Eli Lilly and Co. v. Teva Parenteral Medicines, Inc.

Case Name: Eli Lilly and Co. v. Teva Parenteral Medicines, Inc., No. 2015-2067, 2017 U.S. App. LEXIS 555 (Fed. Cir. Jan. 12, 2017) (Circuit Judges Prost, Newman, and Dyk presiding; Opinion by Prost, C.J.) (Appeal from S.D. Ind., Walton Pratt, J.) 

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

Nature of the Case and Issue(s) Presented: Around 2008-2009, Defendants notified Eli Lilly that they had submitted ANDAs seeking approval to market generic versions of Alimta. After the ’209 patent issued, Defendants sent Eli Lilly additional notices regarding their ANDAs, including notices that they had filed Paragraph IV certifications. Eli Lilly subsequently brought this consolidated action against Defendants for infringement under 35 U.S.C. § 271(e)(2). Specifically, Eli Lilly alleged that Defendants’ generic drugs would be administered with folic acid and vitamin B12 pretreatments and, thus, result in infringement of the ’209 patent. Defendants raised non-infringement and invalidity defenses.

Eli Lilly and Defendants tried the invalidity case first. The district court held that the asserted claims were not invalid for obviousness or obviousness-type double patenting. The district court had also previously rejected Defendants’ contention that the asserted claims were invalid for indefiniteness of the term “vitamin B12.” The district court held a second bench trial and found that Defendants would induce infringement of the ’209 patent. The parties agreed for purposes of this appeal that no single actor performed all steps of the asserted claims; rather, the steps were divided between physicians and patients. Though physicians administered vitamin B12 and pemetrexed, patients self-administered folic acid with guidance from physicians. Eli Lilly’s theory of infringement therefore required establishing liability for divided infringement. The Federal Circuit affirmed.

Why Eli Lilly Prevailed: The performance of method steps is attributable to a single entity in two types of circumstances: when that entity “directs or controls” others’ performance, or when the actors “form a joint enterprise.” Eli Lilly did not pursue a joint-enterprise theory, so the question of direct infringement before the Federal Circuit was whether physicians direct or control their patients’ administration of folic acid. The district court observed initially that taking folic acid in the manner recited by the asserted claims was a “critical” and “necessary” step to “reduc[e] … potentially life-threatening toxicities caused by pemetrexed.” Based on the product labeling, the district court found that “taking folic acid in the manner specified is a condition of the patient’s participation in pemetrexed treatment.” Next, the district court found that physicians would “prescrib[e] an exact dose of folic acid and direct[] that it be ingested daily.” Therefore, the performance of all steps of the asserted claims would be attributable to physicians. The Federal Circuit found that this holding was supported by the record evidence. For example, The Physician Prescribing Information, which was “directed to the physician,” explained that folic acid is a “[r]equirement for [p]remedication” in order “to reduce the severity of hematologic and gastrointestinal toxicity of [pemetrexed].” Consistent with the importance of folic acid pretreatment, the product labeling repeatedly stated that physicians should “[i]nstruct patients” to take folic acid and includes information about folic acid dosage ranges and schedules. The Patient Information also informed patients that physicians may withhold pemetrexed treatment: “You will have regular blood tests before and during your treatment with [pemetrexed]. Your doctor may adjust your dose of [pemetrexed] or delay treatment based on the results of your blood test and on your general condition.”

The product labeling also established the manner or timing of the claimed method. The Physician Prescription Information instructed physicians not only to tell patients to take folic acid orally, but also to take “400 [03bcg] to 1000 [03bcg] [of folic acid] once daily beginning 7 days before the first dose of [pemetrexed],” accompanied with warnings about the consequences of non-compliance. That dosage range and schedule overlapped with all of the asserted claims’ dosage ranges and schedules. Thus, the Federal Circuit found that the product labeling included repeated instructions and warnings regarding the importance of and reasons for folic acid treatment, and there was testimony that the Physician Prescribing Information, as the name indicates, is directed at physicians. Thus the court found that “the instructions are unambiguous on their face and encourage or recommend infringement.”

Next, the Federal Circuit turned to whether or not the term Vitamin B12 were indefinite. There was no dispute that, depending on the context, “vitamin B12” could be used in the art to refer either to cyanocobalamin specifically or, more broadly, to a class of compounds including pharmaceutical derivatives of cyanocobalamin. There was further no dispute that the written description of the ’209 patent used the term both ways. Defendants argued that because “vitamin B12” was used in two different ways in the intrinsic record, it was impossible to determine which meaning applies to the claims under the Supreme Court’s standard in Nautilus. Eli Lilly responded that the claims of the ’209 patent involved administering a vitamin B12 supplement to a patient, and in that context, the one and only meaning of vitamin B12 to a person of ordinary skill was cyanocobalamin. Eli Lilly’s expert testified that, although “vitamin B12” can refer to a class of compounds in other contexts, it refers specifically to cyanocobalamin when “vitamin B12” is prescribed in the medical field. The Federal Circuit found no clear error on the part of the district court in accepting this opinion. Moreover, the claim language informed a skilled artisan that “vitamin B12” in this context referred to “cyanocobalamin.” First, the claims were directed to administering vitamin supplements, including vitamin B12, followed by chemotherapy treatment. This context informed a skilled artisan that “vitamin B12” was being used to refer to the supplementation form of vitamin B12, cyanocobalamin. Second, the structure of the claims also supported such an understanding. Claim 1 required administering a “methylmalonic acid lowering agent … selected from the group consisting of,” inter alia, vitamin B12 and cyanocobalamin. Claim 2, which depends from claim 1, further required that “the methylmalonic acid lowering agent is vitamin B12.” If “vitamin B12” were to refer to a class of compounds, then claim 2 would be the same scope as claim 1. The doctrine of claim differentiation presumed that dependent claims were of a scope narrower than that of the independent claims from which they depend. Thus, the term “vitamin B12” was not indefinite.

Finally, the Federal Circuit affirmed the district court’s finding of non-obviousness. The defendants’ arguments failed to raise reversible error with respect to at least the findings that a skilled artisan would not have been motivated to use vitamin B12 pretreatment with pemetrexed, let alone the appropriate doses and schedules or such vitamin B12 pretreatment. In particular, there was nothing in the literature as of the critical date describing cancer patients’ being provided with vitamin B12 supplementation prior to receiving any antifolate, with or without folic acid. Moreover, there were no prior-art references where any amount of vitamin B12 pretreatment had been used with an antifolate in the treatment of cancer.