UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
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`SANDOZ INC.,
`Petitioner,
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`v.
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`ELI LILLY & COMPANY,
`Patent Owner.
`__________________
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`Case No: IPR2016-00318
`Patent No. 7,772,209
`__________________
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`DECLARATION OF BRUCE A. CHABNER, M.D.
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`Table of Contents
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`INTRODUCTION ............................................................................................... 1 
`I. 
`II.  QUALIFICATIONS AND BACKGROUND .................................................... 2 
`III.  THE ’209 PATENT ......................................................................................... 7 
`IV.  THE PERSON OF ORDINARY SKILL IN THE ART ................................. 8 
`V.  CLAIM CONSTRUCTION .............................................................................. 10 
`VI.  GROUNDS .................................................................................................... 13 
`VII.  SUMMARY OF OPINIONS ......................................................................... 14 
`VIII.  BACKGROUND INFORMATION ON FOLATES AND VITAMIN B12 .
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`22 
`A.  Folates ............................................................................................................ 22 
`B.  Vitamin B12 ................................................................................................... 24 
`IX.  BACKGROUND ON THE TREATMENT OF CANCER ........................... 27 
`A.  Cancer and Chemotherapy ............................................................................. 27 
`B.  Antifolates ...................................................................................................... 28 
`X.  THE DEVELOPMENT OF PEMETREXED ................................................... 32 
`A.  As of June 1999, Pemetrexed Had Been Successful in Both Phase I and II
`Trials ..................................................................................................................... 32 
`(i)  Pemetrexed Had Shown Efficacy in Clinical Trials .................................. 33 
`Pemetrexed Exhibited Tolerable and Manageable Toxicity in Clinical
`(ii) 
`Trials 34 
`XI.  THE POSA WOULD NOT HAVE A REASON TO USE FOLIC ACID
`PRE-TREATMENT WITH PEMETREXED .......................................................... 38 
`A.  Folic Acid Pre-Treatment Would Be Expected to Interfere with the Efficacy
`of Pemetrexed ....................................................................................................... 39 
`B.  Folic Acid Pre-Treatment Ran a Significant Risk of Causing the Cancer to
`Progress ....................................................................................................................
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` ....................................................................................................................... 42 
`C.  Folic Acid Pre-Treatment Had Only Been Used on an Experimental Basis
`and Without Success ............................................................................................. 43 
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`D.  The Prior Art Suggested that Folic Acid Pre-Treatment Undermined the
`Efficacy of Pemetrexed ........................................................................................ 46 
`XII.  THE POSA WOULD NOT HAVE A REASON TO USE VITAMIN B12
`PRE-TREATMENT ................................................................................................. 54 
`THE POSA WOULD NOT HAVE A REASONABLE EXPECTATION
`XIII. 
`OF SUCCESS .......................................................................................................... 62 
`XIV.  EVEN IF THE POSA HAD A REASON TO USE FOLIC ACID AND
`VITAMIN B12 WITH PEMETREXED, THE POSA WOULD NOT HAVE A
`REASON TO PRE-TREAT A CANCER PATIENT WITH THOSE VITAMINS 63 
`XV.  THE REFERENCES IN THE GROUNDS DO NOT SHOW THAT THE
`CLAIMS OF THE ’209 PATENT ARE OBVIOUS ............................................... 64 
`A.  Hammond I .................................................................................................... 65 
`B.  Niyikiza .......................................................................................................... 69 
`C.  EP 005 ............................................................................................................ 86 
`D.  Calvert I ......................................................................................................... 90 
`E.  Rusthoven ...................................................................................................... 91 
`F.  Worzalla ......................................................................................................... 98 
`G.  ’974 Patent ...................................................................................................104 
`XVI.  THE ADDITIONAL REFERENCES AND ARGUMENTS RAISED BY
`PETITIONERS AND THEIR EXPERTS DO NOT SHOW THAT THE CLAIMS
`OF THE ’209 PATENT ARE OBVIOUS .............................................................107 
`Whether the Claims Require Efficacy ............................................................107 
`5-Fluorouracil ..................................................................................................108 
`Folic Acid versus Folinic Acid. ......................................................................112 
`Carrasco ...........................................................................................................115 
`Mendelsohn .....................................................................................................117 
`Masking ...........................................................................................................117 
`Grindey ............................................................................................................121 
`Leukemia and the “Acceleration Phenomenon” .............................................122 
`Rheumatoid Arthritis .......................................................................................124 
`XVII.  THE POSA WOULD NOT USE THE DOSING REGIMENS CLAIMED
`IN THE ’209 PATENT ..........................................................................................127 
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`(i)  Dosages of Vitamin B12 ..........................................................................128 
`(ii)  Timing and Repetition of Vitamin B12 ................................................130 
`(iii) 
`Intramuscular Vitamin B12 ..................................................................131 
`(iv)  Dosage of Folic Acid ............................................................................132 
`(v)  Timing of Administration of Folic Acid ...............................................136 
`XVIII.  SKEPTICISM ..........................................................................................138 
`XIX.  CONCLUSION ........................................................................................139 
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`I, Bruce A. Chabner, hereby declare as follows:
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`I.
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`INTRODUCTION
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`1. My name is Bruce A. Chabner. I am the Clinical Director Emeritus
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`and the Paul G. Allen Distinguished Investigator at the Massachusetts General
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`Hospital Cancer Center. I am also a Professor of Medicine at Harvard Medical
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`School.
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`2.
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`I have been asked by counsel for Patent Owner Eli Lilly to review
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`United States Patent No. 7,772,209 (“the ’209 patent”) and other materials, and to
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`provide my opinion as to whether claims 1-22 of the ’209 patent would have been
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`obvious to the person of ordinary skill in the art as of June 1999. I also have been
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`asked to respond to opinions offered by Dr. Archie Bleyer and Dr. Ron Schiff
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`concerning the validity of the ’209 patent, both in their declarations and at their
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`depositions.
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`3.
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`I understand that there are three proceedings that involve the ’209
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`patent. Because there are a number of common issues to the three proceedings, I
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`am providing a single declaration across all three.
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`4.
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`In this declaration, I provide opinions regarding the ’209 patent, the
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`prior art, the level of skill of the person of ordinary skill in that art, and how such a
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`person would understand the prior art. The bases and reasons for my opinions,
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`including the particular references I am relying upon for the opinions in this
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`declaration, are set forth herein.
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`5.
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`For my work on this matter, I am being compensated at a rate of
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`$1,250 per hour. This compensation does not depend on the outcome of these
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`proceedings.
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`6.
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`I understand that each of the three proceedings at issue has its own set
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`of exhibit numbers. I will therefore refer to the exhibits by name; a chart of the
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`relevant exhibit numbers in each proceeding and the short names I am using to
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`refer to different documents is attached to the end of this declaration.
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`II. QUALIFICATIONS AND BACKGROUND
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`7.
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`I am an expert in the field of medical oncology and in the following
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`fields of special interest: biochemistry and pharmacology of anticancer agents,
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`including antifolates, and the development of new anticancer agents. I have over
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`40 years of experience in these areas. My curriculum vitae are found at Exhibit
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`2121.
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`8.
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`Folates and antifolates have been a major focus of my work
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`throughout my career. I have personally engaged in preclinical research on various
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`antifolates, have been involved with or overseen clinical trials that studied various
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`antifolates, and have prescribed or overseen the prescription of antifolates to
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`patients.
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`9.
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`After my formal education (B.A. from Yale, M.D. from Harvard), I
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`undertook a series of postdoctoral training posts. One of these posts was as a
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`Research Associate in the Department of Medicine and Pharmacology at Yale
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`University School of Medicine, where I worked under the tutelage of Joseph
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`Bertino, a pioneer in the antifolate field. In 1970-71, in Dr. Bertino’s laboratory, I
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`studied the role of a particular enzyme (carboxypeptidase G) in cleaving folates
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`and antifolates, including methotrexate. As part of this research, I discovered that
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`this enzyme could rescue animals from toxicity induced by high doses of
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`methotrexate. It is now approved by the FDA for that clinical use.
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`10.
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`In 1971, I joined the National Cancer Institute at the National
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`Institutes of Health, the federal government’s principal agency for cancer research
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`and training as a senior staff fellow, and one year later became a faculty member in
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`the U.S. Public Health Service. While at the NCI, I maintained an active
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`laboratory program in cancer pharmacology with a particular focus on the
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`pharmacology and biochemistry of antifolate cancer drugs.
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`11. One aspect of my NCI research concerned the biochemical aspects of
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`antifolate cancer drugs, including the investigation of the cellular transport and
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`polyglutamation of antifolate drugs (the processes of transport and polyglutamation
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`of folates and antifolates are discussed further below). My laboratory was the first
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`to clone the folate receptor (also called the folate binding protein) and define its
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`role in the transport of folates and antifolates. My close colleagues at NCI were
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`the first to clone the reduced folate carrier, a second transporter of antifolates.
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`12. My NCI research also involved the clinical evaluation of a number of
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`antifolate cancer compounds, in particular methotrexate. I oversaw clinical studies
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`with methotrexate in a variety of tumor types including breast cancer, ovarian
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`cancer, and lymphomas, and investigated safety aspects of methotrexate, such as
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`determinants of methotrexate toxicity (drug concentration and duration of
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`exposure) to normal and malignant cells. My group published the first clinical
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`report of drug resistance related to gene amplification, which had developed in
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`patients treated with methotrexate, and also discovered that the process of
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`polyglutamation (a process central to the cellular retention and mode of action of
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`methotrexate, pemetrexed, and other antifolates) extended the drug’s action and
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`determined treatment outcome.
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`13. Another aspect of my NCI research involved efforts to improve the
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`clinical utility of methotrexate. For example, we performed pharmacokinetic
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`studies to evaluate the mechanisms by which high-dose methotrexate caused sepsis
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`and renal failure—serious toxicities that resulted from this regimen. We
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`discovered that methotrexate-induced renal failure resulted from precipitation of
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`the drug (and its metabolites) in patients’ kidneys, and based on that finding, we
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`developed an in-patient regimen of fluid administration, urine alkalinization, and
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`drug level monitoring that has since become a standard approach with high dose
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`chemotherapy, preventing the frequent deaths that previously occurred with this
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`important regimen.
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`14. My tenure at NCI culminated in my service, from 1982 to 1995, as the
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`Director of the Division of Cancer Treatment, the largest of the four divisions at
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`NCI, and the one concerned with drug discovery and development. My
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`responsibilities in that position included overseeing intramural research programs,
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`and supporting grants, cooperative groups, and contracts for extramural anticancer
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`drug development. Our division discovered and developed many important cancer
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`drugs, including paclitaxel, cisplatin, and the first anti-AIDS drugs, AZT, DDI, and
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`DDC.
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`15.
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`In 1995, I joined the academic faculty at Harvard Medical School as
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`Professor of Medicine. I served as Chief of MGH’s Division of Hematology and
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`Oncology from 1995 to 2006, Clinical Director of MGH’s Cancer Center from
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`1995 to 2010, and Director of Clinical Research from 2010 to 2015. In addition,
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`from 1999 to 2010, I was the Associate Director for Clinical Sciences at the Dana
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`Farber-Harvard Cancer Center. My responsibilities at MGH have focused on
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`supervision of cancer treatment services, cancer clinical investigations, and
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`training of medical oncology fellows. Throughout this time, I also have served as
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`an attending physician for the inpatient general medicine service and for oncology.
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`I have been responsible for overseeing the prescription of ALIMTA® to patients,
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`and have been an investigator in a high-dose ALIMTA® study for lymphomas of
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`the central nervous system.
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`16.
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`I am an author of approximately 500 peer-reviewed publications,
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`reviews, chapters, monographs, and editorials, of which a substantial number are
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`related to antifolates. I am an editor of over twenty books and textbooks for the
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`medical and scientific community, including the standard text, Cancer
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`Chemotherapy and Biotherapy, soon to be in its sixth edition. I served as Editor of
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`the 12th edition of Goodman and Gilman’s textbook of pharmacology, the standard
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`text in its field. I served as a Senior Editor of the journal Clinical Cancer Research
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`from 2001 to 2006, and I have served as the Editor-in-Chief of the journal The
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`Oncologist from 1994 to present.
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`17. One of the major cancer research organizations in the United States is
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`the American Society of Clinical Oncology, also known as ASCO. ASCO is the
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`national organization of clinical oncologists. I am privileged to have been awarded
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`the David A. Karnofsky Memorial Award, which is given for lifetime achievement
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`in cancer research. I received this award in 1985 at the age of 45.
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`18. The other major cancer research organization in the United States is
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`the American Association for Cancer Research, also known as AACR. I am
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`privileged to have received the Bruce F. Cain Memorial Award, which is the main
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`award of the AACR for drug development. I was elected to Fellowship in the
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`AACR Academy, a major honor for cancer researchers, in 2015.
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`19. The National Cancer Advisory Board (“NCAB”) was created in the
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`1970s as part of the War on Cancer. Its 18 members are appointed by the
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`President, and they are tasked with providing advice and oversight concerning
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`cancer policy in the United States. I was a member of the NCAB from 2006-2012,
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`and served as its chair from 2010-2012.
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`20. Most recently, I was honored with the distinguished Investigator
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`Award and lectureship of the American College of Clinical Pharmacology at their
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`annual meeting in Bethesda, Maryland.
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`III. THE ’209 PATENT
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`21. The ’209 patent relates to Lilly’s anti-cancer product ALIMTA®,
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`which has as its active ingredient pemetrexed (also referred to as “pemetrexed
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`disodium,” “LY231514” (the internal Lilly name for the compound), and “MTA”).
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`Generally speaking, the claims of the ’209 patent relate to methods of
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`administration of folic acid and a methylmalonic acid lowering agent (such as
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`vitamin B12) to a cancer patient prior to administration of pemetrexed disodium, as
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`well as repeated administration of vitamin B12. The claims specify various
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`regimens and dosages for such administration, including the additional
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`administration of cisplatin.
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`IV. THE PERSON OF ORDINARY SKILL IN THE ART
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`22.
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` I have been asked to provide my opinion as to the qualifications of
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`the hypothetical “person of ordinary skill in the art” (“POSA”) to whom the
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`inventions disclosed and claimed in the ’209 patent were directed, as of June 29,
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`1999, which I have been informed is more than one year prior to June 30, 2000, the
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`filing of the first patent application related to the ’209 patent. I understand that
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`each of Dr. Bleyer and Dr. Schiff has used June 1999 as the timeframe for their
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`opinions as well. Bleyer 237 Decl. at ¶ 3; Bleyer 240 Decl. at ¶ 3; Schiff Decl. at ¶
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`13.
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`23.
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`In my opinion, the POSA to whom the ’209 patent is addressed is a
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`medical doctor who specializes in oncology, specifically medical oncology. Such
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`a person would have knowledge and experience concerning the use of
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`chemotherapy agents, including antifolates, in the treatment of cancer, as well as
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`knowledge and experience regarding the management of toxicities associated with
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`such treatment.
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`24.
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`I have reviewed the definition of the POSA offered by Dr. Bleyer. Dr.
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`Bleyer focuses on a medical oncologist, although at his deposition he appeared to
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`rely heavily on the notion that the POSA would have significant input from, and
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`would even defer to, a nutritionist. Bleyer 237 Decl. at ¶ 21; Bleyer 240 Decl. at ¶
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`21; Bleyer Dep. (Part I) at 117-21, 270-72, 289-90. I disagree. I understand that
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`the POSA is a hypothetical person who can possess the skills of individuals in
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`different disciplines. As a practical matter, medical oncologists may sometimes
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`need to consult with individuals with different skills and experience during the
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`course of treating patients with chemotherapeutic agents. However, I do not
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`believe that the POSA would defer to a nutritionist on whether a cancer patient
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`receiving an antifolate should also receive vitamin supplementation. In my
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`experience, medical oncologists do not rely on nutritional scientists in that way.
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`Rather, in my experience, consultation with nutritionists as of June 1999 typically
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`arose in circumstances involving treatment of individual patients for whom food
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`intake was compromised and significant weight loss had occurred (such as a
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`patient with head and neck cancer who was unable to take food by mouth), and
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`thus providing parenteral nutrition was necessary.
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`25. With regard to Dr. Schiff, his definition is “a medical doctor
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`experienced in oncology with knowledge of and/or several years of experience
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`regarding the use of antifolates in the treatment of cancer and additional
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`qualifications or experience in the field of nutritional sciences involving vitamin
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`deficiencies.” Schiff Decl. at ¶ 13. With respect to the phrase “additional
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`qualifications or experience in the field of nutritional sciences involving vitamin
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`deficiencies.” Dr. Schiff explained at his deposition that medical oncologists need
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`to be familiar with nutritional issues that arise from a cancer patient’s disease or
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`treatment and how to manage them. Schiff Dep. at 43-44. To the extent that Dr.
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`Schiff is saying that a medical oncologist, and hence the POSA, would need to
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`have an understanding of how nutritional issues relate to the use of chemotherapy
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`agents, I agree. In that regard, the POSA would have an understanding of the
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`interrelationships between antifolates, the folic acid pathway, and pathways related
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`to vitamin B12.
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`26. However, whether Dr. Bleyer’s or Dr. Schiff’s definitions were used,
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`it would not change the opinions I express in this declaration, as in both cases the
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`POSA would include an individual with the skills of a medical oncologist.
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`V. CLAIM CONSTRUCTION
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`27.
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`I have been informed by counsel for Patent Owner Lilly that, in this
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`proceeding, claim terms are to be given their broadest reasonable interpretation in
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`light of the specification. I have also been informed that Petitioners Neptune and
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`Sandoz have proposed the following constructions for the following phrases. I will
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`use these constructions for purposes of my analysis.1
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`1 I have been informed by counsel for Patent Owner that Neptune has proposed
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`constructions for “toxicity” and “antifolate”/”antifolate drug.” Those terms,
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`however, do not appear in the claims of the ’209 patent.
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`Petitioners’ Proposed Construction(s)
`“amounts of folic acid and a
`methylmalonic acid lowering agent that
`are capable of reducing the prevalence or
`severity of one or more toxicities
`associated with the administration of
`pemetrexed disodium”
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`“an agent such as vitamin B12 which can
`be used to lower the concentration of
`methylmalonic acid in a mammal”
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`“vitamin B12 or its derivative that
`lowers the concentration of
`methylmalonic acid in a mammal”2
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`Claim Term or Phrase
`“an effective amount of folic acid
`and an effective amount of a
`methylmalonic acid lowering agent”
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`“methylmalonic acid lowering
`agent”
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`2 I have been informed by counsel for Patent Owner that the first construction was
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`proposed by Sandoz. I have also been informed that the second construction was
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`proposed by Neptune and is described by Neptune as “similar” to the first
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`construction. For purposes of my analysis in this declaration, either construction
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`could be used—it would not change my opinions.
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`“an effective amount of pemetrexed
`disodium”
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`“an amount of pemetrexed disodium that
`is capable of providing a therapeutic
`benefit to the patient in need thereof”
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`28.
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`I note that Dr. Bleyer has proposed that the claim term “patient”
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`should be construed to mean “a human undergoing medical treatment.” Bleyer 237
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`Decl. at ¶ 59; Bleyer 240 Decl. at ¶ 59. Dr. Schiff, however, offered the opinion in
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`his declaration that “patient” means “mammal.” Schiff Decl. at ¶ 19. I agree with
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`Dr. Bleyer and disagree with Dr. Schiff. Dr. Bleyer, Dr. Schiff, and I all appear to
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`agree that the POSA includes a medical oncologist/medical doctor with experience
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`in oncology. Bleyer 237 Decl. at ¶ 20; Bleyer 240 Decl. at ¶ 20; Schiff Decl. at ¶
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`13. For such a person, “patient” does not encompass non-human mammals. The
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`POSA would not understand it to refer to a mammal generally, nor would the
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`POSA understand the term to be synonymous with human. Rather, the word
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`“patient” would be understood by the POSA to refer to a human undergoing
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`medical treatment. I note that this understanding is consistent with various
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`dictionary definitions of the word “patient.” Oxford Dictionary pg. 3 (“A person
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`receiving or registered to receive medical treatment; a sick person, esp. one staying
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`in a hospital.”) (emphasis in original); Random House Dictionary pg. 3 (“a person
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`who is under medical care or treatment”).
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`29. The understanding of the POSA would be reinforced further by the
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`fact that the POSA would not understand the ’209 patent to be directed toward
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`providing chemotherapy in a veterinary context. While the patent does refer to
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`preclinical experiments in laboratory mice, see ’209 patent at col. 6, ll. 57 – col. 8,
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`ll. 38, those mice would not be understood to be “veterinary patients” (veterinary
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`being a qualifier to distinguish veterinary care from the care of a “patient,” which
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`involves a human). Those mice were test subjects in a study in which healthy mice
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`had human tumors implanted and then were given pemetrexed to evaluate its
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`effects in vivo. Id. at col. 6, ll. 57-67. Consistent with the POSA’s understanding,
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`the ’209 patent does not refer to those mice as “patients.” Rather, they are
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`identified as “animals.” Id. at col. 6, l. 63, col. 7, l. 1, col. 7, l. 15, col. 7, ll. 41-42,
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`col. 7, ll. 46-47, col. 7, l. 56, col. 7, 1. 66, col. 8, l. 15.
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`VI. GROUNDS
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`30.
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`I understand there are three proceedings at issue here: (1) the Neptune
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`237 proceeding; (2) the Neptune 240 proceeding; and (3) the Sandoz 318
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`proceeding. I also understand that Dr. Bleyer has submitted declarations in each of
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`the Neptune proceedings, and that Dr. Schiff has submitted a declaration in the
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`Sandoz proceeding.
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`31.
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`I understand from counsel for Patent Owner Lilly that each of these
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`proceedings has at least one “ground,” that is, a particular combination of
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`references that is alleged to make claims 1-22 of the ’209 patent invalid for
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`obviousness. I have been informed that the obviousness grounds are as follows:
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`Ground
`Niyikiza [I] in view of the ’974 patent
`and further in view of EP 005
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` Rusthoven in view of EP 005
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`Calvert [I] in view of Niyikiza I,
`Worzalla, EP 005 and the ’974 patent
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`Calvert [I] in view of Niyikiza I,
`Hammond I, EP 005 and the ’974 patent
`
`Proceeding
`IPR 2016-00237 (Neptune
`Petitioner, Dr. Bleyer expert
`declaration)
`
`IPR 2016-00240 (Neptune
`Petitioner, Dr. Bleyer expert
`declaration)
`
`IPR 2016-00318 (Sandoz Petitioner,
`Dr. Schiff expert declaration) –
`Ground I
`
`IPR 2016-00318 (Sandoz Petitioner,
`Dr. Schiff expert declaration) –
`Ground II
`
`
`
`
`VII. SUMMARY OF OPINIONS
`
`32. As set forth in greater detail in this declaration, I disagree that claims
`
`1-22 of the ’209 patent would have been regarded as obvious by the POSA as of
`
`June 1999. In particular, I have the following opinions:
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`33. The POSA would not regard the subject matter of claims 1-22 of the
`
`’209 patent to be obvious3 in light of the prior art as of June 1999, for at least the
`
`following reasons:
`
`a. As of June 1999, the POSA would recognize that there was not a
`
`problem with respect to pemetrexed-induced toxicity that was not
`
`adequately addressed by known, conventional methods used at the
`
`time. The prior art—such as Rusthoven, Calvert II, and Calvert
`
`III—taught that pemetrexed-induced toxicities were likely to be
`
`tolerable and manageable, and that toxicity could be addressed
`
`
`3 I have been informed by counsel for Patent Owner Lilly that an obviousness
`
`analysis involves a review of the scope and content of the prior art, the differences
`
`between the prior art and the claims at issue, the level of ordinary skill in the
`
`pertinent art, and “objective indicia of non-obviousness” such as skepticism. In
`
`particular, I have been advised that, for an invention to be regarded as “obvious,”
`
`the POSA must have had a reason to modify the prior art or to combine one or
`
`more prior art references in a manner that would yield the claimed invention. I
`
`have also been informed that, for a claim to be obvious, the POSA must have a
`
`reasonable expectation of success with respect to the claimed invention. I have
`
`analyzed each of those questions.
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`using standard techniques for managing antifolate toxicity such as
`
`conventional dose and schedule adjustments, or rescue therapy
`
`with leucovorin.
`
`b. The POSA would not have reason to employ a clinical regimen
`
`involving the administration of folic acid to a cancer patient prior
`
`to administration of pemetrexed. Pemetrexed was treatment for a
`
`life-threatening disease—cancer. However, the POSA would
`
`expect that pre-treatment with folic acid would undermine its anti-
`
`cancer efficacy, an understanding reflected in the results described
`
`in the Hammond abstracts and Rinaldi I. Worse still, the POSA
`
`would recognize that there was a significant risk that pre-treatment
`
`with folic acid would cause the tumor to progress. While folic acid
`
`pre-treatment had been studied with various antifolates, it had only
`
`been used on an experimental basis in cancer patients and with
`
`clearly negative therapeutic results, and in any event the prior art
`
`suggested that pre-treating patients with folic acid would
`
`undermine pemetrexed’s efficacy. As such, the prior art taught
`
`away from using folic acid pre-treatment with pemetrexed, and the
`
`POSA would not use it at all.
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`c. Even if the POSA were to employ a clinical regimen in which folic
`
`acid were administered to a cancer patient prior to the
`
`administration of pemetrexed—a position with which I disagree—
`
`the POSA would not have a reason to include vitamin B12 as part
`
`of the pre-treatment regimen. There is no indication in the prior art
`
`that a cancer patient on antifolate therapy was ever pre-treated with
`
`vitamin B12, and the POSA would not have a reason to use such a
`
`novel regimen. Moreover, the prior art taught away from pre-
`
`treatment with vitamin B12. Not only would the POSA expect that
`
`vitamin B12 would undermine the efficacy of pemetrexed by
`
`expanding intracellular stores of reduced folate to an unpredictable
`
`degree, but the POSA would further expect that it could cause the
`
`cancer to progress—especially when used in combination with
`
`folic acid. As such, the POSA would not use vitamin B12
`
`pretreatment with pemetrexed.
`
`d. The POSA would not pre-treat a cancer patient receiving
`
`pemetrexed with folic acid and vitamin B12 in order to lower
`
`homocysteine levels. Although the prior art—and in particular, the
`
`Niyikiza abstracts—indicated that there was a correlation between
`
`homocysteine levels and the development of various toxicities in
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`patients who received pemetrexed, the prior art specifically
`
`recognized that a cancer patient on an antifolate should not receive
`
`folate to lower homocysteine levels, as that would be expected to
`
`interfere with the anti-tumor effect of the antifolate. Quinn. In
`
`addition, the POSA would understand that the toxicities observed
`
`in the Niyikiza abstracts were caused by the direct antifolate action
`
`of pemetrexed, not the direct action of homocysteine.
`
`Furthermore, the POSA would understand that methylmalonic
`
`acid—not homocysteine—was the unique marker for a vitamin
`
`B12 deficiency, but Niyikiza II taught that no correlation was
`
`identified between methylmalonic acid levels and toxicity.
`
`Moreover, the POSA would recognize that the Niyikiza abstracts
`
`only identified a correlation between homocysteine and toxicity—
`
`not a causation—and thus would not expect that lowering
`
`homocysteine levels would necessarily address the toxicities.
`
`Instead, the POSA would rely on homocysteine as a marker for