On Dec. 31, 2020, District Court for the District of Columbia denied summary judgment motion by Teva for inclusion of Glatiramer as “biological product” under under the Public Health Service Act (“PHSA”).
USFDA approved Teva’s Glatiramer product (Copaxone) initially in Dec. 1996 under the Food, Drug, and Cosmetics Act (“FDCA”). Glatiramer is a chemically synthesized “mixture of peptide co-polymers containing four specific amino acids in a defined molar ratio.” On Mar. 14, 2016, FDA announced a new draft guidance document for implementing the Biologics Price Competition and Innovation Act of 2009 (BPCIA) transition provision, which applied the definitions of “protein” and “chemically synthesized polypeptide”. FDA read § 7002(e)(4) to require that “on March 23, 2020, applications for biological products that have been approved under [the FDCA] will no longer exist as [NDAs or ANDAs] and will be replaced by approved [BLAs] under [the PHSA].” The agency also provided a list of examples of biological products then approved under NDAs or ANDAs that would be transitioned to BLAs. Glatiramer acetate products were not on this 2016 list of biological products to be transitioned to BLAs. Teva brought this lawsuit, seeking an order compelling FDA to regulate Copaxone as a “biological product” rather than as a “drug”.
Teva challenged the FDA decision on several grounds. First, it contended that FDA’s Final Rule interpreting the term “protein” is invalid because the Rule is procedurally deficient and the interpretation is contrary to section 351 of the PHSA. Next, Teva submitted that, even if FDA’s interpretation of “protein” is valid on its face, FDA’s application of that definition in the Decision Memorandum to refuse to treat Copaxone as a protein, as well as its determination that Copaxone is not a product “analogous” to a protein, was arbitrary and capricious.
With respect to procedural irregularity, Teva argued that FDA “gave no opportunity to comment on Congress’s decision to change the term being construed, by removing the parenthetical exclusion for ‘chemically synthesized polypeptides’ from ‘protein’” after the passage of the 2019 Act. Therefore, Teva and other interested parties were deprived of both fair notice and the ability to submit comments on FDA’s proposed interpretation of the term
“protein” in section 351 as amended by the 2019 Act. Court, however, said that FDA provided sufficient notice and multiple opportunities to comment on its interpretation of the statutory term “protein,” even in light of the 2019 Act. Court said that from 2010 until the promulgation of the Final Rule in 2020, FDA consistently made plain that it was interpreting “protein” and “chemically synthesized polypeptide” independent of each other, as two distinct statutory terms. Given the minimal relationship between the terms “protein” and “chemically synthesized polypeptide” in FDA’s interpretive framework, the 2019 Act’s deletion of the parenthetical exception did nothing to change the meaning of the term “protein” standing alone. FDA responded appropriately to this change in its Final Rule, which preserved and finalized the interpretation of “protein” FDA had first publicized in the 2011 Memorandum and 2012 Guidance Document, and, in light of the 2019 Act, removed FDA’s separate interpretation of “chemically synthesized polypeptide.” This background makes clear that FDA was not required to provide a new comment period after the enactment of the 2019 Act. The deletion of the parenthetical exclusion did not alter the term “protein” that FDA interpreted in its Final Rule, nor did it change the background statutory assumptions against which FDA developed its interpretation.
With respect to interpretation of term “protein”, Teva argued that FDA’s interpretation of “protein” is contrary to section 351, such that the definition is “not in accordance with law,” because it requires that molecules have a “specific, defined sequence” of amino acids to qualify as protein. Court said that FDA’s this interpretation falls within the range of scientifically accepted meanings of “protein,” as described in various literature. The FDA developed this definition after convening a working group of experts to analyze the term “protein,” surveying the relevant scientific literature, considering various scientific, regulatory, and statutory factors, and engaging with the regulated industry for nearly a decade. The FDA determined that, in light of the key role amino acid sequences play in the production and function of proteins in nature, a “specific, defined sequence” was an essential characteristic of proteins. FDA determined, after reviewing the scientific literature, that a specific, defined sequence is characteristic of both natural and synthetic proteins. Further, the “specific, defined sequence” requirement does not operate to exclude all chemically synthesized molecules from the protein category, as Teva implied. Therefore, it is not how the proteins are made is important, but it is the specific, defined sequence that matters.
Thus, according to this interpretation, Copaxone is not a protein because it does not have specific, defined sequence of amino acids. Copaxone is not made through the predictable process, but rather through “reaction chemistry,” which generates recurring but not identical or pre-defined results across batches. Indeed, Teva has acknowledged that, far from being dictated by a predetermined template, Copaxone’s amino acid sequences are “determined during the chemical solution polymerization process.” As a result, FDA correctly determined that “‘there is a negligible likelihood of having identical amino acid sequences along entire copolymer chains from batch to batch” and Copaxone exhibits “sequence variability.” Moreover, FDA’s determination that Copaxone is not “Analogous” to a protein was also reasonable because Copaxone lacks “specific, defined sequence” which is an absolute criteria for defining protein.