The Federal Circuit during 2019 and 2020 has issued a spate of decisions on the proper application of the Doctrine of Equivalents (see, e.g., UCB, Inc. v. Watson Laboratories Inc. and Galderma Laboratories, L.P. v. Amneal Pharmaceuticals LLC) and its related limiting doctrines, prosecution history estoppel (Amgen Inc. v. Coherus BioSciences Inc. and Pharma Tech Solutions, Inc. v. Lifescan, Inc.) and the dedication-disclosure doctrine (Eagle Pharmaceuticals Inc. v. Slayback Pharma LLC and Indivior Inc. v. Dr. Reddy's Laboratories, S.A.).  There then followed, like night follows day, a slew of petitions for certiorari.  The Supreme Court has already denied cert in Actavis Laboratories FL, Inc. v. Nalproprion Pharmaceuticals, Inc., and on Monday, the Court showed equal disinterest in the issue, denying certiorari in Eli Lilly & Co. v. Hospira, Inc.

To recap, this case arose in ANDA litigation over Eli Lilly's U.S. Patent No. 7,772,209 directed to "improved" methods for administering its anticancer drug Alimta® (pemetrexed disodium), a frequent target for generic drugmakers.  The drug itself, an antifolate metabolic inhibitor of thymidylate synthase, inhibits cell growth (normal and malignant) by interfering with production of DNA precursors and hence inhibiting replication.  The anticancer efficacy for this drug (like many anticancer drugs) relies on the greater replicative activity of cancer cells compared with normal cells.

Pemetrexed, and its disodium salt, is not a new drug, being disclosed and claimed in U.S. Patent No. 5,344,932, and Eli Lilly's licensed U.S. Patent No. 4,997,838, that disclosed a large genus of structurally related compounds that encompass pemetrexed but did not disclose the molecule itself.  This reference also taught that "pharmaceutically acceptable bases," such as "alkali metals, alkali earth metals, non-toxic metals, ammonium, and substituted ammonium" could be prepared from the disclosed antifolate inhibitors.

Eli Lilly's own investigations showed that Alimta® administration is nevertheless associated with significant side-effects, including "severe hematologic and immunologic side effects, resulting in infections, nausea, rashes, and even some deaths," which are not uncommon with antifolates according to the '209 patent specification.  The '209 patent claims methods for pemetrexed administration supplemented with folic acid and a methylmalonic acid-lowering agent (including, e.g., vitamin B12), "improved" to the extent that these side effects are reduced.  Claim 12 is representative:

12. An improved method for administering pemetrexed disodium to a patient in need of chemotherapeutic treatment, wherein the improvement comprises:
    a) administration of between about 350 μg and about 1000 μg of folic acid prior to the first administration of pemetrexed disodium;
    b) administration of about 500 μg to about 1500 μg of vitamin B12, prior to the first administration of pemetrexed disodium; and
    c) administration of pemetrexed disodium.

In a parent application to the '209 patent, broader claims directed to methods for reducing antifolate toxicity recited administration of a broad class of antifolates with methylmalonic acid lowering agents with or without folic acid.  These claims were rejected as being anticipated by an earlier prior art reference or for being obvious over a combination of references.  In response, Eli Lilly amended the rejected claims to pemetrexed disodium and argued that the asserted art either did not recite the pemetrexed disodium or, for overcoming the obviousness rejection, that the art did not suggest vitamin supplementation.

The defendants in ANDA litigation did not request FDA approval for pemetrexed disodium but for a different salt -- the ditromethamine salt -– and argued to the agency that "their choice of the tromethamine cation was immaterial because pemetrexed dissociates from its counterion in solution" and that this salt was known to be safe for pharmaceutical use.  At trial against Dr. Reddy's Laboratories, the District Court construed the term "administration of pemetrexed disodium" to mean "liquid administration of pemetrexed disodium," which "is accomplished by dissolving the solid compound pemetrexed disodium into solution."  Using this construction, the District Court denied defendant's motion for summary judgment of noninfringement on the ground that Eli Lilly was not precluded by prosecution history estoppel to assert that Dr. Reddy's ditromethamine pemetrexed salt was an equivalent to Eli Lilly's claimed disodium salt.  The Court reasoned that the amendment made during the earlier prosecution was only tangentially related to the differences in these salts, the amendment being made to distinguish different antifolate species and not different salt forms thereof.  The District Court also rejected defendant's "dedication to the public" argument with regard to the earlier known antifolate compounds disclosed in the '838 patent because that patent disclosed a large genus comprising thousands of compounds.

In litigation with Hospira, Eli Lilly argued both literal infringement as well as infringement under the doctrine of equivalents, based on Hospira's label that permitted pemetrexed ditromethamine to be reconstituted in saline.  Hospira conceded (subject to appeal) that its product would infringe, and the District Court granted summary judgment against Hospira on both literal infringement and infringement under the doctrine of equivalents.

The Federal Circuit reversed-in-part (regarding literal infringement) and affirmed-in-part (regarding infringement under the Doctrine of Equivalents), in an opinion by Judge Lourie joined by Judges Moore and Taranto.  With regard to DOE infringement, the Court found that the District Court had not erred in finding the substitute salts to be equivalents. With regard to prosecution history estoppel, under Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushki Co., 535 U.S. 722, 733 (2002) the question was whether the amendments made in the earlier patent from which the '209 patent claims priority were made for reasons related to patentability and do not fall within Supreme Court-recognized exceptions.

Eli Lilly did not dispute that its amendments satisfied the fundamental requirements of behavior that raises the estoppel:  that "the amendment in question was both narrowing and made for a substantial reason relating to patentability."  But the District Court found and the Federal Circuit affirmed that prosecution history estoppel did not bar DOE infringement because the amendments made to the claims during prosecution "[bore] no more than a tangential relation to the equivalent in question," citing Festo.  Hospira and Dr. Reddy's Laboratories colorfully argued that "the tangential exception is not a patentee's-buyer's-remorse exception" and that the tangential relationship exception should be construed narrowly, but the Federal Circuit held that appellants had advanced a "too rigid" application of prosecution history estoppel.  The Court agreed with the District Court's assessment that Lilly had narrowed the claims of the earlier, related application to overcome rejection based on treatment with methotrexate, and that "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 directed to methotrexate administration.  The panel also refused to adopt Dr. Reddy's position as a bright-line rule, stating that "such a bright-line rule is both contrary to the equitable nature of prosecution history estoppel, [citing Festo], and inconsistent with the equitable spirit that animates the doctrine of equivalents," citing Graver Tank & Mfg. Co. v. Linde Air Prods. Co., 339 U.S. 605, 608 (1950).

The panel also rejected Dr. Reddy's Laboratories' argument that the "disclosure-dedication" rule, Johnson & Johnston Assocs. Inc. v. R.E. Serv. Co., 285 F.3d 1046, 1054 (Fed. Cir. 2002) (en banc), prevented Lilly from asserting its claims under the Doctrine of Equivalents.  The Federal Circuit agreed with Eli Lilly that this doctrine did not apply where, as here, the patent did not disclose the specific embodiment at issue (here, pemetrexed ditromethamine) and thus the patentee could not have dedicated it to the public.  Despite reference to earlier disclosure comprising about 50 antifolate compounds (none of them pemetrexed) and disclosure related to pharmaceutically acceptable salts thereof (but not ditromethamine), in the absence of express disclosure of pemetrexed ditromethamine the Court did not apprehend a "reason why a skilled artisan would set out on DRL's winding path to cobble together pemetrexed ditromethamine" and thus held that the dedication-disclaimer rule did not preclude Eli Lilly from asserting infringement under the doctrine of equivalents.

This case provided a full-throated analysis of proper application of the DOE and both prosecution history estoppel and the disclosure-dedication rule.  The Supreme Court found no reason to disturb the Federal Circuit's treatment of its doctrines, providing a refreshing affirmance (or at least a resistance to meddle) for how the appellate court charged with harmonizing U.S. patent law had properly fulfilled its unique role in the Federal appellate regime on this issue.