UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
`
`
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`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
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`v.
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`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-01479
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`Patent No. 9,006,224
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`
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`
`
`EXPERT DECLARATION OF DR. MATTHEW H. KULKE
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`NOVARTIS EXHIBIT 2001
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`Table Of Contents
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`I.
`
`Introduction ...................................................................................................... 1
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`II.
`
`Qualifications ................................................................................................... 4
`
`III. Legal Principles ............................................................................................... 7
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`IV. Person Of Ordinary Skill In The Art ............................................................... 9
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`V.
`
`State Of The Art ............................................................................................... 9
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`VI. Summary Of The ’224 Patent ........................................................................ 13
`
`VII. No Prior Art In Grounds 3 Or 4 Teaches Or Suggests The
`Claim Element “Advanced [PNETs] After Failure Of Cytotoxic
`Chemotherapy” .............................................................................................. 15
`
`A.
`
`B.
`
`C.
`
`D.
`
`Boulay 2004 Does Not Teach Or Suggest The Claim
`Element “Advanced [PNETs] After Failure Of Cytotoxic
`Chemotherapy” .................................................................................... 15
`
`O’Donnell Does Not Teach Or Suggest The Claim
`Element “Advanced [PNETs] After Failure Of Cytotoxic
`Chemotherapy” .................................................................................... 17
`
`Duran Does Not Teach Or Suggest The Claim Element
`“Advanced [PNETs] After Failure Of Cytotoxic
`Chemotherapy” .................................................................................... 18
`
`Tabernero Does Not Teach Or Suggest The Claim
`Element “Advanced [PNETs] After Failure Of Cytotoxic
`Chemotherapy” .................................................................................... 22
`
`VIII. A Person Of Ordinary Skill In The Art Would Not Have Had A
`Reasonable Expectation That Everolimus Would Be Effective
`In A Method Of Treating “Advanced [PNETs] After Failure Of
`Cytotoxic Chemotherapy” In View Of The Prior Art In
`Grounds 3 And 4 ............................................................................................ 24
`
`A.
`
`Boulay 2004 Does Not Teach Or Suggest That
`Everolimus Would Be Effective In A Method Of
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`B.
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`C.
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`D.
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`E.
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`F.
`
`Treating “Advanced [PNETs] After Failure Of Cytotoxic
`Chemotherapy” .................................................................................... 25
`
`O’Donnell Does Not Teach Or Suggest That Everolimus
`Would Be Effective In A Method Of Treating “Advanced
`[PNETs] After Failure Of Cytotoxic Chemotherapy” ........................ 26
`
`Duran Does Not Teach Or Suggest That Everolimus
`Would Be Effective In A Method Of Treating “Advanced
`[PNETs] After Failure Of Cytotoxic Chemotherapy” ........................ 28
`
`Tabernero Does Not Teach Or Suggest That Everolimus
`Would Be Effective In A Method Of Treating “Advanced
`[PNETs] After Failure Of Cytotoxic Chemotherapy” ........................ 29
`
`No Other Reference Cited In Connection With Grounds 3
`And 4 Teaches Or Suggests That Everolimus Would Be
`Effective In A Method Of Treating “Advanced [PNETs]
`After Failure Of Cytotoxic Chemotherapy” ........................................ 31
`
`A Person Of Ordinary Skill In The Art Would Not Have
`Had A Reasonable Expectation That Everolimus Would
`Be Effective In A Method Of Treating “Advanced
`[PNETs] After Failure Of Cytotoxic Chemotherapy” ........................ 33
`
`1.
`
`2.
`
`3.
`
`A Person Of Ordinary Skill Would Not Have
`Extrapolated The Results Reported In O’Donnell
`Or Tabernero To “Advanced [PNETS] After
`Failure Of Cytotoxic Chemotherapy” ....................................... 35
`
`A Person Of Ordinary Skill Would Not Have
`Drawn Conclusions Regarding The Efficacy Of
`Everolimus From The Preliminary Temsirolimus
`Data In Duran ............................................................................ 39
`
`A Person Of Ordinary Skill Would Have Known
`That Advanced PNETS After Failure Of Cytotoxic
`Chemotherapy Would Generally Be More
`Resistant And Harder To Treat ................................................. 41
`
`IX. A Person Of Ordinary Skill In The Art Would Not Have Had A
`Reasonable Expectation That Everolimus Would Be Effective
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`ii
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`In A Method Of Treating “Advanced [PNETs] After Failure Of
`Cytotoxic Chemotherapy” In View Of The Prior Art In
`Grounds 1 And 2 ............................................................................................ 44
`
`A. Oberg 2004 Does Not Teach Or Suggest That
`Everolimus Would Be Effective In A Method Of
`Treating “Advanced [PNETs] After Failure Of Cytotoxic
`Chemotherapy” .................................................................................... 45
`
`B.
`
`C.
`
`Boulay 2004, O’Donnell And Tabernero Do Not Teach
`Or Suggest That Everolimus Would Be Effective In A
`Method Of Treating “Advanced [PNETs] After Failure
`Of Cytotoxic Chemotherapy” .............................................................. 47
`
`A Person Of Ordinary Skill In The Art Would Not Have
`Had A Reasonable Expectation That Everolimus Would
`Be Effective In A Method Of Treating “Advanced
`[PNETs] After Failure Of Cytotoxic Chemotherapy” ........................ 48
`
`X.
`
`The Methods Of Claims 1-3 Of The ’224 Patent Have
`Demonstrated Unexpected Results ................................................................ 50
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`XI. Conclusion ..................................................................................................... 54
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`iii
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`I.
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`Introduction
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`1.
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`Challenged claims 1-3 of U.S. Patent No. 9,006,224 (“the ’224
`
`Patent”) recite methods of using everolimus monotherapy for the treatment of
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`patients with pancreatic neuroendocrine tumors (PNETs) “wherein the tumors are
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`advanced tumors after failure of cytotoxic chemotherapy.”
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`2.
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`At this preliminary stage of these proceedings, I have been asked by
`
`counsel for Novartis AG (“Novartis”) to provide my opinion on three issues: (1)
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`whether any of the prior art relied on by Dr. Mark J. Ratain in Grounds 3 and 4
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`teaches or suggests the claim element “advanced [PNETs] after failure of cytotoxic
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`chemotherapy”; (2) whether a person of ordinary skill in the art would have had a
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`reasonable expectation that everolimus would be effective in a method of treating
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`“advanced [PNETs] after failure of cytotoxic chemotherapy” in view of the art
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`cited in (a) Grounds 1 and 2 or (b) Grounds 3 and 4; and (3) whether the methods
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`of claims 1-3 of the ’224 Patent have demonstrated unexpected results.
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`3.
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`As to the first issue, in Grounds 3 and 4, Dr. Ratain relies on Boulay
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`2004, Duran, O’Donnell, and Tabernero. None of those references alone or in
`
`combination teaches or suggests the claim element “advanced [PNETs] after
`
`failure of cytotoxic chemotherapy.” Boulay 2004 reports the results of in vivo
`
`testing of everolimus against the CA20948 “rat pancreatic tumor model.” It does
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`not teach or suggest the use of everolimus for treating “advanced [PNETs] after
`
`
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`1
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`failure of cytotoxic chemotherapy.” Duran is only an abstract that describes a
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`single ongoing Phase II temsirolimus clinical trial. Dr. Ratain does not suggest
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`that all patients enrolled in the Duran clinical trial had advanced PNETs. And
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`Duran does not disclose that any of the patients had “advanced [PNETs] after
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`failure of cytotoxic chemotherapy.” O’Donnell and Tabernero each describe a
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`Phase I everolimus clinical trial in patients with “solid tumors,” but no patients
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`were reported to have advanced PNETs, and neither O’Donnell nor Tabernero
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`teaches or suggests that all patients enrolled in the Phase I trials had previously
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`failed to respond to cytotoxic chemotherapy. Because neither O’Donnell nor
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`Tabernero, nor any other reference cited by Dr. Ratain in these grounds teaches or
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`suggests the use of everolimus for the treatment of “advanced [PNETs] after
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`failure of cytotoxic chemotherapy,” this claim element is missing from the cited
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`prior art and therefore, the challenged claims of the ’224 Patent would not have
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`been obvious under Grounds 3 or 4.
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`4.
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`As to the second issue, no prior art cited in (a) Grounds 1 and 2 or (b)
`
`Grounds 3 and 4, alone or in combination, teaches or suggests the efficacy of
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`everolimus for the treatment of “advanced [PNETs] after failure of cytotoxic
`
`chemotherapy.” And a person of ordinary skill would have known that patients
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`with advanced PNETs who had previously failed treatment with cytotoxic
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`chemotherapy would generally have had a more resistant or aggressive disease,
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`2
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`and therefore would have been more difficult to treat than patients who had not
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`undergone and failed cytotoxic chemotherapy. Accordingly, a person of ordinary
`
`skill would not have had a reasonable expectation that everolimus would be
`
`effective for the treatment of “advanced [PNETs] after failure of cytotoxic
`
`chemotherapy” and therefore, the challenged claims of the ’224 Patent would not
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`have been obvious under Grounds 1 and 2 or Grounds 3 and 4.
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`5.
`
`As to the third issue, which pertains to all Grounds 1 to 4, in the Phase
`
`III RADIANT-3 clinical trial, everolimus resulted in a statistically significant
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`improvement in progression free survival (PFS) in patients with “advanced
`
`[PNETs] after failure of cytotoxic chemotherapy.” The results of the RADIANT-3
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`clinical trial have been described as “unprecedented.” The FDA approval and the
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`underlying clinical trial data from the RADIANT-3 clinical trial represent results
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`of the methods in the challenged claims of the ’224 Patent that would have been
`
`unexpected to a person of ordinary skill as of the November 2005 priority date.
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`Only O’Donnell and Tabernero report the results of any clinical testing of
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`everolimus for the treatment of non-PNET solid tumors, but only in Phase I
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`clinical trials. There is no basis in O’Donnell or Tabernero for a person of
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`ordinary skill to have reasonably expected the clinical efficacy of everolimus in the
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`treatment of patients with “advanced [PNETs] after failure of cytotoxic
`
`chemotherapy” that was demonstrated in the RADIANT-3 clinical trial. And while
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`3
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`Duran discloses preliminary results of clinical testing with temsirolimus, it does
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`not disclose any testing of everolimus, and it does not disclose that either the single
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`instance of tumor shrinkage or the stable disease occurred in any patient with
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`“advanced [PNETs] after failure of cytotoxic chemotherapy.” Dr. Ratain does not
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`provide any reasons why a person of ordinary skill would have expected the results
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`of the RADIANT-3 clinical trial. The person of ordinary skill would not have
`
`done so. In fact, prior to November 2005, it was reported that only 5% of
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`oncology drugs make it from first-in-human trials to regulatory approval.
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`6.
`
`In forming these opinions, I have considered the materials referenced
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`in this declaration, including the declaration of Dr. Ratain (Ex. 1003). My
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`opinions are based on those materials and my education, knowledge and
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`experience as a practicing physician and as a professor of medicine.
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`II. Qualifications
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`7.
`
`I am a board certified oncologist and the Director of the Dana-Farber
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`Cancer Institute (“DFCI”)/Brigham and Women’s Hospital Program in
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`Neuroendocrine and Carcinoid Tumors in Boston, Massachusetts. The Program
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`evaluates and treats approximately 200 new neuroendocrine tumor patients each
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`year. Through this work, I have played a leading role in advancing the
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`understanding of the biology of and identifying treatments for neuroendocrine
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`tumors. I also am a Professor of Medicine at the Harvard Medical School, where I
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`4
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`teach postgraduate courses in both general internal medicine and gastrointestinal
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`malignancies.
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`8.
`
`I obtained my B.A. in molecular biology from Princeton University in
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`1987, my Doctor of Medicine degree from the University of California, San
`
`Francisco School of Medicine in 1992, and my Master of Medical Science
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`(M.M.Sc.) degree from Harvard Medical School in 2007. I completed my
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`postdoctoral training, including an internship and residency in internal medicine at
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`Brigham and Women’s Hospital and a fellowship in oncology at DFCI. Since
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`1997, I have served in active teaching roles in the Harvard Medical School
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`community, including regularly leading conferences at DFCI and providing annual
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`lectures on neuroendocrine tumors in the Cancer Medicine and Hematology course
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`at Harvard. In addition, I have supervised and trained numerous medical residents
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`and medical oncology fellows at DFCI.
`
`9.
`
`I currently chair several committees concerning the research and
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`treatment of neuroendocrine tumors, including: the National Comprehensive
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`Cancer Network (“NCCN”) Neuroendocrine Tumor Guidelines Panel; and the
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`Dana-Farber Gastrointestinal Cancer Center Clinical Information and Biospecimen
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`User Committee. In addition, I have chaired the National Cancer Institute’s
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`Neuroendocrine Tumor Task Force and the North American Neuroendocrine
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`Tumor Society (“NANETS”), and I have been selected as a member of the
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`
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`5
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`Gastrointestinal Cancer Core Committee of the Cancer and Leukemia Group B
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`(“CALGB”) and a member of the External Advisory Board for the European
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`Neuroendocrine Society (“ENETS”).
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`10.
`
`I currently serve as editor of the Neuroendocrine Tumor Section of
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`UpToDate in Medicine and previously served on the editorial board of the Journal
`
`of Clinical Oncology. I am an ad hoc reviewer for several prominent professional
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`journals including the Journal of Clinical Oncology, Cancer, Clinical Cancer
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`Research, Endocrine Related Cancer, and the New England Journal of Medicine.
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`11. Over the course of my career, I have received a number of
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`professional honors, including: the Young Investigator Award from the American
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`Society of Clinical Oncology; the George Canellos Award for Contributions to
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`Clinical Research; the Kenneth E. Schwarz Center Compassionate Care Giver
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`Award; the Lee Nadler Extra Mile Award from DFCI; and the prestigious Ruth
`
`Brufsky Award for Excellence in Clinical Research on Pancreatic Cancer from the
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`University of Pittsburgh School of Medicine.
`
`12.
`
`I have been Principal Investigator or Co-Investigator of over 30
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`clinical trials, including more than 25 involving neuroendocrine tumors. I have
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`published more than 100 peer-reviewed publications, including the results of a
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`number of clinical trials investigating treatments for PNETs. In addition, I have
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`6
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`authored more than 30 reviews, manuscripts, chapters, and guidelines on the
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`diagnosis and treatment of cancer, especially relating to neuroendocrine tumors.
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`13. Finally, I have given over 90 invited lectures, predominately on the
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`diagnosis and management of neuroendocrine tumors and I have presented on this
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`topic at a number of professional meetings including meetings of the American
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`Society of Clinical Oncology (“ASCO”), the American Association for Cancer
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`Research (“AACR”), NANETS, and ENETS.
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`14. My curriculum vitae is attached to this declaration as Exhibit 2002.
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`III. Legal Principles
`
`15. Counsel for Novartis has informed me that the claims of the ’224
`
`Patent are “obvious” only if their subject matter, as a whole, would have been
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`obvious to a person of ordinary skill in the art as of the invention date.
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`16.
`
`I understand that in assessing obviousness the Patent Trial and Appeal
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`Board (the “Board”) interprets the terms in patent claims according to their
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`broadest reasonable construction in light of the specification of the patent. Absent
`
`any special definitions, claim terms are assigned their ordinary and customary
`
`meaning, as would be understood by a person of ordinary skill in the art at the time
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`of the invention, in the context of the entire patent disclosure.
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`17.
`
`I understand the Board will determine whether an invention is obvious
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`by assessing: (i) the level of ordinary skill in the art; (ii) the scope and content of
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`the prior art; (iii) the differences between the prior art and subject matter claimed;
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`and (iv) the existence of any objective evidence of non-obviousness, such as
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`unexpected results.
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`18. When considering the differences between the prior art and the subject
`
`matter claimed, I understand that the Board will assess whether each element of the
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`challenged claim is taught or suggested by the prior art.
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`19.
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`I further understand that the Board will consider whether the prior art
`
`would have provided a person of ordinary skill with a motivation to combine the
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`teachings of the references that the Petitioner has relied upon to arrive at the
`
`claimed invention with a reasonable expectation of successfully practicing the
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`claimed method.
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`20.
`
`I also understand that the Board will consider the existence of any
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`objective evidence of non-obviousness (also called “secondary considerations”)
`
`where there is a causal relationship or “nexus” between the objective evidence and
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`the claimed invention.
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`21.
`
`I understand that unexpected results of a claimed method of use are
`
`one type of objective evidence that can show that a claimed invention would not
`
`have been obvious. I understand that the Board will consider whether the claimed
`
`method yields results that a person of ordinary skill in the art, as of the invention
`
`date, would have found surprising or unexpected. To be evidence of non-
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`8
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`obviousness, the results must be shown to be unexpected as compared to the
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`closest prior art. However, there is no requirement that the claimed method’s
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`results be fully known as of the invention date, or that the patent contain all of the
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`work done in studying the claimed method.
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`22. Finally, I also understand that it is improper in the obviousness
`
`analysis to use hindsight knowledge of the claimed invention itself.
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`IV. Person Of Ordinary Skill In The Art
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`23. For the purposes of this declaration, I have been asked to consider the
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`state of the art as of November 21, 2005 and like Dr. Ratain, to analyze the three
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`obviousness issues identified above (in paragraph 2) as of that date. (Ex. 1003,
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`Ratain Decl. at ¶ 17.) I have also analyzed the obviousness issues (in paragraph 2)
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`from the perspective of a person of ordinary skill in the art and for the purposes of
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`this declaration, I have adopted the definition of such a person provided by Dr.
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`Ratain. (Ex. 1003, Ratain Decl. at ¶ 21.)
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`V.
`
`State Of The Art
`
`24.
`
`“Neuroendocrine tumors [“NETs”] are generally classified into two
`
`groups: carcinoid tumors or [PNETs].” (Ex. 2013, Kulke 2003 at 1133.)
`
`Carcinoid tumors may arise from multiple different organs and are classified
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`according to their site of origin, e.g., foregut (lungs, bronchi, or stomach), midgut
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`(small intestine, appendix, and proximal large bowel) or hindgut (distal colon and
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`rectum). (Ex. 2020, Kulke 1999 at 858.) PNETs are a type of NET that arise from
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`endocrine cells, i.e., hormone-producing cells, in the pancreas.1 (Ex. 2018, WHO
`
`at 177.)
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`25. While all PNETs are neuroendocrine tumors, not all neuroendocrine
`
`tumors are PNETs and there are substantial differences between PNETs and
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`carcinoid tumors, i.e., between the different types of neuroendocrine tumors. By
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`November 2005, it was known that PNETs and carcinoid tumors caused “diverse”
`
`clinical symptoms. (Ex. 2013, Kulke 2003 at 1133.) For example, carcinoid
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`tumors often secrete serotonin and other hormones into the blood that cause
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`carcinoid syndrome, the manifestations of which are flushing, wheezing, diarrhea,
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`and eventual right-sided valvular heart disease. (Ex. 2020, Kulke 1999 at 858.)
`
`PNETs, on the other hand, may be nonfunctional, meaning that they do not
`
`produce hormones that result in overt clinical symptoms, or functional, meaning
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`that they produce hormones that do result in a clinical syndrome, e.g., gastric
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`ulcers in the case of gastinomas (a type of PNET) or severe secretory diarrhea in
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`1 The cells of the endocrine pancreas secrete hormones, e.g., insulin or glucagon,
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`directly into the blood. (Ex. 2003, Seeley at 585.) The endocrine cells are distinct
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`from the exocrine cells of the pancreas, which secrete digestive enzymes, e.g.,
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`amylase, lipase and trypsin, via ducts into the small intestine. (Ex. 2003, Seeley at
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`585.)
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`10
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`the case of VIPomas (another type of PNET). (Ex. 2018, WHO at 177; Ex. 2013,
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`Kulke 2003 at 1134 (Table 110-1).) In addition, it was known that carcinoid
`
`tumors and PNETs responded differently to pharmacotherapies. (Ex. 2010, Pazdur
`
`at 311 (reporting that PNETs were known to be “more sensitive [i.e., more likely to
`
`respond] to chemotherapy than are carcinoid tumors”); Ex. 1027, Oberg 2004 at 57
`
`(noting that “differences in the molecular genetics and tumor biology play a role
`
`for the diagnosis and treatment of [NETs]”).)
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`26. NETs may pursue a clinical course that is either benign or malignant,
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`i.e., have the potential to spread to other areas of the body. Malignant NETs have
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`been referred to as neuroendocrine carcinomas (NECs) and include both malignant
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`PNETs and malignant carcinoid tumors.
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`27. PNETs that had spread to nearby areas (locally advanced) or more
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`distant areas of the body (metastatic) and were generally unresectable (i.e., they
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`would not be cured by surgery) were referred to as “advanced” PNETs. (Ex. 1023,
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`Moertel at 520 (describing patients with “advanced” PNETs (referred to as islet-
`
`cell carcinomas) as having proof of “unresectable or metastatic” disease).)
`
`28. However, the term “advanced” is not specific to PNETs. (Ex. 2005,
`
`Laughlin Cancer Glossary at 4 (defining “advanced cancer” as “[a] general term
`
`describing the stages of cancer in which the disease has spread from the primary
`
`site to other parts of the body. When the cancer has spread only to the surrounding
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`11
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`areas, it is called locally advanced. If it has spread further by traveling through the
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`bloodstream or lymph system, it is called metastatic.” A person of ordinary skill
`
`would have known that when the tumor has spread it is generally unresectable.).)
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`Dr. Ratain agrees that “[a]s used by those of skill in the field of oncology, an
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`‘advanced tumor’ is a tumor that is unresectable or metastatic.” (Ex. 1003, Ratain
`
`Decl. at ¶ 59.) Dr. Ratain does not suggest that “advanced” means that the tumor
`
`had previously failed to respond to cytotoxic chemotherapy. And as discussed
`
`further below (paragraphs 33-34), the ’224 Patent also uses the term “advanced”
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`consistently with its ordinary meaning in the art.
`
`29. The types of NETs and their relationships are summarized below:
`
`Neuroendocrine
`tumors (NETs)
`
`Carcinoid tumors
`
`PNETs
`
`Benign carcinoid
`tumors
`
`Malignant carcinoid
`tumors (carcinomas)
`
`Benign PNETs
`
`Malignant PNETs
`(carcinomas)
`
`Localized carcinoid
`tumors
`
`Advanced
`carcinoid tumors
`(i.e., locally
`advanced,
`metastatic or
`unresectable)
`
`Localized PNETs
`
`Advanced PNETs
`(i.e., locally
`advanced,
`metastatic or
`unresectable)
`
`Prior to failure of
`cytotoxic
`chemotherapy
`
`After failure of
`cytotoxic
`chemotherapy
`
`Prior to failure of
`cytotoxic
`chemotherapy
`
`After failure of
`cytotoxic
`chemotherapy
`
`
`
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`12
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`VI. Summary Of The ’224 Patent
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`30. The ’224 Patent is entitled “Neuroendocrine Tumor Treatment.”
`
`Claim 1 of the ’224 Patent recites “[a] method for treating pancreatic
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`neuroendocrine tumors, comprising administering to a human subject in need
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`thereof a therapeutically effective amount of 40-O-(2-hydroxyethyl)-rapamycin
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`[everolimus] as a monotherapy and wherein the tumors are advanced tumors after
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`failure of cytotoxic chemotherapy.” Claim 2 of the ’224 Patent recites “[t]he
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`method of claim 1, wherein a unit dose of [everolimus] is 10 mg/day.” And claim 3
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`of the ’224 Patent recites “[t]he method of claim 1, wherein the tumor is islet cell
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`tumor.”
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`31. The ’224 Patent specification explains that PNETs are tumors that
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`arise in the pancreas and “include islet cell tumors, APUDomas, insulinomas,
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`glucagonomas, nonfunctioning pancreatic NETs, pancreatic NETs associated with
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`hypercalcemia, gastrinomas, VIPomas, somatostatinomas, GRFomas.” (Ex. 1001,
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`’224 Patent at col. 2 ll. 54-58, col. 8 ll. 13-17.)
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`32. Consistent with the state of the art in November 2005 (see paragraphs
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`24-25), the specification of the ’224 Patent clearly distinguishes “pancreatic
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`neuroendocrine tumors” or PNETs from carcinoid tumors, and states that carcinoid
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`tumors are “a special type of tumor” that originates in “the foregut (e.g., bronchial,
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`pulmonary or gastric carcinoid), midgut (e.g., small intestine or appendiceal
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`carcinoid), or hindgut (e.g., rectal carcinoid).” (Ex. 1001, ’224 Patent at col. 2 ll.
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`41-67, col. 2 ll. 13-19, col. 7 ll. 49-51.)
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`33. The ’224 Patent specification further indicates that “advanced”
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`PNETs refer to tumors that are “metastatic,” which means that they have spread
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`outside of the pancreas, or “unresectable,” which means that they cannot be cured
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`by surgery, for example, because they have spread to nearby areas (locally
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`advanced). (Ex. 1001, ’224 Patent at col. 26 ll. 57-58.) The ’224 Patent
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`specification also states that “[m]ost [PNETs] are overtly malignant at the time of
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`diagnosis, and 60% or more present with liver metastases.” (Ex. 1001, ’224 Patent
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`at col. 3 ll. 2-4.) If a patient “presents” with liver metastases it means his or her
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`PNET has spread to the liver at the time of diagnosis. Because a patient can have
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`an advanced PNET at the time of diagnosis, i.e., before he or she has received any
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`treatment, the specification confirms that the ’224 Patent uses the term “advanced”
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`consistently with its ordinary meaning in the art, and that the term does not mean
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`the tumors have already failed cytotoxic chemotherapy.
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`34. Consistent with my opinion, the ’224 Patent describes a clinical trial
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`in patients with “advanced (metastatic or unresectable) [PNETs] after failure of
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`cytotoxic chemotherapy.” (Ex. 1001, ’224 Patent at col. 26 ll. 56-60.) If the term
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`“advanced” meant that the PNET patients had previously failed to respond to
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`cytotoxic chemotherapy, it would not have been necessary to specify that the
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`patients were enrolled “after failure of cytotoxic chemotherapy.”
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`VII. No Prior Art In Grounds 3 Or 4 Teaches
`Or Suggests The Claim Element “Advanced
`[PNETs] After Failure Of Cytotoxic Chemotherapy”
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`35.
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`In Ground 3, Dr. Ratain opines that claims 1-3 of the ’224 Patent are
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`rendered obvious by Boulay 2004 in view of O’Donnell and Duran. (Ex. 1003,
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`Ratain Decl. at ¶¶ 162, 169, 172.) In Ground 4, Dr. Ratain additionally relies on
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`Tabernero in support of his opinion that claim 2 of the ’224 Patent is obvious. (Ex.
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`1003, Ratain Decl. at ¶ 176.) No prior art cited by Dr. Ratain in Grounds 3 or 4
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`either alone or in combination teaches or suggests the use of everolimus for the
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`treatment of “advanced [PNETs] after failure of cytotoxic chemotherapy,” as
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`required by the challenged claims. Accordingly, that claim element is missing
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`from the prior art relied on by Dr. Ratain in Grounds 3 and 4 and therefore, the
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`challenged claims of the ’224 Patent would not have been obvious.
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`A. Boulay 2004 Does Not Teach Or Suggest The Claim Element
`“Advanced [PNETs] After Failure Of Cytotoxic Chemotherapy”
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`36. Boulay 2004 reports the results of testing to determine the in vivo
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`antitumor activity of daily or weekly administered everolimus against cells from
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`the CA20948 “rat pancreatic tumor model” that had been injected into rats
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`subcutaneously (s.c.), i.e., under the skin. (Ex. 1005, Boulay 2004 at 252, 253.)
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`While Boulay 2004 states that everolimus “[was] being clinically developed . . . as
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`a novel therapeutic in the fight against human cancer” (Ex. 1005, Boulay 2004 at
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`252), it does not report the results of any clinical testing of everolimus. Boulay
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`2004 also does not report the results of any testing of everolimus against
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`“advanced [PNETs] after failure of cytotoxic chemotherapy” or suggest the use of
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`everolimus in such a setting. Dr. Ratain opines only that the CA20948 cell line
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`used in Boulay 2004 is a model for PNETs, he does not suggest that it is model for
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`“advanced [PNETs] after failure of cytotoxic chemotherapy.”2 (Ex. 1003,
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`Ratain Decl. at ¶¶ 112, 117, 137, 163, 167.) It is not. As discussed further below
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`2 Boulay 2004 describes the CA20948 cell line as a “rat model of pancreatic
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`cancer.” (Ex. 1005, Boulay 2004 at 254, 258.) Pancreatic cancer generally refers
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`to pancreatic adenocarcinomas, which are distinct from PNETs. (Ex. 1003, Ratain
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`Decl. at ¶ 54.) While I disagree with Dr. Ratain that the CA20948 cell line is a
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`model for PNETs or that activity in vivo against the CA20948 cell line would
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`reasonably predict efficacy against PNETs in vivo or in humans, I have not been
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`asked to address that issue at this preliminary stage of the proceedings and have
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`only considered whether Boulay 2004 teaches or suggests the claim element
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`“advanced [PNETs] after failure of cytotoxic chemotherapy” or would have
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`provided a reasonable expectation that everolimus would be effective in such a
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`setting.
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`(paragraphs 75-76), a person of ordinary skill would have known that “advanced
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`[PNETs] after failure of cytotoxic chemotherapy” are generally more aggressive
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`and less likely to respond to subsequent therapies and thus, the alleged disclosure
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`of a model for PNETs in Boulay 2004 is not a disclosure of a model for
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`“advanced [PNETs] after failure of cytotoxic chemotherapy.”
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`B. O’Donnell Does Not Teach Or Suggest The Claim Element
`“Advanced [PNETs] After Failure Of Cytotoxic Chemotherapy”
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`37. O’Donnell is an abstract that describes a single Phase I everolimus
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`clinical trial in solid tumors of the liver (hepatocellular carcinoma), soft-tissue
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`(fibrosarcoma), lung (non-small-cell lung cancer (“NSCLC”)), and other
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`unspecified tissues. (Ex. 1029, O’Donnell at 803.) O’Donnell does not disclose
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`that any of the patients in the clinical trial had PNETs or advanced tumors, let
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`alone advanced PNETs. O’Donnell also does not disclose whether any of the
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`tumors included in the study had previously failed to respond to cytotoxic
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`chemotherapy. (Ex. 1029, O’Donnell at 803.) Dr. Ratain opines that O’Donnell
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`discloses “everolimus administered to human patients with solid tumors,” but Dr.
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`Ratain does not contend tha