Pemetrexed - USA

On Jun 22, 2018, U.S. District Court for the Southern District of Indiana ruled in favor of Lilly finding that Dr. Reddy’s alternate salt would infringe dosing regimen patent of ALIMTA® (pemetrexed disodium).

This is a Hatch-Waxman patent infringement action brought by Eli Lilly against Dr. Reddy’s for filing of NDA No. 208297 with USFDA seeking approval to market the product, pemetrexed ditromethamine.   US 7,772,209 patent owned by Lilly covers the method of administration of ALIMTA®, requiring that physicians co-administer the drug with folic acid and vitamin B12.  The primary focus of this infringement trial is on whether Dr. Reddy’s label, specifically the use of pemetrexed ditromethamine product described therein, infringes the ‘209 Patent, which uses pemetrexed disodium, under the doctrine of equivalents.

A. Prosecution History Estoppel:

The Court found Lilly was not barred, as a matter of law under prosecution history estoppel, from asserting the doctrine of equivalents. Specifically, claim was narrowed to overcome a rejection in view of Arsenyan, a prior art article about a different antifolate, methotrexate. Accordingly, the Court concluded that Lilly’s rationale for limiting its claim to pemetrexed disodium (to avoid a rejection based on the prior art Arsenyan) is tangential to the accused equivalent—pemetrexed ditromethamine.

B. Disclosure-Dedication Rule:

It was undisputed that the ‘209 Patent’s specification did not expressly disclose pemetrexed ditromethamine. Rather, Dr. Reddy’s based its disclosure-dedication argument on the fact that the ‘209 Patent referenced U.S. Patent No. 4,997,838 to Akimoto and that from Akimoto the hypothetical person of skill in the art (“POSA”) could find pemetrexed ditromethamine disclosed among the alternatives disclosed in Akimoto. Court held that because Akimoto was not expressly incorporated, as required, in the ‘209 Patent, and in any event Akimoto does not specifically disclose pemetrexed ditromethamine as an alternative to pemetrexed disodium, the disclosure-dedication rule does not bar Lilly’s doctrine of equivalents claim.

C. Doctrine of Equivalents:

Lilly asserted that healthcare providers using the proposed Dr. Reddy’s product will directly infringe under the doctrine of equivalents, and that Dr. Reddy’s is liable as an indirect infringer under 35 U.S.C. §§ 271(b) and (c). Court said that under the relevant context that the claim relates to medical treatment, pemetrexed ditromethamine treats the patient’s cancer in exactly the same way as pemetrexed disodium. It is undisputed that when both pemetrexed disodium and pemetrexed ditromethamine are placed in solution, that both compounds dissociate completely in solution resulting in free pemetrexed and therapeutically irrelevant counter-ions. In fact, in aqueous solution, the two products will be identical.

The differences in the chemical properties between pemetrexed disodium and pemetrexed ditromethamine with regards to solubility, stability, pH, and buffering capacity are irrelevant in the context of the claimed method which is a liquid administration of pemetrexed sodium. What is in fact ultimately administered to the patient is injectable pemetrexed ions that enter the patient’s cells.

D. Inducement and contributory infringement:

Court said that as Dr. Reddy’s product infringes the ‘209 Patent under the doctrine of equivalents, it cannot avoid intent or infringement on the bases that it possessed a “good faith belief that its proposed product[s] would not infringe.” Moreover, the Court found, based on a preponderance of the evidence, Dr. Reddy’s label instructs users to perform the patented method by both inducing and contributing to infringement and that Dr. Reddy’s had the requisite specific intent and knowledge that its label would cause such infringement. Dr. Reddy’s product does not have a substantial non-infringing use to avoid contributory infringement. A physician administering Dr. Reddy’s product would constitute direct infringement under § 271(a); thus, the use the Dr. Reddy’s NDA products would constitute inducement and contributory infringement of the ‘209 Patent by Dr. Reddy’s under 35 U.S.C. § 271(b),(c).