
`A. Legal Standard ........................................................................................... 32
`B. Construction of Claim Terms .................................................................... 32
`1. "Inhibiting Growth of Solid Excretory System Tumors in a
`Subject" .............................................................................................. 32
`a. "Inhibiting Growth" ....................................................................... 33
`b. "Solid Excretory System Tumors" ................................................ 34
`c. "Subject " ....................................................................................... 36
`
`
`i
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`Breckenridge Exhibit 1010
`Pantuck Declaration
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`Page 008
`
`

`

`2. "advanced solid excretory system tumor" ........................................... 37
`3. "kidney tumor" .................................................................................... 39
`4. "unit dosage form" ............................................................................... 39
`VIII. STATE OF THE PRIOR ART TO THE '131 PATENT ................................ 40
`A. Rapamycin (Sirolimus) .............................................................................. 40
`B. Rapamycin Derivatives .............................................................................. 45
`1. Everolimus .......................................................................................... 46
`
`2. Temsirolimus ....................................................................................... 51
`
`C. Activity of Sirolimus, Temsirolimus, and Everolimus .............................. 56
`D. Understanding of Excretory System Tumors ............................................ 62
`E. Understanding of Metastasis ...................................................................... 67
`IX. TREATMENTS FOR RENAL CELL CARCINOMA AND RENAL
`ANGIOMYOLIPOMA ...................................................................................... 70
`X. THE PRIOR ART RELIED UPON .................................................................. 73
`A. Schuler ....................................................................................................... 76
`B. Crowe ......................................................................................................... 80
`C. Neumayer ................................................................................................... 82
`D. Alexandre ................................................................................................... 86
`E. Hidalgo ....................................................................................................... 88
`F. Luan ........................................................................................................... 96
`G. Wasik ......................................................................................................... 98
`1. A POSA would understand that Wasik describes using everolimus
`to inhibit growth of advanced kidney tumors ..................................... 107
`H. Navarro ....................................................................................................111
`
`ii
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`Breckenridge Exhibit 1010
`Pantuck Declaration
`
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`Cho Declaration
`Page 009
`
`

`

`XI. MOTIVATIONS TO COMBINE THE PRIOR ART ..................................... 113
`A. Motivation to Combine Wasik with Navarro ..........................................113
`B. Motivation to Combine Wasik, Navarro, Crowe, and Luan ....................113
`C. Motivation to Combine Hidalgo, Alexandre, Crowe, Schuler,
`Neumayer, and Navarro ...........................................................................114
`D. Motivation to Combine Hidalgo, Alexandre, Crowe, Schuler,
`Neumayer, Navarro, and Luan.................................................................117
`XII. GROUNDS OF INVALIDITY .................................................................... 118
`A. Ground 1: Claims 1-3 and 5-9 of the '131 patent are invalid under
`35 U.S.C. § 102(a) or §102(e)(1) on the ground that they are
`anticipated by Wasik ................................................................................119
`1. Claims 1-3 ......................................................................................... 119
`
`2. Claims 5-9 ......................................................................................... 125
`
`
`
`
`
`
`
`a. Claim 5 ........................................................................................ 126
`
`b. Claim 6 ......................................................................................... 126
`
`c. Claims 7-9 ..................................................................................... 128
`
`B. Ground 2: Claims 1-3 and 5-9 of the '131 patent are invalid under
`35 U.S.C. § 103(a) on the ground that they are rendered
`obvious by Wasik alone or in combination with Navarro .......................130
`C. Ground 3: Claims 1-3 and 5-9 of the '131 patent are invalid under
`35 U.S.C. § 103(a) on the ground that they are rendered
`obvious by the combination of Wasik, Navarro, Crowe, and Luan ........132
`D. Ground 4: Claims 1-3 and 5-9 of the '131 patent are invalid under
`35 U.S.C. § 103(a) on the ground that they are rendered
`obvious by the combination of Hidalgo, Alexandre, Crowe, Schuler,
`Neumayer, and Navarro ...........................................................................135
`1. Claims 1-3 ......................................................................................... 136
`
`iii
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`Breckenridge Exhibit 1010
`Pantuck Declaration
`
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`Cho Declaration
`Page 0010
`
`

`

`2. Claims 5-9 ......................................................................................... 143
`
`E. Ground 5: Claims 1-3 and 5-9 of the '131 patent are invalid under
`35 U.S.C. § 103(a) on the ground that they are rendered
`obvious by the combination of Hidalgo, Alexandre, Crowe, Schuler,
`Neumayer, Navarro, and Luan.................................................................145
`XIII. SECONDARY CONSIDERATIONS .......................................................... 147
`
`iv
`
`Breckenridge Exhibit 1010
`Pantuck Declaration
`
`West-Ward Exhibit 1112
`Cho Declaration
`Page 0011
`
`

`

`I, Allan J. Pantuck, resident of Los Angeles, California, hereby declare as follows:
`
`I.
`
`INTRODUCTION AND QUALIFICATIONS
`1.
`I have been
`retained by Breckenridge Pharmaceutical,
`
`Inc.
`
`("Breckenridge") to provide my opinion concerning the validity of U.S. Patent No.
`
`8,410,131 (Ex. 1001; "the '131 patent") in support of Breckenridge's Petition for
`
`Inter Partes Review of the '131 patent.
`
`2.
`
`I graduated from Columbia University in 1989 with a B.A. I obtained
`
`my M.D. in 1993 from the University of Medicine and Dentistry of New Jersey
`
`("UMDNJ"). In 2005, I completed a Master's degree in clinical research from the
`
`UCLA David Geffen School of Medicine.
`
`3.
`
`From 1993-1995, I was an intern and then resident in the Division of
`
`Surgery at UMDNJ. From 1995-1999, I was a resident in the Division of Urology
`
`at UMDNJ. I served as the Chief Resident in my last year at UMDNJ.
`
`4.
`
`I joined UCLA's Department of Urology in 1999 as a Clinical
`
`Instructor and since that time I advanced to the position of Professor, and maintain
`
`that position to the present.
`
`5.
`
`During my academic career, I have received numerous grants where I
`
`acted as the sole principal investigator ("PI"), a co-PI, or as a sub-investigator as a
`
`part of larger grants. I have been a named co-author of over 200 peer-reviewed
`
`
`
`1
`
`Breckenridge Exhibit 1010
`Pantuck Declaration
`
`West-Ward Exhibit 1112
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`Page 0012
`
`

`

`publications related to urologic oncology, in which more than 100 of these studies
`
`are related to renal cell carcinoma and metastatic renal cell carcinoma.
`
`6.
`
`I have served as a reviewer for numerous medical journals, including
`
`The Journal of Urology, Urology, British Journal of Urology International,
`
`European Urology, Urologic Oncology, Clinical Cancer Research, among others.
`
`Additionally, I have served on editorial boards of several medical publications,
`
`including The Journal of Cancer Integrative Medicine, The Bladder Journal,
`
`European Urology, Kidney Cancer Journal, among others.
`
`7.
`
`I have extensive experience
`
`in clinical pharmacokinetics and
`
`development of cancer therapeutics, including chemotherapeutic agents, other
`
`small molecules (e.g., targeted compounds) and biologics. I have been involved in
`
`the design, conduct, and analysis of clinical trials for cancer therapeutics.
`
`8. My curriculum vitae is attached as Exhibit 1028. My work in this
`
`matter is being billed at my standard rate of $650 per hour, with reimbursement for
`
`necessary and reasonable expenses. My compensation is not in any way contingent
`
`upon the outcome of any Inter Partes Review. I have no financial or personal
`
`interest in the outcome of this proceeding or any related litigation.
`
`
`
`
`
`
`
`2
`
`Breckenridge Exhibit 1010
`Pantuck Declaration
`
`West-Ward Exhibit 1112
`Cho Declaration
`Page 0013
`
`

`

`II. UNDERSTANDING OF THE GOVERNING LAW
`A.
`Invalidity by Anticipation
`9.
`I understand an anticipation analysis involves comparing a claim to
`
`the prior art to determine whether a hypothetical person of ordinary skill ("POSA")
`
`would understand the claimed invention is anticipated in view of the prior art, and
`
`in light of the general knowledge in the art. I understand that to anticipate a claim,
`
`a prior art reference must disclose each and every claim limitation, either expressly
`
`or inherently. I also understand that to explain the meaning of a prior art reference,
`
`a POSA can refer to a secondary reference. For instance, I understand that
`
`information incorporated by reference by the prior art may be considered when
`
`understanding the meaning of that prior art.
`
`B.
`10.
`
`Invalidity by Obviousness
`I understand that obviousness is analyzed from the perspective of a
`
`POSA at the time of the alleged invention. I also understand that a POSA is
`
`presumed to have been aware of all pertinent prior art at the time of the alleged
`
`invention.
`
`11.
`
`I understand that an obviousness analysis involves comparing a claim
`
`to the prior art to determine whether the claimed invention would have been
`
`obvious to a POSA in view of the prior art, and in light of the general knowledge
`
`in the art. I also understand that the invention may be deemed obvious when a
`
`POSA would have reached the claimed invention through routine experimentation..
`3
`
`
`
`Breckenridge Exhibit 1010
`Pantuck Declaration
`
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`Cho Declaration
`Page 0014
`
`

`

`12.
`
`I understand that obviousness can be established by combining or
`
`modifying the disclosures of the prior art to achieve the claimed invention. It is
`
`also my understanding that where there is a reason to modify or combine the prior
`
`art to achieve the claimed invention, there must also be a reasonable expectation of
`
`success in so doing to render the claimed invention obvious. I understand that the
`
`reason to combine prior art references can come from a variety of sources, not just
`
`the prior art itself or the specific problem the patentee was trying to solve. I also
`
`understand that the references themselves need not provide a specific hint or
`
`suggestion of the alteration needed to arrive at the claimed invention; the analysis
`
`may include recourse to logic, judgment, and common sense available to a POSA.
`
`13.
`
`I understand that when a patent claims a genus, that claim is obvious
`
`if a single embodiment falling within the scope of the claims is obvious. I also
`
`understand that a claimed use of a prior art compound may be obvious when the
`
`prior art shows that structurally similar compounds exhibit the same uses claimed
`
`for the prior art compound. I also understand that claims may be considered
`
`obvious if they recite subject matter that would have been obvious to a POSA to
`
`try and develop. I further understand that claims are obvious to try when there is
`
`market pressure to solve a problem and there are only a finite number of identified,
`
`predictable solutions to that problem.
`
`
`
`4
`
`Breckenridge Exhibit 1010
`Pantuck Declaration
`
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`Cho Declaration
`Page 0015
`
`

`

`14.
`
`I understand that when there is some recognized reason to solve a
`
`problem, and there are a finite number of identified, predictable solutions, a POSA
`
`has good reason to pursue the known options within his or her technical grasp. If
`
`such an approach leads to the anticipated success, it is likely the product not of
`
`innovation but of ordinary skill and common sense. In such a circumstance, when a
`
`patent simply arranges old elements with each performing the same function it had
`
`been known to perform and yields no more than one would expect from such an
`
`arrangement, the combination is obvious.
`
`15.
`
`I understand that when considering the obviousness of an invention,
`
`one should also consider whether there are any objective indicia that support the
`
`non-obviousness of the invention. I further understand that objective indicia of
`
`non-obviousness include failure of others, copying, unexpectedly superior results,
`
`information that "teaches away" from the claimed subject matter, perception in the
`
`industry, commercial success, and long-felt but unmet need. I also understand that
`
`in order for objective indicia of non-obviousness to be applicable, the indicia must
`
`have some sort of nexus to the subject matter in the claim that was not known in
`
`the art. I understand that this nexus includes a factual connection between the
`
`patentable subject matter of the claim and the objective indicia alleged. Finally, I
`
`understand that an independently made invention that is made within a
`
`
`
`5
`
`Breckenridge Exhibit 1010
`Pantuck Declaration
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`Page 0016
`
`

`

`comparatively short period of time is evidence that the claimed invention was the
`
`product of ordinary skill.
`
`16.
`
`I understand
`
`that
`
`the patent application (International Patent
`
`Application No. PCT/EP02/01714, Ex. 1014) leading to the '131 patent was filed
`
`on February 18, 2002, and that the patent application leading to the '131 patent is
`
`based on two earlier-filed Great Britain patent applications. The first-filed Great
`
`Britain patent application (GB 0104072.4, "the '072 priority application," Ex.
`
`1012) was filed on February 19, 2001, and the second-filed Great Britain patent
`
`application (GB0124957.2, "the '957 priority application," Ex. 1013) was filed on
`
`October 17, 2001. I have therefore analyzed anticipation and obviousness as of
`
`February 18, 2002 or before, with the understanding that my conclusions remain
`
`the same even if the analysis is performed as of February 18, 2001 or before.
`
`C.
`17.
`
`Interpreting Claims Before the Patent Office
`I understand that Inter Partes Review is a proceeding before the
`
`United States Patent & Trademark Office ("USPTO") for evaluating the validity of
`
`issued patent claims. I understand that in an Inter Partes Review a claim term is
`
`given the broadest reasonable interpretation that is consistent with the patent's
`
`specification. I understand that a patent's "specification" includes all the figures,
`
`discussion, and claims within the patent. I understand that the USPTO will look to
`
`the specification to see if there is a definition for a given claim term, and if not,
`
`
`
`6
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`Pantuck Declaration
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`Page 0017
`
`

`

`will apply the broadest reasonable interpretation from the perspective of a POSA at
`
`the time in which the alleged invention was made. I present a more detailed
`
`explanation of certain claim terms in the '131 patent in Section VII ("CLAIM
`
`CONSTRUCTIONS") below.
`
`D. Materials Relied on in Forming My Opinions
`18.
`In forming my opinions, I have relied on the '131 patent's claims,
`
`specification, and the prosecution history, on the prior art exhibits to the IPR
`
`Petition for the '131 patent, any other materials cited in this declaration, and my
`
`own knowledge, experience, and expertise, and the knowledge of the person of
`
`ordinary skill in the art in the relevant timeframe.
`
`III. THE PERSON OF ORDINARY SKILL IN THE ART OF THE '131
`PATENT
`19. The claims of the '131 patent are directed to a method for inhibiting
`
`growth of solid excretory system tumors in a subject, said method consisting of
`
`administering to said subject a therapeutically effective amount of a compound of
`
`formula I,1 which is alternatively known as 40-O-(2-hydroxyethyl)-rapamycin (i.e.,
`
`everolimus).
`
`
`1 Section V includes a brief discussion of the alternative names used for rapamycin
`
`and its derivatives.
`
`
`
`7
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`Pantuck Declaration
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`Page 0018
`
`

`

`20. Based on this, in my opinion, a POSA as of as of February 18, 2001 or
`
`as of February, 18, 2002 would have had, at a minimum:
`
`a.
`
`a medical degree (e.g., MD) with several years of specific experience
`
`in medical or surgical oncology, which may include board certification, as
`
`well as knowledge of oncology drug development and clinical
`
`pharmacology; or
`
`b.
`
`a Ph.D. in cancer biology, molecular biology, medicinal chemistry, or
`
`a related field with several years of experience in oncology drug
`
`development and clinical pharmacology, including evaluating cancer
`
`therapeutics in in vitro and/or in vivo assays, as well as familiarity with the
`
`practice of medical oncology.
`
`This description is approximate, and a higher level of education or skill might
`
`make up for less experience, and vice-versa, and access to someone with
`
`knowledge of oncological drug development and clinical pharmacology could
`
`substitute for knowledge of the same.
`
`IV. PERSPECTIVE APPLIED IN THIS DECLARATION
`21.
`I believe that I would qualify as a POSA as of February 18, 2001 or as
`
`of February, 18, 2002, and that I have a sufficient level of knowledge, experience,
`
`and expertise to provide an expert opinion in the field of the '131 patent.
`
`
`
`
`
`
`
`8
`
`Breckenridge Exhibit 1010
`Pantuck Declaration
`
`West-Ward Exhibit 1112
`Cho Declaration
`Page 0019
`
`

`

`V. ALTERNATIVE NAMES FOR RAPAMYCIN AND ITS
`DERIVATIVES
`22. The '131 patent and the prior art considered herein refers to rapamycin
`
`and its derivatives. For the sake of convenience, I have summarized alternative
`
`names for rapamycin and its derivatives (temsirolimus and everolimus) in the
`
`section that follows.
`
`23. Rapamycin is a known compound derived from Streptomyces
`
`hygroscopicus having a chemical structure as depicted in U.S. Patent No.
`
`5,665,772, O-Alkylated Rapamycin Derivatives and their use, particularly as
`
`Immunosuppressants, which issued on September 9, 1997 to Cottens et al.
`
`("Cottens '772 patent," Ex. 1019),2 as shown below.
`
`
`2 I understand that the Cottens '772 patent is listed in the FDA's Approved Drug
`
`Products with Therapeutic Equivalence Evaluations ("2015 Orange Book," Ex.
`
`1029), 35th Edition (2015) with respect to AFINITOR®. See 2015 Orange Book
`
`(Ex. 1029) at 77.
`
`
`
`9
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`Pantuck Declaration
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`Page 0020
`
`

`

`
`
`See Cottens '772 patent (Ex. 1019) at 1:10-32.
`
`24. Rapamycin is alternatively known as sirolimus. See RAPAMUNE®
`
`(sirolimus) Oral Solution RAPAMUNE® Approval Letter and approved labeling
`
`("Rapamune Approval Letter," Ex. 1011). Additional manufacturing codes and
`
`abbreviated terms include: AY-22,989 and "RPM." See, e.g., infra ¶¶93, 98, and
`
`152. I have used the names "rapamycin" and "sirolimus" interchangeably.
`
`25. Temsirolimus, an ester of rapamycin, is also referred to as CCI-779,
`
`where the CCI acronym means Cell Cycle Inhibitor. See Alexandre, Raymond, et
`
`al., La rapamycine et le CCI-779, Bull. Cancer (1999) 86(10): 808-811
`
`("Alexandre and Raymond," Ex. 1030) at 808. As explained below, temsirolimus
`
`is also referred to as rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic
`
`acid, rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic
`
`
`
`10
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`Breckenridge Exhibit 1010
`Pantuck Declaration
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`West-Ward Exhibit 1112
`Cho Declaration
`Page 0021
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`

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`acid, or 40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin. For
`
`ease of reference, I have primarily used the term "temsirolimus" unless a particular
`
`reference uses one of the alternative names.
`
`26. Everolimus
`
`is alternatively known as 40-O-(2-hydroxyethyl)-
`
`rapamycin or SDZ RAD. See, e.g., Schuler et al., SDZ RAD, A New Rapamycin
`
`Derivative, Transplantation (1997) 64(1): 36-42 ("Schuler," Ex. 1008) at 40;
`
`Sedrani et al., Chemical Modification of Rapamycin: The Discovery of SDZ RAD,
`
`Transplantation Proc. (1998) 30(5): 2192-2194 ("Sedrani," Ex. 1020) at 2192; and
`
`Sorbera et al, SDZ-RAD, Drugs of the Future (1999) 24(1): 22-29 ("Sorbera," Ex.
`
`1017) at 24. Claim 10 of Cottens specifically covers 40-O-(2-hydroxyethyl)-
`
`rapamycin, and thus, everolimus. See Cottens '772 patent (Ex. 1019) at 22:28-29
`
`and the Certificate of Correction that issued on June 30, 1998. As explained
`
`below, everolimus is also referred to as 40-O-(2-hydroxy)ethyl-rapamycin,
`
`compound 8, Compound A, RAD, RAD001, or Certican. See Section VIII.B.1,
`
`¶110. For ease of reference, I have primarily used the term "everolimus" unless a
`
`particular reference uses one of the alternative names.
`
`27. The chemical structures for sirolimus, temsirolimus, and everolimus
`
`are identical but for the R–O-group bound to the C40 position, as shown below,
`
`
`
`11
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`Breckenridge Exhibit 1010
`Pantuck Declaration
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`West-Ward Exhibit 1112
`Cho Declaration
`Page 0022
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`
`
`where R is H for sirolimus, R is –C(O)C(CH3)(CH2OH)2 for temsirolimus, and R is
`
`–CH2CH2OH for everolimus. See Cottens '772 patent (Ex. 1019) at 1:10-32;
`
`Alexandre and Raymond (Ex. 1030) at 808; and Sorbera (Ex. 1017) at 22.
`
`28. The parent compound, sirolimus, has a hydroxyl (HO–) group at the
`
`C40 position. See Cottens '772 patent (Ex. 1019) at 1:10-32.
`
`29. Temsirolimus, an ester derivative of sirolimus, has a 2,2-bis-
`
`(hydroxymethyl) propionic acid ester ((HOCH2)2(CH3)(O)CO–) group at the C40
`
`position. See Alexandre and Raymond (Ex. 1030) at 1 and 6. A POSA would
`
`understand that temsirolimus can be properly considered to be a prodrug of
`
`rapamycin since it was reported that an ester is "susceptible to hydrolytic cleavage
`
`under physiological conditions." See Schuler (Ex. 1008) at 40; see also Boni et al.,
`
`Pharmacokinetics of escalating doses of CCI-779 in Combination with 5-
`
`Fluorouracil and Leucovorin in Patients with Advanced Solid Tumors, Eur. J.
`12
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`
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`Breckenridge Exhibit 1010
`Pantuck Declaration
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`West-Ward Exhibit 1112
`Cho Declaration
`Page 0023
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`

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`Cancer (2001) 37(Suppl. 6): S68 (Abstr. No. 242) (The 11th ECCO October 21-25,
`
`2001 meeting held in Lisbon, Portugal) ("Boni," Ex. 1031). (reporting the "mean
`
`ratio of sirolimus-to-CCI-779 AUC was 2.4 to 3.8"). Accordingly, results related
`
`temsirolimus would have been expected to be based primarily on the activity of
`
`sirolimus.
`
`30. Everolimus has a 2-hydroxyethyloxy (–OCH2CH2OH) group at the
`
`C40 position. See Sorbera (Ex. 1017) at 22. Everolimus is not a prodrug of
`
`rapamycin. See Schuler (Ex. 1008) at 41. However, Crowe et al., Absorption and
`
`Intestinal Metabolism of SDZ-RAD and Rapamycin in Rats, Drug Metab. Disp.
`
`(1999), 27(5): 627-632 ("Crowe," Ex. 1004) at 630 states that "SDZ-RAD is a
`
`structural analog of rapamycin, sharing the same mechanisms of action."
`
`Likewise, Schuler states that at the molecular level SDZ RAD, like rapamycin,
`
`binds to FKBP and blocks the activation of p70 S6 kinase. See Schuler (Ex. 1008)
`
`at 38 and 40.) Further, Sedrani states that FKBP12-everolimus complex binds to
`
`mTOR. See Sedrani (Ex. 1020) at 2193.
`
`VI. OVERVIEW OF THE '131 PATENT
`A. Disclosure of the '131 Patent
`31. The '131 patent states that "[t]he present invention relates to a new
`
`use, in particular a new use for a compound group comprising rapamycin and
`
`derivatives thereof." See the '131 patent (Ex. 1001) at 1:3-5. The '131 patent also
`
`
`
`13
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`Pantuck Declaration
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`West-Ward Exhibit 1112
`Cho Declaration
`Page 0024
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`states that "[r]apamycin is a known macrolide antibiotic produced by Streptomyces
`
`hygroscopicus." See the '131 patent (Ex. 1001) at 1:6-7). The '131 patent
`
`generally describes rapamycin derivatives of formula I, as follows:
`
`
`
`wherein
`R1 is CH3 or C3-6alknyl, R2 is H or –CH2–CH2OH, and
`X is ═OH, (H,H) or (H,OH) provided that R2 is other
`than H when X is ═O and R1 is CH3.
`
`
`See the '131 patent (Ex. 1001) at 1:7-35, as corrected by the Certificate of
`
`Correction issued on October 20, 2015.
`
`32. The
`
`'131 patent specifically discloses six preferred rapamycin
`
`derivatives,
`
`including
`
`32-deoxorapamycin,
`
`16-pent-2-ynyloxy-32-
`
`deoxorapamycin,
`
`16-pent-2-ynyloxy-32(S)-dihydro-rapamycin,
`
`16-pent-2-
`
`ynylo