Defining Active Ingredient: The U.S. Food and Drug Administration’s Legal Interpretation of Regulatory Exclusivities

December 10, 2019 – August 8, 2023 R46110

Defining Active Ingredient: The U.S. Food and
August 8, 2023
Drug Administration’s Legal Interpretation
Erin H. Ward
of Regulatory Exclusivities
Legislative Attorney

Whether many provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act) apply to a
particular drug product turns in part on the novelty of the “active ingredient” of the drug in

question. In particular, the Food and Drug Administration (FDA) must assess the novelty of the
active ingredient in a new drug, comparing it to a previously approved drug’s active ingredient to determine whether the new
drug qualifies for the five-year “new chemical entity” (NCE) exclusivity. FDA generally cannot accept new drug applications
that refer to a drug with NCE exclusivity (i.e., rely on its clinical data and FDA’s approval of the drug) for five years.
Companies that receive approval for drugs with new active ingredients generally enjoy a competitive advantage in the market
while the exclusivity is in effect—and after, depending how long it takes for generic versions to receive approval once
applications can be submitted.
Comparing active ingredients can be technically quite complicated. For instance, compounds in a final drug product may
convert to other compounds through chemical reactions inside the body before arriving at the site of the therapeutic effect. In
addition, related but distinct drug molecules may be clinically indistinguishable or convert into the same pharmacologically
or physiologically active component inside the body. Alternatively, two drug molecules with the same core compound may
have different compounds appended to them by either covalent or noncovalent bonds. For example, replacing a hydrogen
atom in an acid molecule with “a metal or its equivalent” forms a salt, while replacing the hydrogen atom with “an organic
radical” forms an ester. These derivatives may or may not vary from each other in clinically significant ways. This raises the
question of which derivative(s), if any, should be considered to be the same active ingredient as the core or base molecule.
Generally, a more expansive interpretation of phrase “active ingredient,” that is, one that considers more types of derivatives
to be the same active ingredient, reduces the number of drugs eligible for NCE regulatory exclusivity by expanding the drug
ingredients considered previously approved, which allows for earlier introduction of generic versions of those drugs.
Historically, for the exclusivity provisions, FDA interpreted “active ingredient” to mean “active moiety,” as defined by FDA
regulations. FDA generally defines active moiety as the core molecule or ion of a drug (i.e., the drug molecule without
certain appendages) that is “responsible for the physiological or pharmacological action of a drug substance.” FDA’s
interpretation generated disputes between FDA and pharmaceutical companies, as FDA’s approach tends to exclude some
drugs from being afforded five-year NCE exclusivity under the FD&C Act. In 2015, a federal district court rejected FDA’s
interpretation as inconsistent with the statutory language, though it did not explicitly invalidate FDA’s regulations.
On April 23, 2021, the 117th Congress enacted legislation that generally codified FDA’s long-standing approach to
evaluating NCE exclusivity and extended that approach to certain other provisions under the FD&C Act. This legislation
effectively mooted questions about the validity of FDA’s interpretation and clarified when chemical entities are sufficiently
similar to be considered identical for purposes of drug approval and exclusivity.
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Introduction
Whether many provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act) apply to a
particular drug product turns in part on the novelty of the “active ingredient” of the drug in
question. In particular, the Food and Drug Administration (FDA) must assess the novelty of the
active ingredient in a new drug, comparing it to a previously approved drug’s active ingredient to
determine whether the new drug qualifies for the five-year “new chemical entity” (NCE)
exclusivity.1 FDA generally cannot accept new drug applications or abbreviated new drug
applications that refer to a drug with NCE exclusivity (i.e., rely on its clinical data and FDA’s
approval of the drug) for five years.2 Companies that receive approval for drugs with new active
ingredients generally enjoy a competitive advantage in the market while the exclusivity is in
effect until generic drugs enter the market.3 Given how expensive it can be to bring a new drug to
market,4 when Congress passed the Hatch-Waxman Amendments in 1984 to allow an abbreviated
pathway for approval of generic drugs, it also created NCE exclusivity to reward innovators of
new pharmaceutical products with an opportunity to recoup their investment.5
To determine whether FD&C Act provisions that depend in part on the drug’s “active ingredient”
apply, FDA must evaluate the “active ingredient(s)” of both the drug under review and any
previously approved drug that may contain the same active ingredient.6 This process can be
technically quite complicated. For instance, compounds in a final drug product may convert to
other compounds through chemical reactions inside the body before arriving at the site of the
therapeutic effect, and related but distinct drug molecules may be clinically indistinguishable or
convert into the same pharmacologically or physiologically active component inside the body.7
This phenomenon raises the question of which molecule—the one existing before or after
ingestion—should be the relevant molecule for purposes of determining active ingredient.8
Alternatively, two drug molecules with the same core compound may have different compounds
appended to them by either covalent (i.e., shared electrons) or noncovalent (i.e., no shared
electrons) bonds.9 For example, replacing a hydrogen atom in an acid molecule with “a metal or
its equivalent” forms a salt, whereas replacing the hydrogen atom with “an organic radical” forms
an ester.10 These derivatives may or may not vary from each other in clinically significant ways,11

1 21 U.S.C. §§ 355(j)(5)(F)(ii) & 355(c)(3)(E)(ii).
2 Id. Abbreviated new drug applications that challenge nonexpired listed patents may be submitted after four years. Id.
3 Generic Competition and Drug Prices, FOOD & DRUG ADMIN. (Nov. 28, 2017), https://www.fda.gov/about-fda/center-
drug-evaluation-and-research-cder/generic-competition-and-drug-prices (finding association between generic
competition and lower drug prices).
4 See generally Joseph A. Di Masi, Henry G. Grabowski, & Ronald W. Hansen, Innovation in the Pharmaceutical
Industry: New Estimates of R&D Costs, 47 J. HEALTH ECON. 20 (2016).
5 See, e.g., King Drug Co. of Florence, Inc. v. Smithkline Beecham Corp., 791 F.3d 388, 394 (3d Cir. 2015) (“Congress
attempted to balance the goal of ‘mak[ing] available more low cost generic drugs, H.R. Rep. No. 98-857, pt. 1, at 14-15
(1984), reprinted in 1984 U.S.C.C.A.N. 2647, 2647-48, with the value of patent monopolies in incentivizing beneficial
pharmaceutical advancement, see H.R. Rep. No. 98-857, pt. 2, at 30 (1984), reprinted in 1984 U.S.C.C.A.N. 2686,
2714.”); Yaniv Heled, Patents v. Statutory Exclusivities in Biological Pharmaceuticals—Do We Really Need Both?, 18
MICH. TELECOMM. & TECH. L. REV. 419, 427-30, 434-36 (2012).
6 See, e.g., 21 U.S.C. § 355(c)(3)(E).
7 See, e.g., Actavis Elizabeth LLC v. FDA, 625 F.3d 760, 762-63, 766 (D.C. Cir. 2010); Abbott Laboratories v. Young,
920 F.2d 984, 986 (D.C. Cir. 1990).
8 See infra “FDA’s Definition of Active Moiety.”
9 Actavis Elizabeth LLC, 625 F.3d at 765-66.
10 Amarin Pharm. Ireland Ltd. v. FDA, 106 F. Supp. 3d 196, 199 n.1 (D.D.C. 2015).
11 Actavis Elizabeth LLC, 625 F.3d at 765-66.
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raising the question of which derivative(s), if any, should be considered as the same active
ingredient as the core or base molecule.12 Generally, a more expansive interpretation of the phrase
“active ingredient,” that is, one that considers more types of derivatives to be the same active
ingredient, reduces the number of drugs eligible for NCE regulatory exclusivity by expanding the
drug ingredients considered previously approved, which, in turn, allows for earlier introduction of
generic versions of those drugs.
As discussed in more detail below, historically, for purposes of the exclusivity provisions, FDA
interpreted “active ingredient,” as the term appears in statute, to mean “active moiety,” as defined
by FDA regulations.13 FDA generally defines active moiety as the core molecule or ion of a drug
(i.e., the drug molecule without certain appendages) that is “responsible for the physiological or
pharmacological action of a drug substance.”14 FDA’s interpretation generated disputes between
FDA and pharmaceutical companies, as FDA’s approach tends to exclude some drugs from being
afforded five-year NCE exclusivity under the FD&C Act.15 In 2015, a federal district court
rejected FDA’s interpretation as inconsistent with the statutory language, though it did not
explicitly invalidate FDA’s regulations.16
On April 23, 2021, the 117th Congress enacted legislation that generally codified FDA’s long-
standing approach to evaluating NCE exclusivity and extended that approach to other provisions
under the FD&C Act that formerly included the phrase “active ingredient (including any ester or
salt of the active ingredient).”17
This report discusses FDA’s historical interpretation of the FD&C Act as referring to active
moieties, judicial review of FDA’s interpretation before the legislative amendment, and how
FDA’s rationale changed over time.
FDA’s Historical Interpretation of Active Ingredient
Until the statute was amended in 2021, multiple provisions of the FD&C Act used the phrase
“active ingredient (including any ester or salt of the active ingredient).”18 Among them were a
provision for five-year exclusivity to drugs approved under a new drug application (NDA) with
active ingredients that FDA has not previously approved,19 a provision for three-year exclusivity
for drugs with the same active ingredient as previously approved drugs that required additional
clinical studies for approval due to other changes,20 and provisions authorizing priority review
vouchers for certain types of drugs.21 In the context of the five-year-exclusivity, which FDA has

12 See infra “FDA’s Definition of Active Moiety.”
13 See 21 C.F.R. § 314.3; 59 Fed. Reg. 50,338, 50,357-58, 50,368-69 (Oct. 3 1994).
14 21 C.F.R. § 314.3(b).
15 See generally, Actavis Elizabeth LLC v. FDA, 625 F.3d 760 (D.C. Cir. 2010); Abbott Labs. v. Young, 920 F.2d 984
(D.C. Cir. 1990); Otsuka Pharm. Co. v. Burwell, 302 F. Supp. 3d 375 (D.D.C. 2016); Ferring Pharm., Inc. v. Burwell,
169 F. Supp. 3d 199 (D.D.C. 2016).
16 Amarin Pharm. Ireland Ltd. v. FDA, 106 F. Supp. 3d 196, 217-19 (D.D.C. 2015).
17 S. 1636, 116th Cong. (2019); S. 1895, 116th Cong. § 208 (2019).
18 21 U.S.C. § 355(c)(3)(E)(i),(ii), (iii) & (v); id. § 355(j)(5)(F)(i), (ii), (iii) & (v); id. § 355(l)(2)(A)(i); id. § 355(s); id.
§ 355(u)(1); id. § 360b(c)(2)(F)(i), (ii), and (v); id. § 360n(a)(4)(C); id. § 360ff(a)(4)(A)(ii); & id. § 360bbb-
4a(a)(4)(D).
19 21 U.S.C. § 355(c)(3)(E)(ii) & (j)(5)(F)(ii).
20 Id. § 355(c)(3)(E)(iii) & (j)(5)(F)(iii).
21 Id. §§ 360ff(a)(4)(A)(ii), 360n(a)(4)(C), 360bbb-4a(a)(4)(D).
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Defining Active Ingredient: FDA's Legal Interpretation of Regulatory Exclusivities

coined “new chemical entity” or NCE exclusivity,22 FDA interpreted the term “active ingredient”
to mean “active moiety.”23 FDA reasoned that this definition, which allows a wider range of
molecules to be considered previously approved, was warranted in the new drug context to
encourage innovation by ensuring that a new drug is truly innovative.24 This interpretation of
“active ingredient” in the NCE exclusivity context was the subject of a decades-long debate.
Before its amendment, the statutory provision on NCE exclusivity stated, in relevant part,
If an application submitted under subsection (b) of this section for a drug, no active
ingredient (including any ester or salt of the active ingredient) of which has been approved
in any other application under subsection (b) of this section, is approved ... no application
may be submitted under this subsection which refers to the drug for which the subsection
(b) application was submitted before the expiration of five years from the date of approval
of the application under subsection (b) of this section.... 25
Disputes over how FDA should interpret this provision centered on the meaning of the phrase
“active ingredient (including any ester or salt of the active ingredient).”26 The FD&C Act did not
define the term “active ingredient.”27 Rather than define “active ingredient” for purposes of the
exclusivity provisions, FDA examined the relevant drugs’ active moieties.28 Specifically, FDA
defines NCE exclusivity in its regulations as “a drug that contains no active moiety that has been
approved by FDA in any other application submitted under section 505(b) of the act.”29 The
various other exclusivity regulations also refer to active moieties.30
FDA defines “active moiety” in its regulations as follows:
Active moiety is the molecule or ion, excluding those appended portions of the molecule
that cause the drug to be an ester, salt (including a salt with hydrogen or coordination

22 Id. § 355(j)(5)(F)(ii); 21 C.F.R. § 314.108. See also 21 U.S.C. § 355(c)(3)(E)(ii) & (iii), 355(j)(5)(F)(iii). The three-
year exclusivity for drugs with previously approved active ingredients that require additional clinical studies to be
approved (e.g., for new indications or methods of use) includes similar statutory language and has been similarly
interpreted by FDA to refer to active moieties. See 21 U.S.C. § 355(j)(5)(F)(iii) & (iv); 21 C.F.R. § 314.108.
23 21 C.F.R. § 314.108.
24 Abbreviated New Drug Application Requirements; Patent and Exclusivity Provisions, 59 Fed. Reg. 50,338, 50,358
(Oct. 3, 1994).
25 21 U.S.C. § 355(j)(5)(F)(ii) (emphasis added). See also id. § 355(c)(3)(E)(ii).
26 See, e.g., Amarin Pharm. Ireland Ltd. v. FDA, 106 F. Supp. 3d 196, 206-07 (D.D.C. 2015); Actavis Elizabeth LLC v.
FDA, 625 F.3d 760, 761-62 (D.C. Cir. 2010); Abbott Labs. v. Young, 920 F.2d 984, 985-86 (D.C. Cir. 1990). “Esters
and salts are molecules that form in chemical reactions when the hydrogen atom of an acid molecule is replaced by
another substance.” Amarin Pharm. Ireland Ltd., 106 F. Supp. 3d at 199.
27 FDA did not define “active ingredient” when it originally enacted regulations to implement the Hatch-Waxman
Amendments. See generally 59 Fed. Reg. 50,338. However, it did define the term outside of the exclusivity context in
2016 when implementing the Medicare Prescription Drug, Improvement, and Modernization Act of 2003. See 81 Fed.
Reg. 69,580, 69,580, 69,637 (Oct. 6, 2016). FDA regulations now define “active ingredient” as
[A]ny component that is intended to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any
function of the body of man or other animals[,] includ[ing] those components that may undergo
chemical change in the manufacture of the drug product and be present in the drug product in a
modified form intended to furnish the specified activity or effect.
21 C.F.R. § 314.3. However, FDA has not changed its approach to NCE exclusivity, as the agency continues to
examine the active moiety of the relevant drugs. See id. § 314.108.
28 See, e.g., 54 Fed. Reg. 28,872, 28,896-98 (July 10, 1989); 59 Fed. Reg. 50,338, 50357-58, 50,368-69 (Oct. 3 1994);
New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products: Guidance for
Industry, U.S. DEP’T OF HEALTH AND HUMAN SERV., FOOD & DRUG ADMIN. (2014).
29 21 C.F.R. § 314.108(a) (emphasis added).
30 Id. § 314.108(b)(2) & (4).
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bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the
molecule, responsible for the physiological or pharmacological action of the drug
substance.31

Key Terms
Ester. An organic compound formed by reaction between alcohols and acids.
Salt. A chemical compound formed by reaction of an acid with a base, in which the hydrogen of the acid has been
replaced by metal or other positive ions.
Covalent bond. A chemical bond created by sharing electrons.
Noncovalent bond. A chemical bond that does not entail sharing electrons.
Source: Rennie, R., & Law, J. (Eds.), A Dictionary of Chemistry. Oxford University Press.

As one court put it, “[f]or salts, esters, and noncovalent derivatives, a molecule’s ‘active moiety’
can be thought of as its core; salt, ester and noncovalent derivative versions of the same basic
molecule have different appendages, but they share the same active moiety.”32 Put another way,
because these specified derivatives would be considered to have the same “active moiety,” if FDA
approved a drug containing any one of the specified derivatives as the active ingredient, a later
approved drug containing another form of a specified derivative or even the core molecule would
not be entitled to NCE exclusivity.
For instance, under this approach (which has subsequently been codified in legislation), if Drug A
contains as its active ingredient a salt, ester, or other noncovalent derivative of a molecule that
FDA previously approved as part of Drug B, Drug A would not be entitled to NCE exclusivity
because FDA had previously approved that active moiety.33 Similarly, if Drug B contains as its
active ingredient a salt derivative of a molecule, and Drug A contains that same molecule or an
ester derivative of that molecule and is approved after Drug B, Drug A would not be entitled to
NCE exclusivity.34 In contrast, if Drug A contained as its active ingredient a non-ester covalent
derivative of a molecule that FDA previously approved in Drug B, Drug A could be considered to
have a new active moiety and be eligible for NCE exclusivity if other relevant conditions are met.
If a drug molecule is converted to a different but related compound after ingestion, under this
interpretation of the FD&C Act, the relevant molecule for determining active moiety is the
compound in the final drug product before the drug is ingested.
Challenges to FDA’s Approach
In the NCE exclusivity context, FDA’s interpretation of “active ingredient” as “active moiety,” as
well as its definition of “active moiety,” were both subject to dispute. Challenges to FDA’s
approach to NCE exclusivity generally addressed two questions:
1. Whether FDA could permissibly interpret the phrase “no active ingredient
(including any ester or salt of the active ingredient) of which has been approved”
as “a drug that contains no active moiety that has been approved.”35

31 Id. § 314.3.
32 Amarin Pharm. Ireland Ltd. v. FDA, 106 F. Supp. 3d 196, 199-200 (D.D.C. 2015).
33 21 U.S.C. §§ 355(c)(3)(E)(ii) & (iii), 355(j)(5)(F)(iii).
34 21 C.F.R. § 314.108.
35 Related to this question is what language FDA has determined to be ambiguous to allow room for FDA’s
interpretation.
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2. Whether FDA correctly defined “active moiety,” including whether FDA may
permissibly deny exclusivity for—in addition to “salts and esters,” which appear
in the statute—other noncovalent derivatives of the underlying drug molecule.36
FDA’s Interpretation of the Exclusivity Provision
Proposed Rule. In 1989, in its implementing regulations for the Hatch-Waxman Amendments,
FDA first interpreted the FD&C Act’s exclusivity provisions to distinguish between NCEs, which
are entitled to a five-year term of regulatory exclusivity, and previously approved active
ingredients, which are entitled to three years of regulatory exclusivity, based on active moieties.37
To support its interpretation in the proposed rule, the agency relied on the statutory text, FDA’s
preexisting classification scheme for drugs that included a “new molecular entity” class based on
active moieties, and the legislative history of the Hatch-Waxman Amendments.38 FDA reasoned
that “Congress was aware of FDA’s classification scheme” when it passed the Hatch-Waxman
Amendments, including FDA’s “longstanding interpretation of the term ‘new molecular entity’
[as] a compound containing an entirely new active moiety.”39 In support of its definition of active
moiety, which includes other noncovalent derivatives of a drug molecule in addition to the drug
molecule itself and its salt and esters, FDA reasoned that Congress “did not intend to confer
significant periods of exclusivity on minor variations of previously approved chemical
compounds.”40 FDA did not specifically identify which part of the statutory phrase “an active
ingredient (including any ester or salt of the active ingredient)” it had determined to be
ambiguous when adopting the interpretation of “active moiety.”41
Initial Litigation Rejecting FDA Approach. Between FDA’s proposed rule in 1989 and its final
rule in 1994 implementing the exclusivity regulations, two cases addressed the agency’s
interpretation of the phrase “active ingredient (including any ester or salt of the active
ingredient)” to mean active moiety. In Abbott Laboratories v. Young, the U.S. Court of Appeals
for the D.C. Circuit (D.C. Circuit) considered FDA’s denial of 10-year exclusivity42 for Depakote,
an anticonvulsant seizure medication that used divalproex sodium as its active ingredient.43 FDA
based its decision on findings that (1) divalproex sodium is a salt of valproic acid that converts
into valproic acid in the body, and (2) the agency previously approved valproic acid as the active
ingredient in Depakene.44 The court determined that the FD&C Act’s use of the phrase “the active

36 Related to this question is whether the term active moiety must include other covalent derivatives that convert into
the same compound to achieve the therapeutic effect.
37 See, e.g., 54 Fed. Reg. at 28,896-98; 59 Fed. Reg. at 50357-58, 50,368-69.
38 54 Fed. Reg. at 28,897-98.
39 Id.
40 Id. at 28,898.
41 Under the Chevron doctrine, established by the Supreme Court in Chevron U.S.A. v. Natural Resources Defense
Council, when reviewing agency interpretations of statutes, the court first asks “whether Congress has directly spoken
to the precise question at issue.” 467 U.S. 837, 842 (1984). “If so, the court must ‘give effect to the unambiguously
expressed intent of Congress.’” Amarin Pharm. Ireland Ltd., 106 F. Supp. 3d at 205 (quoting Chevron U.S.A., 467 U.S.
at 843). Only if the court “concludes that Congress has left an ambiguity or ‘gap’ to fill on the ‘precise question at
issue’” does the court proceed to ask “whether the agency’s construction of the statute is a ‘permissible’ one,” in which
case the court defers to the agency. Id. at 206. Finding ambiguity in the statutory provision accordingly allows the court
to consider FDA’s interpretation.
42 For drugs approved between January 1, 1982, and September 24, 1984 (before the Hatch-Waxman Amendments
were passed), Congress provided a 10-year period of exclusivity for drugs with new chemical entities and a 2-year
period of exclusivity for all other drugs. 21 U.S.C. § 355(j)(5)(F).
43 920 F.2d 984, 986 (D.C. Cir. 1990).
44 Id.
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ingredient” is ambiguous, as it could refer to the active ingredient in the original approved drug or
in the later approved drug.45 However, the D.C. Circuit rejected FDA’s reliance on the term
“including” to justify using its definition of active moiety, which extends beyond salts and esters
of the active ingredient to other noncovalent derivative molecules, as “linguistically infeasible.”46
Specially, the court concluded that Congress used the term “including” in the provision at issue
not to provide examples of molecular derivatives undeserving of regulatory exclusivity but to
extend the covered active ingredients to the two particular derivatives—esters and salts.47 Upon
concluding that the statute is ambiguous and that FDA failed to provide a reasonable construction,
the D.C. Circuit remanded the case to FDA for further actions.48
Around the same time, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit)
considered the U.S. Patent and Trademark Office’s (USPTO’s) denial of Glaxo’s request for a
patent-term extension for its patent claiming cefuroxime axetil, the active ingredient in Ceftin
tablets.49 The Hatch-Waxman Amendments require the USPTO to extend the terms of a patent
claiming a product or a method of using or manufacturing a product when (1) the product is
“subject to a regulatory review period” (e.g., the FDA drug approval process) and (2) the
permission to market the product following the regulatory review (e.g., FDA approval of the
drug) is the “first permitted commercial marketing or use of the product.”50 In turn, the statute
defines “product” to mean “the active ingredient of a new drug ... including any ester or salt of
the active ingredient.”51 Interpreting the product as the active moiety, the USPTO found that
cefuroxime (an acid) rather than cefuroxime axetil (an ester of cefuroxime) was the active moiety
in Ceftin.52 Because FDA had previously approved two drugs with cefuroxime salts as active
ingredients,53 the USPTO determined that FDA’s approval of Ceftin was not the “first permitted
commercial marketing or use of the product” and denied the patent-term extension.54
The Federal Circuit held that the USPTO’s denial of the patent term extension was contrary to
law, affirming the district court’s judgment.55 In contrast to the D.C. Circuit, which viewed the
relevant statutory language as ambiguous, the Federal Circuit held that the terms in the phrase
“active ingredient of a new drug ... including any ester or salt of the active ingredient” all have a
plain meaning.56 The court determined—without discussing its reasoning in any detail—that the
USPTO’s interpretation was inconsistent with the plain meaning of these terms.57 While
acknowledging that legislative history can reveal “a clearly expressed legislative intention
contrary to the statutory language,” it identified no such support for the USPTO’s interpretation
here.58 Because the court found there was no clear legislative intent that the phrase be interpreted
to refer to variations on the approved active ingredients beyond that product’s ester or salt, an

45 Id. at 987-88.
46 Id. at 988.
47 Id.
48 Id. at 989-90.
49 Glaxo Operations UK Ltd. v. Quigg, 894 F.2d 392, 393-94 (Fed. Cir. 1990).
50 35 U.S.C. § 156(a) & (f).
51 Id. § 156(f)(2).
52 Glaxo Operations UK Ltd., 894 F.2d at 394.
53 Glaxo Operations UK Ltd. v. Quigg, 706 F. Supp. 1224, 1225-26 (E.D. Va. 1989).
54 Glaxo Operations UK Ltd., 894 F.2d at 394.
55 Id. at 399-400.
56 Id. at 395.
57 Id.
58 Id. at 395-400.
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extension of the term for the patent claiming cefuroxime axetil was warranted because FDA had
not approved that drug product or an ester or salt of it.59 While the appellate court did not
elaborate on how it arrived at its interpretation, the district court had included more detail on the
plain meaning of the operative statutory phrase, concluding that cefuroxime—the acid from
which cefuroxime axetil is derived—could not be an “active ingredient” of Ceftin because it was
not an ingredient, as that term is commonly understood because it did not appear in the Ceftin
tablets in that form.60
Final Rule. In the wake of these rulings, public comments to FDA’s proposed rule contended that
Abbott Laboratories and Glaxo Operations rejected the agency’s proposed interpretation of the
NCE exclusivity provision, particularly its reliance on the phrase active moieties.61 Nonetheless,
when FDA finalized its NCE exclusivity regulations in 1994, the agency included its proposed
definition of “active moiety,” but modified its justification.62 Rather than interpreting the
parenthetical phrase (i.e., “(including any ester or salt of the active ingredient)”) “broadly to
include all active ingredients that are different but contain the same active moiety,” which the
D.C. Circuit in Abbott Laboratories had rejected as “linguistically impermissible,” the agency
concluded that the term “active ingredient,” as used in the relevant provision, means active
moiety.63 FDA did not, however, directly address the Federal Circuit’s opinion.
FDA also disagreed with comments objecting to its inclusion of other noncovalent derivatives in
the definition of “active moiety,” meaning that such derivatives would not receive NCE
exclusivity. The agency reaffirmed that it “does not believe that providing exclusivity for ...
noncovalent derivatives of a previously approved active moiety would be consistent with the
statutory intent” because such derivatives “generally do[] not affect the active moiety of a drug
product.”64 FDA accordingly enacted the definition of active moiety as proposed.
D.C. Circuit Upholds FDA Use of Pre-Ingestion Rather than Post-Ingestion to Interpret
Active Ingredient. In 2010, in Actavis Elizabeth LLC v. FDA, the D.C. Circuit revisited FDA’s
interpretation of “active ingredient,” nearly two decades after the agency finalized its regulations
in 1994.65 That opinion focused specifically on the term “active ingredient” in the context of
whether the relevant molecule should be considered prior to its ingestion in the human body (i.e.,
the compound in the final drug product pre-ingestion) or after ingestion where the compound may
convert to another related compound (e.g., from an ester to an acid) that is responsible for the
drug’s therapeutic effects (i.e., post-ingestion).66 A generic manufacturer challenged FDA’s award
of NCE exclusivity for Vyvanse, a drug that treats attention deficit hyperactivity disorder.67
Vyvanse’s active ingredient is lisdexamfetamine dimesylate, a salt of lisdexamfetamine, meaning

59 Id. at 395-99.
60 Glaxo Operations UK Ltd. v. Quigg, 706 F. Supp. 1224, 1227-28 (E.D. Va. 1989).
61 59 Fed. Reg. 50,338, 50,357-58 (Oct. 3, 1994).
62 Id.
63 Id.
64 Id. at 50,358.
65 Actavis Elizabeth LLC v. FDA, 625 F.3d 760, 764-66 (D.C. Cir. 2010).
66 Id. Note that the court in Abbott Laboratories v. Young had explained the distinction between active ingredient and
active moiety as the former being “the substance prior to introduction into the human body” and the latter being “the
substance that creates the actual therapeutic effect within the body.” 920 F.2d 984, 986 (D.C. Cir. 1990). While this
distinction may be accurate for some drugs if the active ingredient converts to the active moiety inside the body, this
explanation is not fully consistent with FDA’s regulatory definition of “active moiety” or with FDA’s analysis in
practice. See, e.g., Actavis Elizabeth LLC v. FDA, 625 F.3d 760, 764-66 (D.C. Cir. 2010).
67 Actavis Elizabeth LLC, 625 F.3d at 762.
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that lisdexamfetamine is the active moiety under FDA regulations.68 Lisdexamfetamine uses an
amide bond (a type of covalent bond involving nitrogen) to connect a portion of lysine, a
common amino acid, with dextroamphetamine.69 Once in the body, a chemical reaction converts
lisdexamfetamine to dextroamphetamine.70 FDA had approved drugs with dextroamphetamine
but had not yet approved drugs with lisdexamfetamine.71
Actavis, a generic manufacturer seeking to market a generic version of Vyvanse, alleged that
because dextroamphetamine is responsible for the therapeutic effect inside the body and FDA had
previously approved drugs with dextroamphetamine, Vyvanse had no right to NCE exclusivity.72
Focusing on the term “active,” Actavis contended that “active ingredient” necessarily must refer
to “the drug molecule that reaches the ‘site’ of the drug’s action” because that is the part of the
drug responsible for its “activity,” which Actavis argued meant the therapeutic effect.73
The court rejected Actavis’s arguments. First, the court observed that the FD&C Act does not
define the term “active ingredient” and that the statute’s legislative history “is silent on what
determines novelty” for NCE exclusivity.74 The court also concluded that the statute’s structure
and purpose did not preclude FDA’s interpretation.75 Accordingly, the court held that (1) “active
ingredient” was ambiguous as to whether it referred to the pre-ingestion or post-ingestion
molecule, and (2) FDA’s interpretation of “active ingredient” to refer to the pre-ingestion
molecule was reasonable.76
The court further affirmed FDA’s choice of a bright-line distinction between noncovalent
derivatives (which do not receive NCE exclusivity) and non-ester covalent derivatives (which can
receive NCE exclusivity and was at issue for Vyvance). While the D.C. Circuit acknowledged that
some noncovalent bonds might alter a drug’s properties and some covalent bonds might not,77 the
court deferred to FDA’s explanation that “its policy is based in part on the ‘difficulty in
determining precisely which molecule, or portion of a molecule, is responsible for a drug’s
effects.’”78 The court did not, however, directly address FDA’s use of the term “active moiety,” its
inclusion of the other noncovalent derivatives in the definition, or the interaction between FDA’s
definition of active moiety and the statutory parenthetical.
District Court Rejects FDA Interpretation of Active Ingredient as Active Moiety. Five years
later, in Amarin Pharmaceuticals Ireland Ltd. v. FDA, a federal district court in the District of
Columbia expressly considered FDA’s interpretation of “active ingredient” to mean “active
moiety,” as defined in its regulations.79 Amarin had obtained FDA approval for Vascepa, whose
active ingredient is icosapent ethyl, the ethyl ester of eicosapentaenoic acid (EPA), a type of
omega-3 fatty acid.80 But FDA denied Amarin’s request for NCE exclusivity for Vascepa because

68 Id. at 762-63.
69 Id. at 763.
70 Id.
71 Id.
72 Id. at 762.
73 Id.
74 Id.
75 Id.
76 Id. at 765-66.
77 Id. at 766.
78 Id.
79 106 F. Supp. 3d 196, 208 (D.D.C. 2015).
80 Id. at 202.
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it had previously approved Lovaza, a drug whose active ingredient is “a mixture that is primarily
composed of seven kinds of omega-3 fatty acid ethyl esters” including the ester of EPA.81 When
FDA approved Lovaza, it considered the mixture as a whole the “active ingredient,” and it later
denied a petition from Lovaza’s sponsor requesting FDA to recharacterize Lovaza as having
multiple active ingredients on the grounds that “the Lovaza mixture has not been ‘fully
characterized.’”82 In other words, in approving Lovaza, FDA did not specifically approve an ester
of EPA (or any other component omega-3 fatty acid ethyl esters) as an active ingredient. But
when evaluating Vascepa’s eligibility for NCE exclusivity, FDA relied on new studies to find that
EPA was an active moiety of Lovaza and that, accordingly, FDA had previously approved
Vascepa’s active moiety.83
Rather than recognize multiple active ingredients in Vascepa, FDA provided a new interpretation
framework for certain mixtures to treat them as having one active ingredient but multiple active
moieties. In its decision letter to Amarin, FDA acknowledged that the agency had previously
taken an inconsistent approach to identifying the active ingredients and active moieties for
naturally derived mixtures, such as Lovaza, when evaluating NCE exclusivity.84 FDA “explained
that, although they are often conflated, it is important to distinguish between the meaning of the
terms active ingredient and active moiety.”85 Also, while “the distinction between active moiety
and active ingredient[] generally is negligible” for “drugs that are composed of a single, well-
characterized molecule,” “the distinction between active ingredient and active moiety ... becomes
crucial” “[f]or naturally derived mixtures comprising multiple molecules.”86
Critically, the agency distinguished between (1) “poorly characterized” and (2) “well-
characterized mixtures” based on how difficult it is “‘to determine with any certainty ... which
molecules in the mixture are consistently present or potentially are responsible for the
physiological or pharmacological activity of the drug.’”87 For poorly characterized mixtures,
FDA stated that it had “of necessity” treated the whole mixture as both the active ingredient and
the active moiety.88 However, for well-characterized mixtures, FDA outlined “a three-part
‘framework’ ‘for identifying the active moiety or moieties of such mixtures.’”89 FDA would
consider component parts of well-characterized mixtures to be previously approved active
moieties if
1. specific molecules in the mixture have been identified;
2. those specific molecules are “consistently present in the mixture”; and
3. those molecules are “responsible at least in part for the physiological or
pharmacological action of the mixture, based on a finding that they make a
meaningful contribution to the activity of the mixture.”90

81 Id. at 201.
82 Id.
83 Id. at 203-04.
84 Id. at 203.
85 Id. at 204 (internal quotations omitted) (referencing FDA decision letter).
86 Id. (internal quotations omitted).
87 Id.
88 Id.
89 Id.
90 Id.
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Defining Active Ingredient: FDA's Legal Interpretation of Regulatory Exclusivities

In effect, for single-molecule and poorly characterized drugs, FDA would apply a one-to-one
approach between the active ingredient and active moiety, but for well-characterized mixtures, it
would apply a one-to-many approach: one active ingredient with multiple active moieties.91
The district court set aside FDA’s decision denying NCE exclusivity for Vascepa based on its
interpretation of “active ingredient” to mean “active moiety”.92 The court first relied on the canon
against surplusage, finding that FDA’s interpretation of the term “active ingredient” “would
render the parenthetical clause in the exclusivity provisions either redundant or
incomprehensible.”93 By defining active moiety to exclude “those appended portions of the
molecule that cause the drug to be an ester, salt ... or other noncovalent derivative,”94 the court
concluded that FDA rendered the statutory parenthetical “(including any ester or salt of the active
ingredient)” either unnecessary or incomprehensible.95 The court reasoned that FDA in effect read
the parenthetical out of the statute by inserting “active moiety” in place of “active ingredient,”
violating the canon against surplusage that assumes Congress does not include unnecessary
language in a statute.96
The court then used the presumption of consistent usage to reject FDA’s view of active ingredient
as synonymous with active moiety.97 Significantly, FDA only interpreted active ingredient to
mean active moiety with respect to the FD&C Act’s exclusivity provisions, relying on alternative
interpretations of “active ingredient” elsewhere in the statute, such as, perhaps most notably, the
provision allowing sponsors to submit abbreviated NDAs for generic drugs with the same active
ingredient as an approved drug.98 FDA argued that it was justified in adopting different
interpretations of the same phrase in different parts of the statute because the provisions had
different statutory purposes.99 The agency contended that because the abbreviated NDA process
focuses on safety and efficacy, a narrower range of molecules should be considered identical to
previously approved drugs to ensure that FDA conducts a full review for safety and efficacy of
any drugs that may clinically differ from previously approved drugs.100 In contrast, FDA argued
that the exclusivity provisions aim to encourage innovation, requiring a wider range of molecules
to be considered previously approved to ensure the new drug is truly innovative.101
While acknowledging that “the presumption of consistent usage is not unrebuttable,” the court
considered FDA’s justifications for the differing interpretations of active ingredient
unpersuasive.102 The court observed that Congress passed both provisions at the same time in the
same part of the same statute, that the abbreviated NDA provisions and exclusivity provisions
were two sides of the same coin intended to balance competition and innovation, and that

91 Id. at 204-205.
92 Id. at 217-19.
93 Id. at 209.
94 21 C.F.R. § 314.3.
95 Amarin Pharm. Ireland Ltd. v. FDA, 106 F. Supp. 3d 196, 209 (D.D.C. 2015).
96 Id. FDA offered an alternative interpretation that active moiety replaced the entire phrase “an active ingredient
(including any ester or salt of the active ingredient)” rather than simply “active ingredient.” Id. at 215-16. The court
rejected this interpretation as well. Id. First, the court found that FDA had not relied on this interpretation in either its
final rule or its decision letter. Id. Second, the court determined that this interpretation raises the same issues identified
by the D.C. Circuit in Abbott Laboratories v. Young. Id.
97 Id. at 210.
98 Id.
99 Id. at 210-11.
100 Id.
101 Id.
102 Id. at 211-12.
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Congress included the parenthetical “including any ester or salt of the active ingredient” in the
exclusivity provision but not the abbreviated NDA provision, thus already distinguishing between
the two provisions.103
Finally, the court determined that FDA’s use of active moiety was inconsistent with the statutory
requirement that the active ingredient “has been approved.”104 It noted that FDA approves active
ingredients, not active moieties, and that under FDA’s proposed framework it would not even
determine the relevant active moiety under another drug applied for exclusivity.105 Accordingly,
an active moiety would never have previously been approved.106
Rejecting each of FDA’s arguments and concluding FDA’s interpretation invalid on multiple
grounds, the court set aside the specific administrative decision being challenged in that case—
that is, FDA’s exclusivity determination for Vascepa—and remanded to FDA.107 The court did
not, however, explicitly invalidate or set aside FDA’s implementing regulations.108 FDA
regulations therefore remain in place, but with questions looming as to their validity and
defensibility.109
FDA’s Definition of Active Moiety
Beyond whether FDA can interpret the phrase “active ingredient” in the FD&C Act’s exclusivity
provisions to mean active moiety, how FDA has defined “active moiety” has also been the subject
of legal challenges. (Although Congress amended the FD&C Act, as detailed below, FDA’s
regulatory definition of “active moiety” has not changed.) The statutory parenthetical includes
esters and salts of an active ingredient as the same active ingredient for determining exclusivity,
meaning that an ester and salt of an active ingredient is ineligible for exclusivity.110 FDA’s
definition of active moiety extends beyond those two derivatives, however, to also include
molecules with other noncovalent appendages.111 At the same time, the agency excludes from its
definition of active moiety molecules with appendages attached through non-ester covalent
bonds, meaning that drug molecules that differ from previously approved drugs based on such
appendages would be eligible for NCE exclusivity.112 Brand name manufacturers have challenged
including other noncovalent derivatives, which limits the availability of NCE exclusivity, while
generic manufacturers have challenged excluding non-ester covalent derivatives, which expands
the availability of NCE exclusivity.

103 Id.
104 Id. at 213.
105 Id. at 214.
106 Id.
107 Id. at 219. On remand, FDA determined that Vascepa was eligible for NCE exclusivity. Letter from Janet
Woodcock, Director, Center for Drug Evaluation and Research, Food & Drug Admin, to Robert A. Dormer, Hyman,
Phelps & McNamara, P.C. (Counsel for Amarin Pharmaceuticals Ireland Ltd.) (May 31, 2016)
http://www.fdalawblog.net/wp-content/uploads/archives/docs/VASCEPA%20-%20Exclusivity%20Determination%
20on%20Remand.pdf (conveying decision on exclusivity for Vascepa (icosapent ethyl) capsules (NDA 202057)).
108 See Letter from Janet Woodcock to Robert A. Dormer, supra note 107, at 13.
109 Watson Laboratories filed an appeal, but the D.C. Circuit dismissed the appeal on the grounds that the district court
order remanding the decision to FDA was not a final appealable order. Amarin Pharm. Ireland Ltd. v. FDA, No. 15-
5214, 2015 WL 9997417 (D.C. Cir. 2015).
110 21 U.S.C. §§ 355(c)(3)(E)(ii), 355(j)(5)(F)(ii).
111 21 C.F.R. § 314.3.
112 Id.
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Defining Active Ingredient: FDA's Legal Interpretation of Regulatory Exclusivities

Other Derivatives with Noncovalent Bonds. As discussed above, Abbott Laboratories v. Young
also addressed FDA’s inclusion of other noncovalent derivative forms of the molecule in addition
to salts and esters, which the statute explicitly includes.113 At the time, FDA relied on a broad
interpretation of the word “including” to justify examining the base molecule without salts, esters,
or any other component connected by noncovalent bonds.114 The agency viewed the term
“including” as providing examples of molecules that would be considered minor modifications
that do not merit five-year NCE exclusivity, rather than an exhaustive list.115 While the Abbott
Laboratories court considered FDA’s approach defensible on policy grounds, it considered the
agency’s approach “linguistically infeasible.”116 It stated that it “cannot agree with [FDA’s]
unconvincing attempts to employ the ‘including’ clause to cover all possible permutations of
active ingredient,” distinguishing the NCE exclusivity “including” clause “from instances where
an ‘including’ clause is designed to merely illustrate a few examples of the general category.”117
Rather than provide its own interpretation, however, the court remanded the decision to FDA.118
FDA subsequently modified its interpretation of the statutory language in its 1994 final
regulations. Rather than interpret the parenthetical phrase, the agency concluded that the term
“active ingredient” means “active moiety,” as defined in its regulations.119 In so doing, FDA
reaffirmed its view that allowing NCE exclusivity for other noncovalent derivatives would be
inconsistent with statutory intent.120
In 2015, as explained above, Amarin Pharmaceuticals Ireland Ltd. v. FDA rejected FDA’s revised
interpretation.121 However, because the court only set aside the challenged agency action at issue
in that case without invalidating FDA regulations, FDA regulations remain in force with its
original definition of “active moiety.”122
Derivatives with Non-Ester Covalent Bonds. As discussed above, in Actavis Elizabeth LLC v.
FDA, the D.C. Circuit upheld FDA’s decision to exclude derivatives with different covalent bonds
from its definition of active moiety.123 Unlike noncovalent bonds, covalent bonds entail the
sharing of electrons between molecules, which tends to create a stronger bond.124 The court held
that FDA’s policy was reasonably “based on its view that drug derivatives containing non-ester
covalent bonds are, on the whole, distinct from other types of derivative drugs such that the
former are uniquely deserving of ‘new chemical entity’ status and the resulting five-year
exclusivity.”125 In particular, the court pointed to a 1989 response letter from FDA to a citizen
petition. In that letter, the agency explained that “even minor covalent structure changes are
capable of producing not only major changes in the activity of the drug but changes that are not
readily predicted.” Nonetheless, FDA observed that “the formation of a salt ... or of an ester, is
not intended to, and generally cannot, alter the basic pharmacologic or toxicologic properties of

113 920 F.2d 984, 988 (D.C. Cir. 1990).
114 Id. at 987.
115 Id. at 987-88.
116 Id. at 988.
117 Id.
118 Id. at 989-90.
119 59 Fed. Reg. 50,338, 50,358.
120 Id.
121 Amarin Pharm. Ireland Ltd. v. FDA, 106 F. Supp. 3d 196, 217-19 (D.D.C. 2015).
122 Id. at 219.
123 625 F.3d 760, 765-66 (D.C. Cir. 2010).
124 HARVEY LODISH ET AL., MOLECULAR CELL BIOLOGY §§ 2.1 & 2.2 (4th ed. 2000).
125 Actavis Elizabeth LLC, 625 F.3d at 765-66.
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the molecule.”126 Accordingly, without holding directly on whether FDA reasonably included
other noncovalent derivatives in its active moiety definition, the court held that FDA’s exclusion
of non-ester covalent derivatives was reasonable.127
Legislative Amendment by the 117th Congress
Against this backdrop of decades of complex litigation over FDA’s interpretation of active
ingredient, the 117th Congress enacted legislation that addressed this issue.128 The law generally
(1) codified FDA’s interpretation that eligibility for NCE exclusivity is based on the drug’s active
moiety and (2) incorporated FDA’s definition of active moiety by reference.129 Specifically, the
law replaced the entire phrase “active ingredient (including any ester or salt of the active
ingredient)” with “active moiety (as defined by the Secretary in section 314.3 of title 21, Code of
Federal Regulations (or any successor regulations))” wherever it is found, except for a few
expired provisions that the legislation repealed instead.130 This change amended several FD&C
Act provisions, including the NCE exclusivity provision, three-year exclusivity for other changes,
and provisions providing priority review vouchers for tropical disease treatments, rare pediatric
disease treatments, and countermeasures for agents that threaten national security. 131
Adopting this interpretation resolved certain legal uncertainties under existing case law. In
Amarin Pharmaceuticals v. FDA, the court had rejected FDA’s interpretation but had not
explicitly invalidated FDA’s regulations.132 Though it left FDA’s interpretation in place, the
court’s decision left uncertain FDA’s ability to defend its interpretation going forward. The
enacted legislation addressed these questions by adopting FDA’s interpretation into law.
The enacted legislation also resolved the questions that had been raised as to whether FDA’s
decision to include other noncovalent derivative forms of the molecule in its definition of active
moiety, but not other covalent derivatives, accorded with congressional intent and a justifiable
distinction. The law both adopted FDA’s approach, by incorporating FDA’s definition, and
allowed FDA to modify its approach going forward as its understanding changed, by including
any successor regulations.133 In effect, the law committed the decision as to which molecules
should be deemed effectively the same and therefore not innovative enough to merit NCE
exclusivity to FDA’s judgment.

126 Id.
127 Id.
128 Pub. L. No. 117-9, 135 Stat. 256 (2021).
129 Id.
130Id. Specifically, the law amended 21 U.S.C. § 355(c)(3)(E)(ii) & (iii); 21 U.S.C. § 355(j)(5)(F)(ii) & (iii); 21 U.S.C.
§ 355(l)(2)(A)(i); 21 U.S.C. § 355(s); 21 U.S.C. § 355(u)(1); 21 U.S.C. § 360b(c)(2)(F)(i), (ii), and (v); 21 U.S.C.
§ 360n(a)(4)(C); 21 U.S.C. § 360ff(a)(4)(A)(ii); and 21 U.S.C. § 360bbb-4a(a)(4)(D).
131 S. 1636; S. 1895; H.R. 4955.
132 106 F. Supp. 3d 196, 219 (D.D.C. 2015). See also supra note 108.
133 S. 1636; S. 1895; H.R. 4955.
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Defining Active Ingredient: FDA's Legal Interpretation of Regulatory Exclusivities

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Erin H. Ward

Legislative Attorney

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