UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`PAR PHARMACEUTICAL,INC.
`Petitioner
`
`V.
`
`NOVARTIS AG
`Patent Owner
`
`Case IPR2016-
`U.S. Patent No. 9,006,224
`
`DECLARATION OF MARK J. RATAIN, M.D. INSUPPORT OF PETITION
`FOR INTER PARTES REVIEW OFU.S. PATENT NO.9,006,224
`
`West-Ward Pharm.
`Exhibit 1003
`Page 001
`
`West-Ward Pharm.
`Exhibit 1003
`Page 001
`
`

`

`CONTENTS
`
`I.
`
`Il.
`
`Ill.
`
`IV.
`
`INTRODUCTION AND QUALIFICATIONS..........ccccsssssceesseesseesseesseeseeees 1
`
`UNDERSTANDING OF THE GOVERNING LAW........ceecceeeceesessseeteeeeeeees 4
`
`Invalidity by ODVIOUSNESS................cessecsssceessseesseeeeseecssecesenteessnsessneeeses 4
`A.
`Interpreting Claims Before the Patent Office..............ceseessecesteesereeeees 6
`B.
`C. Materials Relied on in Forming My Opinions...............ccscccesteeesteeeseees 7
`
`The Person of Ordinary Skill in the Art of the ’224 Patent... eeeeeeees 7
`
`Perspective Applied in This Declaration................cscccsssccsstecssecesssecsseeessneeeees 8
`
`OVERVIEW OF THE ’224 PATENT........cccecccesccseecsseeseeeceseeeseeeeeeneeeeeeseeees 9
`
`A.
`B.
`
`Disclosure of the ’224 Patent ......... ce eeessceeseeeseeseeceenceeaneeneeesaeeeaeessees 9
`Prosecution History of the ’224 Patent .............cecesscssseeesseesseeeseeees 12
`
`VI.
`
`CLAIM CONSTRUCTIONS.......cccccccsccssccsseeseessecseceeesssessaecaneneessaeeenesessaeeaes 16
`
`A.—_Legal Standard... eececcccssscessceseceseceeeceeeeceeeeceseeeseeeeeeeeaeeeaeeeeeeeeaeens 16
`B.
`“pancreatic neuroendocrine tuMOr”............cccccesccesseceseeeesseseneeeseenens 17
`C.—““Sadvanced tumors” ..........ceeecesseeceseessecseecensesecsaeceeeesesnaeseneneesseesanesnes 18
`D.
`“SUM COSC”... eee eeesecssecessseessecssseecsseecssnseesauecsueeesaeessenecenesseeseseanecss 19
`E.
`“islet cell tumor”........... cc ccsssccsssecessecesesecsseecsseeecseecsssueeseeecseasecsenecseneees 20
`
`VIL.
`
`State of the Prior Art to the ’224 Patent .............cscccssscessecesteecsseesssseesseeessees 21
`
`A.—The Prior Art Taught Rapamycin and Its Derivatives Were
`Potent Immunosuppressants and Antitumor Agents..............csccseeee 22
`The Prior Art Taught the Mechanism of Action for the
`Immunosuppressant and Antitumor Activity of Rapamycin and
`Its Derivatives......cccccccccccccccccsscssssesssececussssesesssecscecssceeesususeseesneeseseauacens 32
`Understanding and Classification of NETS.............cscccsseseseessereessneeees 36
`
`B.
`
`C.
`
`VII.
`
`THE PRIOR ARTRelied Upon ..........ccccccssccsssecsssseceseeesseecsseeeeeeeecsseeeesanessas 40
`
`Oberg 2004... eee ececcestecsseccssceessncessnecesneeseneecseeeesseeeeseeesseeecseeessneees 40
`A,
`Boublay 2004 oui... eee cecccscssesssccssecssecesseesenesseeeseeesseeesseeseeesensesseesaseess 44
`B.
`O'Donnellou... ccccecececsssssscssecececesescececnsscsccncusecessususeuuenseceeeseusacuese 46
`C.
`D.—-_Tabernero... ccccccccecssssscccsceesusessessessesecessssceeessesssssencsseeueeseeeesseeees 47
`E.
`DUPLAM 0... cece ccccccccecscsceensnsessscacacaccscscscscscacseessesscsccsssssssssssseseeseseseseseeseeeees 49
`
`i
`
`West-Ward Pharm.
`Exhibit 1003
`Page 002
`
`West-Ward Pharm.
`Exhibit 1003
`Page 002
`
`

`

`IX.
`
`MOTIVATIONS TO COMBINE THE PRIOR ART ooo. eeeeseeeseeeeeeeees 50
`
`A. Motivation to Combine Oberg 2004 with Boulay 2004 and
`O’Dontttell 0... ccc eccsccsscessscecsseeesseecesseecssseeeseeceseeeesaeeceeeecenauessaesessaneseas 50
`B. Motivation to Combine Boulay 2004 with O’Donnell and
`DULAN ......ccccccssccccsscecessscecssseceesesaceecseaeeecsseuecesauaeeeeeaeeceseaeecesnaneeessaeeeees 53
`C. Motivation to Combine Oberg 2004, Boulay 2004, O’Donnell,
`and Duran with Tabernero...........cccccsscccssseccssecssseeecseecssnseeeatecssneessaeeess 55
`
`GROUNDS OFINVALIDITY ..........ccceesscsssesssseseecseecstecseeeseeseaneseeeessseseneeens 56
`
`A.
`
`B.
`
`C.
`
`D.
`
`Ground 1: Claims 1-3 of the ’224 Patent are invalid under 35
`U.S.C. § 103 on the ground that they are rendered obvious by
`Oberg 2004 in view of Boulay 2004 and O’Donnell....................00 56
`1. Cai 1 oe eeeseceseceseneccscccensecssecesensecsseceseusesseesesauecseneeeensessgs 56
`2.
`Claim 2 0... cccccccssecsssccssneccseessesecesesecsesecsaeeessnsesseeeesaueceseeeesaneeags 58
`3.
`Claim 3 0... ceeeccesessscceseeceseeeseeeceseeecsnsecsaeeessneesseeeesaneceseeeesneeesgs 60
`Ground 2: Claim 2 of the ’224 Patent is invalid under 35 U.S.C.
`§ 103 on the groundthatit is rendered obvious by Oberg 2004,
`Boulay 2004, and O’Donnell in view of Tabernero...............ccccceseees 61
`Ground 3: Claims 1-3 of the ’224 Patent are invalid under 35
`U.S.C. § 103 on the ground that they are rendered obvious by
`Boulay 2004 in view of O’Donnell and Duran .............cccsecsssseeeeeeeee 62
`1.
`Claim 1... eeeccessecessecssneccsecesseeceseeecsnsecsaeeessnsessaeeesaueceeeeesaneeags 62
`2.
`Claim 2 oo. eecccsccssccssccseeccssecssecesacesscesseceesceseeesseeenscesseeseeeesesenaes 64
`3. Cai 3 00... eeeccessecssecesenecescecensecssecesensecseceseusesseeeesauecseneeeensessas 65
`Ground 4: Claim 2 of the ’224 Patent is invalid under 35 U.S.C.
`§ 103 on the groundthatit is rendered obvious by Boulay 2004,
`O’Donnell, and Duran in view of Tabernero ..............cccceceseseseeeeeeeee 66
`
`XI.
`
`Secondary Considerations..........:.cccscccsssccsssecesseecsseeceseseceseeeesesesseeeeseuesesaeeeeans 67
`
`ii
`
`West-Ward Pharm.
`Exhibit 1003
`Page 003
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`West-Ward Pharm.
`Exhibit 1003
`Page 003
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`

`

`I, Mark J. Ratain, M.D., resident of Chicago, Illinois, hereby declare as
`
`follows:
`
`I
`
`INTRODUCTION AND QUALIFICATIONS
`
`1.
`
`I have been retained by Par Pharmaceutical, Inc. (“Par”) to provide
`
`my opinion concerning the validity of U.S. Patent No. 9,006,224 (Exhibit 1001;
`
`“the ’224 patent”) in support of Par’s Petition for Inter Partes Review of the ’224
`
`patent (“224 Petition”).
`
`2.
`
`I graduated from Harvard University magna cum laude in 1976 with
`
`an A.B.
`
`in Biochemical Sciences.
`
`I obtained my M.D. from Yale University
`
`School of Medicine in 1980.
`
`I completed my internship and residencyat the Johns
`
`Hopkins Hospital in Baltimore, MD from 1980-1983.
`
`I completed a fellowship in
`
`Hematology/Oncology at the Department of Medicine at the University of Chicago
`
`from 1986-1988.
`
`3.
`
`In 1986,
`
`I
`
`joined the Department of Medicine, Section of
`
`Hematology/Oncology and Committee on Clinical Pharmacology at the University
`
`of Chicago as an Instructor and become a Professor in that department in 1995. In
`
`2002, I became the Leon O. Jacobson Professor in the Department of Medicine,
`
`Section of Hematology/Oncology and Committee on Clinical Pharmacology and
`
`Pharmacogenomics, and Comprehensive Cancer Center at
`
`the University of
`
`Chicago.
`
`West-Ward Pharm.
`Exhibit 1003
`Page 004
`
`West-Ward Pharm.
`Exhibit 1003
`Page 004
`
`

`

`4.
`
`In 1991, I became the Director of the Developmental Therapeutics
`
`Program at the Cancer Research Center at the University of Chicago.
`
`In 1992, I
`
`became Chairman
`
`of
`
`the Committee
`
`on Clinical Pharmacology
`
`and
`
`Pharmacogenomicsat the University of Chicago.
`
`In 1995, I became Co-Director
`
`of the Clinical and Experimental Therapeutics Program of the Cancer Research
`
`Center at the University of Chicago.
`
`In 1999, I became the Associate Director for
`
`Clinical Sciences at
`
`the Comprehensive Cancer Center at
`
`the University of
`
`Chicago.
`
`In 2010, I became the founding Director of the Center for Personalized
`
`Therapeutics and Chief Hospital Pharmacologist at the University of Chicago.
`
`5.
`
`I have received numerous honors and awards over my career. These
`
`include election to the Association of American Physicians in 2007, and awards
`
`from multiple institutions (MD Anderson Cancer Center, University of North
`
`Carolina, University
`
`of Nebraska, University
`
`of Utah),
`
`foundations
`
`(Pharmaceutical Research and Manufacturer’s Association of America Foundation)
`
`and professional societies (American Association of Pharmaceutical Scientists,
`
`American Society for Clinical Pharmacology and Therapeutics, American Society
`
`of Clinical Oncology, American College of Clinical Pharmacology).
`
`6.
`
`I have also had extensive involvement with the American Society of
`
`Clinical Oncology (ASCO), dating back to 1990 when I was appointed Chair of
`
`ASCO’s Audit and Finance Committee.
`
`I was subsequently elected to the position
`
`West-Ward Pharm.
`Exhibit 1003
`Page 005
`
`West-Ward Pharm.
`Exhibit 1003
`Page 005
`
`

`

`of Secretary-Treasurer of ASCO, and served in that capacity as an Officer and
`
`Director from 1994 to 1997.
`
`I also served as the Chair of ASCO’s Continuing
`
`Medical Education Committee from 1997 to 1999. In my capacities as Committee
`
`Chair, Officer, and Director, I participated actively in ASCO Board meetings and
`
`am familiar with ASCO’s policy and lobbying efforts to modify Medicare
`
`reimbursement policies for oral oncology drugs during the period from 1990 to
`
`1999.
`
`7.
`
`I have served as a research reviewer for a number of committees and
`
`working groups at the National Institutes of Health, as well as for several cancer
`
`societies and state departmentsofhealth.
`
`8.
`
`I have served as an editor for numerous journals, including Journal of
`
`Clinical Oncology (Investigational New Drugs (1995 to present; Editorial Board);
`
`Pharmacogenetics and Genomics (2005 to present; Co-Editor-in-Chief); and
`
`Clinical Cancer Research (1994 to 2002 and 2012 to present; Editorial Board and
`
`Associate Editor).
`
`9.
`
`I have written more than 400 articles in peer-reviewed journals.
`
`I am
`
`additionally a named inventor on five United States and two foreign patents.
`
`10.
`
`I have extensive experience in clinical pharmacokinetics and
`
`development of cancer therapeutics,
`
`including chemotherapeutic agents, other
`
`small molecules (e.g., targeted compounds) andbiologics.
`
`I have been involved in
`
`West-Ward Pharm.
`Exhibit 1003
`Page 006
`
`West-Ward Pharm.
`Exhibit 1003
`Page 006
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`

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`the design, conduct and analysis of clinical phaseI, phaseII, and phaseIII trials for
`
`cancer therapeutics, including studies of rapamycin andits derivatives. Many of
`
`these studies have been conducted in our Developmental Therapeutics Clinic (at
`
`the University of Chicago), which was previously known as the Advanced Solid
`
`Tumors Clinic.
`
`(I have served as the director of that clinic since its founding more
`
`than 20 years ago.)
`
`11. My curriculum vitae is attached as Exhibit 1004. My work in this
`
`matter is being billed at my standard rate of $750 per hour, with reimbursementfor
`
`necessary and reasonable expenses. My compensation is not
`
`in any way
`
`contingent upon the outcome of any Jnter Partes Review.
`
`I have nofinancial or
`
`personalinterest in the outcome ofthis proceedingor anyrelatedlitigation.
`
`Il.
`
`UNDERSTANDING OF THE GOVERNING LAW
`
`A.
`
`Invalidity by Obviousness
`
`12.
`
`Iam informed by counsel for Par that obviousness is analyzed from
`
`the perspective of a hypothetical person of ordinary skill in the art at the time of
`
`the alleged invention.
`
`I am also informed by counsel for Par that a person of
`
`ordinary skill in the art is presumed to have been aware ofall pertinent priorart at
`
`the time of the alleged invention.
`
`13.
`
`Iam informed by counsel for Par that 35 U.S.C. § 103 governs the
`
`determination of obviousness. According to 35 U.S.C. § 103:
`
`West-Ward Pharm.
`Exhibit 1003
`Page 007
`
`West-Ward Pharm.
`Exhibit 1003
`Page 007
`
`

`

`A patent
`
`for
`
`a
`
`claimed
`
`invention may not
`
`be
`
`obtained,
`
`notwithstanding that the claimed invention is not identically disclosed
`
`as set forth in section 102, if the differences between the claimed
`
`invention and the prior art are such that the claimed invention as a
`
`whole would have been obviousbefore the effective filing date of the
`
`claimed invention to a person having ordinary skill in the art to which
`
`the claimed invention pertains. Patentability shall not be negated by
`
`the mannerin which the invention was made.
`
`14.
`
`Iam also informed by counsel for Par that the first three factors to be
`
`considered in an obviousness inquiry are:
`
`(1) the scope and content of the prior
`
`art; (2) the differences between the prior art and the claims; and (3) the level of
`
`ordinary skill in the pertinent art.
`
`I have also been informed by counsel for Par that
`
`when a patent claims a genus, that claim is obvious if a single embodimentfalling
`
`within the scope of the claims is obvious.
`
`15.
`
`I am also informed by counsel for Par that when there is some
`
`recognized reason to solve a problem, and there are a finite numberofidentified,
`
`predictable solutions, a person of ordinary skill in the art 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
`
`West-Ward Pharm.
`Exhibit 1003
`Page 008
`
`West-Ward Pharm.
`Exhibit 1003
`Page 008
`
`

`

`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.
`
`16.
`
`Iam also informed by counsel for Par that certain factors, sometimes
`
`known as “secondary considerations,” must be considered, if present, when in an
`
`obviousness determination. These secondary considerations include:
`
`(i) long-felt
`
`need,
`
`(11) unexpected results,
`
`(111) skepticism of others of the invention,
`
`(iv)
`
`teaching away from the invention, (v) commercial success, (vi) praise by others for
`
`the invention, and (vii) copying by other companies.
`
`17.
`
`I am also informed by counsel
`
`for Par that
`
`the earliest patent
`
`application leading to the ’224 Patent was filed on November 21, 2005.
`
`I have
`
`therefore analyzed obviousness as of that day or somewhat before, understanding
`
`that as time passes, the knowledge of a person of ordinary skill in the art will
`
`increase.
`
`B.
`
`Interpreting Claims Before the Patent Office
`
`18.
`
`I understand that Inter Partes Review is a proceeding before the
`
`United States Patent & Trademark Office (“PTO”) 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” includesall the figures,
`
`West-Ward Pharm.
`Exhibit 1003
`Page 009
`
`West-Ward Pharm.
`Exhibit 1003
`Page 009
`
`

`

`discussion, and claims within the patent. I understand that the PTO will look to the
`
`specification to see if there is a definition for a given claim term, and if not, will
`
`apply the broadest reasonable interpretation from the perspective of a person of
`
`ordinary skill in the art at the time in which the alleged invention was made.
`
`I
`
`present a more detailed explanation of the interpretation of certain terms in the
`
`’224 patent in the section titled “Claim Construction” below.
`
`C. Materials Relied on in Forming My Opinions
`
`19.
`
`In forming my opinions, I have relied on the ’224 patent’s claims,
`
`specification, and file history, on the prior art exhibits to the ’224 Petition, any
`
`other materials cited in this declaration, and my own experience, expertise, and
`
`knowledge ofthe person of ordinary skill in the art in the relevant timeframe.
`
`ll. THE PERSON OF ORDINARY SKILL IN THE ART OF THE ’224
`PATENT
`
`20.
`
`The claims of the ’224 patent are directed to treating pancreatic
`
`neuroendocrine tumorsin patients by administering the rapamycin,(i.e., rapamycin
`
`or a derivative thereof) 40-O-(2-hydroxyethyl)-rapamycin.
`
`21.
`
`Based on this, in my opinion, a person of ordinary skill in the art in
`
`November 2005 would have had, at a minimum:
`
`West-Ward Pharm.
`Exhibit 1003
`Page 010
`
`West-Ward Pharm.
`Exhibit 1003
`Page 010
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`

`

`a.
`
`a medical degree (e.g., MD) with several years of specific experience
`
`in medical oncology, which generally includes boardcertification, 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 andclinical pharmacology, including evaluating cancer
`
`therapeutics in in vitro and/orin 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.
`
`IV.
`
`PERSPECTIVE APPLIED IN THIS DECLARATION
`
`22.
`
`I believe that I would qualify as a person of at least ordinary skill in
`
`the art
`
`in November 2005, and that I have a sufficient
`
`level of knowledge,
`
`experience, and education to provide an expert opinion in the field of the ’224
`
`patent.
`
`23.
`
`Because of my work experience and the earlier date on which I
`
`received my medical degree, by November 2005 my own level of skill likely
`
`exceeded the ordinary level of skill in the art.
`
`In the mid-2000s, I served as
`
`Professor at the University of Chicago, supervised and worked with those of
`
`ordinary skill
`
`in the art, and served on editorial boards for multiple journals
`
`West-Ward Pharm.
`Exhibit 1003
`Page 011
`
`West-Ward Pharm.
`Exhibit 1003
`Page 011
`
`

`

`specializing in cancer research. Accordingly, I am well acquainted with the actual
`
`performance of a person of ordinary skill in the art as defined above, and can
`
`approachtechnical issues from the perspective of such a person.
`
`24.
`
`My opinions in this declaration are based on the perspective of a
`
`person of ordinary skill in the art as of November 2005. This is true even if the
`
`testimony is stated in the present tense. Each of the statements below reflects my
`
`opinion based on myreview ofthe priorart, the disclosures of the ’224 patent, its
`
`file history, and the challenged claims.
`
`V.
`
`OVERVIEW OF THE ’224 PATENT
`
`A.
`
`Disclosure of the ’224 Patent
`
`25.
`
`The °224 patent claims methods of treating advanced pancreatic
`
`neuroendocrine tumors (pNETs) by administering everolimus as a monotherapy
`
`after failure of cytotoxic chemotherapy. Everolimus is the common namefor 40-
`
`O-(2-hydroxyethyl)-rapamycin.
`
`°224 patent at 1:46-47. The ’224 patent also
`
`refers to everolimus as Compound A. /d. at 11:66-67.
`
`26.
`
`Claim 1 of the ’224 patent recites
`
`A method for treating pancreatic neuroendocrine tumors, comprising
`
`administering to a human subject in need thereof a therapeutically
`
`effective
`
`amount
`
`of
`
`40-O-(2-hydroxyethyl)-rapamycin
`
`as
`
`a
`
`West-Ward Pharm.
`Exhibit 1003
`Page 012
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`West-Ward Pharm.
`Exhibit 1003
`Page 012
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`

`

`monotherapy and wherein the tumors are advanced after failure of
`
`cytotoxic chemotherapy.
`
`27.
`
`Claim 2 of the ’224 patentrecites
`
`The method of claim 1, wherein a unit dose of 40-O-(2-
`
`hydroxyethyl)-rapamycin is 10 mg/day.
`
`28.
`
`Claim 3 of the ’224 patentrecites
`
`The method of claim 1 wherein the tumorisislet cell tumor.
`
`29. According to the ’224 patent specification, rapamycin and other
`
`mTORinhibitors, including everolimus, inhibit mTORactivity through a complex
`
`with FKBP12. Rapamycin andits derivatives, including everolimus, have potent
`
`antiproliferative properties which make them useful for cancer chemotherapy,
`
`particularly for advancedsolid tumors. Ex. 1001, ’224 patent at 2:35-40.
`
`30.
`
`pNETs comprise only 1-2% of pancreatic tumors and, according to
`
`the ’224 patent specification, a recent review showed that the 5 year survival rate
`
`of patients with pNETs was merely 55.3%. Id. at 2:49-54, 3:7-12.
`
`31. According to the ’224 patent, it was found that mTOR inhibitors like
`
`rapamycin and everolimusare useful for the treatment of pNETs. Jd. at 7:10-11.
`
`32.
`
`The ’224 patent does not include any data demonstrating the activity
`
`of everolimus, or any other rapamycin derivative or mTOR inhibitor, in treating
`
`10
`
`West-Ward Pharm.
`Exhibit 1003
`Page 013
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`West-Ward Pharm.
`Exhibit 1003
`Page 013
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`

`

`any tumor, including pNET,either in human patients or in preclinical laboratory
`
`experiments.
`
`33.
`
`The ’224 patent describes two in vitro assays for assessing the
`
`antiproliferative activity of mTOR inhibitors such as everolimus.
`
`Jd. at 25:54-
`
`26:20. First, the specification describes incubating two cancer cell lines with
`
`mTOR inhibitors alone or in combination with other antineoplastic agents and
`
`measuring ICs) values to determine the antiproliferative effect of the compounds
`
`and/or combinations.
`
`Jd. at 25:54-26:10.
`
`Second,
`
`the specification describes
`
`measuring the phosphorylation of $6, for example by using the p70S6 kinase I
`
`assay, aS a measure of mTORinhibition. Jd. at 26:11-20.
`
`34.
`
`The °224 specification also describes in vitro studies to assess
`
`everolimus’s ability to restore activity of endocrine agents in cells resistant to
`
`endocrine agent treatment. Jd. at 26:21-27.
`
`35.
`
`Finally,
`
`the ’224 specification describes
`
`four clinical
`
`trials
`
`to
`
`investigate the activity of everolimus.
`
`First,
`
`the
`
`specification describes
`
`administering 5 mg of everolimus daily to patients with carcinoid or islet cell
`
`cancer either alone or in combination with the somatostatin analogue Sandostatin
`
`LAR.
`
`Id. at 26:29-36. The active ingredient of Sandostatin LAR is octreotide
`
`acetate, and it was approvedfor the treatment of symptoms of VIPomas, a type of
`
`pNETin 1998. Ex. 1060.
`
`West-Ward Pharm.
`Exhibit 1003
`Page 014
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`West-Ward Pharm.
`Exhibit 1003
`Page 014
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`

`

`36.
`
`The specification describes evaluating the response of the treatment
`
`and obtaining synergistic effects from the combination.
`
`Jd.
`
`Second,
`
`the
`
`specification describes administering 5 mg or 10 mg daily (5 to 70 mg weekly)
`
`alone or in combination with Sandostatin LAR to patients with advanced midgut
`
`carcinoid tumors.
`
`Jd. at 26:37-55. The specification describes evaluating the
`
`progression free
`
`survival, overall
`
`survival,
`
`carcinoid-associated symptoms,
`
`“pharmakinetics and pharmadynamics
`
`[sic].”
`
`Jd. at 26:46-49.
`
`Third,
`
`the
`
`specification describes administering 10 mg/day of everolimus to patients with
`
`advanced pNETafter failure of cytotoxic chemotherapy. Jd. at 26:56-60. Finally,
`
`the specification describes administering 10 mg/day everolimus to patients with
`
`secretory pancreatic tumors in combination with Sandostatin LAR.
`
`Jd. at 26:61-
`
`64.
`
`37.
`
`The ’224 patent specification does not include any data demonstrating
`
`the preclinical or clinical activity of everolimus or any other mTOR inhibitor in
`
`pNETs.
`
`The specification provides no data demonstrating the activity of
`
`everolimus or any other mTORinhibitor in laboratory models of pNET or in any
`
`humanpatient populations diagnosed with pNET.
`
`B.
`
`‘Prosecution History of the ’224 Patent
`
`38.
`
`Ihave reviewed the prosecution history of the ’224 patent and present
`
`a short overview ofit.
`
`West-Ward Pharm.
`Exhibit 1003
`Page 015
`
`West-Ward Pharm.
`Exhibit 1003
`Page 015
`
`

`

`39. All originally-pending claims in the application for the ’224 patent
`
`were initially rejected as anticipated by O’Reilly et al.
`
`(Proceedings of the
`
`American Association of Cancer Research Annual Meeting, 03/2002, Vol. 43, pg.
`
`71) CO’Reilly”; Ex. 1030) and Weckbecker (WO 97/47317) (“Weckbecker”; Ex.
`
`1053).
`
`(Ex. 1002 at 2/16/2011 Non-Final Rejection at 4-6). Those originally-filed
`
`claims included within their scope therapy with 40-O-(2-hydroxyethyl)-rapamycin
`
`combined with other therapies for the treatment of endocrine tumors.
`
`(Ex. 1002 at
`
`5/19/2008 Prelim. Am.at 4-5.)
`
`40.
`
`The Examiner
`
`stated
`
`that O’Reilly
`
`teaches
`
`that
`
`40-O-(2-
`
`hydroxyethyl)-rapamycin has demonstrated anti-proliferative activity in human
`
`tumors and is an inhibitor of pancreatic tumor growth in vivo. Ex. 1002 at
`
`2/16/2011 Non-Final Rejection at 4-5.
`
`41.
`
`The Examiner
`
`further
`
`stated that Weckbecker
`
`teaches
`
`a
`
`combination of a rapamycin and a derivative of somatostatin (a hormone that
`
`regulates the endocrine system)
`
`for
`
`the prevention and treatment of cell
`
`hyperproliferation, and that rapamycin derivative are known to inhibit cancer. Ex.
`
`1002 at 2/16/2011 Non-Final Rejection at 5. The Examiner also stated that
`
`Weckbecker identifies 40-O-(2-hydroxyethyl)-rapamycin as a preferred rapamycin
`
`compound and that the combination of a somatostatin analogue and a rapamycin
`
`can be used for preventing or treating endocrine tumors. Jd. at 5-6.
`
`13
`
`West-Ward Pharm.
`Exhibit 1003
`Page 016
`
`West-Ward Pharm.
`Exhibit 1003
`Page 016
`
`

`

`42.
`
`In response, the Applicants amended the claims to recite 40-O-(2-
`
`hydroxyethyl)-rapamycin. Ex. 1002, 8/2/2011 Am. at 2. The Applicants argued
`
`that O’Reilly does not disclose or suggest 40-O-(2-hydroxyethyl)-rapamycin for
`
`treating endocrine or pancreatic neuroendocrine tumors.
`
`Jd. at 3-4.
`
`The
`
`Applicants further argued that Weckbecker only refers to gastroenteropancreatic
`
`(GEP) tumors and does not disclose treating endocrine tumors or pancreatic
`
`neuroendocrine tumors. Jd. at 4.
`
`43.
`
`The Examinerthen issued a Final Rejection, stating that the claims as
`
`amended were still anticipated by O’Reilly and were obvious in light of
`
`Weckbecker. Ex. 1002, 10/13/2011 Final Rejection at 2-4.
`
`44.
`
`The Applicants appealed and entered a request
`
`for continued
`
`examination, arguing that the claims were not anticipated by O’Reilly on the
`
`groundsthat it did not disclose 40-O-(2-hydroxyethyl)-rapamycin as a treatment
`
`for endocrine tumors or pancreatic neuroendocrine tumors in humans, which a
`
`person of ordinary skill in the art would distinguish from each other and from other
`
`pancreatic cancers and tumors, such as adenocarcinomas. Ex. 1002, 1/13/2012
`
`Response After Final Action at 3-5; Ex. 1002, 2/6/2012 Request for Continued
`
`Examination at 5-7.
`
`45.
`
`The Applicants submitted a declaration from the co-inventor, Dr.
`
`Lebwohl, highlighting the distinction between the various cancer types. Ex. 1002,
`
`West-Ward Pharm.
`Exhibit 1003
`Page 017
`
`West-Ward Pharm.
`Exhibit 1003
`Page 017
`
`

`

`9/24/2013 Lebwohl Affidavit at 2-3. Dr. Lebwohl additionally stated in his
`
`declaration that a clinical study of 40-O-(2-hydroxyethyl)-rapamycin in patients
`
`with pNETsindicated that 40-O-(2-hydroxyethyl)-rapamycin “more than doubled
`
`the time without tumor growth and reduced the risk of pNET progression in
`
`patients by 65% when compared with placebo.” Jd. at 2.
`
`46.
`
`The Examinerthen issued a Non-Final Rejection. The Examiner was
`
`persuaded by Dr. Lebwohl’s declaration that
`
`the pending claims were not
`
`anticipated by the O’Reilly abstract given that O’Reilly did not differentiate
`
`between pancreatic tumors and tumorcells derived from pancreatic neuroendocrine
`
`tumors. Ex. 1002, 05/09/2014 Non-Final Rejection at 2. However, the Examiner
`
`maintained the obviousnessrejection based on Weckbeckerin view of Arnoldetal.
`
`Id. at 5-8.
`
`The Examiner stated that Weckbecker
`
`teaches
`
`treatment of
`
`gastroenteropancreatic neuroendocrine (GEP) tumors.
`
`J/d. at 6. The Examiner
`
`further stated that Arnold teaches that GEP tumorsare also called neuroendocrine
`
`tumors. Jd. at 7. Therefore, the Examiner stated that a person of ordinary skill in
`
`the art would have been motivated to combine Weckbecker and Arnold and
`
`administer
`
`a
`
`rapamycin
`
`derivative
`
`together with
`
`somatostatin
`
`to
`
`treat
`
`neuroendocrine tumors. Jd. at 7-8.
`
`47.
`
`Following this rejection, the Applicants amendedthe claims, limiting
`
`the scope to include only the treatment of advanced pancreatic neuroendocrine
`
`15
`
`West-Ward Pharm.
`Exhibit 1003
`Page 018
`
`West-Ward Pharm.
`Exhibit 1003
`Page 018
`
`

`

`tumors using 40-O-(2-hydroxyethyl)-rapamycin as a monotherapy after failure of
`
`cytotoxic chemotherapy. Ex. 1002, 11/7/2014 Am.at2.
`
`48.
`
`The Examiner issued a Notice of Allowance on January 30, 2015. Ex.
`
`1002, Notice of Allowanceat 3-4.
`
`49.
`
`Importantly, Boulay 2004 (discussed below) was submitted to the
`
`Patent Office during prosecution, but the Examiner never discussed or relied upon
`
`it. Oberg 2004, O’Donnell, Duran, and Tabernero (discussed below) were neither
`
`submitted to the Patent Office nor considered by the Examiner during prosecution
`
`of the ’224 patent. Further, Dr. Lebwohl’s declaration did not present any data
`
`comparing 40-O-(2-hydroxyethyl)-rapamycin’s activity with that of rapamycin or
`
`temsirolimus.
`
`VI. CLAIM CONSTRUCTIONS
`
`A.
`
`Legal Standard
`
`50.
`
`I understand that in an Jnter Partes Review a claim term is given the
`
`broadest
`
`reasonable construction in light of the patent
`
`specification and
`
`prosecution history as understood bya person ofordinary skill in the art at the time
`
`of the alleged invention.
`
`I understand that this claim construction standard is
`
`broader than whata district court would applyin litigation.
`
`51.
`
`I applied this broadest reasonable construction standard to my review
`
`of the claimsof the ’224 patent discussed below.
`
`West-Ward Pharm.
`Exhibit 1003
`Page 019
`
`West-Ward Pharm.
`Exhibit 1003
`Page 019
`
`

`

`B.
`
`“pancreatic neuroendocrine tumor”
`
`52.
`
`The term “pancreatic neuroendocrine tumor” is used in challenged
`
`claim 1 of the ’224 patent.
`
`53. A person of ordinary skill in the art would have generally understood
`
`“pancreatic neuroendocrine tumor,” as used in claim 1 of the ’224 patent, to have
`
`the customary meaning that is consistent with its use and definition in the °224
`
`patent specification. A person of ordinary skill in the art would understand that a
`
`neuroendocrine tumor is an abnormal growth of cells of the nervous or endocrine
`
`systems within or proximal to the pancreas. These tumors may be malignant or
`
`benign. Malignant tumors are frequently identified as carcinomas.
`
`54. A person of ordinary skill in the art would understand that not all
`
`neuroendocrine tumors occurin the pancreas andthat not all pancreatic cancers are
`
`neuroendocrine tumors.
`
`(Ex. 1020, Kaltsas et al., “The Diagnosis and Medical
`
`Management of Advanced Neuroendocrine Tumors,” Endocrine Rev. 25:458-511
`
`(June 2004) (“Kaltsas”); Ex. 1019, Levy and Wiersema, “Pancreatic neoplasms,”
`
`Gastrointestinal Endoscopy Clin. N. Am. 15:117-142 (2005) (“Levy”).) Rather,
`
`the majority of pancreatic cancers are adenocarcinomas, or abnormal growths of
`
`the cells of the pancreas that produce digestive enzymes. (Ex. 1019, Levy.)
`
`55.
`
`The ’224 patent specification indicates that “Endocrine, e.g.
`
`neuroendocrine tumors (NETs), are found in the endocrine system. ... Pancreatic
`
`17
`
`West-Ward Pharm.
`Exhibit 1003
`Page 020
`
`West-Ward Pharm.
`Exhibit 1003
`Page 020
`
`

`

`neuroendocrine tumors (islet cell
`
`tumors), which were formerly classified as
`
`APUDomas(tumors of the amine precursor uptake and decarboxylation system),
`
`comprise less than half of all neuroendocrine tumors and only 1-2% of all
`
`pancreatic tumors. Pancreatic NETs can arise either in the pancreas (insulinomas,
`
`glucagonomas, nonfunctioning pancreatic NETs, pancreatic NETs
`
`causing
`
`hypercalcemia) or at both pancreatic and extrapancreatic sites (gastrinomas,
`
`VIPomas, somatostatinomas, GRFomas).” Ex. 1001, ’224 patent at 2:41-58.
`
`56.
`
`The
`
`’224
`
`patent
`
`specification
`
`states
`
`that
`
`“Pancreatic
`
`neuroendocrine tumors
`
`as
`
`indicated herein e.g.
`
`include islet cell
`
`tumors,
`
`APUDomas,
`
`insulinomas, glucagonomas, nonfunctioning pancreatic NETS,
`
`pancreatic NETs
`
`associated with
`
`hypercalcemia,
`
`gastrinomas, VIPomas,
`
`somatostatinomas, GRFomas.” Ex. 1001, ’224 patent at 8:13-17.
`
`57. Accordingly, in my opinion, the broadest reasonable construction of
`
`the term “pancreatic neuroendocrine tumors” is “abnormal growths ofcells of the
`
`nervous or endocrine systems in the pancreas, including, e.g., islet cell tumors,
`
`APUDomas,
`
`insulinomas, glucagonomas, nonfunctioning pancreatic NETS,
`
`pancreatic NETs
`
`associated with
`
`hypercalcemia,
`
`gastrinomas, VIPomas,
`
`somatostatinomas, GRFomas.”
`
`C.
`
`“advanced tumors”
`
`58.
`
`The term “advanced”is used in challenged claim 1 of the ’224 patent.
`
`West-Ward Pharm.
`Exhibit 1003
`Page 021
`
`West-Ward Pharm.
`Exhibit 1003
`Page 021
`
`

`

`59. A person of ordinary skill
`
`in the art would understand the term
`
`“advanced tumors” to have the customary meaning that is consistent with the
`
`specification. As used by those of skill in the field of oncology, an “advanced
`
`tumor”is a tumorthat is unresectable or metastatic. See, e.g., Ex. 1023, Moertelet
`
`al., “Streptozocin-Doxorubicin, Streptozocin-Fluorouracil, or Chlorozotocin in the
`
`Treatment of Advanced Islet-Cell Carcinoma,” NEJM 326(8):519-523 (Feb. 20,
`
`1992) at 520 (describing the patients with advancedislet cell carcinoma as having
`
`been identified with “proof of unresectable or metastatic islet-cell carcinoma”).
`
`This is consistent with the ’224 patent specification, which correlates “advanced”
`
`tumors with “metastatic or unresectable.” Ex. 1001,
`
`’224 patent, 26:57-58
`
`(“measurable advanced (metastatic or unresentable [sic, unresectable]) pancreatic
`
`neuroendocrine tumors”). An unresectable tumor is one that is unable to be
`
`completely removed by surgery.
`
`(This definition is also consistent with