United States District Court, Southern District of Indiana, Indianapolis Division
FINDINGS OF FACT AND CONCLUSIONS OF LAW FOLLOWING BENCH TRIAL AUGUST 19, 2013
Hon. Tanya Walton Pratt, Judge United States District Court Southern District of Indiana
This matter is before the Court for decision on the validity of claims 9, 10, 12, 14, 15, 18, 19 and 21 (the “Asserted Claims”) of the U.S. Patent No. 7, 772, 209 (the “‘209 Patent”). The ‘209 Patent is a method-of-use-patent which covers the co-administration of pemetrexed disodium (“pemetrexed”) with two nutrients-folic acid and vitamin B12-that protect against the side effects of the drug ALIMTA®. The matter was before the Court for a bench trial beginning on August 19, 2013 and concluding on August 29, 2013. This is a Hatch-Waxman patent infringement action brought by Eli Lilly and Company (“Lilly”), the owner of the ‘209 Patent, against Defendants Teva Parenteral Medicines, Inc. (“Teva Parenteral”), Teva Pharmaceuticals USA, Inc. (“Teva Pharmaceuticals”) (collectively with Teva Parenteral, “Teva”), APP Pharmaceuticals, LLC (“APP”), Barr Laboratories, Inc. (“Barr”), and Pliva Hrvatska d.o.o. (“Pliva”) (collectively, “Defendants”) arising out of Defendants’ filing of Abbreviated New Drug Applications (“ANDAs”) with the Food and Drug Administration (“FDA”) seeking approval to market the pemetrexed disodium products identified in Teva’s ANDAs Nos. 90-352 and 90-674, APP’s ANDA No. 90-384, and Barr’s and Pliva’s ANDA No. 91-111 (collectively the “ANDA Products”) and covered under the ‘209 Patent.
As mentioned earlier, the ‘209 patent describes a method of administering a chemotherapy drug, pemetrexed, with vitamins, which is marketed by Lilly under the trade name ALIMTA®. Lilly is only asserting infringement of the Asserted Claims of the ’209 Patent with respect to the ANDA Products. Each Defendant stipulates that under the Court’s claim construction (Dkt. 115) and under the current laws of infringement, the sale of its ANDA Products, in accordance with the proposed labeling for each of those respective ANDA Products, would infringe the Asserted Claims of the ‘209 Patent, to the extent those claims are found valid and enforceable. Having heard testimony and considered the exhibits and arguments of the parties, the Court finds the Defendants have failed to show by clear and convincing evidence that the Asserted Claims of the ‘209 Patent are invalid for obviousness, obviousness-type double patenting, inadequate description or lack of enablement, and the Asserted Claims of the ‘209 Patent are valid and enforceable. In support thereof, the Court makes the following findings of fact and conclusions of law pursuant to Federal Rule of Civil Procedure 52.
I. FINDINGS OF FACT
A. The Parties
Plaintiff Lilly is a corporation organized and existing under the laws of the State of Indiana, having its corporate offices and principal place of business at Lilly Corporate Center, Indianapolis, Indiana 46285. Lilly is engaged in the business of research, development, manufacture and sale of pharmaceutical products throughout the world. Lilly sells pemetrexed in the United States under the trademark ALIMTA® for treatment of specific types of lung cancer and mesothelioma. ALIMTAreg; is covered under U.S. Patent No. 5, 344, 932, which is owned by The Trustees of Princeton University and licensed exclusively to Lilly.
The Defendants are all corporations primarily engaged in the business of making and selling drugs in generic form. Defendant Teva Parenteral is a corporation organized and existing under the laws of the State of Delaware, having its principal place of business at 19 Hughes, Irvine, California 92618. Defendant Teva Pharmaceuticals is a corporation organized and existing under the laws of the State of Delaware, having its principal place of business at 1090 Horsham Road, North Wales, Pennsylvania 19454. Defendant APP is now Fresenius Kabi USA, LLC, a Delaware limited liability company with its principal place of business at Three Corporate Drive, Lake Zurich, Illinois 60047. Defendant Barr is a corporation organized and existing under the laws of the State of Delaware, having its principal place of business at 1090 Horsham Road, North Wales, Pennsylvania 19454. Defendant Pliva is a limited liability company organized and existing under the laws of the Republic of Croatia with its principal place of business at Prilaz baruna Filipovica 25, 10000 Zagreb, Croatia.
B. The Patent-In-Suit
The patent-in-suit U.S. Patent No. 7, 772, 209, was issued to Lilly on August 10, 2010, and Lilly is the current owner of the ‘209 Patent. The ‘209 Patent covers the method of administration of ALIMTA®, requiring that physicians co-administer the drug with folic acid and vitamin B12 to reduce the incidence of patient toxicity caused by ALIMTA®.
C. History of Lilly’s Antifolate Development Prior to the ‘209 Patent
1. Background on Antifolates
The ‘209 Patent describes a method of using an antifolate, pemetrexed, with vitamins. Antifolates are a type of chemotherapy drug used to treat certain types of cancer. Antifolates work by competing with folates, a class of essential nutrients that includes folic acid. Folates participate in chemical reactions in the body that make chemical precursors to DNA. DNA, in turn, is required for division and growth of both normal cells and cancer cells. Antifolates work by interfering with the action of folates and deprive cancer cells of the DNA precursors they need to proliferate, or grow. Antifolates are used for their antiproliferative effect in the treatment of cancer to inhibit cell growth and division, which causes cancer cells to die. Because of the competitive relationship between folates and antifolates, the ability of an antifolate to fight cancer depends on the relative amount of folate and antifolate in the cell. As folate levels are increased, greater amounts of antifolates are needed to achieve an antiproliferative effect.
Cancer cells are fast-growing and thus have a high demand for DNA precursors, making them particularly susceptible to the effects of antifolates. However, fast growing normal cells, such as cells that line the gastrointestinal tract and cells of the bone marrow, also divide rapidly and are therefore also particularly susceptible to antifolates. Accordingly, the same mechanisms by which antifolates kill cancer cells also kill fast-growing normal cells, causing antifolate-related side effects referred to as “toxicities.” Some of these toxicities – such as mucositis, anemia and low white blood cell counts– can be severe and even life-threatening.
Antifolate research began in 1948 with observations by Dr. Sidney Farber (“Dr. Farber”) of children with leukemia. The children were given folic acid contained in liver extract, which Dr. Farber observed caused their tumor growth to accelerate. Based on that finding, Dr. Farber administered an experimental antifolate called aminopterin, which caused some of his patients to go into remission. Between 1950 and 1999, a great number of antifolates were made and tested, but as of 1999 the only antifolate approved by the FDA for treating cancer was methotrexate, which was approved in the 1950s. Methotrexate is also used in the treatment of rheumatoid arthritis (“RA”). Both cancer and RA patients experience toxicity from antifolates due to their antiproliferative effects – i.e. by killing rapidly dividing cells. However, unlike in cancer treatment, this antiproliferative effect is not the mechanism by which methotrexate treats RA.
2. Lilly’s antifolate research and development in the 1990s
In the 1990s, Lilly had multiple antifolates in clinical use or development, including pemetrexed, lometrexol, and LY309887 (the “‘887 compound”). In a few instances, researchers attempted to use folic acid pretreatment with antifolates in order to reduce the toxicities of the drug. Initial clinical trials of lometrexol, without any supplementation, were considered a “complete disaster” resulting in “appalling toxicities.” Calvert Dep. Tr. 92:8-14. In an effort to address these severe toxicities, researchers tried administering lometrexol with folic acid. A Phase I clinical trial was conducted by Laohavinij in 1996, which involved administering a daily oral dose of 5 mg of folic acid seven days before and seven days after lometrexol administration. TX 1036. However, the Laohavinij study of lometrexol with folic acid pretreatment reported only one response among folic acid supplemented patients, which was fewer than had been observed in earlier unsupplemented patients. TX 1036 at 333. Lilly had also pursued clinical development of a related antifolate, the ‘887 compound, which was also tested with folic acid pretreatment for the same reason as lometrexol, but as with lometrexol, those studies that attempted to reduce toxicity with folic acid supplementation proved unsuccessful due in part to the decrease in efficacy. In 1994, Lilly obtained U.S. Patent No. 5, 217, 974 (the “‘974 Patent”). The ‘974 Patent claimed the use of folic acid pretreatment with a class of antifolates, with the preferred antifolate being lometrexol. TX 916.
One of the antifolate drugs Lilly had in development during the 1990s was pemetrexed. By the late 1990s, pemetrexed was viewed as a very promising anticancer drug. In April 1999, it was reported that phase II studies showed responses in six different tumor types, and the activity of the drug was considered “remarkable and unusual in a new drug of any class at this stage of development.” TX 907 at 107. In addition, as of June 1999, the toxicities associated with pemetrexed were considered “manageable and predictable” through dose and schedule adjustments, allowing for a broad scale of clinical use. Id.
D. Development of the ‘209 Patent
Dr. Clet Niyikiza (“Dr. Niyikiza”) is a mathematician that was employed by Lilly in the 1990s to help with the clinical development of cancer compounds. In early 1997, Dr. Niyikiza performed a series of statistical analyses, known as multivariate analyses, on more than 60 variables in patients participating in pemetrexed clinical trials in efforts to better understand which patients were likely to develop the sporadic toxicities observed with pemetrexed. Dr. Niyikiza published the results of his multivariate analyses in two abstracts in 1998. TX 910 at 2139; TX 911 at 609P. The results of the analyses pointed to a correlation between the incidence of pemetrexed toxicities and patients’ levels of homocysteine. Dr. Niyikiza reported that homocysteine levels of at least 10 micromolar correlated with specific pemetrexed toxicities. This amount is below the threshold for finding that a person has clinically high homocysteine levels, which is >15 micromolars. TX 1503 at 84; Green Tr. 540:9 –541:13. Thus, the homocysteine levels identified by Dr. Niyikiza as a marker for pemetrexed toxicity was a subclinical elevation level. Niyikiza Tr. 732:1-13.
Elevated homocysteine levels can be a marker for either folic acid or vitamin B12 deficiencies, among other conditions. Another substance, methylmalonic acid (“MMA”), is a predictor of vitamin B12 deficiency, but not folate deficiency. Thus, elevated homocysteine levels (without information about a patient’s MMA levels) can indicate either folate deficiency or vitamin B12 deficiency, while elevated homocysteine and elevated MMA levels together indicate that the patient at least has a vitamin B12 deficiency. Importantly, elevated homocysteine without elevated MMA levels indicates that the patient does not have a vitamin B12 deficiency. Analyzing data from a small set of patients receiving pemetrexed, Dr. Niyikiza found in his initial analyses, and published in his abstracts (TX 910, 911), that there was no statistical correlation between toxicity and the other variable he measured, including MMA, suggesting at the time that there was no correlation between toxicity and patients’ vitamin B12 levels. Despite what he found in his initial analyses, Dr. Niyikiza still believed there was a connection between toxicity and patients’ B12 levels. He suggested to Lilly, internally, that pretreating patients with a combination of low doses of vitamin B12 and folic acid would help reduce the frequency of sporadic toxicities observed by Lilly in its pemetrexed clinical trials. This idea was widely rejected by oncology experts both inside and outside Lilly, as the toxicities associated with pemetrexed were not viewed as problematic and they were concerned instead, that vitamin supplementation could adversely affect pemetrexed’s efficacy. Calvert Dep. 124:7-125:25.
In late 1999, after the relevant priority date for this litigation, clinicians in the ongoing phase III pemetrexed registration trial in mesothelioma patients witnessed an alarming increase in drug-related patient deaths, around 7%; a 2% death rate was high enough to cause serious concerns with a drug in clinical trials. Niyikiza Tr. 795:16-26. Up until that point, pemetrexed’s toxicity generally appeared to be manageable and tolerable; however, the sudden increase in patient deaths threatened to halt the development of the drug. Dr. Niyikiza reran his multivariate analysis on a larger database of patients, which this time revealed a “very strong” correlation between toxicities and elevated homocysteine, and additionally a stronger collinear nature between homocysteine and MMA, with about 15% of patients having very high levels of MMA. Niyikiza Tr. 796:17-797:2. This information was not previously known or disclosed at the time the Niyikiza abstracts were published. Niyikiza Tr. 797:3-7. Relying on the information about the increase in drug-related deaths, as well as further analyses of additional data by Dr. Niyikiza, Lilly decided to implement Dr. Niyikiza’s invention in the ongoing phase III registration trial by intervening with low levels of folic acid and vitamin B12 supplementation prior to administering pemetrexed. In a letter dated December 3, 1999, Lilly informed the FDA that the study protocol would be changed so that each patient in the study would receive 350 to 1000 µg of folic acid, with 500 µg being the recommended dose, and 1000 µg of vitamin B12 as an intramuscular injection. TX 330 at 3. The FDA response in January 2000 was that it did not support the addition of vitamins to the ongoing pemetrexed mesothelioma trial. TX 2100.
Despite the FDA’s reservations, Lilly went ahead and implemented Dr. Niyikiza’s vitamin supplementation regimen in the phase III mesothelioma trial. The result was that supplementing patients with low doses of folic acid and vitamin B12 prior to and during therapy mitigated pemetrexed’s toxicities without hurting its efficacy. Dr. Niyikiza published his findings, including further analyses of the roles that folic acid and vitamin B12 each played in the observed toxicities, in 2002 in the “Molecular Cancer Therapeutics Journal.” TX 80. Later in 2002, the results of the phase III trial of pemetrexed for mesothelioma, including data demonstrating that Dr. Niyikiza’s vitamin supplementation regimen increased the rate of patients’ response to pemetrexed therapy, were presented at the plenary session of the meeting of the American Society of Clinical Oncology. Niyikiza Tr. 845:4-17. The priority date for Lilly’s patent application on Dr. Niyikiza’s invention is June 30, 2000, and the ‘209 Patent was issued on August 10, 2010. Dr. Niyikiza is listed as the sole inventor of the ’209 Patent.
E. Claims Asserted in the ‘209 Patent
Lilly is asserting claims 9, 10, 12, 15, 18, 19, and 21 of the ‘209 Patent with respect to the ANDA Products. TX 1 at cols. 11-12. Each claim requires pretreatment with a specified amount of folic acid, up to 1000 µg, and with vitamin B12 in the amount of 55-1, 500 µg in claims 12, 14 and 21, and 1000 µg in claims 15, 18, and 19, prior to administering pemetrexed. Claims 19, 21, and 22 further require a specific schedule for those pretreatments, and claims 15, 18 and 19 require administration of vitamin B12 by intramuscular injection.
F. Person of Ordinary Skill in the Arts
The Court previously determined, and the parties no longer dispute, that a person of ordinary skill in the art (“POSA”) can be a medical doctor who specializes in oncology or a medical doctor with extensive experience in the areas of nutritional sciences involving vitamin deficiencies. However, as to the latter person, this individual would need to have collaborated with medical oncologists who ...