Novartis Pharmaceuticals Corporation v. Robert F. Kennedy , J R .

United States Court of Appeals
FOR THE DISTRICT OF COLUMBIA CIRCUIT
Argued April 17, 2025 Decided September 26, 2025
No. 24-5235
NOVARTIS P HARMACEUTICALS C ORPORATION ,
APPELLANT
v.
R OBERT F. KENNEDY , J R ., IN HIS OFFICIAL CAPACITY AS
S ECRETARY OF HEALTH AND HUMAN S ERVICES , ET AL.,
APPELLEES
Appeal from the United States District Court
for the District of Columbia
(No. 1:24-cv-02234)
Catherine E. Stetson argued the cause for appellant. With
her on the briefs were Susan M. Cook and Marlan Golden.
Caroline W. Tan, Attorney, U.S. Department of Justice,
argued the cause for appellees. With her on the brief were Brett
A. Shumate, Acting Assistant Attorney General, and Daniel
Tenny, Attorney.
Chad A. Landmon argued the cause for intervenors in
support of appellees. With him on the brief were Kendall
Gurule and Suzanne E. Bassett.

-- 1 of 12 --

2
Before: M ILLETT, KATSAS , and WALKER , Circuit Judges.
Opinion for the Court filed by Circuit Judge KATSAS .
KATSAS , Circuit Judge: Novartis Pharmaceuticals
Corporation markets a drug called “Entresto,” which is used to
treat chronic heart failure. MSN Pharmaceuticals, Inc. filed an
abbreviated new drug application to market a generic version
of Entresto. The application carved out specific methods of
using Entresto protected by Novartis’s live patents, and it
claimed that the generic drug has the same active ingredients
as Entresto. The Food and Drug Administration approved the
application. Novartis contends that the approval was unlawful.
The district court disagreed, as do we.
I
Section 505 of the Federal Food, Drug, and Cosmetic Act
(FDCA) prohibits the sale in interstate commerce of any “new
drug” without prior approval by the Secretary of Health and
Human Services. 21 U.S.C. § 355(a). For certain drugs, such
as the generic versions of approved brand-name counterparts,
the FDCA authorizes approval through an “abbreviated new
drug application” (ANDA), which is substantially less onerous
than the regular approval process. Id. § 355(j); see Caraco
Pharm. Labs., Ltd. v. Novo Nordisk A/S, 566 U.S. 399, 404–05
(2012). The regular approval process requires studies showing
that the new drug is safe and effective when used as instructed
on its label. 21 U.S.C. § 355(b)(1)(A)(i), (vi). In contrast, the
ANDA approval process turns on whether the new drug is
sufficiently similar, across multiple dimensions, to a drug
previously approved and listed under the statute. Id.
§ 355(j)(2).
Most fundamentally, the ANDA process requires the new
drug to have the same “active ingredients” as those in a

-- 2 of 12 --

3
previously approved drug. 21 U.S.C. § 355(j)(2)(A)(ii).
Implementing regulations define an “[a]ctive ingredient” as
“any component that is intended to furnish pharmacological
activity.” 21 C.F.R. § 314.3(b). They further state that an
“identical active drug ingredient” is “the same salt or ester of
the same therapeutic moiety.” Id. And they define “[a]ctive
moiety” as the part of the molecule “responsible for the
physiological or pharmacological action of the drug.” Id.
Given these various definitions, the parties agree that the drug
specified in an ANDA must contain the same salt or ester of
the same therapeutic moiety as a previously approved drug.
For approval through an ANDA, the “labeling proposed
for the new drug” generally must be “the same as the labeling
approved for the listed drug.” 21 U.S.C. § 355(j)(2)(A)(v).
However, the statute allows “changes required … because the
new drug and the listed drug are produced or distributed by
different manufacturers.” Id. FDA regulations explain that
such changes may include “omission of an indication or other
aspect of labeling protected by patent.” 21 C.F.R.
§ 314.94(a)(8)(iv).1 But such changes may not “render the
proposed drug product less safe or effective than the listed drug
for all remaining, nonprotected conditions of use.” Id.
§ 314.127(a)(7).
These provisions often come into play when the patent for
an approved drug has expired, but its manufacturer still holds
patents on “some approved methods of using the drug.”
Caraco, 566 U.S. at 406. In that circumstance, a generic
manufacturer may seek approval through an ANDA to “market
the drug for one or more methods of use not covered by the
brand’s patents.” Id. And subject to the regulations noted
above, the FDA may approve a “modified label” that “‘carves
1 An “indication” is a particular medical condition that a drug
is approved to address. See 21 C.F.R. § 314.53(b)(1).

-- 3 of 12 --

4
out’ from the brand’s approved label the still-patented methods
of use.” Id.
II
Novartis markets Entresto, a drug widely used to treat
chronic heart failure. According to its label, Entresto “contains
a complex comprised of anionic forms of sacubitril and
valsartan, sodium cations, and water molecules.” J.A. 49.
Novartis currently holds four method-of-use patents
related to Entresto. One of them covers a modified dosing
regimen for patients not taking angiotensin-converting enzyme
inhibitors (“ACE inhibitors”) or angiotensin II receptor
blockers (“ARBs”), which are other drugs used to treat heart
failure. J.A. 336–37. The modified regimen calls for these
patients to start by taking half the normal dose of Entresto and
then gradually increase the dosage over time. Entresto’s label
includes the modified dosing regimen covered by this patent.
Novartis’s other three method-of-use patents cover use of the
drug to treat patients with a preserved (as opposed to reduced)
ejection fraction, which is a measure of how well the heart is
contracting.
The FDA initially approved Entresto in 2015. At first, its
approved use was limited to patients with chronic heart failure
and a reduced ejection fraction. Novartis then conducted a
clinical study involving patients with preserved ejection
fractions. In 2021, the FDA approved updated labeling that
indicated treatment for patients with chronic heart failure
generally. The updated label added new language stating that
Entresto’s benefits are “most clearly evident” in patients with
a reduced ejection fraction and advising doctors to “use clinical
judgment in deciding whom to treat.” J.A. 41.

-- 4 of 12 --

5
In 2019, MSN Pharmaceuticals submitted an ANDA
seeking approval to market a generic version of Entresto.
MSN’s proposed label omitted Novartis’s patented dosing
regimen for patients not taking ACE inhibitors or ARBs. Like
Entresto’s original label, it stated an indication for chronic
heart failure with a reduced ejection fraction, thus avoiding
Novartis’s patented indication for use in patients with a
preserved ejection fraction. The proposed label also stated that
the generic drug “contains anionic forms of sacubitril and
valsartan, and sodium cations.” J.A. 68.
Anticipating this ANDA, Novartis filed a 2019 citizen
petition asking the FDA to reject any generic version of
Entresto that does not present the active ingredients—sacubitril
and valsartan—“in the same chemical structure.” J.A. 168–69.
In 2022, Novartis filed another petition asking the FDA to
reject any generic version of Entresto carving out its patented
uses from the label. According to Novartis, carving out the
modified dosage for patients not taking ACE inhibitors or
ARBs would impermissibly render the generic version less safe
and effective than Entresto. And carving out use of Entresto to
treat patients with a preserved ejection fraction would require
impermissibly adding words to Entresto’s existing label. In
2024, the FDA denied both petitions and then approved MSN’s
application to market its generic alternative to Entresto.
Novartis filed this lawsuit under the Administrative
Procedure Act. It seeks to set aside the FDA’s denial of its
citizen petitions and approval of MSN’s ANDA. The parties
filed cross-motions for summary judgment. The district court
granted the FDA’s motion and denied Novartis’s. Novartis
Pharms. Corp. v. Becerra, No. 24-cv-02234, 2024 WL
4492072 (D.D.C. Oct. 15, 2024). Novartis appealed.

-- 5 of 12 --

6
III
We review a grant of summary judgment de novo.
AstraZeneca Pharms. LP v. FDA, 713 F.3d 1134, 1138 (D.C.
Cir. 2013). Like the district court, we must consider whether
the FDA’s actions were “arbitrary, capricious, an abuse of
discretion, or otherwise not in accordance with law.” 5 U.S.C.
§ 706(2)(A). Under this standard, a discretionary agency
decision must be “reasonable and reasonably explained.” FCC
v. Prometheus Radio Project, 592 U.S. 414, 423 (2021). We
review de novo the FDA’s construction of the governing
statute. Loper Bright Enters. v. Raimondo, 603 U.S. 369, 412
(2024). However, we afford deference to the FDA’s
assessment of relevant scientific questions. Rempfer v.
Sharfstein, 583 F.3d 860, 867 (D.C. Cir. 2009).
On appeal, Novartis contends that the FDA (1) approved
labeling for the new, generic drug that impermissibly deviates
from the Entresto label and (2) unreasonably concluded that the
generic drug has the same active ingredients as Entresto.
IV
The FDCA generally requires the labeling for a generic
drug to be “the same” as that of its listed counterpart, but it
permits “changes required … because the new drug and the
listed drug are produced or distributed by different
manufacturers.” 21 U.S.C. § 355(j)(2)(A)(v). Such changes
include those made to accommodate active patents on certain
uses of the drug. 21 C.F.R. § 314.94(a)(8)(iv); see Caraco, 566
U.S. at 406. Here, all parties agree that the changes were
required to avoid infringement of Novartis’s patents. Novartis
contends that the changes are nonetheless unlawful.

-- 6 of 12 --

7
A
The first contested labeling change concerns omission of
the modified dosing regimen for patients not taking ACE
inhibitors or ARBs. Novartis objects that this omission renders
the generic version “less safe or effective” than Entresto itself,
in violation of 21 C.F.R. § 314.127(a)(7).
The FDA addressed this issue in denying Novartis’s 2022
citizen petition. It found that omitting the modified dosing
regimen “would not render [generic] drugs less safe or
effective than Entresto.” J.A. 354. The agency gave two
reasons for this conclusion. First, the evidence supporting the
modified dosing regimen was limited: It consisted of a single,
“uncontrolled” titration study, which suggested that patients
not taking ACE inhibitors or ARBs “might” have fewer side
effects if Entresto were administered with a lower initial dose
that would be gradually increased as tolerability improved over
time. Id. at 355 (emphasis in denial order). The FDA
concluded that this study did “not provide a scientific basis to
conclude” that the standard Entresto dosing regimen would put
any patients “at a greater risk of adverse reactions.” Id. at 356.
Second, the FDA stressed that the risk of adverse reactions
could be “adequately managed” through warnings, which
appear on the label of both Entresto and the generic. Id. at 356–
57. This analysis turns squarely on the FDA’s expertise in
evaluating the clinical significance of drug studies, which we
will not lightly second-guess. See Rempfer, 583 F.3d at 867.
Novartis objects that the FDA’s analysis in allowing the
generic drug to omit the modified dosage regimen from its label
cannot be reconciled with its approval of the regimen for
Entresto itself. Both decisions rested on the same titration
study. According to Novartis, either the results of that study
were robust enough to require inclusion of the modified

-- 7 of 12 --

8
regimen on both labels, or its results were inconclusive enough
to foreclose the inclusion on either label. Novartis is incorrect
about how the governing legal standards fit together. An initial
determination that Entresto is “safe” and “effective” with the
modified dosing regimen, 21 U.S.C. § 355(b)(1)(A)(i), does
not foreclose a later determination that the generic equivalent
is not “less safe or effective” without it, 21 C.F.R.
§ 314.127(a)(7). Moreover, the FDA’s assessment of the
titration study has not changed over time. In approving the
modified regimen for Entresto, the FDA concluded the study
“suggests” that patients not taking ACE inhibitors or ARBs
“might” benefit from a reduced risk of adverse effects. J.A.
331 & n.83 (FDA determination that “Novartis’s proposed
titration scheme seems reasonable and a longer titration period
with a starting dose of 50mg twice daily may reduce the risk
of” certain side effects “in patients previously on a low dose”
of an ACE inhibitor or ARB (cleaned up)); see also id. at 132,
221. The FDA further hedged in noting that Novartis’s titration
study included a “small number of subjects” which “limit[ed]
certain interpretation[s] of the data.” Id. at 356 n.182. And it
characterized the modified regimen not as the safest one, but as
merely one with “an acceptable safety profile.” Id. at 357
n.186. In sum, the FDA has always viewed the titration study
with a degree of skepticism, despite the prior approval, so there
is no unexplained change in the agency’s position.
B
The second labeling change at issue concerns a difference
in indications. The Entresto label states that the drug “is
indicated to reduce the risk of cardiovascular death and
hospitalization for heart failure in adult patients with chronic
heart failure. Benefits are most clearly evident in patients with
left ventricular ejection fraction (LVEF) below normal.” J.A.
41. The MSN label states that its generic tablets “are indicated

-- 8 of 12 --

9
to reduce the risk of cardiovascular death and hospitalization
for heart failure in adult patients with chronic heart failure and
reduced ejection fraction.” Id. at 67. Both parties agree that
the difference prevents the generic drug from infringing on
Novartis’s patent over use of the drug to treat heart failure in
patients with a preserved ejection fraction.
Novartis contends that the altered indication
impermissibly tracks the original, superseded Entresto label,
which had an indication only for patients with a reduced
ejection fraction. But in reviewing MSN’s proposed label for
the generic drug, the FDA plainly compared it to Entresto’s
current label. See Novartis, 2024 WL 4492072, at *7. And as
the FDA explains, it is entirely unsurprising that the label for a
generic drug would resemble a superseded version of the label
for its listed counterpart when the manufacturer of the brand-
name drug has secured a change in its label to add a patent-
protected use. In that circumstance, the generic’s tracking the
unamended label reflects the intended operation of a scheme
that permits the generic’s label to contain changes required
because the brand-name drug and the generic equivalent are
sold “by different manufacturers.” 21 U.S.C.
§ 355(j)(2)(A)(v). As explained above, those changes include
“omission of an indication … protected by patent.” 21 C.F.R.
§ 314.94(a)(8)(iv).
Novartis further objects that the indication for the generic
drug unlawfully added language, whereas the regulation allows
only omissions. What the regulation allows is the omission “of
an indication,” 21 C.F.R. § 314.94(a)(8)(iv) (emphasis added),
and that is precisely what the labeling change at issue here
accomplishes. The Entresto label indicates use for “heart
failure in adult patients with chronic heart failure,” thus
encompassing patients with preserved and reduced ejection
fractions. J.A. 41. The generic label indicates use for “heart

-- 9 of 12 --

10
failure in adult patients with chronic heart failure and reduced
ejection fraction.” Id. at 67. This label adds four words, but
does so to eliminate the patent-protected use of the drug to treat
patients with a preserved ejection fraction. Again, that is how
this scheme is supposed to work; an ANDA applicant may
“propose labeling for the generic drug that ‘carves out’ from
the brand’s approved label the still-patented methods of use.”
Caraco, 566 U.S. at 406.
V
Finally, Novartis challenges the FDA’s finding that
Entresto and the MSN generic have the same active
ingredients. This turns on whether the drugs contain the same
“salt” of the same “therapeutic moiety.” See 21 C.F.R.
§ 314.3(b). A “therapeutic moiety” is the part of a molecule
that causes the drug’s “physiological or pharmacological
action.” Id. And a “salt” is a chemical compound comprised
of an anion (a negatively-charged atom or group of atoms) and
a cation (a positively-charged atom or group of atoms), linked
by an ionic bond. See Novartis, 2024 WL 4492072, at *2 n.1.
In denying Novartis’s 2019 citizen petition, the FDA
explained its view that the active ingredients of Entresto are
sacubitril sodium and valsartan disodium, J.A. 161, which are
anionic forms of sacubitril and valsartan, respectively, bonded
to sodium cations, id. at 142–43. Novartis disputes that those
are the active ingredients of Entresto. Specifically, Novartis
contends that Entresto does not contain sacubitril sodium and
valsartan disodium as separate salts. Novartis points to
Entresto’s label, which reveals that the drug “contains a
complex comprised of anionic forms of sacubitril and valsartan

-- 10 of 12 --

11
[and] sodium cations.” Id. at 49 (emphasis added).2 According
to Novartis, the presence of this “complex” distinguishes
Entresto from MSN’s generic drug which, according to its
label, “contains anionic forms of sacubitril and valsartan, and
sodium cations” but not a complex. Id. at 68. Along the same
lines, Novartis points to the FDA’s original approval of
Entresto, which described the drug as containing a “co-crystal
… consisting of” sacubitril and valsartan anions and sodium
cations. FDA Ctr. for Drug Evaluation & Rsch., Office
Director Decisional Memo on NDA No. 207620 at 2 (July 7,
2015).
We are not persuaded. For one thing, longstanding FDA
regulations and guidance make clear that drugs can have the
same active ingredients even if they have different solid-state
physical forms or crystal structures. See Final Rule:
Abbreviated New Drug Application Regulations, 57 Fed. Reg.
17,950, 17,959 (Apr. 28, 1992) (only in “some cases” would
the FDA specify that “crystalline structure” is material to an
ingredient’s sameness); FDA, Guidance for Industry: ANDAs:
Pharmaceutical Solid Polymorphisms 5–6 (July 2007). For
another, the FDA convincingly applied that principle in
rejecting Novartis’s request to require generic drugs to have the
same co-crystal structure as Entresto. In essence, the FDA
reasoned that the co-crystal structure has nothing to do with
Entresto’s chemical composition or its pharmacological
effects. The FDA explained that, in Entresto’s co-crystal
structure, the sacubitril sodium and valsartan disodium
molecules “are not ionically bound” to one another. J.A. 143.
Moreover, the co-crystal “dissociates rapidly in vivo to
sacubitril and valsartan,” so “there is no systemic exposure” to
2 According to the FDA, a “complex” is a combined molecular
entity “formed by loose association involving two or more molecular
entities.” J.A. 142 n.7 (cleaned up).

-- 11 of 12 --

12
it. Id. at 143–44. And there is no evidence “demonstrating that
the physical form of the active ingredients in Entresto is known
to impact the safe or effective use of the drug.” Id. at 159.
Novartis’s objection gives us no reason to question the FDA’s
expert judgment regarding these scientific issues.
Affirmed.

-- 12 of 12 --