Case 1:10-cv-01376-TWP-DKL Document 336 Filed 03/31/14 Page 1 of 34 PageID #: 8232
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`UNITED STATES DISTRICT COURT
`SOUTHERN DISTRICT OF INDIANA
`INDIANAPOLIS DIVISION
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`Case No. 1:10-cv-01376-TWP-DKL
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`ELI LILLY AND COMPANY,
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` Plaintiff,
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` v.
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`TEVA PARENTERAL MEDICINES, INC.,
`APP PHARMACEUTICALS, LLC,
`PLIVA HRVATSKA D.O.O.,
`TEVA PHARMACEUTICALS USA INC.,
`BARR LABORATORIES, INC.,
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` Defendants.
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`
`FINDINGS OF FACT AND CONCLUSIONS OF LAW
`FOLLOWING BENCH TRIAL AUGUST 19, 2013
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`This matter is before the Court for decision on the validity of claims 9, 10, 12, 14, 15, 18,
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`19 and 21 (the “Asserted Claims”) of the U.S. Patent No. 7,772,209 (the “‘209 Patent”). The
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`‘209 Patent is a method-of-use-patent which covers the co-administration of pemetrexed
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`disodium (“pemetrexed”) with two nutrients—folic acid and vitamin B12—that protect against
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`the side effects of the drug ALIMTA®. The matter was before the Court for a bench trial
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`beginning on August 19, 2013 and concluding on August 29, 2013. This is a Hatch-Waxman
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`patent infringement action brought by Eli Lilly and Company (“Lilly”), the owner of the ‘209
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`Patent, against Defendants Teva Parenteral Medicines, Inc. (“Teva Parenteral”), Teva
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`Pharmaceuticals USA, Inc. (“Teva Pharmaceuticals”) (collectively with Teva Parenteral,
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`“Teva”), APP Pharmaceuticals, LLC (“APP”), Barr Laboratories, Inc. (“Barr”), and Pliva
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`Hrvatska d.o.o. (“Pliva”) (collectively, “Defendants”) arising out of Defendants’ filing of
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`Abbreviated New Drug Applications (“ANDAs”) with the Food and Drug Administration
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`(“FDA”) seeking approval to market the pemetrexed disodium products identified in Teva’s
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`Wockhardt Exhibit 1028 - 1
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`Case 1:10-cv-01376-TWP-DKL Document 336 Filed 03/31/14 Page 2 of 34 PageID #: 8233
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`ANDAs Nos. 90-352 and 90-674, APP’s ANDA No. 90-384, and Barr’s and Pliva’s ANDA No.
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`91-111 (collectively the “ANDA Products”) and covered under the ‘209 Patent.
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`As mentioned earlier, the ‘209 patent describes a method of administering a
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`chemotherapy drug, pemetrexed, with vitamins, which is marketed by Lilly under the trade name
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`ALIMTA®. Lilly is only asserting infringement of the Asserted Claims of the ’209 Patent with
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`respect to the ANDA Products. Each Defendant stipulates that under the Court’s claim
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`construction (Dkt. 115) and under the current laws of infringement, the sale of its ANDA
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`Products, in accordance with the proposed labeling for each of those respective ANDA Products,
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`would infringe the Asserted Claims of the ‘209 Patent, to the extent those claims are found valid
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`and enforceable. Having heard testimony and considered the exhibits and arguments of the
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`parties, the Court finds the Defendants have failed to show by clear and convincing evidence that
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`the Asserted Claims of the ‘209 Patent are invalid for obviousness, obviousness-type double
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`patenting, inadequate description or lack of enablement, and the Asserted Claims of the ‘209
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`Patent are valid and enforceable. In support thereof, the Court makes the following findings of
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`fact and conclusions of law pursuant to Federal Rule of Civil Procedure 52.
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`A.
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`The Parties
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`I. FINDINGS OF FACT
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`Plaintiff Lilly is a corporation organized and existing under the laws of the State of
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`Indiana, having its corporate offices and principal place of business at Lilly Corporate Center,
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`Indianapolis, Indiana 46285. Lilly is engaged in the business of research, development,
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`manufacture and sale of pharmaceutical products throughout the world. Lilly sells pemetrexed in
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`the United States under the trademark ALIMTA® for treatment of specific types of lung cancer
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`and mesothelioma. ALIMTA® is covered under U.S. Patent No. 5,344,932, which is owned by
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`The Trustees of Princeton University and licensed exclusively to Lilly.
`2
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`Wockhardt Exhibit 1028 - 2
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`The Defendants are all corporations primarily engaged in the business of making and
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`selling drugs in generic form. Defendant Teva Parenteral is a corporation organized and existing
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`under the laws of the State of Delaware, having its principal place of business at 19 Hughes,
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`Irvine, California 92618. Defendant Teva Pharmaceuticals is a corporation organized and
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`existing under the laws of the State of Delaware, having its principal place of business at 1090
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`Horsham Road, North Wales, Pennsylvania 19454. Defendant APP is now Fresenius Kabi USA,
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`LLC, a Delaware limited liability company with its principal place of business at Three
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`Corporate Drive, Lake Zurich, Illinois 60047. Defendant Barr is a corporation organized and
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`existing under the laws of the State of Delaware, having its principal place of business at 1090
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`Horsham Road, North Wales, Pennsylvania 19454. Defendant Pliva is a limited liability
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`company organized and existing under the laws of the Republic of Croatia with its principal
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`place of business at Prilaz baruna Filipovica 25, 10000 Zagreb, Croatia.
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`B.
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`The Patent-In-Suit
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`The patent-in-suit U.S. Patent No. 7,772,209, was issued to Lilly on August 10, 2010, and
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`Lilly is the current owner of the ‘209 Patent. The ‘209 Patent covers the method of
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`administration of ALIMTA®, requiring that physicians co-administer the drug with folic acid and
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`vitamin B12 to reduce the incidence of patient toxicity caused by ALIMTA®.
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`C.
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`History of Lilly’s Antifolate Development Prior to the ‘209 Patent
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`1.
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`Background on Antifolates
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`The ‘209 Patent describes a method of using an antifolate, pemetrexed, with vitamins.
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`Antifolates are a type of chemotherapy drug used to treat certain types of cancer. Antifolates
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`work by competing with folates, a class of essential nutrients that includes folic acid. Folates
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`participate in chemical reactions in the body that make chemical precursors to DNA. DNA, in
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`turn, is required for division and growth of both normal cells and cancer cells. Antifolates work
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`Wockhardt Exhibit 1028 - 3
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`Case 1:10-cv-01376-TWP-DKL Document 336 Filed 03/31/14 Page 4 of 34 PageID #: 8235
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`by interfering with the action of folates and deprive cancer cells of the DNA precursors they
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`need to proliferate, or grow. Antifolates are used for their antiproliferative effect in the treatment
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`of cancer to inhibit cell growth and division, which causes cancer cells to die. Because of the
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`competitive relationship between folates and antifolates, the ability of an antifolate to fight
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`cancer depends on the relative amount of folate and antifolate in the cell. As folate levels are
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`increased, greater amounts of antifolates are needed to achieve an antiproliferative effect.
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`Cancer cells are fast-growing and thus have a high demand for DNA precursors, making
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`them particularly susceptible to the effects of antifolates. However, fast growing normal cells,
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`such as cells that line the gastrointestinal tract and cells of the bone marrow, also divide rapidly
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`and are therefore also particularly susceptible to antifolates. Accordingly, the same mechanisms
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`by which antifolates kill cancer cells also kill fast-growing normal cells, causing antifolate-
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`related side effects referred to as “toxicities.” Some of these toxicities – such as mucositis,
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`anemia and low white blood cell counts– can be severe and even life-threatening.
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`Antifolate research began in 1948 with observations by Dr. Sidney Farber (“Dr. Farber”)
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`of children with leukemia. The children were given folic acid contained in liver extract, which
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`Dr. Farber observed caused their tumor growth to accelerate. Based on that finding, Dr. Farber
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`administered an experimental antifolate called aminopterin, which caused some of his patients to
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`go into remission. Between 1950 and 1999, a great number of antifolates were made and tested,
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`but as of 1999 the only antifolate approved by the FDA for treating cancer was methotrexate,
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`which was approved in the 1950s. Methotrexate is also used in the treatment of rheumatoid
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`arthritis (“RA”). Both cancer and RA patients experience toxicity from antifolates due to their
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`antiproliferative effects – i.e. by killing rapidly dividing cells. However, unlike in cancer
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`treatment, this antiproliferative effect is not the mechanism by which methotrexate treats RA.
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`4
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`Wockhardt Exhibit 1028 - 4
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`2.
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`Lilly’s antifolate research and development in the 1990s
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`In the 1990s, Lilly had multiple antifolates in clinical use or development, including
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`pemetrexed, lometrexol, and LY309887 (the “‘887 compound”). In a few instances, researchers
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`attempted to use folic acid pretreatment with antifolates in order to reduce the toxicities of the
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`drug. Initial clinical trials of lometrexol, without any supplementation, were considered a
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`“complete disaster” resulting in “appalling toxicities.” Calvert Dep. Tr. 92:8-14. In an effort to
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`address these severe toxicities, researchers tried administering lometrexol with folic acid. A
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`Phase I clinical trial was conducted by Laohavinij1 in 1996, which involved administering a daily
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`oral dose of 5 mg of folic acid seven days before and seven days after lometrexol administration.
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`TX 1036. However, the Laohavinij study of lometrexol with folic acid pretreatment reported
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`only one response among folic acid supplemented patients, which was fewer than had been
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`observed in earlier unsupplemented patients. TX 1036 at 333. Lilly had also pursued clinical
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`development of a related antifolate, the ‘887 compound, which was also tested with folic acid
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`pretreatment for the same reason as lometrexol, but as with lometrexol, those studies that
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`attempted to reduce toxicity with folic acid supplementation proved unsuccessful due in part to
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`the decrease in efficacy. In 1994, Lilly obtained U.S. Patent No. 5,217,974 (the “‘974 Patent”).
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`The ‘974 Patent claimed the use of folic acid pretreatment with a class of antifolates, with the
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`preferred antifolate being lometrexol. TX 916.
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`One of the antifolate drugs Lilly had in development during the 1990s was pemetrexed.
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`By the late 1990s, pemetrexed was viewed as a very promising anticancer drug. In April 1999, it
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`was reported that phase II studies showed responses in six different tumor types, and the activity
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`of the drug was considered “remarkable and unusual in a new drug of any class at this stage of
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`1 Laohavinij, et al., A Phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic
`acid, INVESTIGATIONAL NEW DRUGS, 14: 325-335 (1996) (TX1036).
`5
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`Wockhardt Exhibit 1028 - 5
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`development.” TX 907 at 107. In addition, as of June 1999, the toxicities associated with
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`pemetrexed were considered “manageable and predictable” through dose and schedule
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`adjustments, allowing for a broad scale of clinical use. Id.
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`D.
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`Development of the ‘209 Patent
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`Dr. Clet Niyikiza (“Dr. Niyikiza”) is a mathematician that was employed by Lilly in the
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`1990s to help with the clinical development of cancer compounds. In early 1997, Dr. Niyikiza
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`performed a series of statistical analyses, known as multivariate analyses, on more than 60
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`variables in patients participating in pemetrexed clinical trials in efforts to better understand
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`which patients were likely to develop the sporadic toxicities observed with pemetrexed. Dr.
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`Niyikiza published the results of his multivariate analyses in two abstracts in 1998. TX 910 at
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`2139; TX 911 at 609P. The results of the analyses pointed to a correlation between the incidence
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`of pemetrexed toxicities and patients’ levels of homocysteine. Dr. Niyikiza reported that
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`homocysteine levels of at least 10 micromolar correlated with specific pemetrexed toxicities.
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`This amount is below the threshold for finding that a person has clinically high homocysteine
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`levels, which is >15 micromolars. TX 1503 at 84; Green Tr. 540:9 –541:13. Thus, the
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`homocysteine levels identified by Dr. Niyikiza as a marker for pemetrexed toxicity was a
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`subclinical elevation level. Niyikiza Tr. 732:1-13.
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`Elevated homocysteine levels can be a marker for either folic acid or vitamin B12
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`deficiencies, among other conditions. Another substance, methylmalonic acid (“MMA”), is a
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`predictor of vitamin B12 deficiency, but not folate deficiency. Thus, elevated homocysteine
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`levels (without information about a patient’s MMA levels) can indicate either folate deficiency
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`or vitamin B12 deficiency, while elevated homocysteine and elevated MMA levels together
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`indicate that the patient at least has a vitamin B12 deficiency. Importantly, elevated
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`homocysteine without elevated MMA levels indicates that the patient does not have a vitamin
`6
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`Wockhardt Exhibit 1028 - 6
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`Case 1:10-cv-01376-TWP-DKL Document 336 Filed 03/31/14 Page 7 of 34 PageID #: 8238
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`B12 deficiency. Analyzing data from a small set of patients receiving pemetrexed, Dr. Niyikiza
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`found in his initial analyses, and published in his abstracts (TX 910, 911), that there was no
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`statistical correlation between toxicity and the other variable he measured, including MMA,
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`suggesting at the time that there was no correlation between toxicity and patients’ vitamin B12
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`levels. Despite what he found in his initial analyses, Dr. Niyikiza still believed there was a
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`connection between toxicity and patients’ B12 levels. He suggested to Lilly, internally, that
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`pretreating patients with a combination of low doses of vitamin B12 and folic acid would help
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`reduce the frequency of sporadic toxicities observed by Lilly in its pemetrexed clinical trials.
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`This idea was widely rejected by oncology experts both inside and outside Lilly, as the toxicities
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`associated with pemetrexed were not viewed as problematic and they were concerned instead,
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`that vitamin supplementation could adversely affect pemetrexed’s efficacy. Calvert Dep. 124:7-
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`125:25.
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`In late 1999, after the relevant priority date for this litigation, clinicians in the ongoing
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`phase III pemetrexed registration trial in mesothelioma patients witnessed an alarming increase
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`in drug-related patient deaths, around 7%; a 2% death rate was high enough to cause serious
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`concerns with a drug in clinical trials. Niyikiza Tr. 795:16-26. Up until that point, pemetrexed’s
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`toxicity generally appeared to be manageable and tolerable; however, the sudden increase in
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`patient deaths threatened to halt the development of the drug. Dr. Niyikiza reran his multivariate
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`analysis on a larger database of patients, which this time revealed a “very strong” correlation
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`between toxicities and elevated homocysteine, and additionally a stronger collinear nature
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`between homocysteine and MMA, with about 15% of patients having very high levels of MMA.
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`Niyikiza Tr. 796:17-797:2. This information was not previously known or disclosed at the time
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`the Niyikiza abstracts were published. Niyikiza Tr. 797:3-7. Relying on the information about
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`the increase in drug-related deaths, as well as further analyses of additional data by Dr. Niyikiza,
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`Wockhardt Exhibit 1028 - 7
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`Case 1:10-cv-01376-TWP-DKL Document 336 Filed 03/31/14 Page 8 of 34 PageID #: 8239
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`Lilly decided to implement Dr. Niyikiza’s invention in the ongoing phase III registration trial by
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`intervening with low levels of folic acid and vitamin B12 supplementation prior to administering
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`pemetrexed. In a letter dated December 3, 1999, Lilly informed the FDA that the study protocol
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`would be changed so that each patient in the study would receive 350 to 1000 µg of folic acid,
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`with 500 µg being the recommended dose, and 1000 µg of vitamin B12 as an intramuscular
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`injection. TX 330 at 3. The FDA response in January 2000 was that it did not support the
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`addition of vitamins to the ongoing pemetrexed mesothelioma trial. TX 2100.
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`Despite the FDA’s reservations, Lilly went ahead and implemented Dr. Niyikiza’s
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`vitamin supplementation regimen in the phase III mesothelioma trial. The result was that
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`supplementing patients with low doses of folic acid and vitamin B12 prior to and during therapy
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`mitigated pemetrexed’s toxicities without hurting its efficacy. Dr. Niyikiza published his
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`findings, including further analyses of the roles that folic acid and vitamin B12 each played in the
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`observed toxicities, in 2002 in the “Molecular Cancer Therapeutics Journal.” TX 80. Later in
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`2002, the results of the phase III trial of pemetrexed for mesothelioma, including data
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`demonstrating that Dr. Niyikiza’s vitamin supplementation regimen increased the rate of
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`patients’ response to pemetrexed therapy, were presented at the plenary session of the meeting of
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`the American Society of Clinical Oncology. Niyikiza Tr. 845:4-17. The priority date for Lilly’s
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`patent application on Dr. Niyikiza’s invention is June 30, 2000, and the ‘209 Patent was issued
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`on August 10, 2010. Dr. Niyikiza is listed as the sole inventor of the ’209 Patent.
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`E.
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`Claims Asserted in the ‘209 Patent
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`Lilly is asserting claims 9, 10, 12, 15, 18, 19, and 21 of the ‘209 Patent with respect to the
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`ANDA Products. TX 1 at cols. 11-12. Each claim requires pretreatment with a specified amount
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`of folic acid, up to 1000 µg, and with vitamin B12 in the amount of 55-1,500 µg in claims 12, 14
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`and 21, and 1000 µg in claims 15, 18, and 19, prior to administering pemetrexed. Claims 19, 21,
`8
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`Wockhardt Exhibit 1028 - 8
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`Case 1:10-cv-01376-TWP-DKL Document 336 Filed 03/31/14 Page 9 of 34 PageID #: 8240
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`and 22 further require a specific schedule for those pretreatments, and claims 15, 18 and 19
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`require administration of vitamin B12 by intramuscular injection.
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`F.
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`Person of Ordinary Skill in the Arts
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`The Court previously determined, and the parties no longer dispute, that a person of
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`ordinary skill in the art (“POSA”) can be a medical doctor who specializes in oncology or a
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`medical doctor with extensive experience in the areas of nutritional sciences involving vitamin
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`deficiencies. However, as to the latter person, this individual would need to have collaborated
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`with medical oncologists who have knowledge and experience in the treatment of cancer through
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`the use of antifolates. See Dkt. 115 at 8.
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`II. CONCLUSIONS OF LAW
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`The ‘209 Patent is presumed to be valid under 35 U.S.C. § 282. Jones v. Hardy, 727 F.2d
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`1524, 1528 (Fed. Cir. 1984). Defendants, as the parties challenging the validity of the ‘209
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`Patent, bear the burden of proving invalidity by clear and convincing evidence. Abbott Labs. v.
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`Baxter Pharm. Prods., Inc., 334 F.3d 1274, 1282 (Fed. Cir. 2003). The Supreme Court has
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`defined “clear and convincing” evidence as that which gives the finder of fact “an abiding
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`conviction that the truth of [the proponent’s] factual contentions are highly probable.” Colorado
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`v. New Mexico, 467 U.S. 310, 316 (1983).
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`A.
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`The Asserted Claims in the ‘209 Patent are not Obvious
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`Defendants argue that each of the Asserted Claims in the ‘209 Patent are obvious. To
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`prove obviousness, Defendants must show by clear and convincing evidence that “the
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`differences between the subject matter [of the claims] and the prior art are such that the subject
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`matter as a whole would have been obvious at the time the invention was made to a person
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`having ordinary skill in the art to which said subject matter pertains.” 35 U.S.C. § 103; KSR Int’l
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`Co. v. Teleflex, Inc., 550 U.S. 398, 406 (2007). Obviousness is ultimately a legal conclusion
`9
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`Wockhardt Exhibit 1028 - 9
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`based on underlying factual findings, including (1) the scope and content of the prior art; (2) the
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`differences between the claims and the prior art; (2) the level of ordinary skill in the art; and (4)
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`objective considerations of non-obviousness such as commercial success and satisfaction of a
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`long-felt need. Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 994 (Fed. Cir.
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`2009) (citing Graham v. John Deere Co., 383 U.S. 1, 17 (1966)).
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`Thus, the Court must determine whether a POSA “would have been motivated to
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`combine the teachings of the prior art references to achieve the claimed invention.” Id.
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`However, proving obviousness “requires more than a mere showing that the prior art includes
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`separate references covering each separate limitation in a claim under examination. Rather,
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`obviousness requires the additional showing that a person of ordinary skill at the time of the
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`invention would have selected and combined those prior art elements . . . .” Unigene Labs., Inc.
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`v. Apotex, Inc., 655 F.3d 1352, 1360 (Fed. Cir. 2011). Under this legal standard for showing
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`obviousness, Defendants must prove that a POSA would have had reason to (1) administer folic
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`acid pretreatment with pemetrexed, (2) administer vitamin B12 pretreatment with pemetrexed,
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`and (3) administer each of them according to the doses and schedules set forth in the Asserted
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`Claims. Based upon the factual findings, the Court concludes that Defendants have not shown
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`by clear and convincing evidence that a POSA would have been so motivated
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`1.
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`Folic Acid Pretreatment with Pemetrexed was not Obvious
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`a. Worzalla & Hammond prior art
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`Defendants argue that Worzalla2 (TX 384) or Hammond3 (TX 911, 912) would have
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`motivated a POSA to add folic acid pretreatment to pemetrexed in order to reduce toxicity.
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`2 Worzalla, et al., Role of Folic Acid in Modulating the Toxicity and Efficacy of the Multitargeted
`Antifolate, LY23154, ANTI CANCER RESEARCH, 18:32353240 (1998) (TX384).
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` 3
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` Hammond, et at., A phase I and pharmacokinetic (PK) study of the multitargeted antifolate (MTA,
`LY231514) with folic acid (FA0, ANNALS OF ONCOLOGY, 9:129, Abstract 620P (1998)(TX911).
`10
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`Wockhardt Exhibit 1028 - 10
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`Case 1:10-cv-01376-TWP-DKL Document 336 Filed 03/31/14 Page 11 of 34 PageID #: 8242
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`Worzalla, published in 1998, reports the results of a preclinical mouse study of folic acid
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`pretreatment with pemetrexed. In the Worzalla study, folic acid was used in modulating the
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`toxicity of pemetrexed in mice in three study groups: mice on a low-folate diet, mice that were
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`given a low-folate diet along with folic acid supplementation, and a group of mice on a regular
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`diet. The results of the study showed that for the mice on the low-folate diet that were
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`supplemented with folic acid, anti-tumor activity was only maintained at much higher doses of
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`the drug and at levels that would not have been tolerable to humans in clinical trials, or, as
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`Lilly’s expert Dr. Bruce A. Chabner (“Dr. Chabner”) explained at trial, “astronomical doses” of
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`pemetrexed were required to achieve antitumor efficacy in mice receiving folic acid
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`supplementation as compared to unsupplemented mice. Chabner Tr. 1086:3-10; TX 884 at Tbl.
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`1; Zeisel Tr. 1598:17-22 (stating that mice supplemented with folic acid required 100 times the
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`dose to obtain the same lethality of the cancer cells as unsupplemented mice); Green Tr. 524:11-
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`16 (same). Despite the fact that Worzalla did not make a comparison between the standard diet
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`group of mice and the supplemented and unsupplemented low-folate diet mice, the Defendants’
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`expert, Dr. Mark J. Ratain (“Dr. Ratain”), testified that a POSA would compare the toxicity and
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`efficacy observed in the standard diet and low-folate-plus-supplementation group of mice, and
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`would recognize that based on the data from all three mouse groups that folate supplementation
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`improved pemetrexed’s therapeutic index. Ratain Tr. 164:23–165:7. Moreover, this was a
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`comparison that Dr. Ratain made himself; the Worzalla paper contained no specific data on the
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`dose response curve for the standard diet mice. Chabner Tr. 1252:14-1253:12.
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`Dr. Ratain’s analysis does not take into account that a standard mouse diet contains a
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`high amount of folate relative to what is required by humans. Zeisel Tr. 1595:23 – 1596:2. Dr.
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`Ratain’s analysis also does not account for the fact that the mice on the low-folate diets were also
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`given an antibiotic, succinylsulfathiazole, to prevent bacteria in the mouse’s intestine from
`11
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`Wockhardt Exhibit 1028 - 11
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`making folic acid even though it is not in the diet, while the standard diet mice were not. Zeisel
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`Tr. 1596:2 – 1596:11. The lack of antibiotic in the standard diet mice permitted these mice to
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`ingest higher levels of folate than what was contained in their food, as the mice would consume
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`their waste product which contained folic acid produced in their intestines. Zeisel Tr. 1596:2-11;
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`Green Tr. 385:9-20. As Lilly’s expert Dr. Steven H. Zeisel (“Dr. Zeisel”) stated, it would not be
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`proper to compare the low-folate diet mice with the standard diet mice because there was a
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`change in two variables in the study, not just one, and would be like “comparing an apple to an
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`orange; it just isn’t allowed in science.” Zeisel Tr. 1596:23 – 1597:3.
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`A POSA would have recognized that there is difficulty in translating the results of a pre-
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`clinical mouse study to results that would be seen in a human clinical trial, and additionally
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`would not have concluded from the data in Worzalla that folic acid did not have an adverse
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`impact on efficacy. As stated by Worzalla, mouse models have “poor predictive value . . . for
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`antifolates toxicity.” TX 384 at 3237; Chabner Tr. 1251:24–1252:3. It is possible to make
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`qualitative conclusions from a mouse model and apply them to humans, but not quantitative
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`conclusions. Chabner Tr. 1251:4-14. This is due in part to the fact that standard laboratory
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`mice diets contain high levels of folic acid, thus the folate levels of mice on a low-folate diet fall
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`to levels considered normal in humans. TX 384 at 3237. In addition, the tumor line used in the
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`Worzalla mouse study was designed to be particularly sensitive to antifolates. Chabner Tr.
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`1334:10-17. However, even if a POSA did attempt to predict the results of folic acid
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`supplementation in humans based upon the results in the Worzalla study, the POSA would at
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`least be able to recognize that a several fold increase in the pemetrexed dose would be needed to
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`maintain the same level of anti-tumor activity as would be needed in an unsupplemented subject.
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`A POSA would have also recognized that the comparison of standard diet mice to the low-folate
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`diet mice was not appropriate due to the administration of an antibiotic to the low-folate diet
`12
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`Wockhardt Exhibit 1028 - 12
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`Case 1:10-cv-01376-TWP-DKL Document 336 Filed 03/31/14 Page 13 of 34 PageID #: 8244
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`mice. A POSA would have likely interpreted these findings as showing a decrease in efficacy of
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`the drug, not just that some therapeutic effects were maintained or that a decrease in lethality
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`permitted higher doses of pemetrexed.
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`Hammond reports the results of a phase I clinical trial in which patients received 5
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`mg/day of folic acid starting two days before treatment with pemetrexed at doses ranging from
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`600 to 925 mg/m2. TX 912; Ratain Tr. 151:17-22. Out of 33 patients, only one partial response
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`was observed. TX 912. In contrast, the results of an unsupplemented phase I pemetrexed study
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`were published by Rinaldi4 that showed 4 partial responses and 6 minor responses. TX 1303.
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`Defendants argue that a POSA would have regarded this one partial response as promising and
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`would not have compared it to the results in Rinaldi, and Hammond would have taught a POSA
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`that folic acid supplementation does not decrease pemetrexed’s efficacy and does not “teach
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`away” from the claimed invention.
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`The Court finds that Hammond does meet the legal definition of “teaching away” from
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`the claimed invention or, at the very least, Defendants have not shown by clear and convincing
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`evidence that Hammond would have motivated a POSA to pursue the regimen in Hammond or
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`the claimed invention. “A reference may be said to teach away when a person of ordinary skill,
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`upon reading the reference, would be discouraged from following the path set out in the
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`reference, or would be led in a direction divergent from the path that was taken by the applicant.”
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`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)
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`(quoting Ricoh Co., Ltd. v. Quanta Computer Inc., 550 F.3d 1325, 1332 (Fed. Cir. 2008))
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`(additional citations omitted). The results of the Hammond study, viewed within the context of
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`the general view that pemetrexed’s toxicities were not of great concern to oncologists as of June
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`4 Rinaldi, et al., A phase I evaluation of LY231514, a novel multitargeted antifolate, administered every 21
`days, AMERICAN SOCIETY OF CLINICAL ONCOLOGY, 15:489, Abstract 1559 (TX 1303).
`13
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`Wockhardt Exhibit 1028 - 13
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`Case 1:10-cv-01376-TWP-DKL Document 336 Filed 03/31/14 Page 14 of 34 PageID #: 8245
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`1999, as well as within the context of other pemetrexed studies, including Rinaldi, would not
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`have encouraged a POSA to pursue vitamin supplementation to decrease pemetrexed’s toxicity.
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`While it is true that the Hammond study did show that folic acid reduced the toxicity of
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`pemetrexed, a POSA would not have ignored the implications of folic acid supplementation’s
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`impact on efficacy. The Hammond study showed only one partial response, as compared to 4
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`partial responses and 6 minor responses in Rinaldi, and Hammond also involved much higher
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`doses of pemetrexed than what was used in Rinaldi. Even if a POSA would not have made any
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`definitive conclusions about the efficacy of pemetrexed based upon these two phase I studies, a
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`POSA would have compared the results in Rinaldi against the results in Hammond in deciding
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`what impact folic acid supplementation had on the efficacy and toxicity of pemetrexed, and
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`would have selected the regimen that had the most therapeutic benefit, not just some therapeutic
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`benefit.
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`The Court finds that Lilly’s experts, Dr. Chabner and Dr. Zeisel, are more credible with
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`respect to their opinions on how a POSA would view the teachings of Worzalla and Hammond
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`than Defendants’ experts. A POSA would not have merely focused on the reduction of toxicity
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`associated with pemetrexed in both of these studies, but would have also looked at the fact that
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`much higher doses of the drug were necessary in order to maintain some antitumor activity. The
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`goal of a POSA would not have been to reduce toxicity at the expense of either reducing the
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`efficacy of pemetrexed or requiring higher doses of the drug, as a POSA would have been
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`concerned with other types of toxicity (such as kidney toxicity) associated with high doses of
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`pemetrexed in humans. Chabner 1318:7-1319:6. Considering that pemetrexed was regarded, as
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`of June 1999, to be a promising antifolate with toxicities that were manageable through dose and
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`schedule modification, Defendants have not shown by clear and convincing evidence that a
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`14
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`Wockhardt Exhibit 1028 - 14
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`Case 1:10-cv-01376-TWP-DKL Document 336 Filed 03/31/14 Page 15 of 34 PageID #: 8246
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`POSA would have been motivated to add folic acid supplementation to the administration of
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`pemetrexed based upon the findings in Worzalla and Hammond.
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`b.
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`‘974 Patent as prior art
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`Defendants argue that the ‘974 Patent also encourages a POSA to use folic acid
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`supplementation with pemetrexed. The ‘974 Patent explains
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`that GAR-transformylase
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`(“GARFT”) inhibitors and antifolates that bind to the folate binding protein can be administered
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`with folic acid pretreatment to reduce toxicity without affecting therapeutic efficacy; however,
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`the only antifolate specifically mentioned and discussed in the ‘974 Patent is lometrexol. TX
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`916 at 1. Defendants argue