Teva Pharmaceuticals USA, Inc. v. United States Food and Drug Administration

UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF COLUMBIA
TEVA PHARMACEUTICALS USA,
INC., et al.,
Plaintiffs, Civil Action No. 20-808 (BAH)
v. Chief Judge Beryl A. Howell
UNITED STATES FOOD AND DRUG
ADMINISTRATION, et al.,
Defendants,
and
SANDOZ INC., et al.,
Intervenor-Defendants.
MEMORANDUM OPINION
Plaintiffs Teva Pharmaceuticals USA, Inc. and Teva Pharmaceutical Industries Ltd.
(together, “Teva”) and intervenor-defendants Sandoz Inc. (“Sandoz”) and Mylan
Pharmaceuticals Inc. (“Mylan”) are pharmaceutical companies that manufacture therapeutic
products using glatiramer acetate to treat relapsing-remitting forms of multiple sclerosis. Almost
25 years ago, in 1996, the Food and Drug Administration (“FDA”) approved Teva’s glatiramer
acetate product, Copaxone, as a drug under the Food, Drug, and Cosmetics Act (“FDCA”), 21
U.S.C. § 301 et seq. Years later, and in the face of concerted resistance by Teva, the agency
approved generic glatiramer acetate products, including those manufactured by Sandoz and
Mylan. Now, in yet another effort to stifle Copaxone competitors, Teva brings this lawsuit,
seeking an order compelling FDA to regulate Copaxone as a “biological product” under the
Public Health Service Act (“PHSA”), 42 U.S.C. § 201 et seq., rather than as a “drug” under the
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FDCA. According to Teva, such a change was mandated by the Biologics Price Competition
and Innovation Act of 2009 (“BPCIA”), Pub. L. No. 111-148, tit. VII, subtit. A, 124 Stat. 119,
804–21 (2010), and subsequent amendments, which expanded the definition of “biological
product” to include “proteins” and therapeutic products “analogous” to proteins and required
FDA to transition qualifying drugs to biological product status by March 23, 2020.
Teva instituted this action on March 24, 2020 against FDA and the Department of Health
and Human Services, as well as the heads of those agencies in their official capacities (together,
the “federal defendants”), challenging FDA’s determination that Copaxone is neither a protein
nor a product analogous to a protein and therefore cannot be transitioned from the FDCA to the
PHSA. See generally Compl., ECF No. 1. Shortly after, Mylan and Sandoz intervened as
defendants. Mot. Intervene by Sandoz Inc., ECF No. 9; Mot. Intervene as Def., ECF No. 19;
Min. Order (Apr. 20, 2020) (granting Sandoz’s motion to intervene); Min. Order (Apr. 27, 2020)
(granting Mylan’s motion to intervene).
Now pending before the Court are cross-motions for summary judgment filed by Teva,
ECF No. 31, the federal defendants, ECF No. 36, Mylan, ECF No. 34, and Sandoz, ECF No. 38.
For the reasons explained below, Teva’s motion is denied and the motions of the federal
defendants and the intervenor-defendants are granted.
I. BACKGROUND
A. Statutory and Regulatory Background
FDA administers two statutory frameworks for the regulation and approval of two
distinct categories of therapeutic products. The FDCA’s section 505 governs the approval of
new “drugs,” 21 U.S.C. § 355, while the PHSA’s section 351 governs the approval of new
biological products or biologics, 42 U.S.C. § 262. “A biologic is a type of drug derived from
natural, biological sources such as animals or microoorganisms,” in contrast to “traditional
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drugs, which are typically synthesized from chemicals.” Sandoz Inc. v. Amgen Inc. (“Sandoz”),
137 S. Ct. 1664, 1669–70 (2017). Both drugs and biological products are used to treat and
prevent disease in the human body. See 21 U.S.C. § 321(g)(1)(B)–(C) (defining a “drug” as an
“article[] intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease”
or “intended to affect the structure or any function of the body of man”); 42 U.S.C. § 262(i)(1)
(stating that a “biological product” must be “applicable to the prevention, treatment, or cure of a
disease or condition of human beings”).
1. Approval of Drugs Under the FDCA
The FDCA controls the approval of “drugs” by FDA through any of three pathways
available under section 505. First, an applicant may file a new drug application (“NDA”)
containing scientific data collected by the applicant, 21 U.S.C. § 355(a), (b)(1), which
demonstrates that the drug is safe and effective for use as labeled, id. § 355(d). Second, an
applicant may file an NDA relying on scientific investigations “not conducted by or for the
applicant and for which the applicant has not obtained a right or reference or use” to show safety
and efficacy, if accompanied by additional information specified in the statute. Id. § 355(b)(2).
Drugs approved through either of these pathways are commonly referred to as “brand-name”
drugs.
Finally, an applicant may file an abbreviated new drug application (“ANDA”) to bring a
generic version of a previously approved brand-name drug (the “reference listed drug”) to
market. Id. § 355(j). An ANDA relies on FDA’s previous finding that the reference listed drug
is safe and effective. Thus, to gain approval for an ANDA, an applicant must show that the
proposed generic drug is “the same as” the reference listed drug, id. § 355(j)(2)(A) (ii), (iii), a
standard that requires the generic drug to be “identical in active ingredient(s), dosage form,
strength, route of administration, and conditions of use,” 21 C.F.R. § 314.92(a)(1). The applicant
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must also establish that the proposed generic is “bioequivalent to” the reference listed drug,
meaning that the generic drug “can be expected to have the same therapeutic effect” as the
reference listed drug. 21 U.S.C. § 355(j)(2)(A)(iv). FDA makes active-ingredient-sameness
determinations for ANDAs “on a case-by-case basis.” Admin. Record (“AR”) at 728.1
As part of the NDA process, applicants seeking FDA approval must provide information
about “any patent which claims the drug” that is the subject of the NDA “or which claims a
method of using” the drug “with respect to which a claim of patent infringement could
reasonably be asserted.” 21 U.S.C. § 355(b)(1), (2)(A), (c)(2). The FDA lists all such patents in
a publication entitled Approved Drug Products with Therapeutic Equivalence Evaluations and
commonly known as the “Orange Book.” See id. § 355(j)(7); FDA, Approved Drug Products
with Therapeutic Equivalence Evaluations iv–xi (40th ed. 2020), https://www.fda.gov/
media/71474/download. “Process patents” (that is, patents claiming methods of manufacturing
or producing a drug) are not among the patents provided during the NDA process and therefore
are not included in the Orange Book. See 21 C.F.R. § 314.53(b)(1).
If an ANDA applicant seeks to market a generic version of a brand-name drug before a
related patent in the Orange Book has expired, the ANDA applicant must file a “Paragraph IV
certification,” certifying that the unexpired patent “is invalid or will not be infringed by the
manufacture, use, or sale of the new drug for which the [ANDA] is submitted.” 21 U.S.C.
§ 355(j)(2)(A)(vii)(IV); see also Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661, 676–77 (1990).
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FDA submitted a certified list of the contents of the administrative record, in accordance with Local Civil
Rule 7(n)(1), see Index of Admin. Record, ECF No. 29; Index of Suppl. Admin. Record, ECF No. 33, and, as agreed
by the parties and approved by the Court, see Joint Mot. Entry of Scheduling Order at 3, ECF No. 32; Min. Order
(June 22, 2020), also submitted the entire administrative record, totaling 1151 pages and including documents dating
from 1995 to 2020, see ECF No. 42-1 (AR at 1–278); ECF No. 42-2 (AR at 279–555); ECF No. 42-3 (AR at 556–
1132); ECF No. 42-4 (AR at 1133–51). Consistent with Local Civil Rule 7(n)(1), the portions of the administrative
record cited or otherwise relied upon in the parties’ briefing have been separately docketed. See J.A., ECF No. 46.
For clarity, “AR” citations are to the full administrative record, rather than to the joint appendix.
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The ANDA applicant must also provide notice of the Paragraph IV certification, setting forth “a
detailed statement of the factual and legal basis of the opinion of the applicant that the patent is
invalid or will not be infringed,” to both the patent holder and the NDA holder. 21 U.S.C.
§ 355(j)(2)(B)(iv)(II). The filing of a Paragraph IV certification is deemed “an [artificial] act of
infringement,” sufficient to form the basis of a patent infringement action, if the purpose of the
certification “is to obtain approval under” the FDCA “to engage in the commercial manufacture,
use, or sale of a drug . . . claimed in a patent or the use of which is claimed in a patent before the
expiration of such patent.” 35 U.S.C. § 271(e)(2). The NDA or patent holder may therefore
bring a patent infringement suit based on the Paragraph IV certification alone. See id. § 271(a)–
(c), (e)(2); Eli Lilly & Co., 496 U.S. at 678; Caraco Pharm. Lab’ys., Ltd. v. Forest Lab’ys., Inc.,
527 F.3d 1278, 1283 (Fed. Cir. 2008). In contrast, the potential infringement of a process patent
does not require a Paragraph IV certification and thus does not trigger a patent holder’s right to
bring a preapproval infringement suit.
2. Approval of Biological Products Under the PHSA
Section 351 of the PHSA, as amended by the BPCIA, provides two avenues to FDA
approval of biologics. First, applicants seeking to bring a new biological product to market must
submit a biologics license application (“BLA”) for FDA approval. 42 U.S.C. § 262(a). FDA
may license a new biologic if, among other criteria, the manufacturer shows that the product is
“safe, pure, and potent.” Id. § 262(a)(2)(C)(i)(I).
Second, the PHSA provides an abbreviated pathway to approval, created by the BPCIA,
for “biosimilars,” which are “biologic product[s] that [are] highly similar to a biologic product
that has already been approved by the [FDA].” Sandoz, 137 S. Ct. at 1669. An applicant
seeking approval of a biosimilar must submit an abbreviated biologics license (“aBLA”). 42
U.S.C. § 262(k). An aBLA need not replicate the “safe, pure, and potent” showing made in the
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BLA for the previously approved biologic product (the “reference product”). See id.§ 262(k)(2)(A)(iii). Instead, an aBLA applicant must show that its product is “highly similar” to
the previously approved biologic product (the “reference product”) and that “no clinically
meaningful differences” with respect to “safety, purity, and potency” exist between the two
products. 42 U.S.C. § 262(i)(2)(A), (B); see also id. § 262(k)(2)(A)(i)(I).
The BPCIA’s amendments to the PHSA “establish[] processes both for obtaining FDA
approval of biosimilars and for resolving patent disputes between manufacturers of licensed
biologics and manufacturers of biosimilars.” Sandoz, 137 S. Ct. at 1669. As soon as the initial
approval process for a biosimilar is underway, the patent dispute process commences. FDA
notifies an aBLA applicant when its application has been accepted for review, triggering a
twenty-day period during which the applicant “shall provide” a copy of the aBLA and
information about how the biosimilar is made to the manufacturer of the reference product (the
“sponsor”), 42 U.S.C. § 262(l)(2)(A), and “may provide” additional information requested by the
sponsor, id. § 262(l)(2)(B). This notice requirement “enable[s] the sponsor to evaluate the
biosimilar for possible infringement of patents it holds on” the underlying biologic, Sandoz, 137
S. Ct. at 1670–71, and initiates the so-called “patent dance,” an optional process in which “the
parties exchange information to identify relevant patents and to flesh out the legal arguments that
they might raise in future litigation,” id. at 1671.
At the close of the patent dance, the BPCIA allows the parties immediately to litigate any
disputed patents included on a list developed by the parties through negotiation or, failing a
negotiated agreement, formed through statutory procedures, in an artificial patent infringement
action brought by the sponsor. See 42 U.S.C. §§ 262(l)(3)–(6); 35 U.S.C. § 271(e)(2)(C);
Sandoz, 137 S. Ct. at 1671–72. Disputed patents that are not litigated at this phase may be
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challenged in a second phase of litigation initiated by the aBLA applicant’s notice of commercial
marketing, which notice the applicant “shall provide” to the sponsor “not later than 180 days
before the date of the first commercial marketing” of the biosimilar. 42 U.S.C. § 262(l)(8)(A).
“In this second phase of litigation, either party may sue for declaratory relief,” Sandoz, 137 S. Ct.
at 1672 (emphasis omitted) (citing 42 U.S.C. § 262(l)(9)(A)), and “the sponsor may ‘seek a
preliminary injunction prohibiting the [biosimilar] applicant from engaging in the commercial
manufacture or sale of [the biosimilar]’” while second-phase challenges are pending, id.(alterations in original) (quoting 42 U.S.C. § 262(l)(8)(B)).
If an aBLA applicant fails to provide the application and information to the sponsor as
required by 42 U.S.C. § 262(l)(2)(A), thereby dodging the patent dance entirely, the sponsor may
immediately bring an action “for a declaration of infringement, validity, or enforceability of any
patent that claims the biological product or a use of the biological product.” 42 U.S.C.
§ 262(l)(9)(C). “[35 U.S.C. §] 271(e)(2)(C)(ii) facilitates this action by making it an artificial act
of infringement, with respect to [such] patent[s] . . . , to submit a biosimilar application.”
Sandoz, 137 S. Ct. at 1672. The declaratory judgment action provided in 42 U.S.C.
§ 262(l)(9)(C) is the exclusive remedy for an applicant’s failure to comply with 42 U.S.C.
§ 262(l)(2)(A)’s disclosure requirement. Id. at 1675.
3. “Proteins” Become “Biological Products”
Until 2010, section 351 of the PHSA defined a “biological product” as “a virus,
therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic
product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other
trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease
or condition of human beings.” 42 U.S.C. § 262(i) (2006). In 2010, Congress passed the
BPCIA, which expanded the definition of “biological products” to include any “protein (except
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any chemically synthesized polypeptide).” BPCIA § 7002(b), 124 Stat. at 814; see also 42
U.S.C. § 262(i)(1) (2012). “Biological product” now meant “a virus, therapeutic serum, toxin,
antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any
chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of
arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention,
treatment, or cure of a disease or condition of human beings.” 42 U.S.C. § 262(i)(1) (2012)
(emphasis added). Congress did not define key terms in the 2010 amendment, including
“protein,” “chemically synthesized,” or “polypeptide.” The BPCIA further provided that NDAs
or ANDAs for any products previously approved as drugs under the FDCA that now qualified as
“biological products” under the revised definition would be transitioned to BLAs or aBLAs
under the PHSA by March 23, 2020. BPCIA § 7002(e)(4), 124 Stat. at 817 (codified at 42
U.S.C. § 262 note).
In late 2019, Congress again revisited the definition of “biological products” and
removed the parenthetical exception for chemically synthesized polypeptides. See Further
Consolidated Appropriations Act, 2020, Pub. L. No. 116-94, § 605, 133 Stat. 2534, 3127 (2019)
(“2019 Act”). Section 351 in its current form thus defines “biological product” as “a virus,
therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic
product, protein, or analogous product, or arsphenamine or derivative of arsphenamine (or any
other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a
disease or condition of human beings,” 42 U.S.C. § 262(i)(1) (emphasis added), and subjects all
such products to the PHSA’s licensing requirements, see id. § 262(a).
4. FDA’s Interpretation of “Protein”
Soon after the passage of the BPCIA, FDA began developing regulations to interpret the
terms “protein” and “chemically synthesized polypeptide” in the amended definition of
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“biological product” and, in turn, to determine which products would be transitioned from
“drug” to “biological product” status under the new definition. The FDA’s application of these
regulations to Teva’s Copaxone product in a decision memorandum prompted this lawsuit.
(a) The 2011 Memorandum
On October 5, 2010, FDA requested comments from the pharmaceutical industry as to
“[w]hat scientific and technical factors” should be considered in “develop[ing] a regulatory
definition” for the terms “protein” and “chemically synthesized polypeptide.” AR at 121. The
agency also created “a cross-center, multi-disciplinary ‘protein definition working group’ that
conducted an extensive analysis of potential approaches that the agency could take” in
interpreting the terms. Id. at 293. The working group’s deliberations, industry comments, and
FDA’s resulting conclusions were described in an August 1, 2011 internal memorandum signed
by the Directors of FDA’s Center for Drug Evaluation and Research and Center for Biologics
Evaluation and Research (“2011 Memorandum”). Id. at 292–310. The 2011 Memorandum
explained the “considerable variability in how scientific sources define” the terms “protein,”
“chemically synthesized,” and “polypeptide.” Id. at 293. Nonetheless, FDA identified scientific
consensus as to at least two elements of the definitions.
First, FDA concluded 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.” Id. at 297. “Proteins are long, complex polymers of amino acids,” id., while
peptides are “simpler, shorter amino acid chains” not considered to be proteins, id. at 298. This
scientific consensus, in combination with the BPCIA’s intent to create “a new abbreviated
approval pathway [the aBLA process] with statutory criteria better suited” to complex
interchangeable products than the “sameness” standard applied to generic drugs under the
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FDCA, id. at 299, led to the determination that “proteins” within the meaning of the BPCIA
should have a minimum size requirement, as a bright-line proxy for complexity, see id. at 299–
300, 302–04. A forty amino acid cut-off, under which amino acid polymers of fewer than forty
amino acids would be treated as peptides rather than proteins, was found to have “significant
support in the literature” and to be “consistent” with other FDA regulations concerning peptides.
Id. at 305.
Second, FDA found that the term “protein,” as used in scientific sources, consistently
referred to “chains containing a specific, defined sequence of amino acids, generally provided by
the DNA [deoxyribose nucleic acid] sequence of a corresponding gene.” Id. at 297. The 2011
Memorandum cited a variety of scientific references in support of this consensus. See, e.g., id. at
295, 295 n.14, 296–97, 297 nn.32–33. Thus, FDA determined that amino acid polymers without
a “specific, defined amino acid sequence,” for example, “chemically synthesized polymers with
random sequences, (e.g., glatiramer),” are not proteins and therefore “are not subject to the
parenthetical exclusion [for chemically synthesized polypeptides] in the first place.” Id. at 307.
In reaching this conclusion, FDA acknowledged that the statutory term “protein” included
chemically synthesized proteins, see, e.g., id. at 306 (“[I]f Congress wished to exclude all
chemically synthesized proteins from the definition of biological product, it would have used
‘protein’ in the parenthetical instead of ‘polypeptide.’”), and reviewed scientific articles about
the chemical synthesis of proteins, see, e.g., id. at 306 nn.60–61.
In its efforts to interpret the parenthetical exclusion—i.e., defining “biological product”
as “a . . . protein (except any chemically synthesized polypeptide), or analogous product,” 42
U.S.C. § 262(i)(1) (2012)—FDA confronted “[t]he challenge” of the absence of scientific
consensus around “a generally accepted meaning” of “polypeptide.” Id. at 306. The agency thus
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sought to craft a definition of “chemically synthesized polypeptide” that “fit[] within the
statutory language and ma[de] regulatory sense.” Id. Looking to the structure of the
parenthetical exception, which was designed to exclude a narrower subset of molecules from the
broader category of proteins, FDA determined that “chemically synthesized polypeptides” must
refer to a smaller group of “molecules that would otherwise fall within the ‘protein’ term.” Id.Further, although emerging technologies continue to push the boundaries of chemical synthesis,
FDA recognized that “chemical synthesis of amino acid polymers with a defined sequence has
historically been restricted to shorter peptide chains,” id., providing some indication of the types
of molecules Congress might have had in mind when drafting the exception, id. at 306–07. FDA
next turned to congressional intent, noting that, because the BPCIA meant to create a regulatory
regime better tailored to highly complex molecules, excluding certain extremely complicated
substances from the definition of “biological product” solely because they are chemically
synthesized would contradict the purpose of the law. See id. For these reasons, FDA “infer[red]
that Congress intended for the parenthetical exclusion to apply only to relatively short, less
complex amino acid polymers,” and, again using length as a proxy for complexity, determined
that polymers of fewer than 100 amino acids in length met this criteria. Id. at 307.
As a result of this analysis, the 2011 Memorandum defined “protein” as “any alpha
amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size”
and “chemically synthesized polypeptide” as “any alpha amino acid polymer is that is (a) made
entirely by chemical synthesis; and (b) less than 100 amino acids in size.” Id. at 292 (footnote
omitted).
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(b) Guidance Documents
On February 15, 2012, FDA announced the availability of a draft guidance document,
open to public comment, on the implementation of the BPCIA (“2012 Guidance Document”)
that, in relevant part, set forth FDA’s interpretation of “protein” and “chemically synthesized
polypeptide.” Id. at 311–30.2 The 2012 Guidance Document adopted the definitions developed
in the 2011 Memorandum, stating that “[t]he term ‘protein’ means any alpha amino acid polymer
with a specific defined sequence that is greater than 40 amino acids in size” and “[t]he term
‘chemically synthesized polypeptide means any alpha amino acid polymer that (1) is made
entirely by chemical synthesis; and (2) is less than 100 amino acids in size.” Id. at 328. In
establishing the elements of these definitions, FDA relied on the analysis described in the 2011
Memorandum. See id. at 311–30. This guidance was finalized, and again made open to public
comment, on April 30, 2015 (“2015 Guidance Document”). See id. at 740–60. The 2015
Guidance Document provided the same definitions of “protein” and “chemically synthesized
polypeptide,” id. at 758, and again relied on substantially the same analysis, as the 2012
Guidance Document and the 2011 Memorandum, see id. at 740–60. A third guidance document,
issued on March 14, 2016 (“2016 Guidance Document”), id. at 782–95, published the identical
definitions again, id. at 787 n.3.
(c) 2018 Proposed Rule and 2020 Final Rule
On December 12, 2018, FDA published a notice of proposed rulemaking and a proposed
rule to codify its interpretations of “protein” and “chemically synthesized polypeptide” (the
“Proposed Rule”). Id. at 800–07. The Proposed Rule, like the earlier Guidance Documents,
canvassed the scientific literature and detailed the scientific, regulatory, and legal considerations
2
Teva submitted comments to the 2012 Guidance Document, but did not address FDA’s interpretation of the
terms “protein” and “chemically synthesized polypeptide.” See AR at 331–41.
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taken into account by the agency (including public comments submitted in response to the 2012
and 2015 Guidance Documents), id. at 802–03, and included the agency’s previously published
definitions of “protein” and “chemically synthesized polypeptide,” unaltered from the Guidance
Documents, id. at 801. FDA again emphasized the scientific consensus at the heart of its
interpretation, that the term “protein refers to chains containing a specific, defined sequence of
amino acids.” Id. at 803 (emphasis omitted). The public comment period for the Proposed Rule
closed on February 25, 2019. Id. at 800.
Nearly ten months later, on December 20, 2019, Congress passed the 2019 Act, removing
the parenthetical exception for chemically synthesized polypeptides from the PHSA’s definition
of “biological product.” FDA did not reopen the Proposed Rule for a new round of comments in
light of the new law. Instead, on February 21, 2020, two months after the 2019 Act was enacted,
FDA published its Final Rule, id. at 1024–30, codifying the definition of “protein” set forth in
the 2011 Memorandum; the 2012, 2015, and 2016 Guidance Documents; and the Proposed Rule
“without change,” id. at 1025. “[I]n light of the [2019] Act,” however, FDA did not “finaliz[e]
its interpretation of ‘chemically synthesized polypeptide’ because it [was] no longer necessary.”
Id. The agency clarified that, “[w]ith the . . . removal of the parenthetical exception . . . all
amino acid polymers that meet FDA’s interpretation of the term ‘protein’ (including an amino
acid polymer that previously would have fallen within the term ‘chemically synthesized
polypeptide’ as interpreted by FDA) will be considered to fall within the statutory definition of
‘biological product.’” Id. at 1026. Aside from these statements, made in the context of
responding to comments that had been submitted with respect to the Proposed Rule’s definition
of “chemically synthesized polypeptide,” FDA offered no further analysis or explanation of the
2019 Act’s impact, if any, on its interpretation of the term “protein.”
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At no time during its nearly decade-long rulemaking process did FDA provide a
regulatory definition for “analogous product” as applied to products “analogous” to proteins. In
the Final Rule, FDA observed that “[a] definition of products that are ‘analogous’ to a
‘protein’ . . . is outside the scope of this rulemaking,” but 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.” Id. at 1028.
B. Approval and Classification of Glatiramer Acetate Products
1. Manufacture and Composition of Copaxone
Copaxone, the therapeutic product at issue in this action, is an injectable used for the
“reduction of relapses in patients with relapsing-remitting multiple sclerosis.” Id. at 3. Its active
ingredient, glatiramer acetate, is a chemically synthesized “mixture of peptide copolymers
containing four specific amino acids in a defined molar ratio.” Id. at 706. Glatiramer acetate is
synthesized “via amino acid polymerization [] followed by a subsequent cleavage or partial
depolymerization step[.]” Id. at 706. In the first step, polymerization, the amino acids are
assembled into chains, or polymers. Id. at 709–13. “[W]hile the addition of . . . amino acids to
the copolymer chain is not determined by a pre-determined sequence, it is also not a purely
random event.” Id. at 712. Rather, the sequence of the polymers (that is, the order in which
amino acids are added to the chains) is determined by reaction chemistry. The reactivities of the
four amino acids in glatiramer acetate differ. As a result, “their corresponding relative rates of
incorporation into the copolymer chains” also differ, id. at 712, and, in a phenomenon known as
“propagational shift,” “the molar fractions of each [amino acid] . . . vary across the synthesized
chain,” id. at 713. The degree of variation is predictable, but not certain, based on the relative
reactivity of the amino acids: more reactive amino acids tend to appear at the beginning of the
chain and less reactive amino acids tend to appear towards the end. Id. at 713. This
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predictability means that “the chance of producing a conserved local amino acid sequence is
increased, which is consistent with the conservation [or replication] of local sequences between
batches of Copaxone.” Id. at 713.
In the second step, partial depolymerization, the copolymer chains formed during
polymerization are “cleaved,” or broken into smaller pieces, to produce chains within a specified
molecular weight distribution characteristic of glatiramer acetate. Id. at 714. The amino acid
sequences are not changed at this stage. Id.
2. NDA and ANDAs for Copaxone and Other Glatiramer Acetate
Products
In 1995, Teva submitted an NDA for Copaxone, which FDA approved on December 20,
1996. Id. at 3. Since that time, Teva has pursued every available avenue to prevent other
glatiramer acetate products from coming to market. See generally Staff of H.R. Comm. on
Oversight & Reform, 116th Cong., Rep. on Drug Pricing Investigation: Teva—Copaxone (2020),
https://oversight.house.gov/sites/democrats.oversight.house.gov/files/Teva%20Staff%20Report
%2009-30-2020.pdf.
First, Teva has initiated numerous patent suits against its competitors. See, e.g., Mylan’s
Combined Mem. Supp. Mylan’s Cross-Mot. Summ. J. & Resp. Pls.’ Mot. Summ. J. (“Mylan
Mem.”) at 2, ECF No. 34-1 (describing Teva’s “near decade-long patent battle in the courts,
filing almost a dozen patent litigations against Mylan, Sandoz, and others”); Sandoz Inc.’s
Consolidated Mem. Opp’n Pls.’ Mot. Summ. J. & Supp. Sandoz Inc.’s Cross-Mot. Summ. J.
(“Sandoz Mem.”) at 1, ECF No. 38-1 (“Teva has . . . pursu[ed] multiple lawsuits to tie up
Sandoz, Mylan and other competitors in the courts.”). Relevant to this litigation, at present, Teva
holds two patents “claim[ing] processes for manufacturing glatiramer acetate by filtering under
specified temperature conditions,” U.S. Patent Nos. 9,155,755 (“’775 Patent”) and 9,763,993
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(“’993 Patent”), and “at least one patent . . . claiming methods of treatment using” Copaxone,
U.S. Patent No. 9,402,874 (“’874 Patent”). Decl. of Colman Ragan ¶ 6 (“Ragan Decl.”), ECF
No. 40-1. The ’775 and ’993 Patents, as process patents, were never listed in the Orange Book;
the ’874 Patent was listed in the Orange Book until this year, “when Teva requested its removal
following court decisions on other patents directed to methods of using” Copaxone. Id.Second, as part of this campaign, from 2008–2015, Teva filed eight Citizen Petitions with
FDA, seeking to block the approval of ANDAs for generic glatiramer acetate products, all of
which were denied. See AR at 19–52 (Sept. 26, 2008 Citizen Petition), 69–106 (Nov. 13, 2009
Citizen Petition), 171–99 (Dec. 10, 2010 Citizen Petition), 342–76 (June 4, 2012 Citizen
Petition), 388–409 (Sept. 12, 2013 Citizen Petition), 410–69 (Dec. 5, 2013 Citizen Petition),
493–555 (July 2, 2014 Citizen Petition), 564–696 (Mar. 31, 2015 Citizen Petition). Among other
arguments, Teva contended that, because of the variability in Copaxone, an ANDA application
could not satisfy the statutory “sameness” requirement for a generic drug. See, e.g., id. at 437.
Indeed, in each of its eight Citizen Petitions, Teva represented to FDA that the sequences of the
polymer chains in Copaxone are neither specific nor predefined. To the contrary, in Teva’s
words, “[t]he . . . manufacturing process [for Copaxone] creates a mixture of polypeptides with
different primary structures, chain lengths and conformations. It has been estimated that this
mixture likely contains more than 1012 different polypeptides and theoretically could contain
more than 1029 possible primary polypeptide sequences.” Id. at 479. Using Teva’s math, “more
than a trillion unique polypeptides,” with distinct sequences, make up glatiramer acetate, a
substance which “could contain more than a trillion times a trillion different polypeptides (i.e.,
100,000,000,000,000,000,000,000,000,000 different polypeptides).” Id. at 479 (emphasis
omitted); see also, e.g., id. at 24, 35, 38, 78, 184.
16
In its fourth Citizen Petition, submitted on June 4, 2012, Teva argued that under the
definition of “protein” set forth in the 2012 Guidance Document, “many of the polypeptides
comprising Copaxone appear to qualify as ‘proteins.’” Id. at 342–43; see also id. at 346 n.10.
FDA’s denial of that Petition explained, based on the 2011 Memorandum and the 2012 Guidance
Document, that the agency “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.” Id. at 383 n.33.
On April 16, 2015, FDA denied Teva’s last Citizen Petition and approved an ANDA for
Sandoz’s generic glatiramer acetate product in a forty-three page letter. Id. at 697, 699; see also
id. at 697–739; Sandoz Mem. at 16. FDA explained that “[c]urrent analytical techniques are
capable of supporting a demonstration of active ingredient sameness between the generic
glatiramer acetate injection and [Copaxone].” AR at 727; see also id. at 727–31. The agency
agreed with Teva’s characterization of Copaxone’s inherent variability and internal diversity,
finding that “active ingredient sameness criteria for a generic glatiramer acetate injection should
incorporate this batch-to-batch variability.” Id. at 718 n.69. FDA developed four criteria to
assess sameness for generic glatiramer acetate products: “(1) Fundamental reaction scheme; (2)
Physiochemical properties including composition; (3) Structural signatures for polymerization
and depolymerization; and (4) Results in a biological assay.” Id. at 700. Just as it did in denying
Teva’s fourth Citizen Petition, FDA again observed that “glatiramer acetate is distinguishable
from proteins because (unlike a protein) it does not . . . have a defined and specific amino acid
sequence,” and “there is a negligible likelihood of having identical amino acid sequences along
entire copolymer chains from batch to batch.” Id. at 708 (footnotes omitted). Additional
ANDAs for Copaxone, including an ANDA for a generic product submitted by Mylan, were
17
approved in 2017 and 2018. Federal Defs.’ Mem. Law Supp. Cross-Mot. Summ. J. & Opp’n
Pls.’ Mot. Summ. J. at 4 (“Fed. Defs.’ Mem.”), ECF No. 36-1.
3. BPCIA Transition Provision and Glatiramer Acetate Products
On March 14, 2016, FDA announced a new draft guidance document, open to public
comment, for implementing the BPCIA’s transition provision, BPCIA § 7002(e)(4), which
applied the definitions of “protein” and “chemically synthesized polypeptide” set forth in its
2011 Memorandum and the 2012, 2015, and 2016 Guidance Documents. See AR at 780–95.
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].” Id. at 790. The agency also provided a list
of examples of biological products then approved under NDAs or ANDAs that would be
transitioned to BLAs. Id. at 795. Glatiramer acetate products were not on this 2016 list of
biological products to be transitioned to BLAs. See id.
On December 12, 2018, the same day that FDA issued its Proposed Rule codifying its
interpretations of “protein” and “chemically synthesized polypeptides,” FDA finalized this
guidance, which was again open to public comment, see id. at 873–99, and posted a preliminary
list of Transition Products, that is, biological products operating under approved NDAs that
would be deemed to be BLAs on March 23, 2020 (the “Preliminary List”), id. at 900–09.
Neither Copaxone nor any other glatiramer acetate product was included on the 2018 list, see id.,
or on FDA’s September 2019 and January 2020 updates to the Preliminary List, see id. at 1133–
42, 1143–51.
On February 19, 2020, Teva submitted its first and only comments to the docket
regarding the Preliminary List. Id. at 1008–23. Raising many of the same arguments as in this
litigation, Teva contended that, because Congress had eliminated the parenthetical exception for
18
chemically synthesized polypeptides in the 2019 Act, Copaxone now qualified as a protein
because, in addition to satisfying FDA’s forty amino acid size requirement, it has a “specific,
defined sequence.” Id. at 1015. In support of this view, Teva argued that “while the overall
sequence of each individual polymer within the glatiramer acetate mixture may differ both
within a single batch and from batch-to-batch, the conservation of local amino acid sequences
among the polymers reflects a sufficiently specific and defined sequence to qualify as a
‘protein,’” id. at 1016, and compared Copaxone to two naturally derived products included on
the Preliminary List, Vitrase (hyaluronidase) and Creon (pancrelipase), that, in Teva’s view,
have “undefined and unspecified overall amino acid sequences,” id., but were nonetheless
classified as proteins, id. at 1016–18. In the alternative, Teva argued that, at a minimum,
Copaxone is “analogous” to either a protein or a vaccine. See id. at 1019–22.
On March 20, 2020, three days before the BPCIA transition deadline of March 23, 2020,
FDA issued an internal decision memorandum in which it determined that Copaxone is not a
biological product and therefore would not be transitioned to a BLA (the “Decision
Memorandum”). Id. at 1117–23. Applying the definition adopted in the Final Rule, the agency
found that “[g]latiramer acetate is not a ‘protein’ because it does not have a specific, defined
sequence,” a criterion which “describes the manner in which specific amino acids are added to a
polymer in a defined sequence.” Id. at 1120. FDA explained that “[n]aturally occurring and
recombinant proteins are made as the result of the synthesis of RNA [ribonucleic acid] from a
DNA template (transcription) followed by translation into a protein molecule” and so “[f]or such
proteins, the existence of a DNA template renders the sequence ‘specific and defined.’” Id.
Synthetic proteins, too, must have a specific, defined sequence, which typically is “generated by
the stepwise addition of specific amino acids in a defined sequence” during synthesis. Id.
19
Copaxone, in contrast, exhibits “sequence variability” because “the sequences are driven by
reaction chemistry rather than a pre-defined template.” Id. Though patterns may recur due to the
chemical properties of the amino acids that compose glatiramer acetate, exact replication of any
single sequence is not assured. FDA next found that Copaxone is not “analogous” to either a
protein or a vaccine, explaining that “it would not be appropriate to interpret the statutory term
‘analogous product’ (with reference to a ‘protein’) in a way that would include amino acid
polymers that are specifically excluded by the interpretation of the term ‘protein’ set forth in
FDA’s” Final Rule. Id. at 1121. Thus, FDA “would not consider an amino acid sequence that
does not have a specific, defined sequence to be ‘analogous’ to a protein.” Id.
On March 23, 2020, FDA transitioned ninety-six NDAs to BLAs, in accordance with
§ 7002(e)(4) of the BPCIA. Id. at 1124–32. The final list of transitioned products included
several amino acid polymers with specific, defined sequences and lengths between forty and
ninety-nine amino acids that initially had been excluded from the Preliminary List because they
were chemically synthesized, but were deemed eligible for transition upon the 2019 Act’s
deletion of the parenthetical exclusion. All transitioned products were determined by FDA to be
a protein or analogous to a protein. Fed. Defs.’ Mem. at 12. Copaxone was not on the list and
therefore was not transitioned to a BLA.
C. Procedural Background
The day after the BPCIA transition deadline, on March 24, 2020, Teva initiated this
action, filing a two-count complaint alleging that FDA’s denial of Teva’s Transition Request
violated section 706(2)(A) of the Administrative Procedure Act (“APA”), 5 U.S.C. § 706(2)(A),
section 351 of the PHSA, 42 U.S.C. § 262(i)(1), and section 7002(e)(4) of the BPCIA and
seeking declaratory and injunctive relief. Compl. ¶¶ 75–89. The parties proposed entry of an
order expediting briefing on the merits in to order to avoid a motion for preliminary injunction.
20
Joint Mot. Entry of Scheduling Order, ECF No. 7. Consistent with the parties’ request, the Court
entered a scheduling order for expedited briefing on cross-motions for summary judgment. Min.
Order (Apr. 9, 2020). On April 17, 2020 and April 24, 2020, respectively, Sandoz and Mylan
filed motions to intervene, see Mot. Intervene by Sandoz Inc.; Mot. Intervene as Def., which
motions were granted, see Min. Order (Apr. 20, 2020); Min. Order (Apr. 27, 2020).
Briefing proceeded under the parties’ schedule, as modified, see Min. Order (June 22,
2020), with the final briefs filed on July 30, 2020, see Federal Defs.’ Reply Mem. Supp. Cross-
Mot. Summ. J. (“Fed. Defs.’ Reply”), ECF No. 43; Sandoz Inc.’s Reply Mem. Supp. Mot.
Summ. J. (“Sandoz Reply”), ECF No. 44; Mylan’s Reply Mem. Supp. Mylan’s Cross-Mot.
Summ. J. (“Mylan Reply”), ECF No. 45. Upon the Court’s order, see Min. Order (Dec. 10,
2020), the parties also submitted supplemental briefing, see Suppl. Br. Supp. Pls.’ Mot. Summ. J.
(“Pls.’ Suppl. Br.”), ECF No. 49; Sandoz Inc.’s Resp. Pls.’ Suppl. Br. (“Sandoz Suppl. Br.”),
ECF No. 50; Mylan’s Resp. Pls.’ Suppl. Br. (“Mylan Suppl. Br.”), ECF No. 51; Fed. Defs.’
Resp. Pls.’ Suppl. Br. on Cross-Mots. Summ. J. (“Fed. Defs.’ Suppl. Br.”), ECF No. 52, which
was completed by December 17, 2020. The parties’ cross-motions for summary judgment are
now ripe for resolution.
II. LEGAL STANDARD
A. Administrative Procedure Act
The APA provides for judicial review of any “final agency action for which there is no
other adequate remedy in a court,” 5 U.S.C. § 704, and “instructs a reviewing court to set aside
agency action found to be ‘arbitrary, capricious, an abuse of discretion, or otherwise not in
accordance with law,’” Cigar Ass’n of Am. v. FDA, 964 F.3d 56, 61 (D.C. Cir. 2020) (quoting 5
U.S.C. § 706(2)(A)). This standard “‘requires agencies to engage in reasoned decisionmaking,’
and . . . to reasonably explain to reviewing courts the bases for the actions they take and the
21
conclusions they reach.” Brotherhood of Locomotive Eng’rs & Trainmen v. Fed. R.R. Admin.,
972 F.3d 83, 115 (D.C. Cir. 2020) (quoting Dep’t of Homeland Sec. v. Regents of Univ. of Cal.
(“Regents”), 140 S. Ct. 1891, 1905 (2020)). Judicial review of agency action is limited to “‘the
grounds that the agency invoked when it took the action,’” Regents, 140 S. Ct. at 1907 (quoting
Michigan v. EPA, 576 U.S. 743, 758 (2015)), and the agency, too, “must defend its actions based
on the reasons it gave when it acted,” id. at 1909.
B. Summary Judgment
Pursuant to Federal Rule of Civil Procedure 56, “‘[a] party is entitled to summary
judgment only if there is no genuine issue of material fact and judgment in the movant's favor is
proper as a matter of law.’” Soundboard Ass’n v. FTC, 888 F.3d 1261, 1267 (D.C. Cir. 2018)
(quoting Ctr. for Auto Safety v. Nat’l Highway Traffic Safety Admin., 452 F.3d 798, 805 (D.C.
Cir. 2006)); see also Fed. R. Civ. P. 56(a). In APA cases such as this one, involving cross-
motions for summary judgment, “the district judge sits as an appellate tribunal. The ‘entire case’
on review is a question of law.” Am. Bioscience, Inc. v. Thompson, 269 F.3d 1077, 1083 (D.C.
Cir. 2001) (footnote omitted) (collecting cases). Thus, this Court need not and ought not engage
in lengthy fact finding, since “[g]enerally speaking, district courts reviewing agency action under
the APA’s arbitrary and capricious standard do not resolve factual issues, but operate instead as
appellate courts resolving legal questions.” James Madison Ltd. by Hecht v. Ludwig, 82 F.3d
1085, 1096 (D.C. Cir. 1996); see also Lacson v. U.S. Dep’t of Homeland Sec., 726 F.3d 170, 171
(D.C. Cir. 2013) (noting, in an APA case, that “determining the facts is generally the agency's
responsibility, not ours”). As a general rule, judicial review is limited to the administrative
record, since “[i]t is black-letter administrative law that in an [APA] case, a reviewing court
should have before it neither more nor less information than did the agency when it made its
22
decision.” CTS Corp. v. EPA, 759 F.3d 52, 64 (D.C. Cir. 2014) (second alteration in original)
(internal quotation omitted).
III. DISCUSSION
Teva challenges the Decision Memorandum on several grounds. First, it contends 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. Thus, Teva argues, both
the Final Rule and the Decision Memorandum applying it are invalid. Next, Teva submits 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. Defendants disagree with each contention and argue that Teva does not have
standing to bring any of its challenges. Teva’s standing to bring this action is considered first
before turning to the parties’ arguments on the merits.
A. Teva Has Standing
Article III requires that plaintiffs establish “the irreducible constitutional minimum of
standing,” Lujan v. Defs. of Wildlife, 504 U.S. 555, 560 (1992), that they have “(1) suffered an
injury in fact, (2) that is fairly traceable to the challenged conduct of the defendant, and (3) that
is likely to be redressed by a favorable judicial decision,” Spokeo, Inc. v. Robins, 136 S. Ct.
1540, 1547 (2016) (citing Lujan, 504 U.S. at 560–61; Friends of the Earth, Inc. v. Laidlaw Env’tl
Servs. (TOC), Inc., 528 U.S. 167, 180–81 (2000)); see also Louie v. Dickson, 964 F.3d 50, 54
(D.C. Cir. 2020). “The absence of any one of these three elements defeats standing.” Newdow v.
Roberts, 603 F.3d 1002, 1010 (D.C. Cir. 2010). Plaintiffs carry the burden of establishing the
elements of standing “‘with the manner and degree of evidence required at the successive stages
of the litigation.’” Bennett v. Spear, 520 U.S. 154, 168 (1997) (quoting Lujan, 504 U.S. at 561).
23
At summary judgment, “the plaintiff ‘must set forth by affidavit or other evidence specific facts’
that prove standing.” Humane Soc’y of U.S. v. Perdue, 935 F.3d 598, 602 (D.C. Cir. 2019)
(quoting Lujan, 504 U.S. at 561) (citing Scenic Am., Inc. v. U.S. Dep’t of Transp., 836 F.3d 42,
49 n.3 (D.C. Cir. 2016)).
The parties’ standing dispute centers on the first element requiring that Teva have
suffered an injury-in-fact “that is ‘concrete and particularized’ and ‘actual or imminent, not
conjectural or hypothetical.’” Spokeo, Inc., 136 S. Ct. at 1548 (quoting Lujan, 504 U.S. at 560).
Teva defends its standing on three grounds, any one of which, in its view, demonstrates
constitutional standing under Article III and statutory standing. Specifically, Teva alleges three
injuries resulting from FDA’s refusal to transition Copaxone from an NDA to a BLA: (1) “an
informational injury”; (2) “the loss of statutory rights,” namely, “the ability to receive
confidential access to a biosimilar applicant’s aBLA and to file an infringement lawsuit”; and (3)
“a competitive injury.” Pls.’ Mem. P. & A. Supp. Mot. Summ. J. (“Pls.’ Mem.”) at 17, ECF No.
31-1; see also Pls.’ Consolidated Opp’n Defs.’ & Intervenor-Defs.’ Cross-Mots. Summ. J. &
Reply Supp. Pls.’ Mot. Summ. J. (“Pls.’ Opp’n”) at 4–15, ECF No. 40. Defendants dispute that
Teva has constitutional standing based on any of these three injuries, which, they contend, are
too speculative to constitute injuries-in-fact. As explained below, Teva’s competitive injury
confers both constitutional and statutory standing.
1. Teva Has Shown Sufficient Injury-in-Fact for Standing
The sufficiency for standing of each of Teva’s alleged injuries in fact is examined in turn.
Teva claims to suffer both an “informational injury” and the deprivation of its statutory process
right to bring a preapproval patent infringement lawsuit due to the continued regulation of
Copaxone and generic glatiramer acetate products under the FDCA. As to the alleged
“informational injury,” Teva explains that manufacturers of competing glatiramer acetate
24
products have no obligation to provide Teva with information about their ANDA applications
and the manner in which they manufacture their products under the FDCA, but these competitors
would have such an obligation to supply, and Teva would have a concomitant right to receive,
that information if Copaxone were classified as a biological product under the PHSA. Pls.’
Mem. at 17–18; Pls.’ Opp’n at 5–11.
Relatedly, Teva contends that FDA’s failure to transition Copaxone to a BLA deprives
Teva of statutory process rights, under the BPCIA’s amendments to the PHSA, to which it would
be entitled as a holder of a BLA. Pls.’ Mem. at 17–18; Pls.’ Opp’n at 5–11. If Copaxone were
regulated as a biologic under the BPCIA’s amendments to the PHSA, manufacturers of
prospective biosimilars would be required to provide Teva with a copy of their aBLA
applications, “information that describes the process or processes used to manufacture the
[biosimilars],” 42 U.S.C. § 262(l)(2)(A), and 180 days’ notice before commercially marketing
the biosimilar, id. § 262(l)(8)(A); see supra Part I.A.2. Teva claims that this information, in
combination with the BPCIA’s detailed provision for the preapproval resolution of patent
disputes, see supra Part I.A.2, would enable enforcement of the patents Teva holds for the
process of manufacturing glatiramer acetate against a prospective biosimilar applicant, facilitate
the “patent dance,” and allow Teva to bring an infringement suit or a declaratory judgment action
prior to approval of the biosimilar. Pls.’ Mem. at 17–18; Pls.’ Opp’n at 5–11. In contrast, the
FDCA does not require ANDA applicants seeking to manufacture generic drugs to provide any
information about their manufacturing processes (or any other information not covered by an
Orange Book patent) in their Paragraph IV certifications and does not provide for preapproval
infringement challenges based on process patents or other patents not included in the Orange
Book. See 21 U.S.C. § 355(b)(1), (j)(2)(B)(iv); supra Part I.A.1; Pls.’ Opp’n at 6. Thus, as long
25
as Copaxone continues to be treated as a drug, Teva has no recourse to enforce its patents against
a prospective ANDA applicant.
Teva contends that these alleged injuries are “actual and imminent” because “a generic
drug manufacturer, through litigation counsel, has informed Teva that it intends to file an ANDA
to market a generic version of COPAXONE.” Pls.’ Opp’n at 7; see also Pls.’ Mem. at 17; Ragan
Decl. ¶ 8. To date, however, no such ANDA has been filed. As a rule, “litigants cannot
establish an Article III injury based on the ‘independent action[s] of some third party not before
th[is] court’ . . . because ‘predictions of future events (especially future actions taken by third
parties)’ are too speculative to support a claim of standing.” Turlock Irrigation Dist. v. FERC,
786 F.3d 18, 25 (D.C. Cir. 2015) (alterations in original) (first quoting Fla. Audubon Soc’y v.
Bentsen, 94 F.3d 658, 670 (D.C. Cir. 1996) (en banc); and then quoting United Transp. Union v.
Interstate Commerce Comm’n, 891 F.2d 908, 912 (D.C. Cir. 1989)). For Teva’s alleged injuries
to occur, a generic manufacturer would have to submit an ANDA that was then accepted for
review and approved by FDA. See Fed. Defs.’ Reply at 4–6. This chain of events, which relies
on the actions of an unidentified third party as its catalyst, is, at first blush, too speculative to
support standing.
Defendants further argue that, even if a prospective generic manufacturer came forward,
Teva would not actually enjoy the rights it asserts to either information or statutory process
under the PHSA for two reasons. As defendants explain, the BPCIA’s information-sharing
provision is enforceable only through the declaratory-judgment action provided in 42 U.S.C.
§ 262(l)(9)(C), see Sandoz, 137 S. Ct. at 1675, and therefore does not create an unambiguous
right for sponsors to receive information from biosimilar applicants. Fed. Defs.’ Mem. at 14–16;
Mylan Mem. at 21–23; Sandoz Mem. at 22–24; Fed. Defs.’ Reply at 4–6; Mylan Reply at 8–10;
26
Sandoz Reply at 4–10. In addition, neither section 351 of the PHSA nor 35 U.S.C.
§ 271(e)(2)(C)(ii) allow patent holders to bring preapproval patent infringement suits to enforce
process patents. Fed. Defs.’ Mem. at 14–17; Mylan Mem. at 21–23; Sandoz Mem. at 22–23;
Mylan Reply at 8–10; Sandoz Reply at 5–10. Neither of these questions of statutory
interpretation need be resolved here, however, because Teva’s alleged competitive injury is
sufficient to confer Article III standing.
(a) Alleged Competitive Injury
Teva alleges a “competitive,” or economic, injury, because, under the automatic
substitution laws applicable to prescriptions for “drugs,” prescriptions written for Copaxone are
automatically filled with a generic glatiramer acetate product manufactured by one of Teva’s
competitors. Indeed, when FDA has approved both an NDA for a brand-name drug and an
ANDA for a generic drug, the relevant laws of every state allow (and in some cases require)
pharmacists filling a prescription for the brand-name drug automatically to dispense the generic
drug in its place, unless the prescribing physician specifically directs the pharmacist to “dispense
as written.” Pls.’ Mem. at 18–19; see, e.g., D.C. Code §§ 48-803.02, .03(2); see also Pls.’ Opp’n
at 11–12; Decl. of Dalton Tomlinson (“Tomlinson Decl.”) ¶¶ 7–8, ECF No. 40-2. Thus, a
pharmacist filling a prescription written for Copaxone is likely to dispense a generic glatiramer
acetate product (for example, those manufactured by Mylan or Sandoz) rather than Teva’s brand-
name product.
These automatic substitution laws do not apply to biologics and, consequently, Teva
contends that, if Copaxone had been transitioned to a BLA, prescriptions written for Copaxone
would be filled with Teva’s product, at least until FDA approved a biosimilar as
“interchangeable” with Copaxone. Pls.’ Mem. at 18–19. In some states, substitution is not
27
available at all if a biological product is prescribed by name. See, e.g., D.C. Code §§ 48-
803.02(a)(1), .03(2)(A); Tomlinson Decl. ¶ 14. If Copaxone were treated as a biological product,
in these jurisdictions, a pharmacist filling a prescription written for Copaxone would have to
dispense Teva’s product rather than a biosimilar produced by Mylan, Sandoz, or any other
manufacturer. The majority of jurisdictions allow biosimilars to be substituted for biological
products, but only after a finding by FDA that the biosimilar is “interchangeable” with the
biological product. See, e.g., Fla. Stat. § 465.0252(1), (2); Va. Code §§ 54.1-3401, 54.1-
3408.04(A). Interchangeability is a heightened requirement separate from aBLA approval, with
no equivalent in the generic drug context. See 42 U.S.C. § 262(i)(3), (k)(4); AR at 960–72.
Thus, even in jurisdictions that allow substitution of biological products, if Copaxone were a
biological product, unless and until FDA determined that a biosimilar was interchangeable with
Copaxone, prescriptions written for Copaxone would be filled with Teva’s product. See Pls.’
Mem. at 18–19; Pls.’ Opp’n at 11–15.
“When determining whether a plaintiff has Article III standing, the court must assume
that the [plaintiff] will prevail on the merits.” Comm. on Judiciary of U.S. House of
Representatives v. McGahn, 968 F.3d 755, 762 (D.C. Cir. 2020) (en banc) (citations omitted);
see also Estate of Boyland v. U.S. Dep’t of Agric., 913 F.3d 117, 123 (D.C. Cir. 2019).
Assuming, then, that Teva will prevail on its claim that Copaxone should have been transitioned
to a BLA on March 23, 2020, Teva is injured every time a pharmacist dispenses a generic
glatiramer acetate product in place of Copaxone because each sale of a generic drug while
Copaxone continues to be regulated under the FDCA would likely translate to a sale of
Copaxone if Copaxone were regulated under the PHSA. In the regulatory landscape described
above, currently, patients who fill prescriptions for Copaxone receive generic glatiramer acetate
28
products unless their provider writes “dispense as written” or “do not substitute” on the
prescription. Tomlinson Decl. ¶ 7.
Teva’s Vice President for Specialty Product Marketing has stated that in April and May
2020, the two months immediately following the BPCIA’s deadline to transition qualifying
products to BLAs and aBLAs, at least 3,925 prescriptions were written for Copaxone without
specifying that the prescription should be dispensed as written. Id. ¶ 8.3 If all glatiramer acetate
products had been transitioned to BLAs and aBLAs on March 23, 2020, pharmacists would have
dispensed, and would continue to dispense, Copaxone in filling these thousands of prescriptions
until FDA determines that another glatiramer acetate product is interchangeable with Copaxone.
As Copaxone continues to be regulated as a drug, these prescriptions were likely filled with a
generic product, depriving Teva of sales it would have enjoyed if Copaxone had been
transitioned on March 23, 2020. Thus, taking as true Teva’s claim that Copaxone should have
been transitioned to a BLA, Teva has accumulated and continues to accumulate monetary losses,
in the form of lost sales, from the improper automatic substitution of generic glatiramer acetate
3
The federal defendants assert that this statistic, provided in a declaration by Vice President for Specialty
Product Marketing, is inadmissible under Federal Rule of Civil Procedure 56(c)(4), which requires that declarations
in support of motions for summary judgment “must be made on personal knowledge, set out facts that would be
admissible in evidence, and show that the affiant or declarant is competent to testify on the matters stated,” Fed. R.
Civ. P. 56(c)(4), because the declarant does not identify its source. Fed. Defs.’ Reply at 7. Rule 56(c)(4)’s
“‘directive with respect to the admissibility of an affidavit’s [or a declaration’s] contents on summary judgment has
been liberally construed,’” Sabra ex rel. Baby M v. Pompeo, 453 F. Supp. 3d 291, 330 (D.D.C. 2020) (quoting
Londrigan v. FBI, 670 F.2d 1164, 1174 (D.C. Cir. 1981)), but its “requirement of personal knowledge . . . is
unequivocal, and cannot be circumvented,” Londrigan, 670 F.2d at 1174 (footnote omitted). The declarant here
attests that his declaration “is based upon [his] personal knowledge, including [his] experience in the pharmaceutical
industry and at Teva,” Tomlinson Decl. ¶ 1, states that he is “responsible for the planning and management of CNS,
Psychiatry, and Pain Care products in the United States,” id. ¶ 3, and “declare[s] under penalty of perjury” that his
declaration is “true and correct,” id. at 5. Given the declarant’s position in Teva’s marketing department and
representations in his sworn statement, the requisite “personal knowledge” of the rate of prescription for Copaxone
and related products may be inferred. Cf. Wye Oak Tech., Inc. v. Republic of Iraq, No. 1:10-cv-01182-RCL, 2018
WL 5983385, at *7–8 (D.D.C. Nov. 14, 2018) (finding a declarant’s statements that they were “authorized and
qualified to make the declaration based on [their] position[s]” and certification that their declarations were “‘true
and correct’ under the penalty of perjury” sufficient to “satisfy the low bar set forth in Rule 56’s personal knowledge
requirement”).
29
products for Copaxone since March 23, 2020. Such “[e]conomic harm . . . clearly constitutes an
injury-in-fact.” Carpenters Indus. Council v. Zinke, 854 F.3d 1, 5 (D.C. Cir. 2017).4
Defendants challenge Teva’s competitive injury on two main grounds. First, they
contend that “[i]t is pure speculation that if the Teva, Mylan, and Sandoz glatiramer acetate
products were transitioned to BLAs, physicians would change their prescribing habits by writing
their prescriptions in a way that would require their patients to use the Teva product.” Fed.
Defs.’ Reply at 8; see also, e.g., id. at 6–8; Fed. Defs.’ Mem. at 16–18; Sandoz Reply at 10–11.
Given that thousands of Copaxone prescriptions are currently written without “dispense as
written” instructions, see Tomlinson Decl. ¶ 8, third-party behavior need not change at all for
Teva to demonstrate actual and imminent harm. The continuation of the status quo with respect
to third-party behavior, accompanied by classification of Copaxone as a biologic, would ensure
an increase in Teva’s sales. Defendants’ theory, that prescribers who currently write
prescriptions for Copaxone would begin to write prescriptions specifically for glatiramer acetate
products made by Mylan or Sandoz were the products transitioned to BLAs and aBLAs, relies
more on a speculative change in prescriber behavior than does Teva’s.
The federal defendants next argue that “Teva’s prediction that FDA would not find
[biosimilars] to be interchangeable with Copaxone is speculative.” Fed. Defs.’ Mem. at 17. This
arguments fails for two reasons. First, in jurisdictions that do not allow substitution of biologics,
4
Defendants argue that because “Teva did not raise this allegation in its complaint,” Teva may not rely on
this theory of standing. Fed. Defs.’ Mem. at 17; see also Mylan Reply at 10 & n.7. In its Complaint, Teva alleged
injury-in-fact resulting from the treatment of competitor glatiramer acetate products as generic drugs rather than
biosimilars, Compl. ¶¶ 68–70, and described the interchangeability requirement for the substitution of biosimilars,
id. ¶ 35. At the pleading stage, “‘general factual allegations of injury resulting from the defendant’s conduct may
suffice’” to demonstrate standing, Osborn v. Visa Inc., 797 F.3d 1057, 1063 (D.C. Cir. 2015) (quoting Lujan, 504
U.S. at 561), and courts “‘grant[] plaintiff[s] the benefit of all inferences that can be derived from the facts alleged,’”
Am. Nat’l Ins. Co. v. FDIC, 642 F.3d 1137, 1139 (D.C. Cir. 2011) (quoting Thomas v. Principi, 394 F.3d 970, 972
(D.C. Cir. 2005)). The allegations in Teva’s Complaint were thus sufficient to support Teva’s claim of competitive
injury at that stage.
30
prescriptions for Copaxone would continue to be filled with Teva’s product even after a finding
of interchangeability and thus Teva’s losses from prescriptions in these states are “actual and
imminent” regardless of FDA’s eventual interchangeability determinations. Second, even if
FDA found a biosimilar to be interchangeable with Copaxone, had Copaxone been transitioned
on March 23, 2020, Teva’s product would still have been dispensed to fill prescriptions for
Copaxone in jurisdictions that allow substitution from that date until the effective date of the
interchangeability decision. These interim losses are not speculative and are sufficient for
standing purposes.
(b) Causation and Redressability
The remaining two elements of standing—causation and redressability—“‘overlap as two
sides of a causation coin.’” Exhaustless Inc. v. FAA, 931 F.3d 1209, 1212 (D.C. Cir. 2019)
(quoting Dynatlantic Corp. v. Dep’t of Def., 115 F.3d 1012, 1017 (D.C. Cir. 1997)). “When a
petitioner itself is the object of the challenged agency action,” as Teva is here, “there usually is
little doubt of causation.” Id. (citing Lujan, 504 U.S. at 561–62). Indeed, none of the parties
dispute causation, but Mylan (though not the federal defendants or Sandoz) contends that Teva’s
requested relief, an injunction directing FDA to reclassify Copaxone as a biological product, is
not likely to redress its alleged competitive injury because, for Teva’s competition from generic
glatiramer acetate products to decrease, FDA would have to reclassify the underlying ANDAs as
aBLAs and then determine that the biosimilars are not interchangeable with Copaxone. The
number of steps required, in Mylan’s view, makes the redressability of Teva’s alleged harm by
an injunction speculative at best. Mylan Mem. at 23–24; Mylan Reply at 10–11.
The chain of events Mylan outlines overlooks the obvious: an injunction reclassifying
Copaxone as a biologic would immediately exempt prescriptions written for Copaxone from
31
automatic substitution laws. That fact alone would redress at least some of Teva’s harms,
regardless of whether or when FDA transitioned the ANDAs to aBLAs or made an
interchangeability finding. The degree to which the reclassification of Copaxone would relieve
Teva’s injuries may be limited by an eventual finding of interchangeability, as Mylan suggests,
but the clear ability of the requested injunction to redress a wide swath of Teva’s economic
harms in the interim is not speculative simply because it may be short-lived.5 Further, the mere
possibility “that a hypothesized future event”—in this case, a prospective interchangeability
determination—“might injure [a plaintiff] in the same way as the challenged agency decision”
does not leave a plaintiff without standing. Braeburn Inc. v. FDA, 389 F. Supp. 3d 1, 16 (D.D.C.
2019). Teva need not disprove any speculative harm it may experience as the result of a future
interchangeability finding in order to access judicial relief. See Duke Power Co. v. Carolina
Env’tl Study Grp., Inc., 438 U.S. 59, 78 (1978) (“Nothing in our prior cases requires a party
seeking to invoke federal jurisdiction to negate the kind of speculative and hypothetical
possibilities suggested in order to demonstrate the likely effectiveness of judicial relief.”); Int’l
Ladies’ Garment Workers’ Union v. Donovan, 722 F.2d 795, 811 (D.C. Cir. 1983) (“The
appellants need not negate every conceivable impediment to effective relief no matter how
speculative, nor are they required to prove that granting the requested relief is certain to alleviate
their injury.” (internal citation and quotation omitted)). Even after an interchangeability
5
In addition, the intervenor-defendants appear to have conceded that, even if FDA ultimately found their
products to be interchangeable with Copaxone, their sales would suffer, and Teva’s would benefit, while FDA
considered the interchangeability question. See Sandoz Inc.’s Mem. Supp. Unopposed Mot. Intervene at 7–8, ECF
No. 9-1 (“[T]o the extent FDA were to transition Sandoz’s ANDAs to BLAs, yet delay in making an
interchangeability determination . . . Sandoz would lose its ability to compete effectively in the market with
Copaxone.”); Mylan’s Mem. P. & A. Supp. Mylan’s Unopposed Mot. Intervene at 8, ECF No. 19-1 (“If the court
were to adopt Teva’s . . . position, Mylan would have to incur substantial costs in resolving uncertainty regarding its
[glatiramer acetate] products.”).
32
determination, an injunction would continue to remedy Teva’s competitive injury in those
jurisdictions that do not allow substitution of biosimilars.
In sum, FDA’s failure to transition Copaxone to a BLA on March 23, 2020 has deprived
and continues to deprive Teva of sales of Copaxone. This competitive and economic harm is an
actual and imminent, concrete and particularized injury, fairly traceable to FDA’s determination,
and redressable by a favorable judicial decision. Teva has constitutional standing.
2. Teva Has Statutory Standing
Next, Sandoz, but not the federal defendants or Mylan, challenges Teva’s statutory
standing under the BPCIA. See Sandoz Mem. at 23–26; Sandoz Reply at 10–12. Statutory
standing is not, as Sandoz contends, a question of “prudential standing,” Sandoz Mem. at 24, but
instead “a straightforward question of statutory interpretation,” Lexmark Int’l, Inc. v. Static
Control Components, Inc., 572 U.S. 118, 129 (2014), that determines “who may invoke the
cause of action in” a particular statute through the “zone-of-interests” test, id. at 130. In the APA
context, “the zone-of-interests test is not ‘especially demanding,’” Indian River Cnty., Fla. v.
U.S. Dep’t of Transp., 945 F.3d 515, 529 (D.C. Cir. 2019) (quoting Match-E-Be-Nash-She-Wish
Band of Pottawatomi Indians v. Patchak, 567 U.S. 209, 225 (2012)), and “‘forecloses suit only
when a plaintiff’s interests are so marginally related to or inconsistent with the purposes implicit
in the [substantive] statute that it cannot reasonably be assumed that Congress intended to permit
the suit,’” id. at 530 (quoting Patchak, 567 U.S. at 225); see also Mendoza v. Perez, 754 F.3d
1002, 1016–17 (D.C. Cir. 2014).
Sandoz contends that Teva falls outside the zone of interests protected by the BPCIA
because, first, “standing does not automatically arise from being regulated by the statute-at-issue,
nor can it arise from a mere failure to impose stricter regulations on competitors,” Sandoz Mem.
at 25, and, second, “increasing competition is within the zone of interests of the BPCIA, but
33
suppressing competition as Teva seeks to do here, is not,” Sandoz Reply at 11; see also Sandoz
Mem. at 24–25. Neither argument is persuasive. The BPCIA expressly requires FDA to
transition NDAs for products that would have been classified as biologics in the first instance
under the revised definition to BLAs. See BPCIA § 7002(e)(4). Teva holds an NDA for
Copaxone that allegedly should have been transitioned to a BLA under that provision and
therefore has an interest in its product being regulated by FDA under the appropriate statute.
That interest is clearly and directly related to the BPCIA’s purpose of regulating all complex
therapeutic products that qualify as biologics under the PHSA rather than the FDCA. The zone-
of-interests test requires nothing more.
B. FDA’s Interpretation of “Protein” Is Reasonable
Turning to the merits, Teva first contends that FDA’s interpretation of the term “protein”
in section 351’s definition of “biological product,” which was applied to Copaxone in the
Decision Memorandum, is contrary to the statute, such that the interpretation, and the Decision
Memorandum that relies on it, are “not in accordance with law.” 5 U.S.C. § 706(2)(A); see Pls.’
Mem. at 20–27; Pls.’ Opp’n at 18–26. An agency’s interpretation of a statute it administers is
reviewed under the familiar two-step inquiry set forth in Chevron U.S.A., Inc. v. Natural
Resources Defense Council, Inc. (“Chevron”), 467 U.S. 837 (1984); see, e.g., Cal. Cmtys.
Against Toxics v. EPA, 928 F.3d 1041, 1053 (D.C. Cir. 2019), so long as “Congress delegated
authority to the agency generally to make rules carrying the force of law” and “the agency’s
interpretation claiming deference was promulgated in the exercise of that authority,” United
States v. Mead Corp., 533 U.S. 218, 226–27 (2001); see also Guedes v. Bureau of Alcohol,
Tobacco, Firearms & Explosives, 920 F.3d 1, 20 (D.C. Cir. 2019), cert. denied, 140 S. Ct. 789(2020) (mem.). Under this standard, “[o]rdinarily, legislative rules receive Chevron deference,”
Guedes, 920 F.3d at 20, “[b]ut Chevron deference is not warranted where the regulation is
34
‘procedurally defective’—that is, where the agency errs by failing to follow the correct
procedures in issuing the regulation,” Encino Motorcars, LLC v. Navarro (“Encino I”), 136 S.
Ct. 2117, 2125 (2016) (quoting Mead Corp., 533 U.S. at 227). Teva contends that the Final
Rule, though a legislative rule, does not merit deference because it was improperly promulgated,
see Pls.’ Mem. at 20–22; Pls.’ Opp’n at 18–21; Pls.’ Suppl. Br. at 2–10, and that even if the Final
Rule is procedurally sound, FDA’s interpretation of “protein” fails under Chevron, see Pls.’
Mem. at 22–27; Pls.’ Opp’n at 21–26.6 Each contention is taken in turn.
1. The Final Rule Is Reviewed Under Chevron
As a preliminary matter, Teva contends that FDA’s interpretation of the term “protein,”
set forth in the Final Rule and applied to Copaxone in the Decision Memorandum, is not entitled
to review under Chevron’s deferential standard because the Final Rule in which the definition
was formally adopted is procedurally invalid. Teva argues that, because 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, 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. Pls.’ Suppl. Br. at 6; see also Pls.’ Mem.
at 20–22; Pls.’ Opp’n at 18–21. This procedural argument, which misconstrues both the effect of
the 2019 Act and the terms FDA interpreted in the Final Rule and throughout the almost decade-
long rulemaking process that preceded it, fails.
6
Although Teva originally appeared to argue that the Final Rule was an interpretive rule, see Pls.’ Mem. at
20, it concedes in its supplemental brief that the Final Rule is a legislative rule, albeit, in Teva’s view, a procedurally
deficient legislative rule, see Pls.’ Suppl. Br. at 4–5.
35
In most cases, the APA requires a federal agency engaged in legislative rulemaking to
follow notice-and-comment procedures. See 5 U.S.C. § 553(b). This process imposes on
agencies the obligation “to provide the public with a notice of proposed rulemaking, an
opportunity to comment, and, ‘[a]fter consideration of the relevant matter presented,’ a ‘concise
general statement’ of the rule’s basis and purpose.” Sherley v. Sebelius, 689 F.3d 776, 784 (D.C.
Cir. 2012) (alteration in original) (quoting 5 U.S.C. § 553); see also Perez v. Mortg. Bankers
Ass’n, 575 U.S. 92, 96 (2015) (describing the APA’s “three-step procedure for . . . ‘notice-and-
comment rulemaking,’” during which “the agency must ‘give interested persons an opportunity
to participate in the rule making through submission of written data, views, or arguments’”)
(quoting 5 U.S.C. § 553(c)); Cigar Ass’n of Am., 964 F.3d at 63–64 (same). A robust notice-and-
comment process serves the “central purpose[s]” of “subject[ing] agency decisionmaking to
public input . . .[,] obligat[ing] the agency to consider and respond to the material comments and
concerns that are voiced,” and “ensur[ing] the parties develop a record for judicial review.”
Make the Road N.Y. v. Wolf, 962 F.3d 612, 634 (D.C. Cir. 2020) (internal quotations and
citations omitted); see also Nat’l Ass’n of Clean Water Agencies v. EPA, 734 F.3d 1115, 1148
(D.C. Cir. 2013) (“A purpose of notice-and-comment provisions under the APA . . . is ‘to ensure
that affected parties have an opportunity to participate in and influence agency decision making
at an early stage, when the agency is likely to give real consideration to alternative ideas.’”)
(quoting N.J., Dep’t of Env’tl Prot. v. EPA, 626 F.2d 1038, 1049 (D.C. Cir. 1980)).
As part of notice-and-comment rulemaking, the notice of proposed rulemaking must
include “either the terms or substance of the proposed rule or a description of the subject and
issues involved,” 5 U.S.C. § 553(b), a requirement that has been construed to “to mean that the
final rule the agency adopts must be a logical outgrowth of the rule proposed,” Long Island Care
36
at Home, Ltd. v. Coke (“Long Island Care”), 551 U.S. 158, 174 (2007) (internal quotation
omitted). “‘A final rule is the logical outgrowth of a proposed rule if interested parties should
have anticipated that the change was possible, and thus reasonably should have filed their
comments on the subject during the notice-and-comment period.”” Chesapeake Climate Action
Network v. EPA, 952 F.3d 310, 319 (D.C. Cir. 2020) (quoting Clean Air Council v. Pruitt, 862
F.3d 1, 10 (D.C. Cir. 2017) (per curiam)); see also Idaho Conservation League v. Wheeler, 930
F.3d 494, 508 (D.C. Cir. 2019) (same). A rule fails the logical outgrowth test if “‘interested
parties would have had to divine the agency’s unspoken thoughts, because the final rule was
surprisingly distant from the proposed rule.’” Chesapeake Climate Action Network, 952 F.3d at
319–20 (quoting Clean Air Council, 862 F.3d at 10). In other words, the public must have one
clear chance to offer feedback on agency proposals, a requirement that is met “‘if a new round of
notice and comment would not provide commentators with their first occasion to offer new and
different criticisms which the agency might find convincing.’” Int’l Union, United Mine
Workers of Am. v. Mine Safety & Health Admin., 626 F.3d 84, 95 (D.C. Cir. 2010) (quoting
Fertilizer Inst. v. EPA, 935 F.2d 1303, 1311 (D.C. Cir. 1991)). “The object, in short, is one of
fair notice,” Long Island Care, 551 U.S. at 174; notice-and-comment processes that result in an
unfair surprise being sprung on regulated entities are therefore deficient.
Set against this standard, FDA provided sufficient notice and multiple opportunities to
comment on its interpretation of the statutory term “protein,” even in light of the 2019 Act. The
adequacy of the notice-and-comment procedures that culminated in FDA’s promulgation of the
Final Rule turns on whether Teva and other regulated entities had fair notice of, and at least one
opportunity to respond to, the definition of “protein” set forth in the Final Rule.
37
Teva contends that the Final Rule is fatally flawed because “the Proposed Rule and the
Final Rule were interpreting two materially different statutes” and FDA’s original notice-and-
comment process became null and void after the 2019 Act was passed. Pls.’ Suppl. Br. at 6.
Thus, Teva argues, FDA was required to undertake a new notice-and-comment process to
provide an opportunity for comment on the impact of Congress’s deletion of the parenthetical
exception on FDA’s interpretation of “protein” in the absence of the carve-out for “chemically
synthesized polypeptides.” Pls.’ Mem. at 21–22; Pls.’ Suppl. Br. at 5–10. This claim rests
primarily on a mischaracterization of the term FDA purported to interpret in its Proposed Rule.
FDA did not, as Teva asserts, “plan[] to adopt an interpretation of ‘protein (except any
chemically synthesized polypeptide),’” Pls.’ Suppl. Br. at 1; see also id. at 6, which
interpretation, after the enactment of the 2019 Act, the agency simply transferred unthinkingly,
and without sufficient process, to the new statutory term “protein.” Nor did FDA “rel[y] in part
on a structural inference contrasting ‘protein’ with ‘polypeptide’ in the parenthetical exclusion,”
id. at 6, to develop its interpretation of protein.
Rather, 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. See, e.g., AR at 121, 292, 328, 758,
787 n.3, 801–03. Indeed, the Proposed Rule indicated FDA’s intent to codify the two definitions
in separate sections of the Code of Federal Regulations. See id. at 807 (proposing to codify
FDA’s definition of “protein” at 21 C.F.R. § 600.3(h)(6) and FDA’s definition of “chemically
synthesized polypeptide” at 21 C.F.R. § 600.3(h)(7)). Further, though the structure of section
351’s parenthetical exclusion informed FDA’s decision to narrowly construe the term
“chemically synthesized polypeptide” as meant to exclude a subset of otherwise-qualifying
38
“proteins” from biologic status, see id. at 305–06, 804, that consideration did not shape FDA’s
definition of “protein,” as the more encompassing of the two terms, see supra Part I.A.4. FDA
consistently understood the term “protein” to include chemically synthesized proteins, and the
term “chemically synthesized polypeptides” to refer to a smaller group of chemically synthesized
molecules that, although they met the agency’s definition of “protein,” would not be regulated as
biologics because of the parenthetical exclusion. See, e.g., AR at 803–05.
Given this 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. Its only effect
was to eliminate the need for a regulatory definition of “chemically synthesized polypeptides”
that, though they met the definitional criteria for “proteins,” would not be treated as such because
of the exception. 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.” See AR at 1025–27.7
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. From 2011 on, the public
had ample opportunities to comment on the exact definition of “protein” that FDA adopted in the
Final Rule, see supra Part I.A.4, and to raise the same argument Teva now makes, that the
7
Teva does not challenge the omission of a definition for “chemically synthesized polypeptide” from the
Final Rule on logical outgrowth grounds. Nor could it, as “‘[o]ne logical outgrowth of a proposal is surely . . . to
refrain from taking the proposed step.’” Idaho Conservation League, 930 F.3d at 508 (alteration and omission in
original) (quoting New York v. EPA, 413 F.3d 3, 44 (D.C. Cir. 2005) (per curiam)).
39
definition “impermissibly favors naturally derived proteins over chemically synthesized ones,”
Pls.’ Suppl. Br. at 9. Teva never availed itself of that opportunity, but FDA’s decision to
formalize the definition consistently set forth over the course of a decade sprung no unfair
surprise on Teva or any other interested party.8 As the federal defendants rightly observe, “[n]o
divination was required on the part of interested parties to predict that that FDA might adopt the
precise definition of the term ‘protein’ that it had proposed” over the course of nearly a decade.
Fed. Defs.’ Suppl. Br. at 11 (citing Agape Church, Inc. v. FCC, 738 F.3d 397, 411 (D.C. Cir.
2013)). Teva, like other interested parties, was afforded adequate notice of and multiple
opportunities to comment on that definition before FDA issued its Final Rule. The 2019 Act’s
deletion of the analytically distinct term “chemically synthesized polypeptide” thus has no
bearing on the procedural validity of FDA’s longstanding interpretation of the term “protein.”9
The Final Rule, as a properly promulgated legislative rule, is owed Chevron deference.
8
In its comments on the exclusion of Copaxone from FDA’s Preliminary List of products to be transitioned
to BLAs, which were filed about two months after the enactment of the 2019 Act, Teva questioned FDA’s
application of the Final Rule to Copaxone, but did not challenge the Final Rule’s definition of “protein” or assert
any procedural impediment to the Final Rule. See AR at 1008–23. Teva raises these arguments for the first time in
this litigation, and makes its procedural arguments partly in response to the Court’s request for clarification of the
procedural challenges alluded to by Teva in its opening briefs. Teva’s requested relief for the alleged procedural
violations, namely, vacatur of the Final Rule and remand to FDA with instructions to adopt Teva’s preferred
construction of the term “protein” and to classify Copaxone as a biologic, see Pls.’ Suppl. Br. at 12–13, clearly
overreaches. The remedy Teva proposes would be extraordinary, see, e.g., Hill Dermaceuticals, Inc. v. FDA, 709
F.3d 44, 46 n.1 (D.C. Cir. 2013) (noting that relief for an APA violation should be “limited only to vacating the
unlawful action, not precluding future agency decisionmaking”), and is poorly tailored to remediate the single
decision of FDA, determining that Copaxone did not qualify as a “protein,” that Teva challenges in its Complaint,
see Compl. ¶¶ 75–89.
9
Relying on the Supreme Court’s decision in Encino I, Teva also contends that the Final Rule is also
procedurally invalid because of “FDA’s failure to address the current version of the statute” in issuing the Final Rule
and that Chevron deference should be withheld on that ground. Pls.’ Suppl. Br. at 3 (emphasis omitted); see also id.at 3–4 (citing Encino I, 136 S. Ct. at 2125); Pls.’ Opp’n at 18–20. As an initial matter, Teva’s argument relies on the
premise that FDA developed its interpretation “by reference to characteristics of natural proteins” and therefore
“should have reconsidered its definition,” Pls.’ Opp’n at 19 (emphasis omitted), a premise that, as explained infra
Part III.B.2.a, is faulty. Further, Encino I denied Chevron deference, on procedural grounds, to a Department of
Labor regulation reversing the agency’s decades-old stance on a question of statutory interpretation. The
Department had offered “barely any explanation” of its shift in policy in the challenged regulation. Encino I, 136 S.
Ct. at 2126. As a result, the Court found that the regulation “was issued without the reasoned explanation that was
required in light of the Department’s change in position and the significant reliance interests involved” to survive
arbitrary and capricious review under the APA and therefore “receive[d] no Chevron deference.” Id. In contrast,
here, FDA explained in detail the development of its interpretation of “protein” in numerous Guidance Documents,
40
2. FDA’s Reasonable Interpretation of “Protein” Is Owed Deference
Teva next challenges the substance of the Final Rule, contending that FDA’s
interpretation of “protein” is contrary to section 351, such that the definition is “not in
accordance with law,” 5 U.S.C. § 706(2)(A), because it requires that molecules have a “specific,
defined sequence” of amino acids to qualify as protein, see Pls.’ Mem. at 20–26; Pls.’ Opp’n at
18–26. This reading of the term, in Teva’s view, imposes a distinction between chemically
synthesized and naturally derived proteins that not only is foreclosed by the 2019 Act, but also is
unreasonable. See Pls.’ Mem. at 20–26; Pls.’ Opp’n at 18–26. Defendants counter that the term
“protein” unambiguously refers to substances with a “specific, defined sequence,” see, e.g., Fed.
Defs.’ Mem. at 21–24; Fed. Defs.’ Reply at 14–17; Mylan Reply at 13–16; Mylan Suppl. Br. at
6–9, and, moreover, that, at a minimum, “protein” is sufficiently ambiguous to permit the
agency’s reasonable interpretation of the term as requiring a “specific, defined sequence,” see,
e.g., Fed. Defs.’ Mem. at 24–28; Mylan Mem. at 25–34; Sandoz Mem. at 27–35.
Under Chevron’s deferential standard, review of an agency’s interpretation of a statute it
administers proceeds in two steps. At Step One, the Court asks “whether Congress has directly
spoken to the precise question at issue.” Chevron, 467 U.S. at 842; see also Cal. Cmtys. Against
Toxics, 928 F.3d at 1053. In making this determination, “using the traditional tools of statutory
interpretation,” courts “‘examine the [statute’s] text, structure, purpose, and legislative history to
determine if the Congress has expressed its intent unambiguously.’” Eagle Pharms., Inc. v.
its Proposed Rule, and its Final Rule. See supra Part I.A.4. Further, the Final Rule addressed the 2019 Act in
describing FDA’s decision not to finalize its definition of “chemically synthesized polypeptide” and in responding to
related comments. See supra Part I.A.4.c. Whether those efforts are substantively sound is a separate question,
discussed infra Part III.B.2, but they at least exceed the “minimal level of analysis” Encino I suggests is required for
a regulation to pass procedural muster, especially where FDA has maintained, not reversed, its consistent
interpretation of “protein.” Encino I, 136 S. Ct. at 2125; cf. Kiewit Power Constructors Co. v. Sec’y of Lab., 959
F.3d 381, 398–99 (D.C. Cir. 2020) (suggesting that Encino I’s lack of deference resulted primarily from “the Court’s
recognition that, under the circumstances, a cursory explanation was inadequate ‘in particular because of decades of
industry reliance on the Department’s prior policy’”) (quoting Encino I, 136 S. Ct. at 2126).
41
Azar, 952 F.3d 323, 330 (D.C. Cir. 2020) (alteration in original) (quoting U.S. Sugar Corp. v.
EPA, 830 F.3d 579, 605 (D.C. Cir. 2016) (per curiam)). If the statute “is susceptible of ‘only
[one] possible interpretation,’” Petit v. U.S. Dep’t of Educ., 675 F.3d 769, 781 (D.C. Cir. 2012)
(alteration in original) (quoting Cnty. of L.A. v. Shalala, 192 F.3d 1005, 1015 (D.C. Cir. 1999)),
or “unambiguously forbids the Agency’s interpretation,” Barnhart v. Walton, 535 U.S. 212, 218
(2002); see also Am. Hosp. Ass’n v. Azar, 964 F.3d 1230, 1241 (D.C. Cir. 2020), the Court “must
give effect to the unambiguously expressed intent of Congress,” Chevron, 467 U.S. at 843; see
also NASDAQ Stock Market, LLC v. SEC, 961 F.3d 421, 426 (D.C. Cir. 2020). If, however, the
contested statute can be read in more than one way, may permit the agency’s interpretation, or is
silent as to the relevant question, the case moves to Step Two. See Util. Air Regul. Grp. v. EPA
(“UARG”), 573 U.S. 302, 315 (2014); Van Hollen, Jr. v. FEC, 811 F.3d 486, 495 (D.C. Cir.
2016).
At Step Two, “the question for the court is whether the agency’s answer is based on a
permissible construction of the statute.” Chevron, 467 U.S. at 843. In other words, the agency’s
statutory interpretation “must come within the zone of ambiguity the court has identified after
employing all its interpretive tools.” Kisor v. Wilkie, 139 S. Ct. 2400, 2416 (2019). In
conducting this analysis, “[d]eference is due to the agency’s permissible interpretation ‘if the
agency has offered a reasoned explanation for why it chose that interpretation.’” Cal. Cmtys.
Against Toxics, 928 F.3d at 1055 (quoting Vill. of Barrington v. Surface Transp. Bd., 636 F.3d
650, 660 (D.C. Cir. 2011)). This “is a requirement an agency can fail.” Kisor, 139 S. Ct. at
2416.
42
(a) Chevron Step One
FDA declined to deem Teva’s NDA for Copaxone an approved BLA pursuant to the
BPCIA’s transition provision because it determined that Copaxone does not have a “specific,
defined sequence” of amino acids and therefore is not a “biological product” within the meaning
of section 351. Thus, the “precise question at issue” is whether section 351 permits FDA to
interpret “protein” to refer to a molecule that, among other features, has a “specific, defined
sequence” of amino acids.10 Both sides contend that their preferred response to this question
prevails at Step One. Teva argues that FDA’s interpretation fails because the 2019 Act
“unambiguously forecloses an interpretation of ‘protein’ that rests on a distinction between
natural proteins and synthetic ones.” Pls.’ Mem. at 22. In Teva’s view, the “specific, defined
sequence” requirement in FDA’s definition does exactly that. See id. at 22–24; Pls.’ Opp’n at
21–24. The federal defendants and Mylan counter that FDA’s interpretation is not only
permitted, but in fact compelled by the scientifically accepted plain meaning of the term
“protein.” Fed. Defs.’ Mem. at 21; see also id. at 21–24; Fed. Defs.’ Reply at 14–17; Mylan
Mem. at 25 n.13; Mylan Reply at 15–16; Mylan Suppl. Br. at 6–9.11
Congress did not specifically define the term “protein” in either the BPCIA or the 2019
Act, an omission that presents an initial obstacle to the parties’ Step One claims. See 42 U.S.C.
§ 262(i)(1); Braeburn Inc., 389 F. Supp. 3d at 20 (finding that Step One “present[ed] a high
hurdle” where the statute did not “‘specifically define the phrase[]’” at issue) (second alteration
in original) (quoting Otsuka Pharm. Co. v. Burwell, 302 F. Supp. 3d. 375, 394 (D.D.C. 2016),
10
Teva does not challenge any other aspect of FDA’s interpretation of protein, for example, the forty amino
acid length requirement.
11
Sandoz, in contrast to the federal defendants and Mylan, submits that “protein” is ambiguous and FDA’s
interpretation is properly evaluated at Step Two of the Chevron analysis. Sandoz Mem. at 27–29; Sandoz Reply at
13–15.
43
aff’d sub nom. Otsuka Pharm. Co. v. Price, 869 F.3d 987 (D.C. Cir. 2017))). A statutory
definition is not required for the meaning of a term to be unambiguous. See Petit, 675 F.3d at781 (citing Nat. Res. Def. Council v. EPA, 489 F.3d 1364, 1373 (D.C. Cir. 2007)). Here,
however, the “traditional tools of statutory interpretation,” Eagle Pharms. Inc., 952 F.3d at 330,
offer little to clarify the meaning of “protein” in section 351.
“In addressing a question of statutory interpretation, [courts] begin with the text.” City of
Clarksville v. FERC, 888 F.3d 477, 482 (D.C. Cir. 2018); see also Eagle Pharms. Inc., 952 F.3d
at 330 (“Of the tools of statutory interpretation, ‘[t]he most traditional tool, of course, is to read
the text.’”) (alteration in original) (quoting Engine Mfrs. Ass’n v. EPA, 88 F.3d 1075, 1088 (D.C.
Cir. 1996))).12 Generally, when a statutory term is undefined, courts look first to “that term’s
‘ordinary, contemporary, common meaning.’” Food Mktg. Inst. v. Argus Leader Media, 139 S.
Ct. 2356, 2362 (2019) (quoting Perrin v. United States, 444 U.S. 37, 42 (1979)); see also Bd. of
Cnty. Comm’rs v. Fed. Housing Fin. Agency, 754 F.3d 1025, 1028–29 (D.C. Cir. 2014)
(“[W]here a statute’s terms are undefined, our interpretation is guided by the terms’ ‘regular
usage.’”) (quoting Lopez v. Gonzales, 549 U.S. 47, 53 (2006)). Ordinary meaning is of limited
utility, however, when determining the proper interpretation of a scientific term employed by
Congress in the context of “a complex statutory regime, laden with scientific language and other
terms of art,” such as the PHSA. ViroPharma, Inc. v. Hamburg, 898 F. Supp. 2d 1, 19 (D.D.C.
2012) (citing Emerson v. Steffen, 959 F.2d 119, 121 (8th Cir. 1992)); cf. AR at 294 n.12 (noting
that “[n]on-scientific references are not particularly helpful in defining” the term “protein”). In
12
The remaining “traditional tools of statutory interpretation” are not particularly illuminating. The
legislative history does not give any insight into Congress’s intended meaning of “protein.” Congress’s original
inclusion, and subsequent deletion, of the parenthetical exception provides some structural evidence that Congress
intended for “protein” to encompass both naturally derived and chemically synthesized molecules, as appropriate,
but otherwise sheds little light on either the characteristics that Congress considered essential to “proteins” or the
scope of the protein category. Nor does the stated purpose of the BPCIA, to establish “a biosimilars pathway
balancing innovation and consumer interests,” BPCIA § 7001(b), help to answer the precise question at hand.
44
such cases, courts may look instead to the “plain and established meanings” of the relevant terms
“in scientific and regulatory parlance.” Abbott Lab’ys. v. Young, 920 F.2d 984, 992 (D.C. Cir.
1990); see also FAA v. Cooper, 566 U.S. 284, 292 (2012) (“[I]t is a ‘cardinal rule of statutory
construction’ that, when Congress employs a term of art, ‘it presumably knows and adopts the
cluster of ideas that were attached to each borrowed word in the body of learning from which it
was taken.’”) (quoting Molzof v. United States, 502 U.S. 301, 307 (1992)); T-Mobile S., LLC v.
City of Roswell, 574 U.S. 293, 301 (2015) (same); McDermott Int’l, Inc. v. Wilander, 498 U.S.
337, 342 (2001) (“In the absence of contrary indication, we assume that when a statute uses such
a term [of art], Congress intended it to have its established meaning.”); Loving v. IRS, 742 F.3d
1013, 1017 (D.C. Cir. 2014) (seeking to identify, at Chevron Step One, “any specialized meaning
that people in the field attach to” the statutory term being construed).
Relying on this principle of statutory interpretation, defendants contend that FDA’s
interpretation prevails at Step One because the “plain and established meaning” of “protein” in
the scientific community unambiguously indicates that all “proteins,” regardless of how they are
made, have a “specific, defined sequence.” Fed. Defs.’ Mem. at 21–24. In support of this
argument, they cite to a number of scientific sources reviewed by FDA during its rulemaking
process, see id. at 22–23 (citing sources); Mylan Reply at 15–16 (same).13 As Teva points out,
13
See also, e.g., AR at 812, Michael D. Larrañaga et al., Hawley’s Condensed Chemical Dictionary 1145
(16th ed. 2016) (defining “protein” as “[a] complex, high polymer containing carbon, hydrogen, oxygen, nitrogen,
and usually sulfur, and composed of chains of amino acids connected by peptide linkages” and noting that “[t]he
sequence of amino acids . . . is of critical importance in genetics”); id. at 817, A Dictionary of Science 666 (6th ed.
2010) (“Protein molecules consist of one or several long chains . . . of amino acids in a characteristic sequence.”); id.
at 831, Thomas E. Creighton, Encyclopedia of Molecular Biology (1999) (“The amino acid sequence defines the
order of the side chains throughout the [protein].”); id. at 839, Jeremy M. Berg et al., Biochemistry 53 (5th ed. 2002)
(“The striking fact is that each protein has a unique, precisely defined amino acid sequence.” (emphasis omitted));
id. at 846, Thomas D. Pollard & William C. Earnshaw, Cell Biology 21 (2002) (“Proteins consist of one or more
linear polymers called polypeptides, which consist of various combinations of 20 different amino acids . . . linked
together by peptide bonds . . . The sequence of amino acids in each type of polypeptide is unique.” (emphasis
omitted)); id. at 858, Harvey Lodish et al., Molecular Cell Biology 66 (6th ed. 2007) (“The primary structure of a
protein is simply the linear arrangement, or sequence, of the amino acid residues that compose it.”); id. at 869, Bruce
Alberts et al., Molecular Biology of the Cell 129 (4th ed. 2002) (“Each type of protein has a unique sequence of
45
however, a closer look at the record evidence reveals that, while the sources defendants cite in
their briefing indeed reference a specific or characteristic sequence in their definitions or
descriptions of “protein,” not all scientific sources FDA consulted appear to include that
requirement, though none reject or otherwise contest it. See Pls.’ Opp’n at 21–24.14
Mylan suggests that the “silence” of these sources does not show ambiguity or
“undermine Congress’[s] intent in having the general scientific understanding of the term
[protein] apply.” Mylan Reply at 16. Congress likely did intend for “protein” to carry its usual
scientific meaning, but the discrepancy in the literature does not provide, for the non-expert
reader, sufficient, unambiguous evidence of that scientific meaning to answer the precise
question at hand at Step One. Defendants appear to acknowledge this flaw in their argument,
encouraging the Court to rely not only on the literature, but also on the fact that “FDA found that
the scientific community understood that a ‘protein’ has a ‘specific, defined sequence’ of amino
acid.” Id. This push towards deference to the agency’s scientific evaluation to prove the
meaning of a statutory term itself shows that defendants cannot prevail at Step One. In the
absence of unambiguous scientific agreement, the identification of a scientific consensus around
the “specific, defined sequence” requirement “is the kind of highly technical, specialized
interstitial matter that Congress often does not decide itself, but delegates to specialized
amino acids, exactly the same from one molecule to the next. Many thousands of different proteins are known, each
with its own particular amino acid sequence.”); id. at 297 n.33 (quoting Encyclopedia of Molecular Biology 2037
(1994)) (“‘[T]he arrangement of amino acid residues in the primary structure of a protein is not random, but is
precisely determined by the genetic information stored in the chromosomal DNA or RNA.’”).
14
See also, e.g., AR at 820, J. Stenesh, Dictionary of Biochemistry and Molecular Biology 387 (2d ed. 1989)
(defining a “protein” as “[a] high molecular weight polypeptide of L-amino acids that is synthesized by living cells”
and describing proteins as “biopolymers with a wide range of molecular weights, structural complexity, and
functional properties”); id. at 825, American Heritage Science Dictionary 507 (2005) (defining “protein” as “[a]ny
of a large class of complex organic chemical compounds that are essential for life[,] . . . consist of long chains of
amino acids connected by peptide bonds and have distinct and varied three-dimensional structures”); id. at 296(“‘Proteins are molecules that consist of one or more polypeptide chains. These polypeptides range in length from
~40 to over 4000 amino acid residues.’”) (quoting Donald Voet & Judith G. Voet, Biochemistry 62 (3d ed. 2004)).
46
agencies,” not to courts, “to decide.” Zuni Pub. Sch. Dist. No. 89 v. Dep’t of Educ., 550 U.S. 81,
90 (2007). Whether FDA acted reasonably in carrying out this delegation is a question to be
answered at Step Two, not Step One.
Nor, however, is FDA’s determination that a “specific, defined sequence” is an essential
characteristic of a protein unambiguously foreclosed by the statute, as Teva submits. In support
of this theory, Teva argues that Congress’s deletion of the parenthetical exception for
“chemically synthesized polypeptides” in the 2019 Act prohibits FDA from imposing “an
interpretation of ‘protein’ that rests on a distinction between natural proteins and synthetic ones.”
Pls.’ Mem. at 22; see also Pls.’ Opp’n at 21–24. This argument fundamentally misunderstands
both the text of section 351 and FDA’s interpretation: contrary to Teva’s representations, neither
the statute nor the rule ever distinguished between naturally derived and chemically synthesized
proteins. Before the 2019 Act was passed, section 351 categorized all “proteins,” whether
naturally derived or chemically synthesized, as biological products, except for “chemically
synthesized polypeptides.” 42 U.S.C. § 262(i)(1) (2012) (emphasis added). The use of these
different terms in the statue signaled that the excluded “polypeptides” were necessarily a distinct
subset of molecules within the broader group of “proteins,” differentiated on some basis other
than method of manufacture, with respect to which the unmodified term protein was apparently
agnostic. See, e.g., Henson v. Santander Consumer USA Inc., 137 S. Ct. 1718, 1723 (2017)
(“[W]hen we’re engaged in the business of interpreting statutes we presume differences in
language . . . convey differences in meaning.”).
The parenthetical exclusion thus did not separate naturally derived proteins from
chemically synthesized proteins, as Teva now argues. Rather, it treated all qualifying molecules
as proteins, regardless of mode of manufacture, except for the subset of “chemically synthesized
47
polypeptides” set out in the exception. The divide, then, was between “proteins,” whether
natural or synthetic, and “chemically synthesized polypeptides.” By deleting the exception in the
2019 Act, Congress did not foreclose a distinction between naturally derived and chemically
synthesized proteins present in the earlier version of section 351; that distinction never existed.
Instead, it eliminated the carve-out to the general rule of treatment as proteins for previously
excluded molecules.
Moreover, standing alone, FDA’s interpretation does not differentiate between natural
and synthetic proteins in the manner Teva suggests. The agency, placing appropriate weight on
Congress’s initial decision to use the term “polypeptide” rather than “protein” in the
parenthetical exception, recognized that the relevant distinction was between those two types of
molecules, not between differently made types of proteins. See, e.g., AR at 306–07, 804, 1027;
id. at 307 (“[T]here seems to be no basis in the legislative history of the [BPCIA] to support a
finding of Congressional intent to regulate all chemically synthesized proteins . . . as drugs under
the [FDCA]” rather than as biologics under the PHSA.). Thus, from 2011 on, its definition of
protein was meant to apply to both naturally derived and chemically synthesized proteins. In the
Final Rule, FDA explained that “all amino acid polymers that meet FDA’s interpretation of the
term ‘protein’” id. at 1026, would be treated as such, “irrespective of the method of
manufacture.” Id. at 1027; see also id. at 307 (same). As further evidence that the interpretation
treats natural and synthetic proteins on equal terms, FDA, applying its definition, transitioned a
number of chemically synthesized proteins, including some that had previously been excluded as
chemically synthesized polypeptides, to BLAs. See id. at 1143–51. Even if the 2019 Act
imposed the restriction that Teva suggests, that limitation would not unambiguously foreclose
48
FDA’s interpretation, which, on its face, does not discriminate between natural and synthetic
proteins.
The term “protein” is thus ambiguous with respect to the “specific, defined sequence”
requirement, which is neither compelled nor foreclosed by the text of section 351. Therefore,
analysis proceeds to Step Two.
(b) Chevron Step Two
At Step Two, FDA’s interpretation of “protein” survives only if the agency reasonably
construed the statutory language, a standard that the agency can fail. Kisor, 139 S. Ct. at 2416.
To satisfy Chevron’s second inquiry, an agency must supply a reasonable explanation of “how
[its] interpretation serves the statute’s objectives.” Mako Commc’ns, LLC v. FCC, 835 F.3d 146,
150 (D.C. Cir. 2016) (internal quotation omitted). Review at this step is “highly deferential,”
Vill. of Barrington, 636 F.3d at 665 (internal quotation omitted), with “‘[p]articular deference . . .
given by the court to an agency with regard to scientific matters in its area of technical
expertise,’” Ctr. for Biological Diversity v. EPA, 749 F.3d 1079, 1088 (D.C. Cir. 2014) (quoting
Nat’l Wildlife Fed’n v. EPA, 286 F.3d 554, 560 (D.C. Cir. 2002)). In cases that touch upon
complex scientific issues, the court “‘must look at the decision not as the chemist, biologist or
statistician that [it is] qualified neither by training nor experience to be,’” id. at 1087–88 (quoting
Ethyl Corp. v. EPA, 541 F.2d 1, 36 (D.C. Cir. 1976) (en banc)), but instead “aims only to discern
whether the agency’s evaluation was rational,” id. at 1088 (quoting Nat. Res. Def. Council v.
EPA, 824 F.2d 1211, 1216 (D.C. Cir. 1987)).
As the Final Rule and Proposed Rule articulate, FDA interprets the term “protein” as
found in section 351 to refer only to molecules that, in addition to meeting the other criteria set
forth in the agency’s definition, have a “specific, defined sequence” of amino acids. AR at 802–
49
03, 1025. This interpretation falls within the range of scientifically accepted meanings of
“protein,” as described above, see supra Part III.B.2.a, and therefore, in the absence of a
statutory definition, within the “zone of ambiguity” invoked by Congress’s use of “protein,” a
scientific term of art. See Barnhart, 535 U.S. at 218. The agency 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. See supra Part I.A.4. FDA proffered, in great
detail, a reasonable explanation of its interpretation in the 2011 Memorandum, stood by that
explanation in each of its Guidance Documents, and reiterated it in the Proposed Rule. Id.
In particular, FDA has consistently emphasized and expanded upon its view, based on
scientific expertise, that the term “protein refers to chains containing a specific, defined sequence
of amino acids.” AR at 803 (emphasis omitted); see also, e.g., id. at 297. The agency appears to
have 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. It next
concluded that this characteristic was shared by synthetic proteins, which are modeled on their
natural predecessors. As a result of these scientific conclusions, FDA decided to interpret the
term “protein” to encompass a “specific, defined sequence” requirement. This analytic process
is itself rational, and, in light of the broad scientific agreement that proteins have a specific,
defined sequence of amino acids, described supra Part III.B.2.a, so too is the definition it
produced.
Nonetheless, Teva contends that FDA’s interpretation is unreasonable for three main
reasons, none of which is persuasive. First, Teva argues that, in the wake of the 2019 Act,
50
“‘proteins’ previously excluded as ‘chemically synthesized polypeptides’” must be treated as
biological products, such that interpretations that distinguish between natural and synthetic
proteins are now unreasonable under the statute. Pls.’ Mem. at 25. It claims that the specific,
defined sequence requirement does exactly that. This argument rests, again, on two faulty
premises that before the enactment of the 2019 Act, section 351, as amended by the BPCIA,
excluded chemically synthesized proteins rather than chemically synthesized polypeptides, and
also that FDA’s interpretation of “protein” in the Guidance Documents and Proposed Rule
likewise excluded chemically synthesized proteins. As explained above, these characterizations
of both section 351 and FDA’s rulemaking process are inaccurate. See supra Part III.B.2.a.
Second, Teva submits that FDA derived the “specific, defined sequence” criterion solely
from an examination of naturally derived proteins and related scientific literature and, as a result,
that requirement “is no longer justified as a starting point for the definition of ‘protein.’” Pls.’
Mem. at 25. The administrative record clearly shows otherwise, however. FDA examined
sources related to both natural and synthetic proteins in developing the “specific, defined
sequence” requirement.15 The scientific literature reviewed by FDA strongly, if not
unambiguously, reflects a consensus view that proteins have a specific, defined sequence of
amino acids. See supra Part III.B.2.a. This characteristic is therefore an essential feature of any
protein, central to its design and efficacy as a therapeutic product. As the sources explain, in
nature, “proteins are made by living organisms” from a DNA template, which “has a specific,
defined sequence.” Fed. Defs.’ Mem. at 23 (citing J.A., William K. Purves et al., Life: The
Science of Biology 218–20 (6th ed. 2000), ECF No. 46-4). The “DNA template is used to create
an RNA template, which is then used to build a protein.” Id. (citing Purves et al., supra, at 218–
15
See, e.g., AR at 812, Larrañaga et al., supra, at 1145 (“Some proteins have been synthesized[.]”); id. at 817,
A Dictionary of Science, supra, at 666; id. at 820, Stenesh, supra, at 387.
51
20). “The specific, defined sequence is passed on each step” and is therefore “an inherent
property endowed by the way organisms make proteins.” Id. (citing Purves et al., supra, at 220–
21). The sequence of a protein also determines its structure, which in turn determines its
function in living organisms, including humans. See, e.g., AR at 856–57, Lodish et al., supra, at
64–65 (“A key concept in understanding how proteins work is that function is derived from
three-dimensional structure, and three-dimensional structure . . . is specified by amino acid
sequence.” (emphasis omitted)).
FDA determined, after reviewing the scientific literature, that a specific, defined
sequence is characteristic of both natural and synthetic proteins. See, e.g., id. at 297, 803. Teva
correctly notes that the requirement in scientific writing appears to have originated from
observations about natural proteins, see Pls.’ Mem. at 25, but that fact alone does not render
FDA’s application of this attribute to synthetic proteins unreasonable. While proteins can now
be synthesized in a laboratory, they originated in nature, and it was with regard to natural
proteins that this category of molecules was first researched and described. See Fed. Defs.’
Mem. at 25–26. Further, the amino acid sequence dictates the function of synthetic proteins just
as it does for their natural equivalents. See, e.g., J.A., Raushan K. Singh et al., Protein
Engineering Approaches in the Post-Genomic Era, 19 Current Protein & Peptide Sci. 5, 5 (2018).
It is thus unsurprising that FDA identified in the scientific literature a consensus that synthetic
proteins, as more recent additions to the protein family, share this fundamental quality of the
naturally derived proteins on which they are modeled, among other common defining properties.
See supra Part III.B.2.a; Fed. Defs.’ Mem. at 25–26. Put simply, as FDA reasonably concluded,
molecules that do not have a specific, defined sequence are not regarded as proteins in the
scientific community, regardless of how they are made. See Fed. Defs.’ Mem. at 26. Indeed, for
52
FDA to find that chemically synthesized proteins need not share a characteristic that the agency,
in reliance on scientific expertise, has identified as a defining trait of the category would deprive
the term “protein” of all set meaning.
Further, the “specific, defined sequence” requirement does not operate to exclude all
chemically synthesized molecules from the protein category, as Teva implies. Under FDA’s
interpretation, backed by the scientific expertise of the agency and of the sources on which it
relied, chemically synthesized polymers without a specific, defined sequence are not proteins;
chemically synthesized polymers with a specific, defined sequences are. The record indicates
that several viable methods of manufacturing synthetic proteins, with the requisite specific,
defined sequence, exist. See, e.g., J.A., Stephen B.H. Kent, Total Chemical Synthesis of
Proteins, 38 Chem. Soc. Rev. 338, 339–41 (2009) (describing “modern methods for the total
chemical synthesis of proteins” with defined amino acid sequences); id., Jeffrey A. Borgia &
Gregg B. Fields, Chemical Synthesis of Proteins, 18 Tibtech 243, 243–49 (2000) (listing “three
general chemical approaches to constructing proteins” with specific amino acid sequences); AR
at 306 & n.60 (citing Kent, supra, at 338). Indeed, FDA applied its interpretation to transition at
least three chemically synthesized proteins from NDAs to BLAs. See AR at 1125, 1130, 1132.
Finally, Teva contends that the “specific, defined sequence” requirement “uniquely
burdens chemically synthesized proteins, because any naturally derived protein with a
‘DNA/RNA templated source’ gets a free pass.” Pls.’ Mem. at 25–26 (quoting AR at 1121); see
also AR at 803 (noting that, for naturally derived molecules, a “specific, defined sequence” is
“generally provided by a corresponding DNA or RNA sequence”).16 Teva’s theory is that the
16
In support of this theory, Teva points to FDA’s classification of Vitrase, a naturally derived product,
compared to its treatment of Copaxone and to a statement in FDA’s Decision Memorandum, finding that Copaxone
is not a protein, that “[s]ynthetic proteins are generated by the stepwise addition of specific amino acids in a defined
sequence.” AR at 1120; see also Pls.’ Mem. at 26–27. These specific arguments challenge FDA’s interpretation or
53
Final Rule treats natural and synthetic proteins unevenly because naturally derived proteins are
assumed to have a specific, defined sequence latent in the DNA/RNA template from which they
are made, while manufacturers of chemically synthesized polymers must show that their
products in fact meet the requirement. The Final Rule in fact holds natural and synthetic proteins
equally to the standard of having a specific, defined amino acid sequence. That makers of
synthetic proteins must do more to demonstrate that this standard is met does not prove the
standard is either, as Teva contends, “weighted . . . toward recognizing natural proteins,” Pls.’
Opp’n at 26, or unreasonable. Instead, this is simply indicative of the scientific reality that
naturally derived proteins are known to have specific, defined sequences, while chemically
synthesized polymers may have this essential trait, but alternatively may have a random
sequence that disqualifies them from classification as proteins.
Teva next contends that, by imposing this further showing on manufacturers of synthetic
products, “FDA has acted unreasonably to ‘frustrate the policy that Congress sought to
implement’” in the 2019 Act. Pls.’ Opp’n at 24 (quoting Shays v. FEC, 528 F.3d 914, 925 (D.C.
Cir. 2008)). This argument relies on the unsubstantiated assumption that Congress intended in
the 2019 Act to “eliminat[e] any process-based distinction for determining whether to regulate a
complex polypeptide product as a biologic.” Pls.’ Opp’n at 25–26. Teva argues that, because
manufacturers of chemically synthesized polymers may show that their products have a specific,
defined sequence by providing information about how they are made, the specific, defined
sequence requirement assures that only polymers made through certain methods will be
classified as proteins. Setting aside the question of whether the 2019 Act in fact reflects any
such congressional intent, Teva overlooks the fact that the “specific, defined sequence”
application of the Final Rule, not the statutory interpretation set forth in the Final Rule, and therefore are not
properly evaluated under Chevron.
54
requirement is not a process-based requirement. It is a requirement that natural and synthetic
products alike exhibit a fundamental characteristic shared by all proteins before being classified
as such. Though certain methods of manufacture may reliably result in specific, defined
sequences and others (among them the process used by Teva to manufacture Copaxone) will not,
the requirement itself is a reasonable effort by FDA to ensure that the category “protein” is
restricted to molecules truly fitting the scientific consensus regarding that definition.
If anything, the 2019 Act reflects Congress’s continuing use of the word “protein,” a term
of art with an accepted scientific meaning, and its accompanying intent that FDA discern and
apply that scientific meaning. FDA did so, determining that all “proteins” have a specific,
defined sequence of amino acids. Teva’s contention that only some chemical processes will
generate proteins under FDA’s interpretation, if true, does not render the interpretation
unreasonable. It merely reflects a limitation inherent in the term selected by Congress and
reasonably construed by FDA. In short, the “specific, defined sequence” requirement is a
reasonable construction of the term “protein” in section 351. It is neither unattainable nor, on its
face, unduly burdensome for chemically synthesized molecules. FDA’s interpretation is
therefore owed deference under Chevron.
C. FDA’s Determination That Copaxone Is Not a “Protein” Is Not Arbitrary
and Capricious
Teva next argues that FDA’s application of the Final Rule to Copaxone, and conclusion
in the Decision Memorandum that Copaxone is not a protein, was arbitrary and capricious. The
law is well-settled that an agency action “is arbitrary and capricious if (1) the agency ‘has relied
on factors which Congress has not intended it to consider’; (2) the agency ‘entirely failed to
consider an important aspect of the problem’; (3) the agency’s explanation ‘runs counter to the
evidence before the agency’; or (4) the explanation ‘is so implausible that it could not be
55
ascribed to a difference in view or the product of agency expertise.’” Am. Bankers Ass’n v. Nat’l
Credit Union Admin., 934 F.3d 649, 663 (D.C. Cir. 2019) (quoting Motor Vehicles Mfrs. Ass’n of
U.S., Inc. v. State Farm Mut. Ins. Co. (“State Farm”), 463 U.S. 29, 43 (1983)). “Agency action
is also arbitrary and capricious if it ‘offered insufficient reasons for treating similar situations
differently.’” Cal. Cmtys. Against Toxics, 928 F.3d at 1057 (quoting Transactive Corp. v. United
States, 91 F.3d 232, 237 (D.C. Cir. 1996)).
Under the arbitrary and capricious standard, the “scope of review is ‘narrow,’”
considering “only whether the [agency] examined ‘the relevant data’ and articulated ‘a
satisfactory explanation’ for [its] decision, ‘including a rational connection between the facts
found and the choice made.’” Dep’t of Commerce v. New York, 139 S. Ct. 2551, 2569 (2019)
(quoting State Farm, 463 U.S. at 43). The court “‘may not substitute [its] own judgment for
that’ of the agency.” Am. Bankers Ass’n, 934 F.3d at 663 (quoting FERC v. Elec. Power Supply
Ass’n, 136 S. Ct. 760, 782 (2016)). Of particular relevance here, “[i]n the context of a challenge
to the FDA’s decisionmaking, [courts] ‘give[] a high level of deference’ to the agency’s
scientific analysis of the evidence before it, and must avoid ‘unduly second-guess[ing] [those]
scientific judgments.’” Pharm. Mfg. Rsch. Servs., Inc. v. FDA, 957 F.3d 254, 262 (D.C. Cir.
2020) (third, fourth, and fifth alterations in original) (first quoting Rempfer v. Sharfstein, 583
F.3d 860, 867 (D.C. Cir. 2009); and then quoting Cytori Therapeutics, Inc. v. FDA, 715 F.3d
922, 923 (D.C. Cir. 2013)).
Applying these standards to the present case, FDA acted reasonably and in accordance
with applicable law in finding that Copaxone is not a protein and in declining to transition
Copaxone to a BLA on that basis. Implementing the Final Rule’s definition of “protein,” FDA
concluded in its Decision Memorandum that Copaxone did not satisfy the “specific, defined
56
sequence” requirement and therefore was not a “protein.” AR at 1120–21. In response to Teva’s
comments to the docket regarding the Preliminary List, the agency 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 pre-defined template that results in an identical
sequence across batches. Id. at 1120. Natural proteins are produced from “a DNA template,”
“the existence of [which] renders the sequence ‘specific and defined,’” and allows FDA to
determine that molecules have a specific, defined sequence based solely on their natural origins.
Id. Synthetic proteins share this quality because of “the stepwise addition of specific amino
acids in a defined sequence” during synthesis, which provides a manmade template for their
production. Id.Copaxone, however, is not made through this predictable process, but rather through
“reaction chemistry,” which generates recurring but not identical or pre-defined results across
batches. Id.; see also supra Part I.B.1. 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.” AR at 184; see also id. at 478, 484. As a result,
FDA determined that “‘there is a negligible likelihood of having identical amino acid sequences
along entire copolymer chains from batch to batch,’” id. at 1121 (quoting id. at 708), and
Copaxone exhibits “sequence variability,” id. at 1120. FDA acknowledged that some
“[c]onserved [i.e., replicated] sequences” occur in glatiramer acetate products like Copaxone, but
noted that they are “limited to short amino acid sequences within the copolymer chain.” Id. at
1121 (quoting id. at 708). This minimal degree of specificity, FDA concluded, did not meet the
“specific, defined sequence” standard.
57
In so reasoning, FDA appears to have considered the appropriate scientific factors and to
have provided a rational distinction between Copaxone and bona fide proteins, whether natural
or synthetic. Teva does not point to any scientific evidence in the record indicating that
Copaxone can meet the standard of specificity FDA outlined. Nonetheless, Teva challenges
FDA’s reasoning as arbitrary and capricious on two grounds: Teva regards FDA’s findings, set
forth in its Decision Memorandum, as inconsistent with respect to, first, FDA’s treatment of
other therapeutic products and, second, FDA’s prior finding that Copaxone is sufficiently well-
defined for the agency to approve generic glatiramer acetate products. As explained below,
neither criticism is persuasive.
First, Teva argues that the Decision Memorandum applied a heightened specificity
standard to Copaxone compared to the standard imposed on Vitrase and Creon, two products that
Teva alleges “are less well characterized than Copaxone, and whose active ingredients may vary
from batch to batch” but were nonetheless transitioned to BLAs. Pls.’ Mem. at 27; see also id. at
27–32; Pls.’ Opp’n at 27–31. Vitrase and Creon are naturally derived compounds, sourced from
animal tissues, that consist of multiple naturally derived proteins. AR at 799, 1107. FDA
responded to this critique, leveled by Teva in its comments on the Preliminary List, in the
Decision Memorandum. The agency wrote that, although the sequences of the discrete proteins
that make up Vitrase and Creon are not “fully characterize[ed],” FDA can determine that each of
the proteins has a specific, defined sequence because they are naturally derived and thus have an
“inherent DNA/RNA templated source.” Id. at 1121. Contrary to Teva’s characterization of
FDA’s treatment of Vitrase and Creon as allowing these products to “ignore [the specific,
defined sequence] requirement entirely” because they are naturally derived, Pls.’ Mem. at 28,
FDA has reasonably explained that Vitrase and Creon in fact satisfy the requirement precisely
58
because they are naturally derived. Though Teva contends that the lack of “characterization”
means that the molecules in Vitrase and Creon lack specific, defined sequences, Pls.’ Mem. at 29
(quoting AR at 9), in fact, the term indicates only that science has not yet been able to identify
the exact sequences, not that they do not exist, see Fed. Defs.’ Mem. at 31.
Teva doubles down on the FDA’s purported inconsistent treatment of Vitrase and Creon,
maintaining that FDA found that Vitrase and Creon have specific and defined sequences despite
their molecular variation, while Copaxone, which has sequence variation but not molecular
variation, does not. Pls.’ Mem. at 29–31; Pls.’ Opp’n at 27–30. FDA acknowledged the
variability of Vitrase and Creon, writing, with respect to Vitrase, that “the amino acid sequence
of [Vitrase] molecules varies based both on the species and the tissue from which they are
sourced . . . [and] the amino acid sequence for [Vitrase] enzymes extracted from a particular type
of tissue from the same species may vary.” AR at 1121 (quoting id. at 10). The key variation
here is not, as Teva would have it, a variation in the sequence of different batches of the same
type of protein molecule, but rather variation in the types of protein molecules in different
batches, with a single type of protein molecule having the same sequence across every batch that
includes it. See id. at 10 (explaining that Vitrase and similar products may contain “a single type
of . . . molecule” or “multiple types of . . . molecules”). As Sandoz helpfully puts it, “this simply
means that, for example, one batch may contain a mixture of ‘HYAL1’ and ‘HYAL2,’ while
another batch may contain a mixture of ‘HYAL1,’ ‘HYAL2’ and ‘HYAL3.’ But . . . the
sequence of ‘HYAL1’ is always the same, and the sequence of ‘HYAL2’ is always the same,
even though ‘HYAL1’ and ‘HYAL2’ have different sequences because they are different
proteins.” Sandoz Mem. at 38.17
17
Teva additionally argues that, because each batch of Creon and Vitrase contains a different mix of
molecules, their treatment as proteins is inconsistent with FDA’s interpretive premise that a “specific, defined
59
Drawing on this scientific backdrop, FDA concluded that because “each of the sequences
is specific and defined for a given species and source,” Vitrase and Creon met the specific,
defined sequence requirement because each individual protein molecule in the mixture has an
identical amino acid sequence across batches, even if a particular molecule is not present in
every batch. AR at 1121. Contrast Copaxone, a product consisting of a single type of molecule
which, by Teva’s own calculations, has anywhere between 1012 (one trillion) to 1029 (a trillion
times a trillion) possible sequences. See id. at 479. Faced with this staggering potential for
variation across entire copolymer chains, FDA reasonably concluded that the short replicated
sequences between batches of glatiramer acetate do not give Copaxone a “specific, defined
sequence” as a whole. See id. at 1121.18 Teva challenges the scientific premises underlying this
conclusion, see Pls.’ Mem. at 29–31, but “[m]eaningful review” in this context “does not require
[the court] to step into the FDA’s shoes and reassess its scientific judgments—a role that [courts]
are ‘ill-equipped’ to play ‘under the guise of the APA’s arbitrary and capricious standard.’”
Pharm. Mfg. Rsch. Servs., Inc., 957 F.3d at 265 (quoting Cytori Therapeutics, 715 F.3d at 927).
FDA’s determination that Copaxone, a product consisting of a single type of molecule with
nearly infinite possible sequences, does not have a specific, defined sequence and therefore is not
sequence” is essential to a “protein” “because sequence specificity is what gives proteins their structure and their
structure determines their function.” Pls.’ Opp’n at 28. In fact, FDA rejected an interpretation of “protein” that
relied on function during its rulemaking because some proteins perform functions that are also carried out by non-
protein molecules. See AR at 300; Fed. Defs.’ Reply at 18–19. Rather, the “specific, defined sequence”
requirement ensures the characteristic molecular consistency of proteins, which Vitrase and Creon exhibit within
discrete types of molecules, while the very heterogeneity of Copaxone molecules is thought to contribute to its
“clinical efficacy,” AR at 27, 71–72.
18
Nor does Teva’s contention that Vitrase and Creon exhibit “broader sequence variability” than Copaxone,
Pls.’ Mem. at 29, hold weight. In contrast to the trillions of possible sequences of Copaxone, the record evidence, at
best, supports the inference that Creon has “possibly hundred of different enzyme variants,” AR at 1018 n.74, see
also id. at 1101, and Vitrase, which consists of a single family of proteins, likely far fewer, id. at 799, perhaps
between two and seven, see id. at 10 & n.10 (citing sources). Further, the relevant variation, under FDA’s test, is
not molecular diversity, which is the type of variation that Vitrase and Creon have, but sequence variation across
different samples of the same molecule. As explained above, FDA has determined that each type of molecule
included in batches of Vitrase and Creon has the same sequence across batches.
60
a protein is not inconsistent with its determination that Vitrase and Creon, compounds made of
multiple molecules that all have a specific, defined sequence, are proteins.
Teva next argues that FDA’s determination that Copaxone lacks a “specific, defined
sequence” is inconsistent with its finding that Copaxone is sufficiently well-defined for the
agency to approve, in the FDCA context, generic glatiramer acetate products. Pls.’ Mem. at 32–
36; Pls.’ Opp’n at 31–33. Under the FDCA, to make the requisite showing that a generic version
of a reference listed drug is “safe and effective,” an ANDA applicant must demonstrate, among
other factors, that the generic drug is “identical in active ingredient(s)” to the reference listed
drug. 21 C.F.R. § 314.92(a)(1); see also 21 U.S.C. § 355(j)(2)(A)(ii), (iii); supra Part I.A.1. In
its letter denying Teva’s eighth and final Citizen Petition, FDA explained that “[c]urrent
analytical techniques are capable of supporting a demonstration of active ingredient sameness
between the generic glatiramer acetate injection and [Copaxone],” AR at 727; see also id. at
727–31, and explained that ANDA applicants are able to show “that the molecular identity and
diversity of [generic] glatiramer acetate is equivalent to that of the active ingredient in
Copaxone,” id. at 739; see also supra Part I.B.2. It articulated criteria for evaluating the
“sameness” of generic glatiramer acetate products, which included replication of the “batch-to-
batch variation” exhibited by Copaxone, AR at 718 n.69, and the “fundamental reaction scheme”
used by Teva to manufacture its product, id. at 718–19; see also supra Part I.B.2. By preserving
the “propagational shift” that is characteristic of Copaxone, FDA concluded, generic products
would contain similar “conserved aspects” (that is, replicated amino acid sequences) to those
present in Copaxone, which are thought to contribute to its therapeutic effects. AR at 718–19.
Teva now submits that this determination reflects a finding by FDA “that the active
ingredient [in Copaxone], glatiramer acetate, has amino acid sequences that are sufficiently well
61
defined, such that the ANDA applicant can demonstrate” active ingredient sameness. Pls.’ Mem.
at 32–33; see also Pls.’ Opp’n at 31–33.19 This argument conflates requirements and standards
under two completely different statutes that FDA has interpreted and applied in completely
different contexts. The active-ingredient sameness criterion derives from the text of the FDCA
and FDA’s regulations interpreting and applying that criterion to the approval of generic drugs.
The “specific, defined sequence” stems from the inclusion of “proteins” in the PHSA’s definition
of “biological products” and FDA’s resulting regulations. The FDCA requirement seeks to
determine whether different therapeutic products will have an equivalent therapeutic effect,
while the PHSA requirement seeks to accurately classify therapeutic products in order to
determine how they should be regulated. Nor was FDA’s sameness standard for glatiramer
acetate products based solely on the presence or absence of replicated sequences. Rather, the
agency set forth four factors, and a forty-three page guide, through which to evaluate glatiramer
acetate products, which included the replicated sequences as one consideration and the batch-to-
batch variation inherent to Copaxone as another. See id. at 700, 697–739; supra Part I.B.2.
Further, FDA’s assessment that Copaxone’s short, conserved sequences are capable of
replication in generic glatiramer acetate products, and its determination that those sequences
should be considered when approving generics, is in no way equivalent to a finding that
Copaxone molecules as a whole have the “specific, defined sequence” characteristic of proteins.
19
Though Teva raised this argument in its comments to the Preliminary List, see AR at 1015–16, FDA did
not specifically respond to it in the Decision Memorandum, see id. at 1117–23. FDA did, however, rely on its letter
denying Teva’s eighth Citizen Petition in the Decision Memorandum. That letter addressed at length the agency’s
determinations both that Copaxone lacks a “specific, defined sequence” and that generic glatiramer acetate products
could be approved, see id. at 708, 716–26, and the Decision Memorandum explicitly incorporated its key conclusion
that “‘[a]lthough [Copaxone’s] preserved local sequences may be reflected in analyses used to establish active
ingredient sameness, there is also broader sequence variability inherent to Copaxone. As such, glatiramer acetate is
best described not as a protein, but rather as a heterogeneous mixture of copolymers,’” id. at 1121 (quoting AR at
708). Thus, the Decision Memorandum may be fairly construed to have “invoked” the grounds articulated in the
letter. Regents, 140 S. Ct. at 1907 (internal quotation omitted).
62
FDA has consistently found that the sequences of the four amino acids in Copaxone are “neither
entirely conserved (i.e., replicated) from batch to batch . . . nor completely random.” AR at 706–
07; see also, e.g., id. at 1121. In the Decision Memorandum, as Teva acknowledges, FDA
explained that Copaxone has “preserved local sequences” that can be “used to establish active
ingredient sameness,” but also exhibits “broader sequence variability” that precluded the agency
from finding that it has the “specific, defined sequence” requisite for classification as a protein.
Id. at 1121 (quoting id. at 708). This explanation for why FDA evaluates Copaxone’s limited
identical sequences differently under different standards appears rational: FDA’s interpretation
of “protein” requires complete sequential identity across molecules, while its understanding of
active ingredient sameness requires only sufficient identity to ensure that a generic product is
safe and therapeutically effective.20
Teva nonetheless persists in attempting to link the two standards, insisting that “the
considerations overlap in substance” and that “both the active-ingredient-sameness and ‘specific,
defined sequence’ inquiries turn on the chemical makeup of the product in question.” Pls.’
Opp’n at 31–32. As the federal defendants point out, however, FDA has never tied its active-
ingredient-sameness determinations and its interpretation of “protein” together. See Fed. Defs.’
Reply at 19–20. To the contrary, FDA made a stray observation in the 2011 Memorandum that
protein products might find it “more difficult” to demonstrate active ingredient sameness,
20
The FDA’s treatment of Vitrase is fully consistent with this explanation, rather than, as Teva contends,
inconsistent. See Pls.’ Mem. at 34–35. Vitrase’s situation is the inverse of Copaxone’s: while FDA has transitioned
Vitrase from a “drug” to a “protein,” it did not approve ANDAs for generic equivalents when Vitrase was classified
as a drug because Vitrase’s active ingredient “ha[d] not yet been sufficiently characterized” to allow FDA to
determine that a generic product had the same active ingredient. AR at 16 n.20. As explained above, FDA has
reasonably concluded that the various molecules in Vitrase, as naturally derived proteins, have specific and defined
sequences by virtue of their inherent DNA/RNA templates, even if those sequences remain unknown to researchers.
In contrast, active ingredient “sameness” determinations require at least some detailed understanding of the active
ingredient in order for FDA to determine whether it is present in generic products. FDA’s conclusion that Vitrase
satisfies one statutory standard but not the other is neither irrational nor inconsistent with its treatment of Copaxone.
63
implicitly recognizing that the standard for qualifying as a protein differs from FDA’s test for
active ingredient sameness under the FDCA. AR at 298; see also id. at 298–99. Though Teva is
correct that amino acid sequence is relevant to both inquiries, FDA has explained that the
“protein” analysis centers on whether a molecule has a “specific and defined,” as opposed to a
“random” sequence, while the active-ingredient-sameness analysis generally considers the
molecular diversity and composition of a product, and looks to amino acid sequences as part of
that evaluation. See id. at 717–27. That FDA has answered these two questions differently with
respect to the same product reflects the differences in the standards, not any inconsistent or
arbitrary treatment of the product.
In short, FDA examined the relevant scientific factors, considered the whole record and
Teva’s objections, and proffered a reasonable explanation for its decision that Copaxone is not a
“protein.” The APA requires nothing more.
D. FDA’s Determination That Copaxone Is Not “Analogous” to a Protein Was
Reasonable
In a last-ditch effort to obtain relief, Teva challenges FDA’s interpretation of section
351’s category of products “analogous” to proteins, set forth only in the Decision Memorandum,
as foreclosed by the statute, and FDA’s application of the “analogous product” provision to
Copaxone as arbitrary and capricious. See Pls.’ Mem. at 35–43; Pls.’ Opp’n at 34–43. Neither
challenge has merit.21
21
Teva further argues, in the alternative, that Copaxone is a biological product that should be deemed
“analogous” to a vaccine. See Pls.’ Mem. at 39–40; Pls.’ Opp’n at 34–35, 41–42. This argument fails because Teva
has not exhausted its administrative remedies with respect to that theory, which was raised for the first time in
Teva’s comments on the docket regarding the Preliminary List. See AR at 1021–22. “[T]he APA requires
exhaustion of administrative remedies ‘ . . . when expressly required by statute or . . . an agency rule.’” L. Xia v.
Tillerson, 865 F.3d 643, 658 (D.C. Cir. 2017) (second omission in original) (quoting Darby v. Cisneros, 509 U.S.
137, 154 (1993)). FDA regulations clearly mandate that “[a] request that the Commissioner take or refrain from
taking any form of administrative action must first be the subject of a final administrative decision based on a
[Citizen Petition] . . . before any legal action is filed in a court complaining of the action or failure to act[.]” 21
C.F.R. § 10.45(b). Teva did not contend that Copaxone was analogous to a vaccine in any of the eight Citizen
64
FDA has not published a legislative rule or guidance document defining the “analogous
product” category with respect to products “analogous” to proteins. See, e.g., AR at 1028 (“A
definition of products that are ‘analogous’ to a ‘protein’ for purposes of section 351(i)(1) of the
[PHSA] is outside the scope of this rulemaking.”). Due to this omission, Teva argues that FDA
“has no claim to deference regarding its application of the statutory phrase to Copaxone.” Pls.’
Mem. at 37; see also Pls.’ Opp’n at 35–37. FDA has, however, tacitly interpreted the phrase in
both the Final Rule, which observes “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,” AR at 1028, and the Decision Memorandum, which states that “it
would not be appropriate to interpret the statutory term ‘analogous product’ (with reference to
‘protein’) in a way that would include amino acid polymers that are specifically excluded by the
interpretation of the term ‘protein’ set forth in FDA’s . . . Final Rule,” id. at 1121.
Moreover, in the Decision Memorandum, FDA wrote, in the course of applying the
“analogous product” provision to Copaxone, that it “would not consider an amino acid polymer
that does not have a specific, defined sequence to be ‘analogous’ to a protein.” Id. In contrast,
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
Petitions it filed. It now claims that inclusion of this contention in its comments on the docket regarding the
Preliminary List suffices to meet the exhaustion requirement because that docket was meant to address “‘questions
about FDA’s interpretation of the ‘transition’ provision’” of the BPCIA, without limitation. Pls.’ Opp’n at 42
(quoting AR at 874). Raising a question about the transition provision’s application to Copaxone is not, however,
equivalent to a formal request for FDA to classify Copaxone as a product “analogous” to a vaccine, particularly
since that category of biological products long predates the BPCIA, and was in fact in place when Teva filed its
initial NDA for Copaxone in 1995. See 42 U.S.C. § 262(a) (1994). Before its comments on the Preliminary List,
Teva never asserted, in any forum, that Copaxone was “analogous” to a vaccine, despite ample opportunity, and an
obligation, to do so before filing suit on that ground. As a result, this argument may not properly be considered
here. See, e.g., Ass’n of Am. Physicians & Surgeons, Inc. v. FDA, 358 F. App’x 179, 180–81 (D.C. Cir. 2009)
(declining to review claims brought by petitioners who failed to file a Citizen Petition as required by 21 C.F.R.
§ 10.45(b)).
65
component(s) is [sic] present in low levels or unknown amounts.” Id. at 1122 n.16.22 These
statements, though not interpretations set forth in a legislative rule or other document specifically
meant to interpret the “analogous product” provision, are interpretations nonetheless. Whether
FDA has sufficiently supported its interpretation of the “analogous product” provision to require
that products “analogous” to “proteins” have a “specific, defined sequence” of amino acids is a
separate question, assessed below.
Agreeing that FDA has provided an interpretation of the “analogous product” provision,
defendants urge that Chevron should apply. See Fed. Defs.’ Mem. at 39; Mylan Mem. at 38–39;
Sandoz Mem. at 42–44; Fed. Defs.’ Reply at 20–21; Mylan Reply at 21–22; Sandoz Reply at 21–
23. Courts in this Circuit “routine[ly] . . . analyze APA claims that arise out of the FDA’s letter-
decision interpretations of the FDCA” under that standard. Otsuka Pharm. Co., 302 F. Supp. 3d
at 389; see also AstraZeneca Pharms. LP v. FDA, 713 F.3d 1134, 1139 (D.C. Cir. 2013)
(applying Chevron to FDA’s letter decision interpreting the FDCA); Mylan Lab’ys., Inc. v.
Thompson, 389 F.3d 1272, 1279–80 (D.C. Cir. 2004) (same, collecting cases); Braeburn Inc.,
389 F. Supp. 3d at 19 (“Chevron’s framework applies to an FDA interpretation of the FDCA set
forth in a letter decision.”). This extension of Chevron deference to FDA’s informal
interpretations of the FDCA stems from “the complexity of the statutory regime under which the
FDA operates, the FDA’s expertise [and] the careful craft of the [regulatory] scheme” FDA
“devised to reconcile the various . . . provisions” of the statutes it administers. Mylan Lab’ys.,
Inc., 389 F.3d at 1280, logic that applies with equal force to FDA’s letter interpretations of the
PHSA, as a second highly technical statute the agency administers.
22
This portion of FDA’s interpretation was explained in greater detail in a March 18, 2020 memorandum,
written by FDA’s Biological Product Classification Subcommittee, that set out recommendations on determining
whether “certain combination products and naturally derived mixtures” should be transitioned to BLAs, including as
products analogous to proteins. See AR at 1084–96.
66
Applying Chevron’s two-step framework, see supra Part III.B.2, to FDA’s limited
interpretation of the “analogous product” provision indicates that FDA’s construction is
reasonable, though not well-defined or well-explained beyond its response to the precise
question at hand, of whether a product “analogous” to a “protein” must have a “specific, defined
sequence” of amino acids. Teva contends that the “analogous product” provision creates a
“residual” category, Pls.’ Mem. at 35, meant to classify as biological products some products that
are not proteins, and that the statute unambiguously indicates, at Chevron Step One, that the
critical shared quality of proteins and products analogous to them is the ability “to induce or
modulate an immune response in the body,” id. at 38. Defendants counter that the term
“analogous” is ambiguous and that, at Chevron Step Two, FDA’s determination that the critical
“analogous” quality is a “specific, defined sequence” of amino acids is reasonable. See Fed.
Defs.’ Mem. at 39–42; Mylan Mem. at 39–41; Sandoz Mem. at 42–44; Fed. Defs.’ Reply at 20–
24; Mylan Reply at 21–24; Sandoz Reply at 21–25.
At Step One, the parties agree both that the “analogous product” provision, as applied to
proteins, brings certain non-protein products into the biological product category and that the
term “analogous,” standing alone, indicates that products within the purview of this provision
must share some defining features with proteins, but does not suggest what those qualities might
be. See, e.g., Pls.’ Mem. at 35–37; Fed. Defs.’ Mem. at 39–41. Teva nonetheless submits that its
preferred interpretation of the provision, that “analogous” products are those that “induce or
modulate an immune response,” is unambiguously compelled by legislative history and statutory
structure, while FDA’s interpretation is unambiguously foreclosed. Pls.’ Mem. at 37–39; Pls.’
Opp’n at 37–39.
67
In support of this theory, Teva relies on Blank v. United States, 400 F.2d 302 (5th Cir.
1968), a decades-old case that was specifically overruled by Congress, see Heart Disease,
Cancer, Stroke, and Kidney Disease Amendments of 1970, Pub. L. No. 91-515, § 291, 84 Stat.
1297, 1308 (1970); Pls.’ Mem. at 37–38; Pls.’ Opp’n at 38–39. The Blank Court, construing the
original 1902 version of section 351, determined that, because the types of biological products
listed in that statute were all “immunological agents,” analogous products must share the
defining feature of being used for immunological purposes. 400 F.2d at 304. The federal
defendants offer persuasive evidence that Congress rejected this construction of the “analogous
products” provision in its 1970 amendments to section 351, see Fed. Defs.’ Mem. at 43–44
(citing H.R. Rep. No. 91-1035 (1970) at 1–2 (“The provisions of the bill are in the nature of
emergency legislation necessitated by [the Blank decision].”)), though Teva contests this
characterization of the legislative history, see Pls.’ Opp’n at 38–39. Regardless, even if Blank’s
reasoning remains relevant to other categories of biological products, the record makes plain that
“proteins,” which were added to section 351 decades after Blank was decided and carry out a
multitude of different functions in the body, are not all “immunological agents,” see, e.g., AR at
798, 1107; see also id. at 869, Alberts et al., supra, at 129 (noting that proteins “execute nearly
all cell functions”), which is one of the reasons that FDA avoided a functional definition of
“protein” in the first place, see id. at 300. The defining feature of this category, for the purpose
of identifying analogous products, cannot be a characteristic that is not shared by all proteins.
Teva next points to FDA’s regulations construing the “analogous product” provision with
respect to other types of biological products, arguing that these interpretations “all focus on
whether a product shares the same immunological function and basic building blocks as the
enumerated biologic.” Pls.’ Mem. at 38; see also id. at 38–39 (citing sections of 21 C.F.R.
68
§ 600.3(h)(5)). Only one of the regulatory definitions of “analogous product” FDA has
published incorporates an “immunological function” criterion.23 If anything, the diverse factors
in the definitions suggest that “analogous product” takes on a meaning appropriate to each
category it modifies, rather than a one-size-fits-all approach.24 Moreover, FDA’s construction of
the statutory phrase in relation to other products has no bearing on whether the phrase itself has
an unambiguous meaning with respect to the precise question at issue here at Step One.
Finally, Teva contends that FDA’s interpretation that a product “analogous” to a protein
must have a “specific, defined sequence” is foreclosed by the statute because this effectively
means that “if a product is not a ‘protein’ under FDA’s regulatory definition, it cannot be
‘analogous’ to a protein either.” Pls.’ Mem. at 41. As a result, in Teva’s view, FDA has
impermissibly “read[] the ‘analogous product’ category out of the statute as applied to proteins.”
Id.; see also id. at 41–43; Pls.’ Opp’n at 35–37. The category of products “analogous” to
23
See 21 C.F.R. § 600.3(h)(5)(i) (A product is analogous “[t]o a virus if prepared from or with a virus or
agent actually or potentially infectious, without regard to the degree of virulence or toxicogenicity of the specific
strain used.”); id. § 600.3(h)(5)(ii) (A product is analogous “[t]o a therapeutic serum, if composed of whole blood or
plasma or containing some organic constituent or product other than a hormone or amino acid, derived from whole
blood, plasma, or serum.”); id. § 600.3(h)(5)(iii) (A product is analogous “[t]o a toxin or antitoxin, if intended,
irrespective of its source of origin, to be applicable to the prevention, treatment, or cure of disease or injuries of man
through a specific immune process.”).
24
Teva contends that this adaptable approach to the “analogous product” phrase itself “‘violate[s] [a] rule of
statutory construction’” that “‘a single use of a statutory phrase must have a fixed meaning across a statute.’” Pls.’
Opp’n at 36 (alterations in original) (quoting Lomax v. Ortiz-Marquez, 140 S. Ct. 1721, 1725 (2020) (explaining the
interpretive canon that the meaning of a word or phrase that appears in different provisions of a single statute should
generally hold constant within the statute)). Likewise, Teva attempts to apply the ejusdem generis canon in support
of its preferred interpretation, which, it claims, appropriately “interpret[s] (and cabin[s]) a general phrase . . . that
appears at the end of a list.” Pls.’ Opp’n at 38 (citing Circuit City Stores, Inc. v. Adams, 532 U.S. 105, 115 (2001)).
This strained effort, which, as Teva would have it, results in a reading of “analogous product” to require that
products “share the same immunological function and basic building blocks as the enumerated biologic,” id.,encounters the obstacle described above, that not all proteins have immunological functions. Further, the
interpretive canon that “‘[t]he words of a statute must be read in their context and with a view to their place in the
overall statutory scheme,’” Sierra Club v. Wheeler, 956 F.3d 612, 616 (D.C. Cir. 2020) (quoting UARG, 573 U.S. at
320), supports a construction of “analogous product,” as a residual phrase that encompasses products “analogous” to
any of nine distinct types of biological products, that captures products that are “analogous” to the enumerated types
of products in category-specific ways. In any event, because the referent qualities of “analogous” are ambiguous
regardless of whether the term has a uniform or a category-specific meaning, this dispute about the import of canons
of construction need not be resolved.
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“proteins” is not, however, a null set under FDA’s construction, as evidenced by the fact that the
agency has identified at least some mixtures with protein components in this category. See AR
at 1084–97. It is simply restricted to products that, although they may not satisfy the criteria to
be a “protein” in other respects, have the characteristic “specific, defined sequence” of amino
acids. The “analogous product” provision requires that some products not capable of
identification as proteins be capable of identification as analogous products, and that the
classification be based on some defining feature of proteins that analogous products share. As to
the specifics, the phrase is ambiguous and therefore cannot foreclose FDA’s selection of the
“specific, defined sequence” requirement as the touchstone. Teva’s arguments to the contrary
notwithstanding, the question of which characteristics render a product “analogous” to a protein
is left to FDA’s determination, and is assessed at Chevron Step Two.
At Step Two, FDA’s interpretation of the “analogous product” provision need only be
reasonable to merit deference. “The analysis of disputed agency action under Chevron Step Two
and arbitrary and capricious review is often ‘the same, because under Chevron step two, [the
court asks] whether an agency interpretation is arbitrary or capricious in substance.’” Agape
Church, Inc., 738 F.3d at 410 (alteration in original) (quoting Judulang v. Holder, 565 U.S. 42,
52 n.7 (2011)). Such is the case here, where Teva’s challenge to FDA’s specific determination
that Copaxone is not “analogous” to a protein rests on the alleged invalidity of FDA’s
interpretation itself, not on the premise that Copaxone in fact satisfies the “specific, defined
sequence” requirement. See Pls.’ Mem at 41–44; Pls. Opp’n at 35–37, 39–41.25
25
Even if Teva did challenge FDA’s application of its interpretation to Copaxone on this ground, it would fail
for the reasons explained supra Part III.C. Teva contends instead that Copaxone is an “analogous product” because
it satisfies the criteria Teva proposes for identifying such products. See Pls.’ Mem. at 39–41. Since the Court does
not adopt Teva’s preferred interpretation, these arguments need not be addressed.
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FDA stated in its Decision Memorandum that Copaxone was not regarded as “analogous”
to a protein because the agency “would not consider an amino acid polymer that does not have a
specific, defined sequence to be ‘analogous’ to a protein,” as substances “that fail to meet a
specific category in the definition of ‘biological product’ because they are specifically excluded
from that category” cannot be considered “analogous” biological products. AR at 1121.
Defendants argue that this finding reflects a reasoned determination by FDA that a specific,
defined amino acid sequence “is a fundamental property of proteins” and that “[c]onsequently, a
product cannot be analogous to a protein if it does not share this fundamental, defining
property.” Fed. Defs.’ Mem. at 41; see also Mylan Mem. at 39–41; Sandoz Mem. at 43–44. As
explained above, see supra Part III.B.2.b, FDA’s conclusion that a “specific, defined sequence”
is a definitional characteristic of proteins is reasonable.
Teva challenges the extension of this conclusion to analogous products on two grounds.
First, it argues that “the entire point of the ‘analogous product’ category” is to regulate as
biological products some substances that “do not fall squarely within any of the enumerated
categories.” Pls.’ Mem. at 41 (emphasis omitted). That premise is true as far as it goes, but does
not indicate how FDA should determine whether a product stands outside of the enumerated
categories but is similar enough to be regulated as a biological product nonetheless. FDA’s
stance, that a product cannot fail entirely to meet one of the agency’s definitional criteria for a
category of biological products yet nonetheless become a biological product, offers a reasonable
method by which to distinguish sufficiently similar products from products that are too distinct to
be considered analogous. The agency appears to understand the “analogous product” category as
a narrow residual provision meant to accommodate products that satisfy the regulatory
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definitions of each category in most, if not all, regards, but are not an exact fit for whatever
reason.
In the case of products “analogous” to proteins, for example, FDA has identified one such
reason, that a product may “include one or more identified biological product component(s) (e.g.,
protein), as well as one or more non-biological product component(s) . . . that can contribute to
the product’s activity.” AR at 1089. These products contain a protein with a specific defined
sequence and therefore are not “specifically excluded” by FDA’s definition of protein, but
because they contain an additional, non-protein component, nor are they a perfect match for the
protein category. Id. at 1094. They are “analogous” to proteins because their protein
components are “necessary . . . to achieving the intended therapeutic effect,” but they are not
simply “proteins” because their non-biological product components also contribute to their
efficacy. Id. FDA’s approach to these products expands the set of proteins and protein-like
substances that qualify as “biological products” beyond the fixed “protein” category, but also
ensures that the category retains some fixed, scientifically valid meaning. In contrast, FDA has
determined that Copaxone does not contain any component with a “specific, defined sequence.”
To consider a substance that does not satisfy this fundamental requirement “analogous” to a
protein would be to stretch the set of protein and protein-like products considered “biological
products” beyond the range that FDA has found to be scientifically and interpretively sound.
Teva next argues that FDA’s interpretation must fail “because it provides no standard for
deciding whether a product is ‘analogous’ to a protein.” Pls.’ Opp’n at 41. As a general matter,
Teva is correct. FDA has not provided a comprehensive definition or standard for identifying
products analogous to proteins. The Chevron inquiry, however, is trained on the “precise
question at issue,” which, here, is the narrow question of whether a product “analogous” to a
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protein must have a specific, defined sequence. As to that discrete prong of the overall
analogous product analysis, FDA has answered yes. The standard is apparent from the
requirement itself.
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. At a minimum, given the ambiguity of the
term “analogous” standing alone, FDA’s choice of the “specific, defined sequence” criterion as
the determining factor is a rational one. Other options, including the alternative construction
suggested by Teva, might offer equally viable or even better interpretations, but a reviewing
court, “‘[i]n an area characterized by scientific and technological uncertainty, . . . must proceed
with particular caution, avoiding all temptation to direct the agency in a choice between rational
alternatives.’” Oceana, Inc. v. Ross, 920 F.3d 855, 864 (D.C. Cir. 2019) (quoting Am. Wildlands
v. Kempthorne, 530 F.3d 991, 1000 (D.C. Cir. 2008)). FDA did not err in formulating its
interpretation or in applying it to determine that Copaxone is not “analogous” to a protein.
Teva’s arguments, in short, all rest on the same premise: that FDA should have
formulated an approach to defining and identifying proteins and analogous products that would
have resulted in Copaxone’s classification as a biological product. The agency’s failure to reach
Teva’s preferred outcome does not, however, indicate that it acted unreasonably, arbitrarily, or
capriciously.26
26
If FDA’s interpretation were not subject to Chevron deference, it would be evaluated instead under the
somewhat less deferential standard set forth in Skidmore v. Swift & Co., 323 U.S. 134 (1944), which would afford
the interpretation “‘respect’ . . . but only to the extent that [it] ha[s] the ‘power to persuade,’” Orton Motor, Inc. v.
U.S. Dep’t of Health & Hum. Servs., 884 F.3d 1205, 1211 (D.C. Cir. 2018) (omission in original) (quoting
Christensen v. Harris Cty., 529 U.S. 576, 587 (2000)). Given the highly technical nature of the interpretive question
at issue and FDA’s expertise in this area, the result would likely be the same.
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IV. CONCLUSION
For the foregoing reasons, Teva’s Motion for Summary Judgment, ECF No. 31, is
denied; and the cross-motions for summary judgment filed by the federal defendants, ECF No.
36, Mylan, ECF No. 34, and Sandoz, ECF No. 38, are granted.
An Order consistent with this Memorandum Opinion will be entered contemporaneously.
Date: December 31, 2020
__________________________
BERYL A. HOWELL
Chief Judge
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