Filed on behalf of Accord Healthcare, Inc., USA
`By: Chidambaram S. Iyer
`Chandran B. Iyer
`SUGHRUE MION, PLLC
`2100 Pennsylvania Avenue, NW
`Washington, DC 20037
`Tel.: (202) 293-7060
`Fax: (202) 293-7068
`Email: AccordIPR@Sughrue.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ACCORD HEALTHCARE, INC., USA,
`Petitioners
`
`v.
`
`Patent Owner of
`U.S. Patent 7,772,209 to Niyikiza
`Appl. No. 11/776,329 filed June 11, 2007
`Issued Aug. 10, 2010
`
`IPR Trial No.
`
`TBD
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 7,772,209
`PURSUANT TO 35 U.S.C. § 312 AND 37 C.F.R. § 42.108
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`
`TABLE OF CONTENTS
`
`I. 
`
`MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(A)(1) .......................... 1 
`REAL PARTY-IN-INTEREST UNDER 37 C.F.R. §
`A. 
`42.8(b)(1) ............................................................................................... 1 
`RELATED MATTERS UNDER 37 C.F.R. § 42.8(b)(2) ..................... 1 
`B. 
`LEAD AND BACK-UP COUNSEL .................................................... 2 
`C. 
`SERVICE INFORMATION ................................................................. 2 
`D. 
`PAYMENT OF FEES — 37 C.F.R. § 42.103 ................................................... 2 
`II. 
`III.  REQUIREMENTS FOR IPR UNDER 37 C.F.R. §§ 42.104 ............................ 2 
`A.  GROUNDS FOR STANDING UNDER 37 C.F.R. §
`42.104(a) ................................................................................................ 2 
`IDENTIFICATION OF CHALLENGE UNDER 37
`C.F.R. § 42.104(B) AND RELIEF REQUESTED ............................... 3 
`1. 
`Effective filing dates ................................................................... 4 
`2. 
`Prior art ....................................................................................... 4 
`CLAIM CONSTRUCTION UNDER 37 C.F.R. §§
`42.104(b)(3) ........................................................................................... 5 
`PERSON OF ORDINARY SKILL IN THE ART ................................ 6 
`D. 
`IV.  SUMMARY OF THE ‘209 PATENT ............................................................... 6 
`V. 
`TECHNICAL BACKGROUND AND STATE OF THE ART ........................ 7 
`VI.  PROPOSED REJECTIONS ............................................................................... 9 
`A.  GROUND 1: CLAIMS 1-10, 12, AND 14-21 ARE
`OBVIOUS IN VIEW OF CARRASCO AND
`HAMMOND ......................................................................................... 9 
`
`B. 
`
`C. 
`
`i
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`
`B.  GROUND 2: CLAIMS 1-10, 12, AND 14-21 ARE
`OBVIOUS OVER CARRASCO AND CALVERT ........................... 19 
`C.  GROUND 3: CLAIMS 1-10, 12, AND 14-21 ARE
`OBVIOUS OVER NIYIKIZA AND EP005 ....................................... 28 
`D.  GROUND 4: CLAIMS 1-10, 12, AND 14-21 ARE
`OBVIOUS OVER NIYIKIZA AND REFSUM ................................. 39 
`GROUND 5: CLAIMS 1-10, 12, AND 14-21 ARE
`OBVIOUS OVER NIYIKIZA AND MALINOW .............................. 48 
`GROUND 6: CLAIMS 11, 13, AND 22 ARE OBVIOUS
`OVER CARRASCO AND CALVERT AND
`THODTMANN ................................................................................... 57 
`VII.  CONCLUSION ................................................................................................. 60 
`
`
`E. 
`
`F. 
`
`ii
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`
`TABLE OF AUTHORITIES
`
`
`
`Page Nos.
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398, 127 S. Ct. 1727 (2007)…………………………………passim
`
`
`
`
`OTHER AUTHORITIES
`
`35 U.S.C. § 103……………………………………………………………....passim
`
`iii
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`
`Exhibit No.
`
`EXHIBIT LIST
`Name
`
`Exhibit 1000: Complaint - Eli Lilly and Company v.
`Accord Healthcare, Inc., USA, filed
`February 28, 2013 (1:13-cv-00335-TWP-
`DKL)
`Exhibit 1001: U.S. Patent No. 7,772,209
`
`Referred To In
`The Petition As
`
`
`(“‘209 Patent”)
`
`Exhibit 1002: File History of U.S. Patent No. 7,772,209
`
`
`
`Exhibit 1003: Carrasco et al., Acute Megaloblastic
`Anemia: Homocysteine Levels Are Useful
`for Diagnosis and Follow-Up,
`HAEMATOLOGICA, 84: 767- 768 (1999)
`Exhibit 1004: Hammond et al., A Phase I and
`Pharmacokinetic (PK) Study of the
`Multitargeted Antifol (MTA) LY231514
`with Folic Acid, PROCEEDINGS OF
`AMERICAN SOCIETY OF CLINICAL
`ONCOLOGY, 17: Abs. No. 866 (1998)
`Exhibit 1005: Calvert, An Overview of Folate
`Metabolism: Features Relevant to the
`Action and Toxicities of Antifolate
`Anticancer Agents, SEMINARS IN
`ONCOLOGY, 26: 3-10 (1999)
`Exhibit 1006: Niyikiza et al., LY231514 (MTA):
`Relationship of Vitamin Metabolite Profile
`to Toxicity, American Society of Clinical
`Oncology, PROCEEDINGS OF AMERICAN
`SOCIETY OF CLINICAL, 17: Abs. No. 2139
`(1998)
`Exhibit 1007: Malinow et al., The Effects of Folic Acid
`Supplementation on Plasma Total
`Homocysteine Are Modulated by
`Multivitamin Use and
`
`(“Carrasco”)
`
`(“Hammond”)
`
`(“Calvert”)
`
`(“Niyikiza”)
`
`(“Malinow”)
`
`iv
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`
`Methylenetetrahydrofolate Reductase
`Genotypes, ARTERIOSCLEROSIS,
`THROMBOSIS, AND VASCULAR BIOLOGY,
`17: 1157-62 (1997)
`Exhibit 1008: Refsum et al., Clinical Significance of
`Pharmacological Modulation of
`Homocysteine Metabolism, TRENDS IN
`PHARMACOLOGICAL SCIENCES, 11: 411-416
`(1990)
`Exhibit 1009: European Patent Application No. 0595005
`
`Exhibit 1010: Thodtmann et al., Clinical and
`Pharmacokinetic Phase I Study of
`Multitargeted Antifolate (LY231514) in
`Combination with Cisplatin, J. CLINICAL
`ONCOLOGY, 17: 3009-3016 (1999)
`Exhibit 1011: Declaration of Dr. Peter Cole, M.D.
`
`Exhibit 1012: C.V. of Dr. Peter Cole, M.D.
`
`(“Refsum”)
`
`(“EP005”)
`
`(“Thodtmann”)
`
`(“Cole
`Declaration”)
`
`
`
`
`
`v
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`
`Pursuant to 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42, real party in interest,
`
`Accord Healthcare, Inc., USA ("Accord" or "Petitioner") respectfully requests inter
`
`partes review (IPR) of Claims 1-22 of U.S. Patent No. 7,772,209 ("the '209
`
`Patent"), which was filed on July 11, 2007, and issued on August 19, 2010 to Clet
`
`Niyikiza and is currently assigned to Eli Lilly and Company ("Lilly" or "Patent or
`
`Owner").
`
`I. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(a)(1)
`A. REAL PARTY-IN-INTEREST UNDER 37 C.F.R. § 42.8(b)(1)
`Petitioner Accord Healthcare, Inc., USA is the real party-in-interest for the
`instant petition.
`
`B.
`RELATED MATTERS UNDER 37 C.F.R. § 42.8(b)(2)
`The ‘209 Patent is asserted by the Patent Owner in the following litigations
`
`pending in the U.S. District Court for the Southern District of Indiana: Eli Lilly and
`
`Company v. Accord Healthcare, Inc., USA, filed February 28, 2013 (1:13-cv-
`
`00335-TWP-DKL) see Ex. 1000; Eli Lilly and Company v. Accord Healthcare,
`
`Inc., USA, Apotex Inc. and Apotex Corp., filed against Accord on January 20, 2012
`
`(1:12-cv-0086-TWP-DKL) and against Apotex Defendants on April 17, 2010 (12-
`
`cv-00499-TWP-DKL); Eli Lilly and Company v. Teva Parental Medicines, Inc., et
`
`al., filed October 29, 2010 (1:10-cv-01376-TWP-DKL).
`
`Petitioner is a party to two of these litigations. Petitioner is not aware of any
`
`pending prosecution concerning the ‘209 Patent.
`
`1
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`
`C.
`LEAD AND BACK-UP COUNSEL
`Petitioner provides the following designation of counsel.
`LEAD COUNSEL
`BACK-UP COUNSEL
`Chandran B. Iyer
`Chidambaram S. Iyer
`(Reg. No. 43,355)
`(Reg. No. 48,434)
`(ciyer@sughrue.com)
`(cbiyer@sughrue.com)
`Sughrue Mion PLLC
`Sughrue Mion PLLC
`2100 Pennsylvania Ave, NW
`2100 Pennsylvania Ave, NW
`Washington, DC 20037
`Washington, DC 20037
`T: 202-293-7060, F: 202-293-7068
`T: 202-293-7060, F: 202-293-7068
`
`
`D.
`SERVICE INFORMATION
`Please address all correspondence to the lead counsel at the address provided
`
`in Section I.C of this Petition. Petitioner also consents to electronic service by
`
`email at: accordipr@sughrue.com
`
`II.
`
`
`PAYMENT OF FEES — 37 C.F.R. § 42.103
`The Petitioner authorizes the Patent and Trademark Office to charge Deposit
`
`Account No. 19-4880 for the fees set in 37 C.F.R. § 42.15(a) for this Petition for
`
`Inter Partes Review, and further authorizes payment for any additional fees to be
`
`charged to this Deposit Account.
`
`III. REQUIREMENTS FOR IPR UNDER 37 C.F.R. §§ 42.104
`A. GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(a)
`
`
`
`Petitioner certifies that the ‘209 Patent is available for IPR and that
`
`Petitioner is not barred or estopped from requesting IPR.
`
`
`
`The relevant statutory provision, 35 U.S.C. § 315(b), provides that “[a]n
`
`inter partes review may not be instituted if the petition requesting the proceeding is
`
`2
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`filed more than 1 year after the date on which the petitioner…is served with a
`
`complaint alleging infringement of the patent.”
`
`
`
`Here, the Patent Owner served Accord with a complaint alleging
`
`infringement of the ‘209 Patent on or around February 28, 2013. This complaint
`
`related to Accord’s Abbreviated New Drug Application (ANDA) for its 1000
`
`mg/vial dosage form of pemetrexed.1 Given that the Patent Owner served Accord
`
`with a complaint alleging infringement of the ‘209 Patent on or around February
`
`28, 2013, this petition is being filed less than one year after the date on which
`
`Accord was served with “a complaint.”
`
`B.
`
`IDENTIFICATION OF CHALLENGE UNDER 37 C.F.R. §
`42.104(B) AND RELIEF REQUESTED
`
`
`
`Petitioner requests inter partes review of claims 1-22 of the ‘209 Patent on
`
`the grounds set forth in the table below and requests that each of the claims be
`
`found unpatentable. An explanation of how claims 1-22 are unpatentable under the
`
`statutory grounds identified below, including the identification of where each
`
`element is found in the prior art references, and the relevance of each of the prior
`
`art references is provided in the form of detailed claim charts in section V below.
`
`
`1 In January 2012, Patent Owner commenced a lawsuit for infringement of the ‘209
`Patent related to Accord’s ANDA for its 100 mg/vial and 500mg/vial dosage
`form of pemetrexed. Although the two lawsuits name Accord, they involve
`entirely different products and are based on different set of facts.
`
`3
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`Additional explanation and support for each ground of rejection is set forth in the
`
`Declaration of Dr. Peter Cole (Ex 11).
`
`‘209 Patent Claims Basis for Rejection
`Ground
`Ground 1 Claims 1-10, 12, and
`Obvious under 35 U.S.C. §103(a) over
`14-21
`Hammond and Carrasco
`Ground 2 Claims 1-10, 12, and
`Obvious under 35 U.S.C. §103(a) over Calvert
`14-21
`and Carrasco
`Ground 3 Claims 1-10, 12, and
`Obvious under 35 U.S.C. §103(a) over
`14-21
`Niyikiza and EP005
`Ground 4 Claims 1-10, 12, and
`Obvious under 35 U.S.C. §103(a) over
`14-21
`Niyikiza and Refsum
`Ground 5 Claims 1-10, 12, and
`Obvious under 35 U.S.C. §103(a) over
`14-21
`Niyikiza and Malinow
`Ground 6 Claims 11, 13, and
`Obvious under 35 U.S.C. §103(a) over
`22
`Calvert, Carrasco and Thodtmann
`1. Effective filing dates
`The earliest application to which the ‘209 Patent claims benefit is U.S.
`
`patent application No. 60/215,310 filed June 30, 2000.
`
`2. Prior art
`Carrasco was published in August 1999 and, therefore, is prior art at least
`
`under 35 U.S.C. §102(a)
`
`Hammond was published in May 1998 and, therefore, is prior art at least
`
`under 35 U.S.C. § 102 (b)
`
`Niyikiza was published in May 1998 and, therefore, is prior art at least under
`
`35 U.S.C. § 102 (b)
`
`4
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`
`Calvert was published in April 1999 and, therefore, is prior art at least under
`
`35 U.S.C. §102 (b)
`
`Refsum was published in October 1990 and, therefore, is prior art at least
`
`under 35 U.S.C. §102 (b)
`
`Malinow was received in April 1996 and published in October 1996 and,
`
`therefore, is prior art at least under 35 U.S.C. §102 (b)
`
`EP005 filed in September 1993 and published in May 1994 and, therefore, is
`
`prior art at least under 35 U.S.C. §102(b)
`
`Thodtmann published in October 1999 and, therefore, is prior art at least
`
`under 35 U.S.C. §102(a)
`
`C.
`
`CLAIM CONSTRUCTION UNDER 37 C.F.R. §§ 42.104(b)(3)
`
`The claim terms in the ‘209 Patent are presumed to take on their ordinary
`
`and customary meaning based on the broadest reasonable interpretation of the
`
`claim language. Petitioner does not believe that any special meanings apply to the
`
`claim terms in the ‘209 Patent. Petitioner’s position regarding the scope of the
`
`claims should not be taken as an assertion regarding the appropriate claim scope in
`
`other adjudicative forums where a different claim interpretation standard may
`
`apply.
`
`5
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`
`D.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`
`
`The qualifications of a person of ordinary skill in the art to whom the ’209
`
`Patent is directed would be an MD with significant experience in the treatment of
`
`oncology patients, a significant understanding of antineoplastic agents including
`
`their efficacies, toxicities, safety, side effects, etc. Accord reserves the right to
`
`refine its POSA definition as additional information becomes available.
`
`IV. SUMMARY OF THE ‘209 PATENT
`
`The ‘209 Patent “relates to a method of administering an antifolate…in
`
`combination with a methylmalonic acid lowering acid and a FBP binding agent.”
`
`Ex. 1001, ‘209 Patent, col. 3, lines 1-5. Folic acid is identified as a “preferred FBP
`
`binding agent.” Id. at col. 3, lines 5-6. Vitamin B12 is described as a preferred
`
`example of the methylmalonic acid lowering agent. Id. at col. 4, lines 49-50.
`
`
`
`The ‘209 Patent states that “life-threatening toxicity remains a major
`
`limitation to the optimal administration of antifolates” including aminopterin,
`
`methotrexate, lometrexel, and pemetrexed. Id. at col. 1, lines 11-61. The ‘209
`
`Patent cites to several prior art references to note that the toxicity associated with
`
`antifolates is caused by increased homocysteine levels. Id. at col. 2, lines 14-31.
`
`The ‘209 Patent further states that the prior art taught supplementation with folic
`
`acid to lower homocysteine levels and thereby reduce cytotoxic activity caused by
`
`the antifolate drugs. Id.
`
`6
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`
`
`Following this introduction, the patent specification turns to the alleged
`
`discovery underlying the ‘209 Patent, which is characterized as “a method for
`
`improving the therapeutic utility of antifolate drugs by administering” vitamin
`
`B12. Id. at col. 2, lines 32-40. The ‘209 Patent asserts that the alleged discovery
`
`was the reduction of toxicity by administration of a “methylmalonic acid lowering
`
`agent,” such as vitamin B12, to a patient undergoing treatment. The ‘209 Patent
`
`also claims to have discovered that “the combination of a methylmalonic acid
`
`lowering agent and folic acid synergistically reduces the toxic events associated
`
`with the administration of antifolate drugs.” Id. at col. 2, lines 47-54.
`
`
`
`Accordingly, the ’209 patent further asserts that another alleged “discovery”
`
`was that administering a combination of folic acid and a methlymalonic acid
`
`lowering agent (such as vitamin B12) “synergistically reduces the toxic events
`
`associated” with antifolate drugs, and that this discovery was “unknown.” See id.
`
`at col. 2, lines 47-50.
`
`V. TECHNICAL BACKGROUND AND STATE OF THE ART
`
`A. Antifolate Toxicity Linked to Elevated Homocysteine
`
`As noted in the ‘209 Patent itself, toxicity was a major limitation to the
`
`admistration of antifolates, such as methotrexate and pemetrexed. See Ex. 1011,
`
`Cole Declaration at ¶ 31. It was known that the toxicity was precited by elevated
`
`homocysteine levels. See Ex. 1011, Cole Declaration at ¶ 31. In view of this
`
`7
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`strong correlation between homocysteine levels and the occurrence of cytotoxic
`
`events caused by the administration of antifolates, those skilled in the art sought to
`
`reduce toxicity by lowering homocysteine levels. See Ex. 1011, Cole Declaration
`
`at ¶¶ 41-51.
`
`B.
`
`Combination of Folic Acid and Vitamin B12 Lowers Homocysteine
`Levels
`
`
`In order to understand why folic acid and vitamin B12 can be used to reduce
`
`the toxicity associated with pemetrexed, an understanding of the metabolism of
`
`intracellular homocysteine is important.
`
`The metabolism of intracellular homocysteine was well known to one of
`
`ordinary skill in the art long before the filing of the application that issued as the
`
`‘209 Patent. See Ex. 1011, Cole Declaration at ¶¶ 36-39. Publications such as
`
`Refsum, which was published in 1990, explain that only two pathways exist for
`
`metabolizing intracellular homocysteine: salvage to methionine through
`
`remethylation, or conversion to cysteine via the trans-sulfuration pathway. See Ex.
`
`1011, Cole Declaration at ¶ 37. In most tissues, the former reaction is catalyzed by
`
`the enzyme methionine synthase This enzyme requires vitamin B12 as a cofactor
`
`and folic acid as a methyl donor cosubstrate. See Ex. 1011, Cole Declaration at ¶
`
`37.
`
`In view of the finite number of identified routes of homocystiene
`
`metabolism (two), a person having ordinary skill in the art would know to focus on
`
`8
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`methionine synthase. See Ex. 1011, Cole Declaration at ¶ 39. As discussed above,
`
`prior to the filing of the ’209 Patent, a number of references disclosed the toxicity-
`
`reducing effects of folic acid, when co-administered with an antifolate. Only one
`
`enzyme involved in metabolism of homocysteine incorporates folic acid –
`
`methionine synthase. See Ex. 1011, Cole Declaration at ¶ 39. Methionine
`
`synthase also requires its cofactor, vitamin B12, to metabolize homocysteine. See
`
`Ex. 1011, Cole Declaration at ¶ 39. In view of this understanding, those skilled in
`
`the art supplemented the administration of antifolates with folic acid and vitamin
`
`B12 to reduce levels of homocysteine and, thereby, the resultant toxicity. See Ex.
`
`1011, Cole Declaration at ¶¶ 39-41.
`
`VI. PROPOSED REJECTIONS
`A. GROUND 1: CLAIMS 1-10, 12, AND 14-21 ARE OBVIOUS IN
`VIEW OF CARRASCO AND HAMMOND
`
`
`Claims 1-10, 12, and 14-21 of the ‘209 patent are obvious over Carrasco in
`
`
`
`view of Hammond. The claims of the ‘209 patent were allowed because the
`
`Examiner could not find any prior art disclosing a method of administering
`
`pemetrexed disodium to a patient in need that included “administration of a
`
`therapeutically effective amount of folic acid and an effective amount of a
`
`methylmalonic acid lowering agent” (i.e., claims 1-10) or a method of
`
`administering pemetrexed to a patient in need, including administration of folic
`
`acid and vitamin B12 “prior to the first administration of pemetrexed disodium”
`
`9
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`(i.e., claims 12, 14-21).
`
`i. Scope and Content of Prior Art
`
`a. Carrasco
`
`Carrasco is a reference that the Examiner would have used to reject all the
`
`claims of the ‘209 Patent.
`
`Carrasco discloses a study of a patient who is administered folic acid and
`
`vitamin B12 to ameliorate toxicity caused by the administration of the antifolate
`
`methotrexate. See Ex. 1003, Carrasco at 767. Specifically, following
`
`chemotherapy for leukemia, the patient was diagnosed with megaloblastic anemia
`
`and exhibited an elevated homocysteine level of 38 µmol/L (wherein the normal
`
`level is less than 16 µmol/L). Id. at 767-768; see also Ex. 1011, Cole Declaration
`
`at ¶ 42. Carrasco provides that "Vitamin B12 (cobalamin) and folic acid
`
`deficiencies lead to megaloblastic anemia (MA), and induce accumulation of
`
`methylmalonic acid (MMA) and homocysteine [HCY]." Ex. 1003, Carrasco at 767.
`
`To lower the homocysteine levels and ameliorate the toxicity caused by the
`
`antifolate methotrexate, the patient was administered folinic acid (12 mg iv in one
`
`single dose), folic acid (5 mg/day for 14 days) and parenteral vitamin B12 (2
`
`mg/day for 4 consecutive days). Id. at 768; see also Ex. 1011, Cole Declaration at
`
`¶ 43. Carrasco reports that after 10 days of treatment “serum HCY [homocysteine]
`
`level decreased to normal value (9 µmol/L).” Ex. 1003, Carrasco at 768.
`
`10
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`
`Carrasco is highly material to the validity of the ‘209 Patent claims because
`
`Carrasco discloses administering an effective amount of folic acid and
`
`methylmalonic acid lowering agent (vitamin B12) before, in conjunction with, and
`
`after administering the antifolate methotrexate to a patient in need thereof. See id.
`
`at 767-768.
`
`While Carrasco does not disclose the order or exact amounts of folic acid
`
`and vitamin B12 administered; the ‘209 Patent concedes that the amount of folic
`
`acid and vitamin B12 that is actually administered “will be determined by a
`
`physician, in light of the relevant circumstances….” Ex. 1001, ‘209 Patent, at col,
`
`5, lines 37-41. This indicates that one of ordinary skill in the art would have
`
`arrived at the order, amount, duration, and manner of administering folic acid and
`
`vitamin B12 without undue experimentation. See Ex. 1011, Cole Declaration at ¶¶
`
`52-54.
`
`b. Hammond
`
`Hamond discloses that folic acid can be used to reduce the toxicity caused
`
`by pemetrexed. Specifically, Hammond reports on a Phase I study to determine
`
`whether administering folic acid before administering pemetrexed to human
`
`patients ameliorates toxicity and permits dose-escalation. See Ex. 1004, Hammond,
`
`at Abstract. In Hammond, twenty-one cancer patients were administered varying
`
`dose levels of pemetrexed and folic acid. Id. Hammond reports that
`
`11
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
`
`“administering folic acid 5 mg daily for 5 days starting 2 days before [beginning
`
`treatment with pemetrexed] reduces toxicity and permits dose escalation.” Id.
`
`ii. Claims 1-10, 12, and 14-21 are Obvious Over Carrasco and
`Hammond
`A person of ordinary skill in the art would have been highly motivated to
`
`combine the teachings of Carrasco and Hammond to reduce toxicity caused by the
`
`antifolate pemetrexed. Ex. 1011, Cole Declaration at ¶ 64. As stated by the
`
`Supreme Court in KSR v. Teleflex, 127 S. Ct. 1727, 1740 (2007) “[i]f a person of
`
`ordinary skill can implement a predictable variation of the prior art in the manner
`
`claimed, § 103 likely bars its patentability.” Given the statements in the ‘209
`
`Patent that the industry was continually attempting to reduce toxicity associated
`
`with antifolates, such as pemetrexed, it would have been obvious for a person
`
`skilled in the art to combine Carrasco - which teaches that vitamin B12 can be
`
`administered along with folic acid in order to reduce the toxicity associated with an
`
`antifolate - with Hammond - which teaches that administering folic acid to patients
`
`before administering pemetrexed reduces the toxicity associated with the drug. Ex.
`
`1011, Cole Declaration at ¶ 65. In other words, administering vitamin B12 and
`
`folic acid along with pemetrexed is obvious at least because it is a predictable
`
`variation of art that teaches administration of vitamin B12 and folic acid along with
`
`methotexate. Ex. 1011, Cole Declaration at ¶ 65.
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
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`
`The tables below show how each limitation of claims 1-10, 12 and 14-23 is
`
`taught by Carrasco and Hammond.
`
`Claims of the '209
`Patent
`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 methylmalonic acid
`lowering agent
`
`followed by
`administering an
`effective amount of
`pemetrexed disodium,
`wherein
`
`the methylmalonic acid
`lowering agent is
`selected from the group
`
`Carrasco and Hammond
`
`See Hammond (Abstract): Hammond discloses
`administering pemetrexed disodium to patients with
`solid cancers in phase I medical trials.
`
`See Hammond (Abstract): Hammond discloses that
`“administering folic acid 5 mg daily for 5 days starting 2
`days before MTA [pemetrexed]” permits dose
`escalation.
`See Carrasco (pg. 768): Carrasco discloses
`administering “folic acid 5 mg/day…for 14 days and
`parenteral vitamin B12 2 mg/day for 4 consecutive
`days” to reduce homocysteine levels and thereby
`ameliorate toxicity caused by the antifolate
`methotrexate. (Emphasis added)
`It would have been obvious to modify Hammond to
`administer vitamin B12 along with folic acid to lower
`homocysteine levels. Ex. 1011, Cole Declaration at ¶¶
`65-66.
`See Hammond (Abstract): Hammond discloses
`“administering folic acid 5 mg daily for 5 days starting 2
`days before MTA [pemetrexed].” (Emphasis added).
`The order in which the vitamins are administered vis-à-
`vis the administration of pemeterxed is a matter of a
`physician’s preference. Ex. 1011, Cole Declaration at
`¶¶ 52-54. As a result, one skilled in the art would have
`arrived at the order in which the vitamins are
`administered without undue experimentation.
`See Carrasco (pg. 768): Carrasco discloses vitamin B12,
`the methylmalonic acid lowering agent.
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
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`consisting of vitamin
`B12,
`hydroxycobalamin,
`cyano-10-
`chlorocobalamin,
`aquocobalamin
`perchlorate, aquo-10-
`cobalamin perchlorate,
`azidocobalamin,
`cobalamin,
`cyanocobalamin, or
`chlorochobalamin
`2. The method of claim
`1, wherein the
`methylmalonic acid
`lowering agent is
`vitamin B12.
`3. The method of claim
`2, wherein the vitamin
`B12 is administered as
`an intramuscular
`injection of about 500
`µg to about 1500 µg.
`
`See Carrasco (pg. 768): As discussed above with respect
`to the “the methylmalonic acid lowering agent is
`selected from…” element of claim 1, Carrasco discloses
`that the methylmalonic acid lowering agent is vitamin
`B12.
`See Carrasco (pg. 768): As discussed above with respect
`to the “and an effective amount of methylmalonic acid
`lowering agent” limitation of claim 1, Carrasco
`discloses parenteral administration of vitamin B12,
`which one skilled in the art would recognize as being an
`intramuscular injection. See Ex. 1011, Cole Declaration
`at ¶ 54.
`The amount and manner in which vitamin B12 is
`administered is a matter of a physician’s preference. Ex.
`1011, Cole Declaration, at ¶¶ 52-54. In fact, the ‘209
`Patent states as much: "it will be understood that the
`amount of the methylmalonic acid lowering agent
`actually administered will be determined by a physician,
`in light of the relevant circumstances…" See Ex. 1001,
`‘290 Patent, Col. 5, lines 37-50.
`Based on the teachings of Carrasco and Hammond, one
`skilled in the art would have known to administer 500
`µg to about 1500 µg of vitamin B12 as an intramuscular
`injection without undue experimentation. See Ex. 1011,
`Cole Declaration, at ¶¶ 52-54, ¶ 62.
`4. The method of claim As discussed above with respect to claim 3, one skilled
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
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`2, wherein the vitamin
`B12 is administered as
`an intramuscular
`injection of about 1000
`µg.
`
`5. The method of claim
`2, 3 or 4, wherein the
`vitamin B12
`administration is
`repeated about every 6
`to about every 12 weeks
`following the
`administration of
`vitamin B12 until the
`administration of the
`pemetrexed disodium is
`discontinued.
`6. The method of claim
`2, wherein the vitamin
`B12 is administered as
`an intramuscular
`injection of about 500
`µg to about 1500 µg.
`
`7. The method of claim
`5 wherein the folic acid
`is administered from
`about 1 to about 24
`hours prior to
`
`in the art would have recognized parenteral
`administration of vitamin B12 as being an intramuscular
`injection, Ex. 1011, Cole Declaration, at ¶ 54, and have
`arrived at the specific dosage amounts for vitamin B12
`and the manner of administering it without undue
`experimentation.
`Accordingly, based on the teachings of Carrasco and
`Hammond, one skilled in the art would have known to
`administer about 1000 µg of vitamin B12 as an
`intramuscular injection without undue experimentation.
`See Ex. 1011, Cole Declaration, at ¶¶ 52-54, ¶ 62.
`As discussed above with respect to claim 3, one skilled
`in the art would have arrived at the specific dosage
`schedule or duration for vitamin B12 without undue
`experimentation.
`Accordingly, based on the teachings of Carrasco and
`Hammond, one skilled in the art would have known to
`administer vitamin B12 about every 6 to about every 12
`weeks following the administration of vitamin B12 until
`the administration of the pemetrexed disodium is
`discontinued without undue experimentation. See Ex.
`1011, Cole Declaration, at ¶¶ 52-54, ¶ 62.
`
`As discussed above with respect to claim 3, one skilled
`in the art would have arrived at the specific dosage
`amounts for vitamin B12 and the manner of
`administering it without undue experimentation.
`Accordingly, based on the teachings of Carrasco and
`Hammond, one skilled in the art would have known to
`administer about 500 µg to about 1500 µg of vitamin
`B12 as an intramuscular injection without undue
`experimentation. See Ex. 1011, Cole Declaration, at ¶¶
`52-54, ¶ 62.
`See Hammond (Abstract): Hammond discloses
`administering folic acid to patients at any time starting 2
`days before administering pemetrexed disodium.
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
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`administration of the
`pemetrexed disodium.
`8. The method
`according to any one of
`claims 1-4, wherein
`between 0.3 mg to about
`5 mg of folic acid is
`administered orally.
`
`9. The method of claim
`8 wherein between 350
`µg to about 1000 µg of
`folic acid is
`administered.
`
`
`10. The method of claim
`9 wherein between 350
`µg to about 600 µg of
`folic acid is
`administered.
`
`
`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
`
`See Hammond (Abstract): Hammond discloses
`administering 5 mg of folic acid starting 2 days before
`administering pemetrexed disodium. A person skilled in
`the art would recognize oral administration as a
`common method of administering folic acid without
`undue experimentation. See Ex. 1011, Cole Declaration,
`at ¶ 54.
`See Hammond (Abstract): Hammond discloses
`administering 5 mg of folic acid starting 2 days before
`administering pemetrexed disodium.
`Based on the teachings of Carrasco and Hammond, one
`skilled in the art would have known to orally administer
`about 350 µg to about 1000 µg of folic acid without
`undue experimentation. See Ex. 1011, Cole Declaration,
`at ¶¶ 52-54, ¶ 62.
`See Hammond (Abstract): Hammond discloses
`administering 5 mg of folic acid starting 2 days before
`administering pemetrexed disodium.
`Based on the teachings of Carrasco and Hammond, one
`skilled in the art would have known to orally administer
`about 350 µg to about 600 µg of folic acid without
`undue experimentation. See Ex. 1011, Cole Declaration,
`at ¶¶ 52-54, ¶ 62.
`See Hammond (Abstract): Hammond discloses
`administering pemetrexed disodium to cancer patients in
`phase I trials.
`
`See Hammond (Abstract): Hammond discloses
`administering 5 mg of folic acid starting 2 days before
`administering pemetrexed disodium.
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,772,209
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`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
`
`c) administration of
`pemetrexed disodium.
`14. The method of claim
`12, wherein the vitamin
`B12 is administered as
`an intramuscular
`injection of about 500
`µg to about 1500 µg.
`
`15. The method of claim
`14, wherein the vitamin
`B12 is administered as
`an intramuscular
`injection of about 1000
`µg.
`
`Based on the teachings of Carrasco and Hammond, the
`amount of and timing of folic acid administration is a
`matter