Filed on behalf of Accord Healthcare, Inc., USA
`By: Chid 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
`
`DECLARATION FOR PETER COLE, M.D. IN SUPPORT OF 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
`
`
`
`
`
`
`ACCORD EX 1011
`
`
`By: Chid 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
`
`DECLARATION FOR PETER COLE, M.D. IN SUPPORT OF 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
`
`
`
`
`
`
`ACCORD EX 1011
`
`
`
`1.
`
`I, Peter D. Cole, resident at Montclair, New Jersey, hereby declare as
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`follows:
`
`2.
`
`I have been retained by Sughrue Mion, PLLC to provide my opinion
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`concerning the validity of U.S. Patent No. 7,772,209 ("'209 Patent"). I am being
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`compensated for my time at the rate of $ 400 per hour. My opinion is not
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`influenced in any way by the compensation that I receive and my compensation
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`will not be affected by the outcome of this matter.
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`QUALIFICATIONS
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`3.
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`I am an Associate Professor at Albert Einstein College of Medicine of
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`Yeshiva University. I received an M.D. from Cornell University Medical College
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`in 1993 and a Bachelor of Science with distinction from Cornell University in
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`Neurobiology in 1989. I completed training in general pediatrics at the Mount
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`Sinai Medical Center in 1996. I completed training in pediatric hematology and
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`oncology at The New York Hospital and Memorial Sloan-Kettering Cancer Center
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`in 1999. While at Memorial Sloan-Kettering Center, I spent 2 years in the
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`laboratory of Joseph R Bertino M.D. studying molecular pharmacology related to
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`antifolate therapy.
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`4.
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`I have authored 30 papers and 4 book chapters and have been a
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`speaker at various venues all over the world. I am an active member of the
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`2
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`
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`American Association of Cancer Research, American Society of Clinical
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`Oncology, American Society of Hematology, American Society of Pediatric
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`Hematology and Oncology, American Society for Pharmacology and Experimental
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`Therapeutics, and the Society of Pediatric Research and serve on Journal and Grant
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`Review Boards for Pediatric Hematology-Oncology, St. Baldrick’s Foundation,
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`Damon Runyon Cancer Research Foundation, and the Beez Foundation, Medical
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`Board.
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`5.
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`In 2012 I was honored as Clinical Research Training Program Mentor
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`of the Year, in 2009 I received the Henry L. Moses Award for Best Clinical Paper,
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`between 1997 to 1998 I served as the Neal Perkell Fellow in Pediatric Oncology, in
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`1996 I received the Kurt Hirschorn MD Award for Academic Excellence, in 1993 I
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`received the Clarence C. Coryell Prize in Medicine, and in 1993 I was admitted to
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`Alpha Omega Alpha Honor Medical Society.
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`6. My clinical research focuses on improving treatment for children,
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`adolescents and young adults with acute lymphoblastic leukemia or Hodgkin's
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`lymphoma, with the goals of both increasing cure rates and decreasing toxicity. To
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`this end, I have designed, conducted, and analyzed clinical trials testing different
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`antifolates for patients with cancer.
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`3
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`
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`7. My laboratory background is in the molecular pharmacology of
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`antifolates, such as methotrexate - drugs that exert their antineoplastic effects by
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`interfering with cellular processes dependent on the vitamin folic acid. My current
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`laboratory research centers on reducing the toxicity of anticancer therapy,
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`including that caused by antifolates.
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`8.
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`I have worked as an expert in various cases and have provided
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`opinions on medical standards of care and medical practices. Of these cases, I
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`have served as a testifying expert twice.
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`9.
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`A copy of the latest version of my CV is attached as Exhibit 1012.
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`LEGAL STANDARD
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`I understand that a claim is invalid if it is obvious.
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`I further understand that obviousness of a claim requires that the claim
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`10.
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`11.
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`be obvious from the perspective of a person of ordinary skill in the relevant art, at
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`the time the invention was made. In analyzing obviousness, I understand that it is
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`important to understand the scope of the claims, the level of skill in the relevant
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`art, the scope and content of the prior art, the differences between the prior art and
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`the claims, and any secondary considerations.
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`12.
`
`I understand that the United States Supreme Court in KSR Int’l Co. v.
`
`Teleflex, Inc., 127 S. Ct. 1727 (2007), noted that “[g]ranting patent protection to
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`4
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`
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`advances that would occur in the ordinary course without real innovation retards
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`progress and may, in the case of patents combining previously known elements,
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`deprive prior inventions of their value or utility.” Id. I understand that the
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`Supreme Court stressed the need for “caution” before validating patents that are
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`merely combinations of elements found in the prior art. Id. at 1741. In view of
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`this caution, the Supreme Court explained that “[t]he combination of familiar
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`elements according to known methods is likely to be obvious when it does no more
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`than yield predictable results.” Id. at 1731.
`
`13.
`
`I further understand that the Court pointed to other factors which may
`
`show obviousness. For example, the Supreme Court observed, “[w]hen a work is
`
`available in one field of endeavor, design incentives and other market forces can
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`prompt variations of it, either in the same field or a different one. If a person of
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`ordinary skill in the art can implement a predictable variation,” it is obvious. Id.
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`And “[i]f a technique had been used to improve one device, and a person of
`
`ordinary skill would recognize that it would improve similar devices in the same
`
`way, using the technique is obvious, unless its actual application is beyond his or
`
`her skill.” Id. Further, “[w]hen there is a design need or market pressure to solve a
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`problem and there are a finite number of identified, predictable solutions, a person
`
`of ordinary skill has good reason to pursue the known options within his or her
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`
`
`5
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`
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`technical knowledge.” Id. at 1732. Also, “[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.” Id. at 1740.
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`14.
`
`I understand that in KSR, the Supreme Court also stated that the
`
`factors articulated in Graham v. John Deere are to be used in the obviousness
`
`analysis. These factors are (1) the scope of the claims, (2) the scope and content of
`
`the prior art, (3) differences between the prior art and the claims asserted, and (4)
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`the level of ordinary skill in the pertinent art. Graham v. John Deere Co., of
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`Kansas City, 383 U.S. 1, 17 (1966). The Supreme Court indicated that analyzing
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`“secondary considerations” may also be done, but is not required. Id. at 17-18.
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`15.
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`I understand that secondary considerations can include evidence of
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`commercial success caused by an invention, evidence of a long-felt need that was
`
`solved by an invention, evidence that others copied an invention, or evidence that
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`an invention achieved a surprising result. I understand that such evidence must
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`have a nexus, or causal relationship to the elements of a claim, in order to be
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`relevant to the obviousness or non-obviousness of the claim. I am unaware of any
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`such secondary considerations.
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`16.
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`I understand that claims in an inter partes review are given their
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`broadest reasonable interpretation that is consistent with the patent specification.
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`
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`6
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`
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`17.
`
`I also understand that the earliest patent applicant filing leading to the
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`'209 Patent was made on June 30, 2000. I have, therefore, analyzed obviousness as
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`of that day or somewhat before with the understanding that as time passes, the
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`knowledge of a person of ordinary skill in the art will increase. I understand that
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`Eli Lilly and Company ("Lilly") might try to prove an earlier date of invention. If
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`this occurs, I reserve the right to revise my opinion.
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`18.
`
`In forming my opinion, I have relied on the '209 Patent claims and
`
`disclosure, the prior art exhibits to the Petition for inter partes review of the '209
`
`Patent, and my own experience and expertise of the knowledge of the person of
`
`ordinary skill in the relevant art in the relevant time frame (before June 30, 2000).
`
`19. During the relevant time frame, I believe that the qualifications of a
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`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. This description is approximate and a higher level of education or
`
`skill might make up for less experience and vice-versa.
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`20.
`
`I believe that I would qualify as at least a person of ordinary skill in
`
`the art and that I have a sufficient level of knowledge, experience, and education to
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`provide an expert opinion in the field of the '209 Patent.
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`
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`7
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`
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`21. My testimony in this declaration is given from the perspective of a
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`person or ordinary skill in the art at the time of the June 30, 2000 filing, and for
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`some time before then, unless otherwise specifically indicated. This is true even if
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`the testimony is given in the present tense.
`
`OPINION
`
`THE ‘209 PATENT
`
`22. The '209 Patent relates to "a method of administering an antifolate in
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`combination with a methylmalonic acid lowering agent and a FBP binding agent."
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`23.
`
`I agree with the statement in the '209 Patent that "life-threatening
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`toxicity remains a major limitation to the optimal administration of antifolates"
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`including aminopterin, methotrexate, lometrexel, and pemetrexed.
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`24. As discussed below, I also agree with the statement in the ‘209 Patent
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`that folic acid was used as a treatment for toxicities associated with antifolate drugs
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`and that homocysteine levels have been shown to be a predictor of clinical toxicity
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`related to the use of antifolate drugs.
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`25.
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`I also agree with the statement in the '209 Patent that one skilled in the
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`art would have known that supplementation with folic acid was shown to lower
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`homocysteine levels as well as clinical toxicity.
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`8
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`26. The '209 Patent, however, also purports to have "surprisingly and
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`unexpectedly" discovered that the toxicity associated with antifolates can also be
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`lowered with a methylmalonic acid lowering agent, such as vitamin B12. I
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`disagree with the characterization that this “discovery” was surprising and
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`unexpected. I understand that according to the ‘209 Patent, the purpose of
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`administering vitamin B12 and folic acid along with pemetrexed was to lower
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`toxicity associated with treatment of the antifolate.
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`27. As explained below, it would have been obvious to one skilled in the
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`art, including myself, before or slightly before June 2000 that the combination of
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`folic acid and vitamin B12 could be used to lower homocysteine levels, as well as
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`the toxicity associated with an antifolate drug, such as pemetrexed. More
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`specifically, administering folic acid and vitamin B12 along with pemetrexed
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`would have been a predictable variation of how toxicity caused by other antifolates
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`was treated.
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`ANTIFOLATE TOXICITY LINKED TO ELEVATED HOMOCYSTEINE
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`28. The properties of antifolate drugs have been extensively studied,
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`following the discovery in the 1940's that the antifolate aminopterin could
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`effectively treat patients diagnosed with leukemia. As of or slightly before June
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`2000, it was well known in the art that antifolates, such as pemetrexed, provide
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`9
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`their clinical effect by inhibiting enzymes involved in the de novo synthesis of
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`purines and thymidylate. More specifically, reduced forms of folic acid are
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`essential cofactors, which serve as single carbon donors in the enzymatic synthesis
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`of thymidylate and purine nucleotides. In this manner, antifolates are able to
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`inhibit the synthesis of DNA precursors in rapidly dividing cancer cells.
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`29. This mechanism can be described as follows: Antimetabolites are
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`compounds that either inhibit the synthesis of the precursors of DNA or, because
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`of their structural similarity to the natural precursors, are incorporated into DNA
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`and/or RNA, causing cell death or stasis. Antifolates can inhibit specifically the
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`synthesis of the pyrimidine or purine bases required for DNA synthesis, as several
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`of the enzymes required for the synthesis of these are folate dependent. As cancer
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`cells are actively proliferating, they require large quantities of DNA and RNA.
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`This makes them susceptible targets for antimetabolites, as interference in cell
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`metabolism has a greater effect when rapid cell division is taking place. This
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`mechanism is also described in Calvert et al., Clinical studies with MTA, BRITISH
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`JOURNAL OF CANCER 78(3):35-40 (1998). It is also known that antifolates target all
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`cells, not just tumors and that their deleterious effect is specifically seen in
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`hematopoetic (blood) and epithelial (skin) cells.
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`10
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`30. Pemetrexed, which is also known as multi-targeted antifolate "MTA,"
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`is a multi-targeted antifolate that is an inhibitory of the folate pathway enzymes:
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`thymidylate synthase (TS), glycinamideribonucleotide formultransferase
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`(GARFT), aminoimidazole carboxamide ribonucleotide transformylase (AICART),
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`and dihydrofolate reductase (DHFR). The toxic effects of pemetrexed include
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`neutropenia, thromboxytopenia, mucositis, skin rash, anemia, fatigue, nausea, and
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`dermatitis.
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`31. Toxicity has been a major limitation to the administration of
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`antifolates, such as methotrexate and pemetrexed. Consequently, researchers have
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`extensively studied the causes of antifolate toxicity. As of or slightly before June
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`2000, it was well known that a patient's levels of homocysteine and folate affect
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`antifolate toxicity. This is because antifolate drugs that inhibit the enzyme DHFR
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`deplete the intracellular pool of reduced folates, which are needed for the
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`metabolism of homocysteine.
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`32. More specifically, folate and vitamin B12 are necessary co-substrates
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`for the enzyme methionine synthase, which converts homocysteine to methionine.
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`Accordingly, as recognized by Calvert,1 "any functional deficiency either of
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`1 The prior art articles I reference in my Declaration are called out in the same
`way they are referred to in the accompanying Petition for Inter Partes Review.
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`11
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`vitaminn B12 or folate will reesult in redduction in tthe flux thrrough methhionine
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`synthase and a connsequent inncrease in the plasmaa level of hhomocysteeine." The
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`figure bbelow fromm Calvert ddiagrams thhis relationnship:
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`33. This correlationn between vitamin levvels, elevaated homoccysteine annd
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`antifolaate toxicity was well kknown as oof or slighttly before JJune 2000
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`examplee, in 1998 Niyikiza reported a sstudy of 1118 patientss who weree treated wwith
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`pemetreexed and mmonitored ffor changess in vitamiin metaboliite levels,
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`including
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`homocyysteine. Niiyikiza repported that there was
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`a strong coorrelation bbetween
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`homocyysteine leveels and thee developmment of clinnical toxiciity from addministratioon
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`of pemeetrexed. Sppecificallyy, Niyikiza reported thhat “[t]oxiicity was seeen in all
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`patientss with hommocysteine levels abovve a threshhold concenntration off 10 [Mu]MM.”
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`12
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`34. Similarly, Refsum reported in 1990 that administration of the
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`antifolate methotrexate induced increased homocysteine levels, which correlate
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`with antifolate toxicity. Accordingly, Refsum recognized that “plasma
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`homocysteine measurements could provide a useful adjunct to serum methotrexate
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`determination in the management of methotrexate therapy.”
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`35.
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`In addition to the knowledge that elevated homocysteine levels
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`correlate with antifolate toxicity, it was also known that administration of folic acid
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`reduced antifolate toxicity. For example, in a 1998 Meeting Abstract for the
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`American Society Clinical Oncology, Hammond shows that patients supplemented
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`with folic acid experienced less toxicity from pemetrexed. More specifically,
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`Hammond discusses a phase I study where 21 cancer patients were administered 5
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`mg of folic acid daily starting 2 days before they were administered pemetrexed.
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`These patients tolerated higher doses of pemetrexed than patients that had not
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`received folic acid. This study demonstrates that administration with folic acid
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`reduces pemetrexed toxicity.
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`36.
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`In view of the strong connection between elevated homocysteine
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`levels and the occurrence of antifolate toxicity, a person of ordinary skill would
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`have had good reason as of or slightly before June 2000 to pursue the known
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`option of reducing homocysteine levels to ameliorate pemetrexed toxicity. To
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`13
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`this end, a person skilled in the art would have considered the metabolism of
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`homocysteine and the role of folic acid therein, both of which were well
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`understood as of or slightly before June 2000.
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`COMBINATION OF FOLIC ACID AND VITAMIN B12 LOWERS
`HOMOCYSTEINE LEVELS
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`In order to understand why folic acid and vitamin B12 are necessary
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`37.
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`to lower homocysteine levels, an understanding of the metabolism of intracellular
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`homocysteine is important. Publications such as Refsum, which was published in
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`1990, explain that only two pathways exist for metabolizing intracellular
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`homocysteine:
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`the fate of intracellular homocysteine is either salvage to methionine
`through remethylation, or conversion to cysteine via the trans-
`sulfuration pathway. In most tissues, the former reaction is catalysed
`by the ubiquitous enzyme methionine synthase (Fig. 1). This enzyme
`requires vitamin B12 [methyl(I)cobalamin] as a cofactor and 5-
`methyltetrahydrofolate [folic acid] as a methyl donor.
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`38. Refsum's Figure 1, reproduced below with an additional red squares to
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`highlight homocysteine, vitamin B12, and folic acid, depicts the metabolism of
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`intracellular homocysteine.
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`14
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`39.
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`In vieew of the ffinite numbber of idenntified rout
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`es of homoocysteine
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`metabollism (two), it would hhave been obvious too one skilleed in the arrt to focus
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`on
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`methionnine synthaase (depictted as “MSS” in Figuree 1 above)
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`. More speecifically, oonly
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`one enzzyme involved in mettabolism off homocyssteine incorrporates foolic acid –
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`methionnine synthaase. Furtheermore, onnly methionnine synthaase also reequires its
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`cofactorr, vitamin BB12, to meetabolize hhomocysteiine. Accorrdingly, it
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`would havve
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` to
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`been obbvious to onne skilled in the art oon or slighttly before JJune 2000
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`supplemment the addministratioon of pemeetrexed witth folic aciid and vitaamin B12 t
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`reduce llevels of homocysteinne.
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`15
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`40. Second, it was known in the art that a negative correlation exists
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`between folate and vitamin B12 levels on one hand and homocysteine levels on the
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`other hand. For example, Refsum explains that "there is a negative correlation
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`between serum cobalamin and total plasma homocysteine" and that elevated levels
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`of homocysteine "may be normalized following cobalamin therapy." Refsum
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`further adds that "folate deficiency is a common cause of elevated plasma
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`homocysteine levels," and that "[f]olic acid (5 mg daily) efficiently decreases
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`plasma homocysteine levels."
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`41. Accordingly, a person skilled in the art as of or slightly before June
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`2000 would have known that administering folic acid and vitamin B12 was
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`effective for lowering homocysteine levels. In view of the knowledge that elevated
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`homocysteine levels strongly correlate with antifolate toxicity, it would have been
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`obvious to one skilled in the art to apply the finite number of predictable solutions
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`for lowering homocysteine levels, i.e., supplementing antifolates with folic acid
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`and vitamin B12. Indeed, many in the art at this time used this approach.
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`42. For example, Carrasco discloses a study of a patient who was
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`administered folic acid and vitamin B12 to ameliorate toxicity caused by the
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`administration of the antifolate methotrexate. Specifically, following
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`chemotherapy for leukemia, the patient was diagnosed with megaloblastic anemia.
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`16
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`The patient exhibited normal levels of serum folate and Vitamin B12, yet had
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`elevated homocysteine levels of 38 µmol/L. Normal homocysteine levels are less
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`than 16 µmol/L.
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`43. To lower the homocysteine levels and ameliorate the toxic side-effects
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`caused by treatment with the antifolate methotrexate, the patient was administered
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`folinic acid (12 mg in one single dose), folic acid (5 mg/day for 14 days) and
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`parenteral vitamin B12 (2 mg/day for 4 consecutive days). Carrasco reports that
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`after 10 days of treatment, the patient no longer exhibited symptoms of
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`megaloblastic anemia, and the patient's “serum HCY [homocysteine] level
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`decreased to [a] normal value (9 µmol/L).”
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`44. Carrasco, which was published in 1999, demonstrates the
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`understanding in the art that administration of folic acid and vitamin B12 could
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`lower elevated homocysteine levels and ameliorate antifolate toxicity.
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`Furthermore, a person of ordinary skill in the art would understand from Carrasco
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`that even a patient having normal folate/B12 levels can benefit from folic acid and
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`vitamin B12 supplementation when they are treated with an antifolate. This
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`supports my opinion that it would have been obvious to a person skilled in the art
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`to reduce toxicity of pemetrexed by administering a combination of folic acid and
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`vitamin B12.
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`45. Other publications similarly show that combined administration of a
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`folic acid and vitamin B12 to lower homocysteine levels. One example is
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`European Patent Application Number 0595005 ("EP005"), which published in
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`1994, and is entitled "Pharmaceutical preparations for lowering homocysteine
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`levels, containing vitamin b6, folic acid and vitamin b12." The claimed
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`pharmaceutical preparation comprises a combination of vitamin B6, folic acid and
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`vitamin B12. EP005 discloses that administration of the pharmaceutical
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`preparation is useful for lowering levels of homocysteine caused by “any known
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`cause, including…[d]rugs which induce elevated homocysteine levels
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`including…methotrexate….” (Emphasis added).
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`46. Moreover, EP005 reports that a “synergism exists when vitamin B12,
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`folate and vitamin B6 are given concurrently." This supports my position that the
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`homocysteine lowering effect of folic acid and vitamin B12 was not discovered in
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`2000 when the application that led to the '209 patent was filed, but rather was
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`known back in 1994.
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`47. EP005 further discloses that the claimed pharmaceutical preparation
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`can be used to treat elevated levels of homocysteine or prophylactically to prevent
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`increases in homocysteine levels. This shows the that it was known in the art to
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`18
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`adminisster folic accid and vittamin B12 prior to treeatment wiith a drug iincreases iin
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`homocyysteine leveels, such as pemetrexxed.
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`448. EP0005 also disccloses exemmplary dossages for VVitamin B66, folic acidd
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`and Vitaamin B12 in (µg/d/kgg body weight) in thee Table repproduced bbelow:
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`UUsing an avverage boddy weight oof 70 kg, EEP005 teachhes the fol
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`lowing do
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`ranges:
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`VVitamin BB6
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`10500 µg - 52,500 µg
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`Foolic Acid
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`Vitammin B12
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`105 µgg - 10,500
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`µg
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`105 µg
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`- 5,250 µgg
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`49. These ranges enncompass tthe dose raanges recitted in the '2209 patent
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`claims. As I discuuss below aat paragrapphs 52-53,
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`selecting aan effectivve dose of ffolic
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`acid andd vitamin BB12 from tthe ranges disclosed iin EP005 wwould dep
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`end on a
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`patient'ss particularr circumstaances. Thiis type of ddeterminatiion is routiine for a
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`physiciaan and wouuld not reqquire unduee experimeentation.
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`50. Malinnow, whichh publisheed in 1996, is anotherr reference
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`the hommocysteine--lowering eeffects of aadministerring folic aacid and vittamin B12
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`19
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`that disclooses
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`. In
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`particular, Malinow reports "a significant negative correlation between tHcy and
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`basal levels of folate, P5'P [vitamin B6', and [vitamin] B12; the simultaneous
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`intake of these vitamin in multivitamins may be involved in interactions that could
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`partially account for these associations."
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`51. Moreover, Malinow reports that "[i]t could be broadly surmised that
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`individuals in whom tHcy levels are not lowered by FA [folic acid]
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`supplementation…additional treatment with other agents, such…cobalamin…may
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`be advisable." This reference, just like Carrasco and EP005, makes clear to a
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`person of ordinary skill in the art that administering a combination of folic acid and
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`vitamin B12 can reduce homocysteine levels. This further supports my position
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`that it would have been obvious to administer folic acid and vitamin B12 with
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`pemetrexed, given the strong correlation between elevated homocysteine levels
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`and pemetrexed toxicity.
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`52. With this knowledge, selection of particular dosage parameters would
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`have been a routine matter of physician preference. The claims of the '209 patent
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`include limitations directed to specific timing, manner, and amount of folic acid
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`and vitamin B12 to be administered; in my opinion, each of these was either
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`known in the art or readily ascertainable without undue experimentation. The
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`disclosure of the '209 patent supports my position. In particular, the '209 patent
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`20
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`states that the conditions for administering folic acid and vitamin B12 will be
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`determined by a physician, in light of the relevant circumstances, including "the
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`condition to be treated, the chosen route of administration, the actual agent
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`administered, the age, weight, and response of the individual patient, and the
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`severity of the patient's symptoms…."
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`53.
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`I agree with the above statement that the particular amount of folic
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`acid and vitamin B12 administered and the timing of administration are both
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`routinely determined by a physician according to the a patient's particular
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`circumstances.
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`54. Furthermore, the manner of administering folic acid and vitamin B12
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`recited in the '209 patent claims was also well known as of or slightly before June
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`2000. Claim 8, for example, states that folic acid is administered orally. Oral
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`administration of folic acid is well known in the art and is the typical method of
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`administration. Claim 3 states that vitamin B12 is administered by intramuscular
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`injection. This too was well known as of or slightly before June 2000. Parenteral
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`administration, which includes intramuscular injection, is the typical method of
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`administration.
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`55. Turning to claims 11, 13, and 22 of the '209 patent, I note that these
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`claims are directed to a combination therapy of pemetrexed and cisplatin.
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`21
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`Combination treatment therapy using an antifolate and cisplatin was well known as
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`of or slightly before June 2000. For example, Thodtmann, which published in
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`1998, discloses a combination therapy of pemetrexed and cisplatin, as well as
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`dosing schedules.
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`56. Thodtmann reports the results of a phase I clinical study of patients
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`with solid tumors who received a combination of pemetrexed and cisplatin. From
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`this study, Thodtmann reports that "MTA [pemetrexed] may be safely combined
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`with cisplatin and that this schedule is clinically active. We recommend MTA 500
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`mg/m2 plus cisplatin 75 mg/m2 as the dose to be used in phase II studies."
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`57.
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`In view of Thodtmann, and the general knowledge in the art as of or
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`slightly before June 2000, one skilled in the art would have recognized the
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`advantages of administering pemetrexed disodium with cisplatin. This
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`combination would have been obvious.
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`GROUNDS FOR REJECTIONS
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`58.
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`I have reviewed Accord’s Petition for inter partes review of the ‘209
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`patent (“the Petition”). The Petition sets forth 6 Grounds by which the claims of
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`the ‘209 patent are proposed to be invalid over prior art references. I have
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`considered each of these Grounds and the prior art references cited therein, and I
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`22
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`agree with the conclusions that the claims of the ‘209 patent are invalid for the
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`reasons stated. Below I discuss each of these Grounds.
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`1. Ground 1: Claims 1-10, 12, and 14-21 are obvious in view of Carrasco
`and Hammond
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`59. Ground 1 asserts that claims 1-10, 12 and 14-21 of the '209 patent
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`would have been obvious in view of Carrasco and Hammond.
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`i. Carrasco
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`60. Carrasco discloses a study of a patient who is administered folic acid
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`and vitamin B12 to ameliorate toxicity caused by the administration of the
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`antifolate methotrexate. See Ex. 1003, Carrasco at 767. Specifically, following
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`chemotherapy for leukemia, the patient was diagnosed with megaloblastic anemia
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`and exhibited an elevated homocysteine level of 38 µmol/L (wherein the normal
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`level is less than 16 µmol/L). Id. at 767-768. Carrasco provides that "Vitamin B12
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`(cobalamin) and folic acid deficiencies lead to megaloblastic anemia (MA), and
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`induce accumulation of methylmalonic acid (MMA) and homocysteine [HCY]."
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`Id. at 767.
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`61. To lower the homocysteine levels and ameliorate the toxicity caused
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`by the antifolate methotrexate, the patient was administered folinic acid (12 mg iv
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`in one single dose), folic acid (5 mg/day for 14 days) and parenteral vitamin B12
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`23
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`(2 mg/day for 4 consecutive days). Id. at 768. Carrasco reports that after 10 days
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`of treatment “serum HCY [homocysteine] level decreased to normal value (9
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`µmol/L).” Ex. 1003, Carrasco at 768.
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`62. While Carrasco does not disclose the order or exact amounts of folic
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`acid and vitamin B12 administered; a physician routinely makes these determines
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`based on a patient's particular circumstances. The ‘209 Patent supports this
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`conclusion, stating that the amount of folic acid and vitamin B12 that is actually
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`administered “will be determined by a physician, in light of the relevant
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`circumstances….” Ex. 1001, ‘209 Patent, at col, 5, lines 37-41. Accordingly, one
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`of ordinary skill in the art would have arrived at the order, amount, duration, and
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`manner of administering folic acid and vitamin B12 without undue
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`experimentation.
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`ii. Hammond
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`63. Hammond discloses that folic acid can be used to reduce the toxicity
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`caused by pemetrexed. Specifically, Hammond reports on a Phase I study to
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`determine whether administering folic acid before administering pemetrexed to
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`human patients ameliorates toxicity and permits dose-escalation. See Ex. 1004.,
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`Hammond, at Abstract. In Hammond, twenty-one cancer patients were
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`administered varying dose levels of pemetrexed and folic acid. Id. Hammond
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`24
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`reports that “administering folic acid 5 mg daily for 5 days starting 2 days before
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`[beginning treatment with pemetrexed] reduces toxicity and permits dose
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`escalation.” Id.
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`iii. Claims 1-10, 12 and 14-21 are obvious in view of Carrasco and
`Hammond
`64. A person of ordinary skill in the art would have been highly motivated
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`to combine the teachings of Carrasco and Hammond to reduce toxicity caused by
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`the antifolate pemetrexed. As discussed above, toxicity has been a major
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`limitation to the administration of antifolates, such as methotrexate and
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`pemetrexed. Consequently, significant efforts have been undertaken to reduce
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`antifolate toxicity.
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`65.
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`In view of this objective, a person having ordinary skill in the art
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`would have been highly motivated to combine Carrasco - which teaches that
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`vitamin B12 can be administered along with folic acid in order to reduce the
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`toxicity associated with an antifolate - with Hammond - which teaches
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`administering pemetrexed to cancer patients and supplementing with folic acid to
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`reduce toxicity associated with the drug. In other words, admi
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