In Otsuka Pharm. Co., Ltd. v. Price, No. 16-5229 (D.C. Cir. Aug. 29, 2017), the U.S. Court of Appeals for the District of Columbia Circuit affirmed the district court decision upholding FDA’s “same moiety” test for defining the zone of FDA market exclusivity periods. The case originated from Otsuka’s Citizen’s Petition asserting that FDA had improperly approved Alkermes’s Section 505(b)(2) application for Aristada® (aripiprazole lauroxil) before expiration of the exclusivity periods for Otsuka’s Abilify Maintena® (aripiprazole) product.

FDA Marketing Exclusivity Periods

The FFDCA provides three categories of drug applications that enjoy different FDA marketing exclusivity periods:

  1. Applications for drug products that contain “new chemical entities,” i.e., for which “no active ingredient (including any ester or salt of the active ingredient) . . . has been approved in any other application.” (Also known as “five-year NCE exclusivity.”) See 21 USC § 355(c)(3)(E)(ii) (“romanette ii ).
  2. Applications for drug products that contain a previously approved active ingredient (including any ester or salt of the active ingredient) where “reports of new clinical investigations” are included. See 21 USC § 355(c)(3)(E)(iii) (“romanette iii”).
  3. Applications that “supplement” a previously approved application, if obtaining approval of the supplement requires submitting additional clinical data. See 21 USC § 355(c)(3)(E)(iv) (“romanette iv”).

Romanette ii confers five years of market exclusivity during which “no [abbreviated] application which refers to the [first-in-time] drug” may be approved. See 21 CFR § 314.3(b).

Romanette iii confers three years of exclusivity and bars approval of abbreviated applications for the same “conditions of approval of such drug in the [first-in-time] application.” See 21 USC § 355(c)(3)(E)(iii).

Romanette iv confers three years of exclusivity and bars approval of abbreviated applications “for a change approved in the supplement” to the first-in-time drug’s application. See 21 USC § 355(c)(3)(E)(iv).

The principal issue in this case involves delineating the scope of second-in-time applications that are barred by the romanette iii and romanette iv exclusivity periods.

Abilify Maintena® versus Aristada®

The first-in-time drug at issue was Otsuka’s Abilify Maintena® (“AM”) product, an extended release injectable suspension containing aripiprazole as the active moiety and active ingredient. (Otsuka’s original orally administered Abilify® product included the same active moiety and active ingredient, and was accorded five-year NCE exclusivity.) In 2013, AM received three-year romanette iii exclusivity because its application relied on “new clinical investigations” to establish safety and efficacy. In 2014, Otsuka received approval for a supplemental NDA for AM when it submitted “the results of a controlled clinical study treating adult patients with schizophrenia experiencing an acute relapse.” In view of this approval, it received three-year romanette iv exclusivity, in addition to the previously awarded romanette iii exclusivity.

Alkermes filed a Section 505(b)(2) application for Aristada® (aripiprazole lauroxil) for the treatment of schizophrenia. Like AM, Aristada® is an extended release injectable suspension, but Aristada® contains a different active ingredient–aripiprazole lauroxil instead of aripiprazole. As explained in the court’s decision, aripiprazole lauroxil is metabolized into N-hydroxymethyl aripiprazole (“NHA”), which is the active moiety of Aristada®, and NHA in turn ultimately metabolizes into aripiprazole. As summarized by the court, to establish safety and efficacy of Aristada®, Alkermes relied partly on Otsuka’s clinical investigations for Abilify® (but not those conducted for AM) and also conducted its own clinical investigations for Aristada®.

FDA’s Same Moiety Ruling

In its Citizen’s Petition, Otsuka contended that the Aristida® application fell within the scope of the romanettes iii and iv exclusivity periods for AM, because of overlapping “conditions of approval,” given that Aristida® treated the same condition in a similar way despite having a structurally different active ingredient and active moiety.

FDA rejected Otsuka’s arguments, finding that the exclusivity provisions did not bar approval of products that contain different active moieties. FDA explained that the exclusivity periods apply to a particular feature of the drug–the active moiety. As summarized in the court decision, FDA cited language in the eligibility clauses of romanettes ii, iii, and iv that conditions eligibility for exclusivity on whether a drug’s “‘active ingredient (including ester or salt of the active ingredient)’ – i.e., its active moiety – has been approved in a previous application.” FDA interpreted the term “such drug” in the bar clause of romanette iii as referring to the drug containing the active moiety of the first-in-time application, as defined in the eligibility clause. Applying the same rationale, the FDA concluded that under romanette iv, the “change approved in the supplement” must be for the same drug, i.e., containing the same active moiety, as in the supplemented application.

The Court Decisions

Otsuka sought judicial review of FDA’s decision, and the district court granted summary judgment in favor of FDA and Alkermes. The district court determined that the FFDCA’s three-year exclusivity bars only subsequent applications for drugs with the same active moiety, and concluded that FDA’s same active moiety test is a reasonable construction of the FFDCA, is consistent with FDA’s own regulations, and did not involve de facto rule making requiring a notice and comment period prior to implementation.

On appeal, the Court of Appeals for the D.C. Circuit agreed with FDA’s rationale and affirmed the district court’s decision. The court rejected Otsuka’s argument that FDA’s same moiety interpretation is inconsistent with the statute and the regulations. Applying the Chevron framework for APA challenges, the court accorded deference to FDA’s interpretation because it was found to be consistent with the statute and regulations and to be reasonable.

With regard to when the exclusivity applies, the court adopted FDA’s interpretation that for the exclusivity to apply, the subsequent application not only must share overlapping “conditions of approval,” but also must be for the same drug as the first-in-time application. With regard to when a subsequent drug is considered to be the “same” as the first-in-time drug, the court found FDA’s interpretation to be reasonable. FDA

Otsuka presented arguments based on a principle of legal equivalence in which two drugs should be considered legally equivalent if:

  • they have the same active moiety;
  • one drug relies on the other for FDA approval; or
  • one drug relies on a drug that is itself legally equivalent to the other drug.

Under this test, Aristada® would be legally equivalent to AM because the Aristada® application relied on Abilify® clinical studies and Abilify® and AM have the same active moiety.

However, the court rejected Otsuka’s arguments because Otsuka had not shown why the FDA’s interpretation is unreasonable. The court also found that Otsuka’s interpretation would lead to much broader exclusivity than Congress intended, such as when a Section 505 (b)(2) applications relies on academic literature to establish safety and efficacy. The court also determined that Otsuka’s legal equivalence test is inconsistent with the court’s prior decision in Actavis Elizabeth LLC v. FDA, 625 F.3d 760 (D.C. Cir. 2010), where the court upheld FDA’s endorsement of granting new chemical entity exclusivity to a prodrug of a previously approved drug, if it has a different active moiety.

The court also rejected Otsuka’s arguments that the requirement that the Aristada® application contain patent certifications pertaining to Otsuka’s aripiprazole method of use patents created legal equivalence. On this issue, the court cited different language in the different statutory provisions at issue, noting that “such drug” in the patent certification provision refers solely to the relied-upon drug, not both relied-upon and applied-for drugs.

Thus, the court affirmed FDA’s decision that the three-year exclusivity periods only bar approval of subsequent applications when the drug at issue contains the same active moiety.

Impact Prodrug Litigation

The court’s decision to uphold FDA’s “same moiety” interpretation rationale is rooted in FDA’s definition of “active moiety,” which excludes ester derivatives and other non-covalent complexes. Thus, the court decision here directly applies only to covalent derivatives such as NHA, the active moiety in Aristada®. Covalent derivatives are usually associated with unpredictably altered pharmacological activity as compared to their first-in-time parent compounds, but some ester ester prodrugs (for example) may exhibit unexpected changes in pharmacological activity. It will be interesting to see how FDA treats such ester prodrugs, and whether it finds that three-year marketing exclusivity applies under Otsuka.