UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`ROXANE LABORATORIES, INC.,
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`Petitioner,
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`v.
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`NOVARTIS AG,
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`Patent Owner.
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`
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`Case IPR2016-01461
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`Patent No. 9,006,224
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`EXPERT DECLARATION OF DR. MATTHEW H. KULKE
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`NOVARTIS EXHIBIT 2001
`Roxane v. Novartis, 2016-01461
`Page 1 of 29
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
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`ROXANE LABORATORIES, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-01461
`
`Patent No. 9,006,224
`
`
`
`
`
`EXPERT DECLARATION OF DR. MATTHEW H. KULKE
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`NOVARTIS EXHIBIT 2001
`Roxane v. Novartis, 2016-01461
`Page 1 of 29
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`Table Of Contents
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`I.
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`Introduction ...................................................................................................... 1
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`II. Qualifications ................................................................................................... 3
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`IV. Legal Principles ............................................................................................... 6
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`V.
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`Person Of Ordinary Skill In The Art ............................................................... 7
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`VI. State Of The Art ............................................................................................... 8
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`VIII. Summary Of The ’224 Patent ........................................................................ 11
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`IX. No Prior Art Teaches Or Suggests The Claim Element
`“Advanced [PNETs] After Failure Of Cytotoxic
`Chemotherapy” .............................................................................................. 12
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`A.
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`Tabernero Does Not Teach Or Suggest The Claim
`Element “Advanced [PNETs] After Failure Of Cytotoxic
`Chemotherapy” .................................................................................... 13
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`B. No Other Cited Art Teaches Or Suggests The Claim
`Element “Advanced [PNETs] After Failure Of Cytotoxic
`Chemotherapy” .................................................................................... 15
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`X. 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 ................................... 18
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`XI. Conclusion ..................................................................................................... 27
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`I.
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`Introduction
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`1.
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`Challenged claims 1-2 of U.S. Patent No. 9,006,224 (“the ’224
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`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
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`counsel for Novartis AG (“Novartis”) to provide my opinion on two issues: (1)
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`whether any of the prior art relied on by Dr. Kenneth Ho-Ming Yu teaches or
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`suggests the claim element “advanced [PNETs] after failure of cytotoxic
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`chemotherapy”; and (2) whether a person of ordinary skill in the art would have
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`had a reasonable expectation that everolimus would be effective in a method of
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`treating “advanced [PNETs] after failure of cytotoxic chemotherapy.”
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`3.
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`As to the first issue, no cited prior art alone or in combination teaches
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`or suggests the claim element “advanced [PNETs] after failure of cytotoxic
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`chemotherapy.” Dr. Yu relies only on Tabernero for disclosure of the “after
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`failure of cytotoxic chemotherapy” aspect of this claim element. Tabernero
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`describes a single Phase I everolimus clinical trial in patients with “advanced solid
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`tumors,” but no patients were reported to have advanced PNETs and Tabernero
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`does not teach or suggest that all patients enrolled in the Phase I study had
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`previously failed to respond to cytotoxic chemotherapy. Because neither
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`Tabernero nor any other reference cited by Dr. Yu teaches or suggests the use of
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`everolimus for the treatment of “advanced [PNETs] after failure of cytotoxic
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`chemotherapy,” this claim element is missing from the cited prior art and
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`therefore, the challenged claims of the ’224 Patent would not have been obvious.
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`4.
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`As to the second issue, no cited prior art alone or in combination
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`teaches or suggests the efficacy of everolimus for the treatment of “advanced
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`[PNETs] after failure of cytotoxic chemotherapy.” A person of ordinary skill
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`would have known that patients with advanced PNETs who had previously failed
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`treatment with cytotoxic chemotherapy would generally have had a more resistant
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`or aggressive disease, and therefore would have been more difficult to treat than
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`patients who had not undergone and failed cytotoxic chemotherapy. Accordingly,
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`a person of ordinary skill would not have had a reasonable expectation that
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`everolimus would be effective for the treatment of “advanced [PNETs] after
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`failure of cytotoxic chemotherapy” and therefore, the challenged claims of the
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`’224 Patent would not have been obvious for this additional reason.
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`5.
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`In forming these opinions, I have considered the materials referenced
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`in this declaration, including the declaration of Dr. Yu. My opinions are based on
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`those materials and my education, knowledge and experience as a practicing
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`physician and as a professor of medicine.
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`II. Qualifications
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`6.
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`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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`teach postgraduate courses in both general internal medicine and gastrointestinal
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`malignancies.
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`7.
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`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
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`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.
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`8.
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`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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`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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`9.
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`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
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`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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`10. 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
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`Brufsky Award for Excellence in Clinical Research on Pancreatic Cancer from the
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`University of Pittsburgh School of Medicine.
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`11.
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`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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`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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`12. 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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`13. My curriculum vitae is attached to this declaration as Exhibit 2002.
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`IV. Legal Principles
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`14. Counsel for Novartis has informed me that the claims of the ’224
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`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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`15.
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`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
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`any special definitions, claim terms are assigned their ordinary and customary
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`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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`16.
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`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.
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`17. When considering the differences between the prior art and the subject
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`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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`18.
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`I further understand that the Board will consider whether the prior art
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`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
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`claimed invention with a reasonable expectation of successfully practicing the
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`claimed method.
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`19. Finally, I also understand that it is improper in the obviousness
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`analysis to use hindsight knowledge of the claimed invention itself.
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`V.
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`Person Of Ordinary Skill In The Art
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`20. For the purposes of this declaration, I have been asked to consider the
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`state of the art as of November 20, 2006 and like Dr. Yu, to analyze the two
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`obviousness issues identified above (in paragraph 2) as of that date. (Ex. 1003, Yu
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`Decl. at ¶ 22.) However, I understand that Novartis has reserved its right to argue
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`that the ’224 Patent is entitled to its earlier priority date of November 21, 2005,
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`should Roxane Laboratories, Inc. or Dr. Yu seek to rely on any patents or
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`publications dated between November 21, 2005 and November 20, 2006. My
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`opinions in this declaration would be the same if I analyzed the obviousness issues
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`as of November 21, 2005.
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`21. For the purposes of this declaration, I do not dispute that a person of
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`ordinary skill as of November 20, 2006 would have had: (1) a Ph.D. in biology,
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`biochemistry, pharmaceutical sciences, molecular biology, cancer biology, or other
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`biological sciences; and/or (2) a medical degree, as well as experience conducting
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`preclinical, clinical, and/or laboratory research relating to cancers of the
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`neuroendocrine system, including PNETs. (Ex. 1003, Yu Decl. at ¶ 18.) I also
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`accept that, to the extent necessary, the person of ordinary skill would also have
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`collaborated with persons having ordinary skill in areas pertinent to the above
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`subject matter, including, for example, pharmacologists, formulators, and
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`biochemists. (Ex. 1003, Yu Decl. at ¶ 18.)
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`22. While I disagree that a person of ordinary skill would have had
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`experience relating to rapamycin and it analogs, or intracellular signaling
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`pathways, because that assumes that a person of ordinary skill would have been
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`interested in the use of rapamycin or one of its analogs and/or a targeted therapy
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`for the treatment for PNETs, I have been asked to adopt this aspect of Dr. Yu’s
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`definition of a person of ordinary skill in the art for the purposes of this
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`declaration.
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`VI. State Of The Art
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`23. PNETs are a type of neuroendocrine tumor (“NET”) that arise from
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`the endocrine cells, i.e., hormone-producing cells, in the pancreas.1 (Ex. 1010,
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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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`Doran at 5.) The prior art relied on by Dr. Yu recognizes that “[PNETs] are
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`relatively rare tumours, often with a slow evolution, that are only diagnosed once
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`they have widespread metastases.” (Ex. 1013, McStay at 48-49.) Another prior art
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`reference on which Dr. Yu relies reported that approximately 60-70%, two-thirds,
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`13-52%, and 50% of patients with glucagonomas, somatostatinomas, gastrinomas,
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`and pancreatic VIPomas (all of which are types of PNETs) were metastatic at the
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`time of diagnosis, respectively. (Ex. 1012, WHO 2004 at 188, 190, 193, 195.)
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`24. As of November 2006 (and before), PNETs that had spread to nearby
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`areas (locally advanced) or more distant areas of the body (metastatic) and were
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`generally unresectable (i.e., they would not be cured by surgery) were referred to
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`as “advanced” PNETs. (Ex. 2004, Moertel at 520 (describing patients with
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`“advanced” PNETs (referred to as islet-cell carcinomas) as having proof of
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`“unresectable or metastatic” disease).) Logically, because most PNETs were
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`metastatic (i.e., advanced) at the time of diagnosis, they could not have been
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`previously treated with cytotoxic chemotherapy.
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`25. However, the term “advanced” is not specific to PNETs. (Ex. 2005,
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`Laughlin Cancer Glossary at 4 (defining “advanced cancer” as “[a] general term
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`describing the stages of cancer in which the disease has spread from the primary
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`site to other parts of the body. When the cancer has spread only to the surrounding
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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
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`would have known that when the tumor has spread it is generally unresectable.).)
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`26. As of November 2006 (and before), the term “advanced” did not mean
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`that that the tumor had previously failed to respond to cytotoxic chemotherapy.
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`(Ex. 1013, McStay at 45 (discussing “Antitumor Treatment in Patients with
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`Advanced Disease” and one study observing “metastatic” gastrinomas (a type of
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`PNET) in “patients who had not received antitumor treatment”); Ex. 2006, Hewitt
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`and Yu at 428 (“[M]ost patients with pancreatic cancer have locally advanced or
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`metastatic disease at the time of presentation,” i.e., at the time of diagnosis, before
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`any treatment is received.); Ex. 2007, Yu et al. (“[B]ecause [pancreatic cancer] is
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`usually advanced at presentation, only 10% to 20% of patients are eligible for
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`attempted curative resection.”).)
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`27. As discussed further below (paragraph 30), the ’224 Patent uses the
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`term “advanced” consistently with its ordinary meaning in the art.
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`VIII. Summary Of The ’224 Patent
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`28. The ’224 Patent is entitled “Neuroendocrine Tumor Treatment.”
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`Claim 1 of the ’224 Patent claims “[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 claims “[t]he
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`method of claim 1, wherein a unit dose of [everolimus] is 10 mg/day.”
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`29. 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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`30. 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. Consistent with my
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`opinion, the ’224 Patent describes a clinical trial in patients with “advanced
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`(metastatic or unresectable) [PNETs] after failure of cytotoxic chemotherapy.”
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`(Ex. 1001, ’224 Patent at col. 26 ll. 56-60.) If the term “advanced” meant that the
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`PNET patients had previously failed to respond to cytotoxic chemotherapy, it
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`would not have been necessary to specify that the patients were enrolled “after
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`failure of cytotoxic chemotherapy.”
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`IX. No Prior Art Teaches Or Suggests The Claim Element
`“Advanced [PNETs] After Failure Of Cytotoxic Chemotherapy”
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`31. No prior art cited by Dr. Yu either alone or in combination 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,” as required by the challenged claims.
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`Accordingly, that claim element is missing from the prior art relied on by Dr. Yu
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`and therefore, the challenged claims of the ’224 Patent would not have been
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`obvious.
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`A. Tabernero Does Not Teach Or Suggest The Claim Element
`“Advanced [PNETs] After Failure Of Cytotoxic Chemotherapy”
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`32. Dr. Yu relies only on Tabernero (Ex. 1006) for disclosure of the “after
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`failure of cytotoxic chemotherapy” aspect of the challenged claims. (Ex. 1003, Yu
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`Decl. at ¶¶ 37-38, 44-45.) Tabernero is an abstract that describes a single Phase I
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`everolimus clinical trial in patients having advanced solid tumors of the colon,
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`kidney (renal cell carcinoma), breast, and other unspecified tissues. (Ex. 1006,
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`Tabernero at 193S.) Tabernero does not disclose that any of the patients in the
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`clinical trial had advanced PNETs. While it states that the tumors were
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`“advanced,” Tabernero does not teach or suggest that any of the tumors had
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`previously failed to respond to cytotoxic chemotherapy. (Ex. 1006 at 193S.)
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`33. As discussed above, the term “advanced” used in Tabernero does not
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`refer to tumors that have already failed cytotoxic chemotherapy. Rather,
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`“advanced” is a general term used by those in the art to describe tumors that have
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`spread to nearby areas (locally advanced) or more distant areas of the body
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`(metastatic) and are generally unresectable (i.e., they cannot be cured by surgery).
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`(See paragraphs 24-26.) The prior art relied on by Dr. Yu recognizes that most
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`PNETs were metastatic (i.e., advanced) at the time of diagnosis, and as such, they
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`could not have been previously treated with cytotoxic chemotherapy. (See
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`paragraphs 23-24.) And papers authored by Dr. Yu recognize that other types of
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`tumors, for example, pancreatic adenocarcinomas are “usually advanced at
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`presentation,” i.e., diagnosis, and as such, could not have been previously treated
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`with cytotoxic chemotherapy. (See paragraph 26.)
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`34. A person of ordinary skill would not have assumed that all of the
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`“advanced solid tumors” in the Phase I study described by Tabernero had
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`previously failed to respond to cytotoxic chemotherapy because he or she would
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`have known that cytotoxic chemotherapy was not always used to treat all types of
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`tumors. For example, one of the tumors mentioned by Tabernero, renal cell
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`carcinoma, was known to be generally resistant to cytotoxic chemotherapy; such
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`patients could readily have been enrolled in the Tabernero Phase I study without
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`having been previously treated with cytotoxic chemotherapy. (Ex. 2008, Motzer at
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`409 (“Studies continue to show that renal cell carcinoma is resistant to cytotoxic
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`chemotherapy.”).)
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`35. Accordingly, there is no basis in Tabernero to conclude that the
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`advanced solid tumors enrolled in the study were all treated with everolimus after
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`failure of cytotoxic chemotherapy, let alone that any of the tumors were advanced
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`PNETs that had previously failed to respond to cytotoxic chemotherapy.
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`B. No Other Cited Art Teaches Or Suggests The Claim Element
`“Advanced [PNETs] After Failure Of Cytotoxic Chemotherapy”
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`36. None of the other references relied on by Dr. Yu in his discussion of
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`the alleged obviousness of claims 1-2 of the ’224 Patent teaches or suggests the
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`claim element “advanced [PNETs] after failure of cytotoxic chemotherapy.”
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`37. First, the ’541 Publication (Ex. 1005) mentions “tumors involving the
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`… pancreas” in the definition of “solid tumors” but only among a very long list of
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`tumor types. (Ex. 1005, ’541 Publication at [0017].) It does not report the results
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`of any testing of everolimus against advanced PNETs after failure of cytotoxic
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`chemotherapy or suggest the use of everolimus in such a setting. While Dr. Yu
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`notes that the ’541 Publication includes testing on the CA20948 pancreatic cell line
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`(Ex. 1005, ’541 Publication at [0088]) and contends that the CA20948 pancreatic
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`cell line was a model for evaluating PNETs, Dr. Yu does not suggest that the
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`CA20948 pancreatic cell line is a model for “advanced [PNETs] after failure of
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`cytotoxic chemotherapy.” 2 (Ex. 1003, Yu Decl. at ¶ 36.) As discussed further
`
`below (paragraphs 52-54), a person of ordinary skill would have known that
`
`“advanced [PNETs] after failure of cytotoxic chemotherapy” are more aggressive
`
`and less likely to respond to subsequent therapies and thus, the alleged disclosure
`
`of a model for PNETs in the ’541 Publication is not a disclosure of a model for
`
`“advanced [PNETs] after failure of cytotoxic chemotherapy.”
`
`38. Second, von Wichert (Ex. 1007) is a basic science paper studying the
`
`role of insulin-like growth factor (IGF-1) on the in vitro growth of the
`
`chemotherapy-naïve BON cell line (Ex. 1030, Evers at 304 (reporting that the
`
`originating tumor specimen for the BON cell line was obtained from a patient who
`
`had “not received any interventional treatment”)). (Ex. 1007, von Wichert at
`
`2 The CA20948 pancreatic cell line is derived from a pancreatic adenocarcinoma,
`
`which is a distinct type of tumor from a PNET. While I disagree with Dr. Yu that
`
`the CA20948 cell line is a model for PNETs or that activity in vivo against the
`
`CA20948 cell line would have reasonably predicted efficacy against PNETs in
`
`vivo or in humans, I have not been asked to address that issue at this preliminary
`
`stage of the proceedings and have only considered whether the ’541 Publication
`
`teaches or suggests the claim element “advanced [PNETs] after failure of
`
`cytotoxic chemotherapy” or would have provided a reasonable expectation that
`
`everolimus would be effective in such a setting.
`
`
`
`
` 16
`
`NOVARTIS EXHIBIT 2001
`Roxane v. Novartis, 2016-01461
`Page 18 of 29
`
`
`
`
`
`4573.) von Wichert does not report any testing of everolimus or suggest the use of
`
`everolimus for the treatment of “advanced [PNETs] after failure of cytotoxic
`
`chemotherapy.” While Dr. Yu contends that BON cells are a useful model to
`
`study the biology of PNETs in vitro and that a POSA would have reasonably
`
`expected rapamycin “to inhibit the proliferation of PNET cells,” Dr. Yu does not
`
`suggest that von Wichert discloses a model for “advanced [PNETs] after failure
`
`of cytotoxic chemotherapy.” 3 (Ex. 1003, Yu Decl. at ¶ 40.) It does not.
`
`39. Third, Dr. Yu contends that Dutcher (Ex. 1008) discloses that
`
`rapamycin and everolimus are both mTOR inhibitors and inhibit tumor
`
`proliferation through the same mechanism. (Ex. 1003, Yu Decl. at ¶ 41.) But Dr.
`
`Yu does not contend that Dutcher teaches or suggests the use of everolimus for the
`
`treatment of “advanced [PNETs] after failure of cytotoxic chemotherapy.” (Ex.
`
`1003, Yu Decl. at ¶ 41.) It does not.
`
`3 While I disagree with Dr. Yu that in vitro activity against the BON cell line
`
`would reasonably predict efficacy against PNETs in vivo or in humans, I have not
`
`been asked to address that issue at this preliminary stage of the proceedings and
`
`have only considered whether von Wichert teaches or suggests the claim element
`
`“advanced [PNETs] after failure of cytotoxic chemotherapy” or would have
`
`provided a reasonable expectation that everolimus would be effective in such a
`
`setting.
`
`
`
`
` 17
`
`NOVARTIS EXHIBIT 2001
`Roxane v. Novartis, 2016-01461
`Page 19 of 29
`
`
`
`
`
`40. Finally, Dr. Yu contends that the ’772 Patent (Ex. 1009) discloses that
`
`everolimus has certain improved properties over rapamycin. (Ex. 1003, Yu Decl.
`
`at ¶ 42.) But Dr. Yu does not contend that the ’772 Patent teaches or suggests the
`
`use of everolimus for the treatment of “advanced [PNETs] after failure of
`
`cytotoxic chemotherapy.” (Ex. 1003, Yu Decl. at ¶ 42.) It does not.
`
`41.
`
` Accordingly, the claim element “advanced [PNETs] after failure of
`
`cytotoxic chemotherapy” is missing from the prior art relied on by Dr. Yu and
`
`therefore, the challenged claims of the ’224 Patent would not have been obvious.
`
`X. 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
`
`42. No cited prior art either alone or in combination teaches or suggests
`
`the efficacy of everolimus for the treatment of “advanced [PNETs] after failure of
`
`cytotoxic chemotherapy.” And for the reasons discussed below (paragraphs 47-
`
`55), a person of ordinary skill would not have had a reasonable expectation that
`
`everolimus would have been effective for the treatment of advanced PNETs after
`
`failure of cytotoxic chemotherapy and therefore, the challenged claims of the ’224
`
`Patent would not have been obvious for this additional reason.
`
`43. First, only Tabernero and the ’541 Publication report the results of
`
`any testing of everolimus. But as discussed above, there is no basis in Tabernero
`
`
`
`
` 18
`
`NOVARTIS EXHIBIT 2001
`Roxane v. Novartis, 2016-01461
`Page 20 of 29
`
`
`
`
`
`to conclude that the advanced solid tumors were treated with everolimus after
`
`failure of cytotoxic chemotherapy, let alone that any were advanced PNETs that
`
`had previously failed to respond to cytotoxic chemotherapy. (See paragraphs 32-
`
`35.) And the ’541 Publication only reports the results of in vivo animal testing, it
`
`does not report the results of any testing of everolimus against advanced PNETs
`
`after failure of cytotoxic chemotherapy or suggest the efficacy of everolimus in
`
`such a setting. (See paragraph 37.) Dr. Yu does not contend that it does. (Ex.
`
`1003, Yu Decl. at ¶ 36 (opining that activity the CA20948 cell lines would have
`
`given rise to a reasonable expectation that everolimus would be active against
`
`PNETs, but not opining on “advanced [PNETs] after failure of cytotoxic
`
`chemotherapy”).) von Wichert reports the results of testing with rapamycin that
`
`was all conducted in vitro with the chemotherapy-naïve BON cell line; it does not
`
`teach or suggest the efficacy of everolimus for the treatment of advanced PNETs
`
`after failure of cytotoxic chemotherapy. Dr. Yu does not contend otherwise. (Ex.
`
`1003, Yu Decl. at ¶ 40 (opining that BON cells are a useful model to study the
`
`biology of PNETs in vitro and that a POSA would have reasonably expected
`
`rapamycin “to inhibit the proliferation of PNET cells”).)
`
`44.
`
`In his discussion of the alleged state of the art but not in his
`
`discussion of the alleged obviousness of claims 1-2 of the ’224 Patent, Dr. Yu also
`
`cited Hidalgo (Ex. 1028) in support of his opinion that everolimus and CCI-779
`
`
`
`
` 19
`
`NOVARTIS EXHIBIT 2001
`Roxane v. Novartis, 2016-01461
`Page 21 of 29
`
`
`
`
`
`(temsirolimus) demonstrated activity against cancers that were advanced,
`
`refractory, and/or resistant to other anticancer treatments. (Ex. 1003, Yu Decl. at
`
`¶ 27.) However, Hidalgo does not teach or suggest the use or efficacy of
`
`everolimus for the treatment of advanced PNETs after failure of cytotoxic
`
`chemotherapy. In fact, Hidalgo does not discuss everolimus at all.
`
`45. Hidalgo concerns CCI-779 and reports that CCI-779 had been
`
`administered only in two Phase I clinical trials “designed to determine the
`
`maximum tolerated dose.” (Ex. 1028, Hidalgo at 6683.) The two CCI-779 Phase I
`
`clinical trials included patients with renal cell carcinoma, non-small cell lung
`
`carcinoma, soft tissue sarcoma, serous papillary carcinoma of the endometrium,
`
`breast carcinoma, squamous cell carcinoma of the skin, non-Hodgkins lymphoma,
`
`and other unspecified tumors. (Ex. 1028, Hidalgo at 6683.) Hidalgo does not
`
`disclose that any of the patients in these two Phase I clinical trials had advanced
`
`PNETs.
`
`46. While Hidalgo reports that some tumor responses had been observed
`
`in “previously treated patients,” it does not specify what therapy the patients had
`
`previously received. A person of ordinary skill would not have assumed that these
`
`patients had been treated with cytotoxic chemotherapy because cytotoxic
`
`chemotherapy was not always used for all tumors, including renal cell carcinoma,
`
`one of the tumors referenced in Hidalgo. (See paragraph 34.) Furthermore,
`
`
`
`
` 20
`
`NOVARTIS EXHIBIT 2001
`Roxane v. Novartis, 2016-01461
`Page 22 of 29
`
`
`
`
`
`Hidalgo doe
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