Opinion ID: 807367
Heading Depth: 2
Heading Rank: 1

Heading: Antifolate Drugs

Text: Folates, which include the B vitamin folic acid and its derivatives, 1 play a critical role in nucleic acid synthesis within human cells and, as such, are required for cell growth and division. To that end, numerous cellular enzymes recognize and process folates—some folatespecific enzymes such as dihydrofolate reductase (“DHFR”) and glycinamide ribonucleotide formyltransferase (“GARFT”) catalyze biochemical reactions important for making both DNA and RNA, while others such as thymidylate synthetase (“TS”) selectively affect DNA production. 2 1 Although folic acid itself predominates in most dietary supplements and fortified foods, the compound naturally occurs in various other chemical forms including folic acid salts and esters. For convenience, we refer to folic acid and such related compounds collectively as “folates.” 2 Purines and pyrimidines are key building blocks in the production of both RNA and DNA. DHFR and GARFT participate in global purine synthesis, so those enzymes affect both DNA and RNA production. In contrast, TS serves only in the production of deoxythymidine monophosphate, a pyrimidine nucleotide that is incorporated into DNA but not RNA. ELI LILLY v. APP PHARMA 4 Given the key role of folates in DNA synthesis, and thus in cellular replication, folate metabolism presents an attractive target for cancer treatments because cancerous cells characteristically exhibit rapid, unchecked division and proliferation. Accordingly, researchers and physicians have developed numerous compounds, known as “antifolates,” intended to inhibit one or more of the folatespecific enzymes necessary for DNA synthesis. Structurally analogous to natural folates, antifolates induce initial recognition by one or more of the folate-specific enzymes yet contain important structural differences that prevent the target enzyme from carrying out its normal function. For example, the chemical structure of folic acid is represented below—highlighting key structural features including the bicyclic core, bridge region, aryl position, and glutamic acid domain—along with the closely related structure of methotrexate, a well-known antifolate that was first introduced around 1950. Folic Acid 5 ELI LILLY v. APP PHARMA Methotrexate Methotrexate is used as a chemotherapy agent for treating certain cancers, including leukemias, lymphomas, and osteosarcoma, among others. In addition to its anticancer effects, however, methotrexate, like many antifolates, exhibits significant toxicity due to deleterious effects on non-cancerous, healthy cells. Such toxicity is thought to arise at least in part because methotrexate primarily inhibits DHFR and therefore substantially impairs DNA and RNA synthesis. While DNA synthesis is of principal importance for actively dividing cells (e.g., cancer cells), ongoing RNA synthesis is necessary for essentially all living cells in the body. Methotrexate and other antifolate drugs that inhibit both the DNA and RNA synthesis pathways are thus prone to undesirable offtarget effects. In the 1980s, researchers sought to develop anti- folates capable of inhibiting TS, which would selectively impede DNA synthesis and presumably mitigate the toxicity issues associated with methotrexate and other then-existing antifolates. One such effort led by Prof. Edward Taylor, a chemist at Princeton University, yielded pemetrexed, the antifolate at the heart of this appeal: ELI LILLY v. APP PHARMA 6 Pemetrexed As with methotrexate, pemetrexed exhibits some structural similarity to folic acid. One key difference that distinguishes pemetrexed from folic acid and methotrexate is that pemetrexed contains a pyrrolo[2,3- d]pyrimidine bicyclic core, characterized by a five-member ring fused with a six-member ring, rather than the dual six-member rings found in the pteridine cores of folic acid and methotrexate. After synthesizing pemetrexed, the Princeton group collaborated with researchers at Eli Lilly to test the new compound for antifolate activity, and the results soon revealed that pemetrexed acts as a potent inhibitor of TS. Princeton and Eli Lilly (together, “Lilly”) thereafter began exploring for related compounds with similar activity as TS inhibitors and pursuing preclinical and clinical studies to evaluate promising candidates for therapeutic use. Among the many pemetrexed-related compounds that were developed and tested, pemetrexed itself proved to be the best therapeutic candidate and ultimately won FDA approval in 2004 for use in treating mesothelioma and then in 2008 for treatment of non-small cell lung cancer. 7 ELI LILLY v. APP PHARMA Lilly manufactures and distributes pemetrexed under the brand name Alimta®.