United States: Court Rejects Theory Of Derivation Based On FDA Requirement

The Federal Circuit decision in Cumberland Pharmaceuticals Inc. v. Mylan Institutional LLC may be more interesting for what Mylan argued than for what the Federal Circuit decided. However, it could be an important decision for pharmaceutical companies who need to innovate in order to satisfy FDA requirements.

The Patent At Issue

The patent at issue was Cumberland's U.S. 8,399,445, directed to method of treating acetaminophen overdose using a formulation of acetylcysteine that is "free of chelating agents":

1. A method of treating acetaminophen overdose, comprising:
using a stable aqueous pharmaceutical composition comprising 200 mg/ml acetylcysteine or pharmaceutically acceptable salts thereof, wherein the composition is free of chelating agents, wherein said composition is in a suitable form for intravenous injection, wherein the pH of the composition is from 6 to 7.5, and wherein said composition is sealed in an airtight container comprising a fill volume of said composition and a headspace volume occupied by a pharmaceutically inert gas;
diluting the composition in an aqueous solution; and
administering the diluted composition to a patient in need thereof.

According to the Federal Circuit opinion, the use of acetylcysteine as an antidote for acetaminophen overdoses was known in the prior art, but it also was known that acetylcysteine had stability problems. In particular, "heavy metal ions, whether inherent in the formula or found as contaminants, catalyze the oxidation of acetylcysteine in solution, causing it to degrade." While the prior addressed this problem by formulating acetylcysteine with a chelator (EDTA), the inventor of the '445 patent discovered an alternative way to prepare a stable formulation without a chelating agent.

The FDA's Role In The Invention

The Federal Circuit opinion summarizes the genesis of the invention as follows:

In 2002, several years before the 2005 filing date of the '445 patent, Cumberland was seeking FDA approval for its Acetadote® product, which was an "EDTA-containing formulation" of acetylcysteine. As part of its usual review process, the FDA asked Cumberland to justify the presence of EDTA in the formulation "since a non-trivial amount" is present. While Cumberland continued to pursue FDA approval of Acetadote®, the inventor (who was involved in the FDA review process) endeavored to determine whether a stable formulation could be prepared without EDTA. The FDA encouraged this research, and approved Acetadote® after Cumberland "committ[ed] to evaluate the potential benefit of [EDTA] on the stability of the drug product" and study "a formulation with a lower concentration and no concentration."

Pursuant to that commitment, the inventor designed a protocol that included a formulation within the scope of the claims of the '445 patent, the FDA approved the experimental design without change, and the results were "encouraging." The patent application was filed in August 2005, and the FDA approved an EDTA-free formulation of Acetadote® in January 2011.

Did Cumberland Derive The Invention From The FDA?

The appeal at issue arose from ANDA litigation filed in response to Mylan's Abbreviated New Drug Application seeking approval to market a generic version of Cumberland's EDTA-free formulation of Acetadote®.

Mylan's argued that the patent is invalid because: (1) the invention was derived from someone at the FDA who suggested to remove EDTA from the prior-art formulation and (2) the EDTA-free formulation would have been obvious. The district court disagreed on both issues, finding that "Mylan had not proved that anyone at the FDA conceived of the invention before Cumberland's inventor did," and that "there was no reasonable expectation that a formulation without any chelating agents would be successful, given the prevailing skilled-artisan view that chelating agents were necessary."

Invalidity due to "derivation" is based on 35 U.S.C. § 102(f), which holds that a person is entitled to a patent "unless ... he did not himself invent the subject matter sought to be patented." To establish invalidity due to derivation, the challenger must establish "prior conception of the claimed subject matter [by a third party] and communication of the conception" to the inventor.

The Federal Circuit Decision

The Federal Circuit decision was authored by Judge Taranto and joined by Judges Moore and Reyna.

The Federal Circuit focused on the legal question embodied in the derivation claim–"whether there was a prior conception" of the invention–and noted that "conception must encompass all limitations of the claimed invention" in the context of a "specific, settled idea." Applying this legal standard to the case at hand, the court summarized Mylan's burden as follows:

Mylan had to show, by clear and convincing evidence, a conception by someone at the FDA that included "the specific idea to remove EDTA ... and not add another chelating agent," and a communication of that conception to Mr. Pavliv.

The Federal Circuit agreed with the district court that there was a "paucity of direct evidence" supporting such a scenario. The court noted that the FDA's requirement that Cumberland justify the presence of EDTA did not amount to "a suggest to remove it, let alone to remove it and not replace it with another chelating agent." The court rejected Mylan's argument that derivation could be based on FDA's "request for data to support the inclusion of EDTA," since that allegedly "required Cumberland to undertake research that would have inevitably led it to the invention."

The kind of general research suggestion at issue here, whatever its role in an obviousness analysis, does not establish the conception required for derivation.

Turning to the obviousness analysis, the Federal Circuit agreed with the district court Mylan had failed to show that a person of ordinary skill in the art would have had a reasonable expectation of success in preparing a stable formulation of acetylcysteine without a chelating agent, as recited in the claims. The Federal Circuit affirmed this finding despite Mylan's citation of prior art that described an acetylcysteine formulation that did not include a chelating agent, since that reference did not provide stability data on that formulation. Thus, the district court's judgment rejecting the invalidity claims was affirmed.

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