DC District Court Provides Guidance as to the Meaning of ‘Protein’ Under the BPCIA

In December 2020, the U.S. District Court for the District of Columbia issued a decision in Teva v. FDA, reviewing FDA’s definition of “protein” in connection with the agency’s determination that Teva’s Copaxone^®, a medication for treating multiple sclerosis, is a “drug” rather than a “biological product.” Biologic products are regulated under the Biologics Price Competition and Innovation Act (BPCIA), which has more arduous requirements for approval of follow-on biosimilar or interchangeable products than those for generic drugs. Following several failed efforts to have FDA reclassify Copaxone^® as a “biological product,” Teva sued FDA, alleging that FDA’s definition of “protein” is arbitrary and capricious. In deciding Teva’s claim, the court reviewed FDA guidances and practices with respect to classifying biological products, particularly with respect to the terms “protein,” “chemically synthesized polypeptide” and “analogous.” The court upheld FDA’s determination that Copaxone^® is a drug, not a biologic, and provided a helpful overview of what a “protein” is under the BPCIA.

FDA’s interpretation of “biological product”

The BPCIA, when enacted in 2010, defined “biological product” as “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product … .” The BPCIA did not define the terms “protein” or “chemically synthesized polypeptide.”

After the passage of the BPCIA, FDA defined “protein” and “chemically synthesized protein” in an internal memorandum (2011 Memorandum), concluding that “proteins,” “polypeptides” and “peptides” in scientific literature are all “amino acid polymers,” or chains, “made up of alpha amino acids linked by peptide bonds.” FDA distinguished proteins from polypeptides based on their length and level of complexity, such that “[p]roteins are long, complex polymers of amino acids,” while peptides are “simpler, shorter amino acid chains” not considered to be proteins. Specifically, FDA defined a “protein” to mean “any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.” “Chemically synthesized polypeptide,” in contrast, was defined as “any alpha amino acid polymer that is (a) made entirely by chemical synthesis; and (b) less than 100 amino acids in size.” FDA explained that “protein” consistently referred to “chains containing a specific, defined sequence of amino acids generally provided by the DNA sequence of a corresponding gene.”

In 2012, FDA issued a Draft Guidance adopting the definitions of “protein” and “chemically synthesized polypeptide” first set forth in the 2011 Memorandum. This Draft Guidance was issued as a Final Guidance in 2015. FDA issued a subsequent Final Guidance Document (2018 Guidance) with the same definitions.

In 2018, FDA published a notice of proposed rulemaking and proposed rule for its interpretations of “protein” and “chemically synthesized polypeptides.” Congress subsequently amended the definition of “biological products” by removing the parenthetical exception for “chemically synthesized polypeptides.”^[1] FDA issued its Final Rule on February 21, 2020, adopting its earlier definition of “protein.” FDA did not provide a definition of “analogous product” as applied to products “analogous” to “proteins.”

Teva’s Copaxone^®

Copaxone^®’s active ingredient is a chemically synthesized “mixture of peptide copolymers containing four specific amino acids in a defined molar ratio.” It is synthesized through amino acid polymerization followed by a subsequent cleavage or depolymerization step. The addition of amino acids is not purely random, but is instead determined by reaction chemistry that generates recurring — but not identical or predefined — amino acid sequences across batches.

FDA approved Teva’s New Drug Application for Copaxone^® in 1996. After a number of patent lawsuits, FDA approved several generic Copaxone^® products.

In 2016, FDA created a Preliminary List of drugs that would be transitioned to “biological products” based on its definitions of “protein” and “chemically synthesized polypeptide.” Copaxone^® products were not included on this list or on FDA’s 2019 or 2020 updated lists. On multiple occasions, Teva petitioned FDA to transition Copaxone^® to a “biological product.” In denying Teva’s petitions, FDA explained that it “interprets the statutory term ‘protein’ to exclude amino acid polymers that lack a specific defined sequence” and that “[a]s a result of its random polymerization process, Copaxone^® does not have a specific, defined sequence.” Thus, FDA determined that Copaxone^® does not qualify as a “protein.” On March 20, 2020, FDA issued an internal memorandum in which it determined that Copaxone^® is not a biological product and would not be transitioned to a Biologics License Application.

Teva’s Lawsuit

On March 24, 2020, Teva filed suit against FDA, seeking reclassification of Copaxone^® from a “drug” to a “biological product.” Two manufacturers of generic Copaxone^® products, Mylan and Sandoz, intervened as defendants. All parties subsequently submitted summary judgment motions. The court denied Teva’s motion and granted the defendants’ motions.

In its suit, Teva challenged FDA’s definitions of “protein” and “analogous” with reference to “protein,” as well as FDA’s application of these terms to Copaxone^®. Teva asserted that even if FDA’s interpretation of “protein” was valid, its application of that definition in refusing to treat Copaxone^® as a protein or analogous to a protein was arbitrary and capricious.

The district court first analyzed whether FDA’s interpretation of the term “protein” should be afforded Chevron deference. Teva challenged the substance of FDA’s Final Rule, asserting that FDA’s requirement that a protein must have a “specific, defined sequence” was unreasonable because it distinguishes between chemically synthesized and naturally derived proteins, a distinction removed by Congress in 2019. The defendants argued that “protein” unambiguously refers to substances with a “specific, defined sequence,” regardless of whether they are natural or synthetic proteins.

The court determined that FDA “surveyed scientific literature related to both natural and synthetic proteins and 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.” The court found that neither the statute nor FDA’s interpretations distinguished between naturally derived and chemically synthesized proteins. The court found that FDA’s “specific, defined sequence” requirement was a reasonable construction of the term “protein” because it falls within the range of scientifically accepted meanings and therefore should be given Chevron deference.

In rejecting Teva’s request for reclassification, FDA explained that the “specific, defined sequence” requirement “describes the manner in which specific amino acids are added to a polymer in a defined sequence,” following a predefined template that results in an identical sequence across batches. The district court agreed that Teva’s Copaxone^® did not meet this requirement.

The court also analyzed Teva’s argument that Copaxone^® should have been reclassified as a biologic because it is “analogous” to a protein. The court found that, although FDA had not issued a guidance document defining the “analogous product” category with respect to proteins, it did state in the Final Rule that “it would not be appropriate for the statutory term ‘analogous product’ to be interpreted in a way that would include products that are specifically excluded by this final rule.” The court explained that “the agency regards substances, including mixtures, that are comprised at least in part of a protein with a specific, defined sequence, as products ‘analogous’ to proteins, even if ‘the protein component(s) [are] present in low levels or unknown amounts.’”

The court found that “FDA’s scientific judgment that a ‘specific, defined sequence’ is an essential enough feature of proteins that it must be shared even by ‘analogous’ products is thus a reasonable interpretation of the ‘analogous product’ provision.” Thus, the court held “FDA did not err in formulating its interpretation or in applying it to determine that Copaxone^® is not ‘analogous’ to a protein.”

The court’s opinion upholds FDA’s Final Rule and provides helpful guidance in determining whether a product is a “biological product” and therefore governed by the BPCIA. Whether a medication is a biological product is critical, not only in setting the proper path for regulatory approval, but also in determining non-patent regulatory exclusivities and the framework for patent litigation.

^[1] _{For a discussion of the 2019 amendment, see https://www.kramerlevin.com/en/perspectives-search/bpcia-scope-widens-2020-spending-bill-moves-chemically-synthesized-polypeptides-to-biologic-status.html.}