UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`APOTEX INC., APOTEX CORP.,
`EMCURE PHARMACEUTICALS LTD.,
`HERITAGE PHARMA LABS INC., HERITAGE PHARMACEUTICALS INC.,
`GLENMARK PHARMACEUTICALS INC., USA,
`GLENMARK HOLDING SA, GLENMARK PHARMACEUTICALS LTD.,
`MYLAN LABORATORIES LIMITED,
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`Petitioners
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`V.
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`ELI LILLY & COMPANY
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`Patent Owner
`_____________________
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`U.S. Patent No. 7,772,209
`Filed: July 11, 2007
`Issued: August 10, 2010
`Inventor: Clet Niyikiza
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`TITLE: ANTIFOLATE COMBINATION THERAPIES
`_____________________
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`Inter Partes Review No.: IPR2016-01429
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`Declaration of Ron D. Schiff, M.D., Ph.D.
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`1
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`JOINT 1004-0001
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`BACKGROUND ............................................................................................. 4
`I.
`QUALIFICATIONS AND EXPERIENCE ..................................................... 4
`II.
`III. MATERIALS CONSIDERED ........................................................................ 5
`IV. SUMMARY OF OPINIONS ........................................................................... 6
`V.
`LEGAL PRINCIPLES ..................................................................................... 6
`VI. THE ’209 PATENT ......................................................................................... 6
`A.
`Person of Ordinary Skill ........................................................................ 6
`B.
`Overview ............................................................................................... 7
`C. Meaning of Claim Terms ...................................................................... 8
`D.
`State of the Art .................................................................................... 14
`E.
`Pemetrexed .......................................................................................... 18
`VII. ANALYSIS OF THE ’209 PATENT ............................................................ 20
`A.
`It Would Have Been Apparent Prior To June 1999 To
`Pretreat Patients with Folic Acid And Vitamin B12 Before
`Administering Pemetrexed .................................................................. 20
`1.
`Folic Acid Pretreatment Was Known ....................................... 20
`a.
`Folic Acid Pretreatment Was Known To
`Ameliorate Antifolate Toxicity ...................................... 20
`Studies Recommended Folic Acid
`Pretreatment With Pemetrexed To Reduce
`Toxicity ........................................................................... 27
`The Literature Suggested That Patients Should
`Also Be Pretreated With Vitamin B12 ....................................... 33
`The Specific Dosage Amounts And Schedules Required
`By The Claims Were Known .............................................................. 46
`1.
`500 µg Dosages Of Folic Acid Were Standard
`Prior To June 1999 .................................................................... 46
`Vitamin B12 Was Commonly Administered Via
`Repeated Intramuscular Injection in 1000 µg
`Doses ......................................................................................... 49
`a.
`Vitamin B12 Was Routinely Administered
`Parenterally in 1000 µg Doses ........................................ 49
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`2.
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`2.
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`b.
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`B.
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`b.
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`It Was Known That Vitamin B12 Injections
`Should Be Repeated “About Every 6 to
`About Every 12 Weeks” ................................................. 52
`Folic Acid Pretreatment From 1-3 Weeks And 1-
`24 Hours Before Pemetrexed Therapy Was Known ................. 53
`Administration of Cisplatin with Pemetrexed was Known ................. 54
`C.
`VIII. CONCLUSION .............................................................................................. 55
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`3.
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`3
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`JOINT 1004-0003
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`I.
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`BACKGROUND
`1. My name is Ron D. Schiff. I hold M.D. and Ph.D. degrees from Saint
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`Louis University, and am currently the principal of Schiff BioMedical Consulting.
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`2.
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`I have been retained by counsel for Petitioners Apotex Inc., Apotex
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`Corp. (“Apotex”), Emcure Pharmaceuticals Ltd., Heritage Pharma Labs Inc,
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`Heritage Pharmaceuticals Inc. (“Emcure”), Glenmark Pharmaceuticals Inc., USA,
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`Glenmark Holding SA, Glenmark Pharmaceuticals Ltd. (“Glenmark”), and Mylan
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`Laboratories Limited (“Mylan”) (collectively, “Petitioners”) to investigate and
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`opine as to the validity of claims 1-22 of U.S. Patent No. 7,772,209 (“the ’209
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`patent”).
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`3.
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`I am being compensated at my usual hourly rate for the time I spend
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`working on this matter. My compensation is not contingent upon the substance of
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`my testimony or the outcome of this matter.
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`II. QUALIFICATIONS AND EXPERIENCE
`4. My qualifications and experience are set forth in my curriculum vitae,
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`which is attached as Appendix A.
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`5.
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`I worked as practicing physician in the field of oncology for 29 years
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`with a specialty in internal medicine and sub-specialties in medical oncology and
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`hematology.
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`JOINT 1004-0004
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`6.
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`I frequently treated patients with antifolates, particularly methotrexate
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`which is used in the treatment of multiple hematologic and solid-organ
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`malignancies, including acute lymphoblastic leukemia, non-Hodgkin’s lymphoma,
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`head and neck cancer, breast cancer, bladder cancer, and meningeal leukemia or
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`lymphoma.
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`7.
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`I have treated hundreds of patients with methotrexate throughout my
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`29 years of practice and since I began my post-graduate training in 1980. I have
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`also administered pemetrexed and am familiar with its vitamin pre-treatment
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`regimen.
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`III. MATERIALS CONSIDERED
`In forming my opinions, I have reviewed, inter alia, the ’209 patent
`8.
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`and its prosecution history, as well as the exhibits referenced in Petitioners’
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`Petition for Inter Partes Review. I understand that the exhibit numbers referenced
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`in this declaration correspond to the same exhibit numbers used in Petitioners’
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`petition. A copy of the exhibit list from Petitioners’ petition is attached as
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`Appendix B.
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`9.
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`A list of the documents I have considered in preparing this declaration
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`is attached as Appendix C.
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`10. This declaration is based upon information currently available to me.
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`To the extent additional information becomes available, I reserve the right to
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`continue my investigation and study.
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`IV. SUMMARY OF OPINIONS
`11. For the reasons explained herein, claims 1-22 would have been
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`obvious to the person of ordinary skill in the art as of June 1999.
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`V. LEGAL PRINCIPLES
`I am a medical, not a legal, expert. Counsel for Petitioners has
`12.
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`advised me concerning the legal principles governing “obviousness” under the
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`Patent Laws. A copy of those legal principles as provided to me by counsel for
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`Petitioners is attached as Addendum E. My analysis is consistent with those
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`principles.
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`THE ’209 PATENT
`VI.
`Person of Ordinary Skill
`A.
`13. The person of ordinary skill in the art (“POSA”) would have been a
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`medical doctor experienced in oncology with knowledge of and/or several years of
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`experience 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. Although my experience and expertise may exceed that of a person
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`of ordinary skill, all opinions and statements made for purposes of this Declaration,
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`unless otherwise noted, reflect the knowledge of the person of ordinary skill as of
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`June 1999, which counsel for Petitioners has informed me is the relevant time
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`period for purposes of my analysis.
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`B. Overview
`14. The ’209 patent includes 22 claims. For convenience, I have copied
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`the text of claims 1 and 12 below:
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`1. A method for administering pemetrexed disodium to a patient
`in need thereof comprising administering an effective amount of folic
`acid and an effective amount of a methylmalonic acid lowering agent
`followed by administering an effective amount of pemetrexed
`disodium, wherein
`the methylmalonic acid lowering agent is selected from the group
`consisting of vitamin B12, hydroxycobalamin, cyano-10-
`chlorocobalamin, aquocobalamin perchlorate, aquo-10-cobalamin
`perchlorate, azidocobalamin, cobalamin, cyanocobalamin, or
`chlorocobalamin.
`12. An improved method for administering pemetrexed disodium to
`a patient in need of chemotherapeutic treatment, wherein the
`improvement comprises:
`a) administration of between about 350 μg and about 1000 μg of
`folic acid prior to the first administration of pemetrexed
`disodium;
`b) administration of about 500 μg to about 1500 μg of vitamin
`B12, prior to the first administration of pemetrexed disodium;
`and
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`c) administration of pemetrexed disodium.
`15. The other claims of the ’209 patent fall into three categories: (1)
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`claims adding specific dosages for folic acid or vitamin B12 (claims 3-4, 8-10, 14-
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`18); (2) claims adding specific dosing schedules for pretreatment with folic acid or
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`vitamin B12 (claims 6-7, 19-21); and (3) claims requiring the administration of an
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`additional chemotherapy agent, cisplatin (claims 11, 13, 22).
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`C. Meaning of Claim Terms
`I have been informed by counsel for Petitioners that for purposes of
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`this proceeding the claim terms of the ’209 patent are to be given their “broadest
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`reasonable interpretation” in light of the specification in which it appears.
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`17.
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`I have reviewed the specification and file history of the ʼ209 patent. I
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`have considered, agree, and have applied Petitioner’s proposed claim constructions
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`in my analysis as set forth in this Declaration. Those constructions are set out
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`below.
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`18.
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`I have reviewed the specification and file history of the ʼ209 patent,
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`and in my opinion there are no special definitions attributed to any of the claim
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`terms. As such, I interpret the claim terms under the “broadest reasonable”
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`standard, and the particular terms below have the following meanings in light of
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`the specification.
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`JOINT 1004-0008
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`19. With respect to the term “patient” in the preamble of claims 1 and 12
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`of the ’209 patent, the person of ordinary skill would understand that the broadest
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`reasonable interpretation of this term when read in the context of the teachings of
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`the ’209 patent is “mammal” and that a patient is not limited to humans.
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`Throughout the patent specification, the ’209 patent uses the term “mammal” and
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`patient” interchangeably. For example, the specification states:
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`The administration of the compounds maybe [sic] simultaneous as a
`single composition or as two separate compositions such that an
`effective amount of the agent first administered is in the patient’s
`body when the second and/or third agent is administered. The
`antifolate drug may be administered to the mammal first, followed by
`treatment with the methylmalonic acid lowering agent.
`Ex. 1001, ’209 patent, col. 4, ll. 9-16 (emphases added).
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`20. The patent also uses the terms “mammal” and “patient”
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`interchangeably when describing a preferred embodiment at column 6. The patent
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`states:
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`In the especially preferred embodiment of this invention, about 0.1 mg
`to about 30 mg, most preferably about 0.3 mg to about 5 mg, of folic
`acid is administered orally to a mammal about 1 to 3 weeks post
`administration of the methylmalonic acid lowering agent and about 1
`to about 24 hours prior to the parenteral administration of the amount
`of an antifolate. However, it will be understood that the amount of the
`methylmalonic acid lowering agent actually administered will be
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`JOINT 1004-0009
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`determined by a physician, in light of the relevant circumstances,
`including the condition to be treated, the chosen route of
`administration, the actual agent administered, the age, weight, and
`response of the individual patient, and the severity of the patient’s
`symptoms . . . .
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`Ex. 1001, ’209 patent, col. 6, ll. 35-47.
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`21.
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`I understand that a person of ordinary skill would view language
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`characterizing “the present invention” as pertaining to “mammals” is indicative of
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`the claims’ scope. The ’209 patent specification also repeatedly characterizes the
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`“present invention” as pertaining to “mammals” generally:
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`• “[T]he present invention relates to a method of administering an antifolate to a
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`mammal in need thereof, comprising administering an effective amount of said
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`antifolate in combination with a methylmalonic acid lowering agent and a FBP
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`binding agent.” Ex. 1001, col. 3, ll. 1-5.
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`• “[T]he present invention relates to a method of reducing the toxicity associated
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`with the administration of an antifolate to a mammal[.]” Ex. 1001, col. 3, ll. 7-9.
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`• “[T]he present invention relates to a method of inhibiting tumor growth in
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`mammals comprising administering to said mammals an effective amount of an
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`antifolate in combination with a methylmalonic acid lowering agent and a FBP
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`binding agent.” Ex. 1001, col. 3, ll. 13-17.
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`JOINT 1004-0010
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`• [T]he present invention relates to the use of a methylmalonic acid lowering agent,
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`alone or in combination with a FBP binding agent, in the preparation of a
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`medicament useful in lowering the mammalian toxicity of an antifolate.”
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`Ex. 1001, col. 3, ll. 19-22.
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`• “[T]he present invention relates to the use of a methylmalonic acid lowering
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`agent in the preparation of a medicament useful in lowering the mammalian
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`toxicity associated with an antifolate . . . .” Ex. 1001, col. 3, ll. 24-27.
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`• [T]he present invention relates to the use of a methylmalonic acid lowering agent
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`in the preparation of a medicament useful in lowering the mammalian toxicity
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`associated with an antifolate . . . .” Ex. 1001, col. 3, ll. 29-32.
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`• “[T]he present invention relates to the use of a methylmalonic acid lowering
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`agent in the manufacture of a medicament for use in a method of inhibiting tumor
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`growth in mammals . . . .” Ex. 1001, col. 3, ll. 34-37.
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`22. The fact that the dosage schedules and ranges recited in several claims
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`as applying to a “patient” match those described in the specification with reference
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`to “mammals” indicates that a “patient” is not limited specifically to humans.
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`Claims 6, 7, 19, and 20 require administration of folic acid “1 to 3 weeks prior to
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`the first administration of the pemetrexed disodium” or “1 to about 24 hours prior
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`to administration of the pemetrexed disodium.” Ex. 1001, ’209 patent, claims 6, 7,
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`19 and 20. Claim 8 requires that the folic acid be administered in a dosage
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`between 0.3 mg to about 5 mg. Claims 6-8 and 19-20 ultimately depend from
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`either claim 1 or claim 12, both of which recite administering to a “patient.” As
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`shown in the reproduction of an excerpt from column 6 of the ’209 patent below,
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`the specification recites the same dosage ranges and schedules as claims 6-8 and
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`19-20 as applying to a “mammal”:
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`In the especially preferred embodiment of this invention, about 0.1 mg
`to about 30 mg, most preferably about 0.3 mg to about 5 mg, of folic
`acid is administered orally to a mammal about 1 to 3 weeks post
`administration of the methylmalonic acid lowering agent and about 1
`to about 24 hours prior to the parenteral administration of the amount
`of an antifolate. However, it will be understood that the amount of the
`methylmalonic acid lowering agent actually administered will be
`determined by a physician, in the light of the relevant circumstances,
`including the condition to be treated, the chosen route of
`administration, the actual agent administered, the age, weight, and
`response of the individual patient, and the severity of the patient’s
`symptoms, and therefore the above dosage ranges are not intended to
`limit the scope of the invention in any way.
`Ex. 1001, ’209 patent, col. 6, ll. 35-49 (emphasis added).
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`23. During prosecution of the parent application of the ’209 patent, U.S.
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`Patent Application No. 11/288,807, the Applicant presented claims that recited a
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`“method of inhibiting tumor growth in humans . . . .” Ex. 1024, ’807 file history at
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`38, 11/29/2005 Preliminary Amendment at 3. During prosecution of the child
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`application that later issued as the ’209 patent, new claims were submitted that
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`instead recited an “improved method for administering pemetrexed disodium to a
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`patient in need of chemotherapeutic treatment . . . .” Ex. 1002, ’209 file history at
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`3, 07/11/2007 Preliminary Amendment at 3. A person of ordinary skill would have
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`understood that if the ’209 patent claims were limited to humans, the language of
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`the claims would not have been altered to change “human” to the broader term
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`“patient.”
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`24.
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`In addition, a person of ordinary skill would recognize that a
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`“mammal” is not solely limited to a human, and that any mammal can be
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`considered a patient in veterinary medicine. However, if the term “mammal” is
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`interpreted to be restricted to “humans,” my opinions as set forth below, will not
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`change.
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`25. With respect to the term “an effective amount of pemetrexed
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`disodium” in claim 1 of the ’209 patent, I have been informed by counsel for
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`Petitioners that Lilly has previously agreed to the following construction: “an
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`amount of pemetrexed disodium that is capable of providing a therapeutic benefit
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`to the patient in need thereof.” Ex. 1035, Joint Claim Construction Statement at 2.
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`I do not disagree with this construction and have therefore adopted this
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`construction for purposes of my evaluation.
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`26. With respect to “an effective amount of folic acid and an effective
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`amount of a methylmalonic acid lowering agent,” I have been informed by counsel
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`for Petitioners that Lilly has previously agreed to the following construction:
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`“amounts of folic acid and a methylmalonic acid lowering agent that are capable of
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`reducing the prevalence or severity of one or more toxicities associated with the
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`administration of pemetrexed disodium.” Ex. 1035, Joint Claim Construction
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`Statement at 1. I do not disagree with this construction and have therefore adopted
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`it for purposes of my evaluation.
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`D.
`27.
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`State of the Art
`In the 1940s, scientists discovered that drugs that inhibit intracellular
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`folate action known as antifolates are effective in the treatment of childhood
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`leukemia. Ex. 1009, Farber at 787; Ex. 1012, Mendelsohn at 270. By the late
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`1990s, a number of antifolates had been, or were in, the process of development,
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`including methotrexate, raltitrexed, 5-fluorouracil (“5-FU”), lometrexol,
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`LY309887, and pemetrexed (LY231514). Ex. 1007, Calvert at 6; Ex. 1012,
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`Mendelsohn at 270-71.
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`28. As their name suggests, antifolates interfere with folate metabolism
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`within mammalian cells. Ex. 1007, Calvert at 3. Folate is an essential vitamin,
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`which is necessary for cells to synthesize purine, a component of deoxyribonucleic
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`acid (“DNA”), which in turn is necessary for cellular proliferation. Additionally,
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`antifolates inhibit synthesis of thymidylate, a necessary component of DNA. See
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`JOINT 1004-0014
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`id. Thus, antifolates work by interfering with the growth and proliferation of
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`cancer cells by disrupting DNA synthesis.
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`29. Antifolates may interfere with DNA synthesis of both normal healthy
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`cells and cancer cells. However, because rapidly-dividing cancer cells generally
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`have higher folate requirements than normal cells, an antifolate has a greater
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`impact on cancer cells than on normal cells. Ex. 1012, Mendelsohn at 270. Thus,
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`antifolates provide an important tool for targeting cancer cells.
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`30. The figure below is reproduced from Victor Herbert’s Folic Acid and
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`Vitamin B12 and shows the details of the folate metabolism pathway in normal
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`cells known prior to June 1999. Antifolates compete with derivatives of folic acid
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`for binding sites on certain enzymes within this pathway. See generally Ex. 1012,
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`Mendelson; Ex. 1007, Calvert; Ex. 1001, ’209 patent, col. 1, ll. 36-41.
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`Several of the enzymatic targets of various antifolates are highlighted in blue in the
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`folate metabolism scheme above, specifically, thymidylate synthetase (“TS”),
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`dihydrofolate reductase (“DHFR”), glycinamide ribonucleotide formyltransferase
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`(“GARFT”), and aminoimidazole carboxamide ribonucleotide formyltransferase
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`(“AICARFT”). The portion of the pathway related to conversion of homocysteine
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`to methionine is outlined in red as it is particularly relevant to the issues involved
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`here and will be discussed in greater detail above.
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`31. Methotrexate (“MTX”) was developed over 50 years ago and was
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`among the first clinically used antifolates. See Ex. 1001, ’209 patent, col. 1, ll. 19-
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`25. Methotrexate interrupts purine synthesis principally by inhibiting the enzyme
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`dihydrofolate reductase (“DHFR”), an enzyme necessary for folate recycling.
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`Ex. 1007, Calvert at 6. In addition to being useful as a component of numerous
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`chemotherapeutic regimens, it is also commonly used in treatment of autoimmune
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`disorders including rheumatoid arthritis, psoriasis, and psoriatic arthritis. See
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`Ex. 1010, Morgan at 833; Ex. 1013, Worzalla at 3235.
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`32. Another antifolate known prior to June 1999 was raltitrexed, which
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`has been marketed since the late 1990s under the name Tomudex® in those
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`European countries where it has been approved. See Ex. 1012, Mendelsohn at 271;
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`Ex. 1007, Calvert at 7. In countries where it is approved, raltitrexed is used to treat
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`advanced colorectal cancer and mesothelioma in combination with cisplatin. See
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`Ex. 1012, Mendelsohn at 271; Ex. 1007, Calvert at 7. Raltitrexed acts by
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`inhibiting the enzyme thymidylate synthase (“TS”), which is involved in purine
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`synthesis.
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`33.
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`In the late 1990s, Lilly worked to develop the antifolate lometrexol,
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`which is also known as 5,10-dideazatetrahydrofolic acid or DDATHF. Ex. 1005,
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`’974 patent, col. 1, ll. 16-24. Lometrexol targeted purine biosynthesis via
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`inhibition of the enzyme GARFT. Ex. 1012, Mendelsohn at 271; Ex. 1021, Shih at
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`1116. Studies showed that lometrexol exhibited efficacy in treating cancer. E.g.,
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`Ex. 1012, Mendelsohn at 276; Ex. 1005, ’974 patent, col. 7, l. 4-col. 8, l. 13. As
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`discussed in greater detail in paragraphs 42-50, studies indicated that folic acid
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`pretreatment reduced toxicity without impacting efficacy of lometrexol.
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`E.
`34.
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`Pemetrexed
`In the 1990s, scientists also developed pemetrexed, which is a
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`biochemically related analogue of lometrexol. See Ex. 1034, U.S. Pat. No.
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`5,344,932 (issued 1994); Ex. 1047, Calvert & Walling at 36. The following
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`depiction of the chemical structures of lometrexol and pemetrexed is reproduced
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`from page 36 of Calvert & Walling (Ex. 1047). The red circles have been added to
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`highlight the sole structural difference between lometrexol and pemetrexed.
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`Specifically, lometrexol has a 6-member bicyclic ring while pemetrexed has a 5-
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`member ring.
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`Lometrexol
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`Pemetrexed
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`35. Pemetrexed is also known as LY231514 or multi-targeted antifolate
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`(“MTA”), a name derived from the fact that the compound is an inhibitor of
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`several enzymes involved in folate metabolism. Ex. 1021, Shih at 1116.
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`Specifically, pemetrexed is a potent inhibitor of the enzyme TS, and to a lesser
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`extent DHFR, GARFT, and AICARFT. Ex. 1021, Shih at 1116; Ex. 1007, Calvert
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`at 9. By the late 1990s, pemetrexed was known to have promising antitumor
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`effects. E.g., Ex. 1007, Calvert at 9; Ex. 1047, Calvert & Walling at 38-39.
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`36.
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`In February 2004, the FDA granted Lilly approval for pemetrexed,
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`which Lilly markets under the brand name Alimta®. Ex. 1038, FDA approval
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`letter. Alimta® is approved for treatment of metastatic nonsquamous non-small
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`cell lung cancer and mesothelioma in combination with cisplatin as well as a single
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`agent in maintenance therapy. Ex. 1051, Alimta® Labeling.
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`37. Because my practice focused on all adult cancers, I administered other
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`chemotherapy agents more frequently than Alimta®, including 5-FU and
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`methotrexate. I typically administered Alimta® to a subset of my patients who
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`have been diagnosed with non-squamous non-small cell lung cancer or
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`mesothelioma. I am knowledgeable about the folic acid and vitamin B12 pre-
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`treatment regimen for Alimta® and understand the mechanisms behind that
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`regimen.
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`VII.
`A.
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`ANALYSIS OF THE ’209 PATENT
`It Would Have Been Apparent Prior To June 1999 To
`Pretreat Patients with Folic Acid And Vitamin B12 Before
`Administering Pemetrexed
`38. As noted previously, the claims of the ’209 patent generally require:
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`(i) treating a patient with the antifolate pemetrexed; (ii) pretreating the patient with
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`folic acid; and (iii) pretreating the patient with vitamin B12. For the reasons
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`explained below, it would have been obvious prior to June 1999 that pretreating a
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`patient with both folic acid and vitamin B12 would reduce pemetrexed toxicity.
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`Folic Acid Pretreatment Was Known
`1.
`39. Prior to June 1999, it would have been understood that pretreating a
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`patient with folic acid before administering pemetrexed would reduce pemetrexed
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`toxicity without compromising efficacy. My opinion is based on literature
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`concerning folic acid pretreatment with pemetrexed specifically as well as other
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`literature disclosing the benefits of folic acid pretreatment with antifolates
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`generally.
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`a.
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`Folic Acid Pretreatment Was Known To Ameliorate
`Antifolate Toxicity
`40. Although antifolates have a greater impact on cancer cells, healthy
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`cells experience lesser inhibition of cellular functions that may nonetheless have a
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`detrimental impact on patients, resulting in a host of potential side-effects known
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`as “toxicities.” See Ex. 1012, Mendelsohn at 270.
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`41.
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`It was known prior to June 1999 that administering folic acid may
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`counteract these antifolate toxicities. For example, it was known prior to June
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`1999, that methotrexate could be administered in conjunction with folic acid to
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`protect patients from toxicity. Ex. 1010, Morgan, Abstract. Morgan described a
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`clinical study investigating the effects of folic acid supplementation on the toxicity
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`of methotrexate (“MTX”) in patients suffering from rheumatoid arthritis. Morgan
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`showed that dietary folate was inversely related to methotrexate toxicity and that
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`negligible effects incurred at dietary folate levels greater than 400 µg/day. Id. at
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`838. In addition, supplemental folate at wide dosage levels of 5 mg/week or 27.5
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`mg/week demonstrated nearly identical reductions in toxicity and maintained
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`therapeutic efficacy. Id. This led Morgan to suggest that a multiple-vitamin pill
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`containing 900 nmol folic acid (400 µg/day) may modulate methotrexate toxicity
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`in patients that also have additional micronutrient deficiencies. Id. Morgan points
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`out that “[t]he flexibility in the dosing range, coupled with its low cost, make folic
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`acid the preferred vitamin form to treat patients with rheumatoid arthritis who are
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`taking methotrexate.” Id. at 839.
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`42. A person of ordinary skill also would have understood that folic acid
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`pretreatment would be beneficial with at least some antifolates, and pemetrexed
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`specifically, based on the literature, including:
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`• Lilly’s ’974 patent (Ex. 1005);
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`• G.B. Grindey, et al., Reversal of the toxicity but not the antitumor activity of
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`Lometrexol by folic acid, Am. Ass’n Cancer Res., 32: 324, Abstract 1921
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`(1991) (“Grindey”) (Ex. 1011); and
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`• Laurane G. Mendelsohn, et al., Preclinical and Clinical Evaluation of the
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`Glycinamide Ribonucleotide Formyltransferase Inhibitors Lometrexol and
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`LY306887, Anticancer Drug Dev. Guide: Antifolate Drugs Cancer Therapy,
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`(Jackman: Editor) Chapter 12: 261-280 (1999) (“Mendelsohn”) (Ex. 1012).
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`43. The ’974 patent is entitled “Method for Treating GAR-
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`Transformylase Tumors in Mammals and Reducing Mammalian Toxicity.”
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`Ex. 1005, ’974 patent. The patent issued on June 8, 1993 and lists “Eli Lilly and
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`Company” as the assignee.
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`44. The ’974 patent instructs that the “toxic effects of lometrexol and
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`related GAR-transformylase inhibitors and other antifolate agents which bind to
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`folate binding protein (FBP) . . . can be significantly reduced by the presence of a
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`FBP binding agent, without adversely affecting therapeutic efficacy.” Ex. 1005,
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`col. 1, ll. 47-53; see also id. col. 7, ll. 58-61, col. 8, ll. 27-29. The patent further
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`instructs that the FBP agent may be folic acid and that “[i]n the most preferred
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`embodiment of the invention, [l]ometrexol is administered to a subject suffering
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`from a solid tumor or other type of cancer and in need of treatment after
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`pretreatment with folic acid, thereby reducing toxic effects of [l]ometrexol while
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`maintaining good antitumor activity.” Id., col. 2, ll. 18-24.
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`45. The ’974 patent also instructs specific dosing schedules and dosages
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`of folic acid that should be used in pretreatment. The ’974 patent states that
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`pretreatment with an “FBP binding agent from about 1 to about 24 hours” prior to
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`folate administration is usually sufficient. Ex. 1005, col. 6, ll. 24-29. The ’974
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`patent further states that administration of the FBP binding agent may be employed
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`for “up to weeks before treatment with the active agent,” i.e., the antifolate. Id. at
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`29-36. The patent also provides, “[i]n the especially preferred embodiment of this
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`invention, about 1 mg to about 5 mg of folic acid is administered orally to a
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`mammal about 1 to about 24 hours.” Ex. 1005, col. 6, ll. 37-43.
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`46. The ’974 patent reports that “the toxic effects of such subsequent
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`treatment [(antifolate)] are greatly reduced without affecting the therapeutic
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`efficacy” from folic acid pretreatment. Ex. 1005, col. 6, ll. 54-56. The ’974 patent
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`supports its conclusions with laboratory data in mice showing an “excellent
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`antitumor activity at low doses [of lometrexol], with little or no toxic effects.”
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`Ex. 1005, col. 7, l. 60-61. The patent also reports that “pilot studies in humans
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`have established that folic acid given to patients receiving lometrexol has effected
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`reduced side effects due to the lometrexol.” Id. at col. 8, ll. 49-52. Lilly’s “pilot
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`studies” appear to involve observation of a single patient with nasopharyngeal
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`carcinoma. Id., col. 8, ll. 52-58.
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`47. While the ’974 patent does not specifically name pemetrexed, it
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`would be understood to apply to pemetrexed for several reasons.
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`• First, the formula listed as the “preferred embodiment of the invention”
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`includes the compound pemetrexed. Ex. 1005, col. 2, l. 66-col. l. 19. More
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`specifically, the general formula supports pemetrexed when ‘A’ is selected
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`to be “pyrrolo.”
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`• Second, I understand that Lilly listed the ’974 patent in the FDA’s Orange
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`Book in relation to pemetrexed, and thus, represented that the ’974 patent
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`covers pemetrexed. Ex. 1025, Alimta® Orange Book Listing.
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`• Third, the compound lometrexol, which is indisputably disclosed in the ’974
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`patent, and pemetrexed are analogues both of which inhibit the enzyme
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`GARFT (e.g., Ex. 1047, Calvert & Walling 36). Grindey suggests that the
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`impact of folic acid pretreatment on “toxicity of related analogs” to
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`lometrexol should be evaluated in further studies. Ex. 1011, Grindey at
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`1921. Notably, the lead author of Grindey is also first-named inventor of the
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`’974 patent.
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`48. Even absent Grindey’s citation regarding “related analogs,” a person
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`of ordinary skill would have been encouraged to pretreat patients receiving
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`pemetrexed with folic acid based on prior art studies like those of the ’974 patent
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`and Grindey, which show that folic acid pretreatment had a beneficial impact on
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`reducing toxicity with lometrexol and other GARFT inhibitors. For example,
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`Grindey also observes that severe toxicity was observed during Phase I trials with
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`lometrexol and that toxicity increased 100-fold when mice were placed on a folate-
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`free diet for two weeks. Grindey reports that “[h]igh doses of folic acid in the
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`drinking water completely reverse both toxicity a