Amarin Pharms. Ireland Ltd v. FDA

Case Name: Amarin Pharms. Ireland Ltd v. FDA, Case No. 14-cv-00324 (RDM), 2015 U.S. Dist. LEXIS 68723 (D.D.C. May 28, 2015) (Moss, J.) 

Drug Product and Patent(s)-in-Suit:  Vascepa^® Capsules (icosapent ethyl); N/A

Nature of the Case and Issue(s) Presented: Congress provided a five-year period of exclusivity for approved new drugs, “no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application.” Esters and salts are typically closely related to their parent acid molecules. Congress also provided a more limited three-year period of exclusivity for new drugs that contain “an active ingredient (including any ester or salt of the active ingredient) that has been approved in another application” in certain circumstances where the drug’s sponsor was required to conduct new research to gain approval. In practice, however, more than two years separates the five- and three-year exclusivity periods, since the five-year exclusivity provision bars the FDA from accepting an application for approval of a competing drug, while the three-year exclusivity provision merely precludes the FDA from approving such an application. Although the statute refers to a new drug’s “active ingredient,” the regulations do not directly define that term. Instead, they grant five-year exclusivity to “new chemical entities” (or “NCEs”). The regulations define a NCE as any “drug that contains no active moiety that has been approved by the FDA in any other application submitted under section 505(b).” “Active moiety,” in turn, is defined as “the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.” In 1994, the FDA promulgated final regulations wherein five-year exclusivity was available only for NCEs, that is, drugs that do not contain any previously approved “active moiety.”

On July 26, 2012, the FDA approved Vascepa. The sole active ingredient of Vascepa is a single molecule: icosapent ethyl, the ethyl ester of eicosapentaenoic acid (“EPA”). EPA is a significant component of a previously-approved drug, Lovaza, the “active ingredient” of which is comprised of a mixture of seven kinds of omega-3 fatty acid ethyl esters. The FDA decided on February 21, 2014 that Vascepa was not entitled to five-year exclusivity because “EPA, the single active moiety in Vascepa, was also an active moiety contained in” Lovaza. Amarin challenged the FDA’s determination that Vascepa was not entitled to a five-year period of market exclusivity. The court set aside the FDA’s decision and remanded the case for further proceedings.

Why Amarin Prevailed:  The FDA based its decision on a newly-laid out framework for identifying the active moiety or moieties of “active ingredient” mixtures. Under that framework, the FDA considers component molecules of a mixture to be previously approved “active moieties” for purposes of determining a subsequent drug’s eligibility for five-year exclusivity where (i) specific molecules in the mixture have been identified; (ii) those specific molecules are “consistently present in the mixture”; and (iii) those molecules are “responsible at least in part for the physiological or pharmacological action of the mixture, based on a finding that they make a meaningful contribution to the activity of the mixture.” The FDA thus identified two different approaches to the five-year exclusivity analysis. When dealing with single molecule drugs, the FDA applies a “one-to-one” approach: the drug product contains a “single active ingredient” and a “single active moiety.” The second approach is to identify the entire mixture as the single “active ingredient” of the drug, yet treat each component molecule that is consistently present and that contributes, at least in part, to the physiological or pharmacological activity of the mixture as containing a distinct “active moiety,” thereby creating a “one-to-many” relationship between the single active ingredient and its many component active moieties.

In determining the propriety of FDA’s new framework, the court conducted a Chevron analysis. Under Chevron step one, the issue presented was whether, for purposes of exclusivity, the Hatch-Waxman Amendments permit the FDA to interpret “active ingredient” that “has been approved” to mean any “active moiety” in a previously approved drug. The court found that the statute’s “text, structure, and purpose do not encompass or permit the construction the Agency has given it.” First, the FDA’s construction is at odds with the canon against surplusage. If “active ingredient” were to mean “active moiety,” and “active moiety” is defined as a molecule excluding (among other things) those portions that render the molecule a salt or an ester, there would be no circumstances in which the parenthetical clause would have any coherent meaning. The second problem with the FDA’s interpretation was that it required the FDA to interpret the phrase “active ingredient” differently for purposes of the ANDA and exclusivity provisions of the statute. Congress explicitly sought to treat certain forms of “active ingredients” (that is, salts and esters) alike for purposes of exclusivity, but not for ANDA purposes, thereby reinforcing the conclusion that it did not intend to delegate to the FDA the authority otherwise to give the phrase “active ingredient” different meanings for exclusivity and ANDA purposes. The third issue with the FDA’s approach was that its focus on a drug component that was never the subject of the FDA’s approval is also inconsistent with the statutory text, which considers whether the new drug contains an “active ingredient” “which has been approved in [a prior] application.” Thus, FDA’s interpretation fails at Chevron’s first step.

Moving to Chevron step two, the court found the FDA’s decision both procedurally and substantively flawed. The FDA’s decision did not offer any reasoned explanation for how its application of the regulatory focus on “active moiety” can be reconciled with the statutory focus on “active ingredient.” To the contrary, the FDA embraced the notion that “active ingredient” and “active moiety” have different meanings. The FDA thus conceded that Vascepa’s “active ingredient”—EPA—is not an “active ingredient” in Lovaza; because it concluded that EPA is an “active moiety” in both Vascepa and in Lovaza’s single-active-ingredient mixture, it improperly denied exclusivity.