Eli Lilly and Co. v. Hospira, Inc.

Case Name: Eli Lilly and Co. v. Hospira, Inc., Nos. 2018-2126, -2127, 2128, 2019 U.S. App. LEXIS 23753 (Fed. Cir. Aug. 9, 2019) (Circuit Judges Lourie, Moore, and Taranto presiding; Opinion by Lourie, J.) (Appeal from S.D. Ind., Pratt, J.) 

Drug Product and Patent(s)-in-Suit: Alimta® (pemetrexed for injection); U.S. Patent No. 7,772,209 (“the ’209 patent”)

Nature of Case and Issue(s) Presented: Lilly markets the compound pemetrexed in the form of a disodium salt as Alimta®, which is indicated, both alone and in combination with other active agents, for treating certain types of non-small cell lung cancer and mesothelioma. Pemetrexed is an antifolate, a class of molecules which, at the time of the invention in 2001, was “one of the most thoroughly studied classes of antineoplastic agents.” Pemetrexed had been known for at least a decade in 2001. By 2001, Lilly had also published the results of several clinical trials investigating the use of pemetrexed disodium as a treatment for different types of cancer. The invention of the ’209 patent is an improved method of treatment with antifolates, particularly pemetrexed disodium, through supplementation with a methylmalonic acid lowering agent and folic acid. Doing so lessens antifolate toxicity without sacrificing efficacy.

DRL, Hospira, and Actavis submitted 505(b)(2) applications relying on Lilly’s clinical data for pemetrexed disodium. DRL and Hospira intended to market pemetrexed ditromethamine. In the DRL case, the district court construed the phrase “administration of pemetrexed disodium” to mean “liquid administration of pemetrexed disodium,” which "is accomplished by dissolving the solid compound pemetrexed disodium into solution.” The district court denied DRL’s motion for summary judgment of non-infringement, holding that prosecution history estoppel does not bar Lilly from asserting that DRL’s proposed pemetrexed ditromethamine product would infringe through the doctrine of equivalents because Lilly amended its claims to distinguish other antifolates and was therefore only tangential to pemetrexed ditromethamine. Following a bench trial, the district court’s opinion largely followed its rationale in the summary judgment decision. In addition, the court found that DRL’s proposed product would be administered in a manner that would meet that portion of the district court’s decision. Actavis agreed to be bound by the district court’s decision in the DRL case.

In the Hospira case, the parties similarly disputed the doctrine of equivalents, but Lilly also asserted literal infringement because Hospira’s proposed product label allows reconstitution of its pemetrexed ditromethamine salt in saline. After the district court issued the DRL summary judgment decision, Hospira conceded that its product would infringe under the relevant claim construction.

The Federal Circuit reversed the district court’s finding of literal infringement in the Hospira decision but affirm its judgment of infringement under the doctrine of equivalents. The judgment of infringement under the doctrine of equivalents in the DRL decision was also affirmed.

Why Lilly Prevailed: Hospira argued that it cannot literally infringe because intravenous administration of pemetrexed ditromethamine dissolved in saline is not “administration of pemetrexed disodium.” Lilly counters that Hospira’s view improperly imposes a “source limitation,” requiring that the pemetrexed disodium salt exist in solid form before administration, even though Hospira’s proposed product label, like that of Alimta, calls for administration of a solution containing pemetrexed anions and sodium cations. Lilly also contends that Hospira’s claim construction arguments are irrelevant because Hospira’s proposed product will be administered intravenously in any event. The Federal Circuit found that it was clearly erroneous for the district court to hold that the “administration of pemetrexed disodium” step was met because Hospira’s pemetrexed ditromethamine product will be dissolved in saline before administration. Pemetrexed disodium no longer exists once dissolved in solution, and, as a corollary, a different salt of pemetrexed dissolved in saline is not pemetrexed disodium. The Federal Circuit concluded that to literally practice the “administration of pemetrexed disodium” step under the district court’s claim construction, the pemetrexed disodium salt must be itself administered. Thus, the district court’s literal infringement finding must be reversed.

But infringement by equivalents was affirmed. Lilly does not dispute that the amendment in question was both narrowing and made for a substantial reason relating to patentability. The parties’ dispute about whether prosecution history estoppel applies is confined to whether Lilly’s amendment narrowing “an antifolate” to “pemetrexed disodium” was only tangential to pemetrexed ditromethamine, which is the accused compound.

Defendants argued that Lilly failed to explain why it did not pursue a narrower amendment literally encompassing pemetrexed ditromethamine, and they emphasize that the tangential exception is “very narrow.” Moreover, defendants argued that Lilly cannot be said to have lacked the words to describe pemetrexed ditromethamine because Lilly’s previous patents, as well as the European ’209 patent counterpart, claimed pemetrexed salts generally and pemetrexed disodium in a dependent claim. In response, Lilly argues that the district court properly held that the reason for its amendment was to distinguish pemetrexed from antifolates generally and that the different salt type is a merely tangential change with no consequence for pemetrexed’s administration or mechanism of action within the body.

The Federal Circuit found defendants’ view of the tangential exception “too rigid.” The reason for Lilly’s amendment was to narrow original claim 2 to avoid a reference that only discloses treatments using methotrexate, a different antifolate. The particular type of salt to which pemetrexed is complexed relates only tenuously to the reason for the narrowing amendment, which was to avoid prior art. Whether an amendment was merely tangential to an equivalent must be decided in the context of the invention disclosed in the patent and the prosecution history. While an amendment that narrows an existing claim element evinces an intention to relinquish that claim scope, here, the Federal Circuit concluded that this consideration is not dispositive because the rest of the prosecution history, and the ’209 patent itself, show that it is implausible that the reason for Lilly’s amendment was to surrender other pemetrexed salts.

DRL next argued that the disclosure-dedication rule bars Lilly from asserting infringement under the doctrine of equivalents. DRL contends that pemetrexed ditromethamine was dedicated to the public when Lilly declined to claim it. Lilly counters that the disclosure-dedication rule requires express disclosure of the subject matter in question in the specification except in narrow circumstances, such as when that subject matter is disclosed in a priority application, or prior art expressly incorporated by reference. Lilly also argues that the district court correctly determined that the relevant portion of Akimoto discloses only a generic formula from which a skilled artisan would not be able to recognize pemetrexed ditromethamine.

The Federal Circuit held the disclosure-dedication rule inapplicable to this case because the ’209 patent does not disclose methods of treatment using pemetrexed ditromethamine, and, as a result, Lilly could not have dedicated such a method to the public. Moreover, the prior-art reference that Lilly incorporated by reference into the ’209 patent contains only a “generic reference” to pemetrexed ditromethamine, therefore that was not a dedication to the public.