`
`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
`
`
`
`
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`West-Ward Exhibit 1010
`Pantuck Declaration
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`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
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`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
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`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
`
`
`
`
`
`
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`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
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`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
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`iv
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`West-Ward Exhibit 1010
`Pantuck Declaration
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`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
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`
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`1
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`West-Ward Exhibit 1010
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`publications related to urologic oncology, in which more than 100 of these studies
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`are related to renal cell carcinoma and metastatic renal cell carcinoma.
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`6.
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`I have served as a reviewer for numerous medical journals, including
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`The Journal of Urology, Urology, British Journal of Urology International,
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`European Urology, Urologic Oncology, Clinical Cancer Research, among others.
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`Additionally, I have served on editorial boards of several medical publications,
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`including The Journal of Cancer Integrative Medicine, The Bladder Journal,
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`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
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`interest in the outcome of this proceeding or any related litigation.
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`2
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`West-Ward Exhibit 1010
`Pantuck Declaration
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`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..
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`12.
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`I understand that obviousness can be established by combining or
`
`modifying the disclosures of the prior art to achieve the claimed invention. It is
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`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
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`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
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`may include recourse to logic, judgment, and common sense available to a POSA.
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`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
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`understand that a claimed use of a prior art compound may be obvious when the
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`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
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`market pressure to solve a problem and there are only a finite number of identified,
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`predictable solutions to that problem.
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`14.
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`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
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`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
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`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,
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`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
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`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
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`comparatively short period of time is evidence that the claimed invention was the
`
`product of ordinary skill.
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`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,
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`
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`6
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`will apply the broadest reasonable interpretation from the perspective of a POSA at
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`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.
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`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.
`
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`8
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`West-Ward Exhibit 1010
`Pantuck Declaration
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`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
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`(Ex. 1029) at 77.
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`See Cottens '772 patent (Ex. 1019) at 1:10-32.
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`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
`
`
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`10
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`West-Ward Exhibit 1010
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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,
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`Transplantation Proc. (1998) 30(5): 2192-2194 ("Sedrani," Ex. 1020) at 2192; and
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`Sorbera et al, SDZ-RAD, Drugs of the Future (1999) 24(1): 22-29 ("Sorbera," Ex.
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`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,
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`compound 8, Compound A, RAD, RAD001, or Certican. See Section VIII.B.1,
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`¶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,
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`
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`11
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`where R is H for sirolimus, R is –C(O)C(CH3)(CH2OH)2 for temsirolimus, and R is
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`–CH2CH2OH for everolimus. See Cottens '772 patent (Ex. 1019) at 1:10-32;
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`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.,
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`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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`Cancer (2001) 37(Suppl. 6): S68 (Abstr. No. 242) (The 11th ECCO October 21-25,
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`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
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`temsirolimus would have been expected to be based primarily on the activity of
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`sirolimus.
`
`30. Everolimus has a 2-hydroxyethyloxy (–OCH2CH2OH) group at the
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`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
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`Intestinal Metabolism of SDZ-RAD and Rapamycin in Rats, Drug Metab. Disp.
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`(1999), 27(5): 627-632 ("Crowe," Ex. 1004) at 630 states that "SDZ-RAD is a
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`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
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`13
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`West-Ward Exhibit 1010
`Pantuck Declaration
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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
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`derivatives,
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`including
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`32-deoxorapamycin,
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`16-pent-2-ynyloxy-32-
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`deoxorapamycin,
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`16-pent-2-ynyloxy-32(S)-dihydro-rapamycin,
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`16-pent-2-
`
`ynyloxy-32(S)-dihydro-40-O-(2-hydroxy-ethyl)-rapamycin,
`
`and
`
`40-O-(2-
`
`hydroxyethyl)-rapamycin. See the '131 patent (Ex. 1001) at 1:42-46. The '131
`
`
`
`14
`
`West-Ward Exhibit 1010
`Pantuck Declaration
`
`
`
`patent identifies 40-O-(2-hydroxyethyl)-rapamycin as a preferred rapamycin
`
`derivative, that is identified therein as "Compound A" and that is described in
`
`Example 8 of the Cottens '772 patent (Ex. 1019). See the '131 patent (Ex. 1001) at
`
`1:45-47.
`
`33. The '131 patent states that the formula I rapamycin derivatives were
`
`known to bind to FK-506 binding protein or FKBP-12 and have been found to be
`
`useful as immunosuppressants and in the treatment of acute allograft rejection. See
`
`the '131 patent (Ex. 1001) at 1:50-55. The '131 patent also states that the formula I
`
`rapamycin derivatives "have potent antiproliferative properties which make them
`
`useful for cancer chemotherapy, particularly of solid tumors, especially of
`
`advanced solid tumors." See the '131 patent (Ex. 1001) at 1:55-57. The '131 patent
`
`does not specifically define the term advanced, but rather, has used that term in
`
`conjunction with a staging system. See the '131 patent (Ex. 1001) at 12:20-21
`
`("Adults with advanced-stage (III-IV) solid tumors."
`
`34. The '131 patent describes five different methods associated with the
`
`formula I rapamycin derivatives, including: (i) a method for treating solid tumors,
`
`(ii) a method for inhibiting growth of solid tumors, (iii) a method for inducing
`
`tumor regression, (iv) a method for treating solid tumor invasiveness or symptoms
`
`associated with such tumor growth, and (v) a method for preventing metastatic
`
`
`
`15
`
`West-Ward Exhibit 1010
`Pantuck Declaration
`
`
`
`spread of tumors or for preventing or inhibiting growth of micrometastasis. See the
`
`'131 patent (Ex. 1001) at 1:65–2:19.
`
`35. The '131 patent defines "solid tumors" to mean "tumors and/or
`
`metastasis (whereever [sic, wherever] located) other than lymphatic cancer." See
`
`the '131 patent (Ex. 1001) at 2:20-21. The '131 patent generally describes twelve
`
`classes of solid tumors, including excretory system tumors, which include tumors
`
`of the kidney, renal pelvis, ureter, bladder, other and unspecified urinary organs.
`
`See the '131 patent (Ex. 1001) at 2:21-57. The '131 patent defines "lymphatic
`
`cancer" to mean "tumors of blood and lymphatic system (e.g. Hodgkin's disease,
`
`Non-Hodgkin's
`
`lymphoma, Burkitt's
`
`lymphoma, AIDS-related
`
`lymphomas,
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`malignant immunoproliferative diseases, multiple myeloma and malignant plasma
`
`cell neoplasms,
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`lymphoid
`
`leukemia, myeloid
`
`leukemia, acute or chronic
`
`lymphocytic leukemia, monocytic leukemia, other leukemias of specified cell type,
`
`leukemia of unspecified cell type, other and unspecified malignant neoplasms of
`
`lymphoid, haematopoletic and related tissues, for example diffuse large cell
`
`lymphoma, T-cell lymphoma or cutaneous T-cell lymphoma)." See the '131 patent
`
`(Ex. 1001) at 4:20-30.
`
`36. The '131 patent describes five alternative embodiments related to the
`
`formula I rapamycin derivatives, as well as CCI779 and ABT578. The '131 patent
`
`states
`
`that CCI779
`
`is a
`
`rapamycin derivative
`
`(i.e., 40-[3-hydroxy-2-
`
`
`
`16
`
`West-Ward Exhibit 1010
`Pantuck Declaration
`
`
`
`(hydroxymethyl)-2-methylpropanoate]-rapamycin) that is disclosed in U.S. Patent
`
`No. 5,362,718, which issued on November 8, 1994 to Skotnicki et al. ("Skotnicki
`
`'718 patent," Ex. 1018). See the '131 patent (Ex. 1001) at 3:25-28. The '131 patent
`
`also states that ABT578 is a 40-substituted rapamycin derivative further
`
`comprising a diene reduction. See the '131 patent (Ex. 1001) at 3:28-29.
`
`37. The '131 patent includes five alternative embodiments related to the
`
`formula I rapamycin derivatives, as well as CCI779 and ABT578. For instance,
`
`the '131 patent states that:
`
`[T]he present invention also provides
`1.6 A method for the treatment of a disease associated
`with deregulated angiogenesis in a subject in need
`thereof, comprising administering to said subject a
`therapeutically effective amount of rapamycin or a
`derivative thereof, e.g. CCI779, ABT578 or a compound
`of formula I.
`1.7 A method for inhibiting or controlling deregulated
`angiogenesis in a subject in need thereof, comprising
`administering to said subject a therapeutically effective
`amount of rapamycin or a derivative thereof, e.g.
`CCI779, ABT578 or a compound of formula I.
`
`See the '131 patent (Ex. 1001) at 2:65–3:7.
`
`38. The '131 patent states that examples of diseases associated with
`
`deregulated angiogenesis include "without limitation e.g. neoplastic diseases, e.g.
`
`solid tumors," and that "[a]ngiogenesis is regarded as a prerequisite for those
`
`tumors which grow beyond a certain diameter, e.g. about 1-2 mm." See the '131
`
`patent (Ex. 1001) at 3:30-34.
`
`
`
`17
`
`West-Ward Exhibit 1010
`Pantuck Declaration
`
`
`
`39. As an aside, a POSA would understand that "[t]he process of cancer
`
`metastasis consists of a series of sequential steps, each of which can be rate
`
`limiting," and
`
`that "[a]fter cellular
`
`transformation, either unicellular or
`
`multicellular, growth of neoplastic cells
`
`is progressive, but extensive
`
`vascularization must occur if a tumor mass is to exceed 2 mm in diameter." See
`
`Dinney et al., Biology of Metastasis: Studies in Renal Cancer (17-24), in Principles
`
`and Practice of Genitourinary Oncology (Raghavan et al. eds., 1997) ("Dinney,"
`
`Ex. 1032) at 17. A POSA would understand that "[t]he growth of tumors and
`
`production of metastasis are known to depend on angiogenesis." See Dinney (Ex.
`
`1032) at 21.
`
`40. The '131 patent describes ten additional alternative embodiments
`
`related to the use of the formula I rapamycin derivatives, CCI779, and ABT578 in
`
`methods, pharmaceutical compositions, and
`
`in combination products and
`
`combination uses. See the '131 patent (Ex. 1001) at 3:37–4:19. The combination
`
`uses relate to the use of the formula I rapamycin derivatives, CCI779, and ABT578
`
`in combination with a "chemotherapeutic agent," which is defined to mean "any
`
`chemotherapeutic agent other than rapamycin or a derivative thereof." See the '131
`
`patent (Ex. 1001) at 4:31-33. The '131 patent generally describes ten categor