Drafting a Pharmaceutical Composition Claim Covering Later-Developed Combination Drugs Without Losing the Disclosure Requirement Challenge: In re Entresto,125 F.4th 1090 (Fed. Cir. 2025)

A. U.S. Patent No. 8,101,659

The 659 Patent stemmed from U.S. Provisional Patent Application No. 60/349,660 filed January 17, 2002, the earliest priority date the 659 Patent enjoys. ¹⁶ However, the expiring date of the 659 Patent is January 15, 2025, due to the grant of Patent Term Extension (“PTE”). ¹⁷

The 659 Patent specifically claims pharmaceutical compositions. ¹⁸ These compositions used to treat cardiac- and renal-related conditions contain two active ingredients: valsartan (or its pharmaceutically acceptable salts) and a neutral endopeptidase (“NEP”) inhibitor (or its pharmaceutically effective salts). ¹⁹ While the 659 Patent provides a laundry list of NEPs, only sacubitril or sacubitrilat (known as the active metabolite of the prodrug sacubitril) is recited in the claims. ²⁰

In addition, the 659 Patent explains that the invention uses a kit form combining two separate units: a valsartan pharmaceutical composition and a NEP inhibitor pharmaceutical composition. ²¹ The kit form is chosen because the invention requires valsartan and sacubitril to be administered at different dosage intervals. ²² Moreover, the dosage unit forms of either valsartan or sacubitril include tablets and capsules. ²³

Valsartan was approved in 1996 by the U.S. Food and Drug Administration (“FDA”) under Novartis’s label Diovan^® for treatment of hypertension. ²⁴ Valsartan is an angiotensin receptor blocker (“ARB”) preventing angiotensin II from binding to its receptor, so as to reduce the blood-vessel-constricting effects of angiotensin II. ²⁵ Angiotensin II, a naturally occurring hormone, participates in the renin–angiotensin–aldosterone system (“RAAS”) activated alongside the sympathetic nervous system to counter abnormalities in cardiac function in heart failure. ²⁶ However, the activation may prolong too much, which results in the progression of heart failure. ²⁷ As a result, valsartan functions to inhibit angiotensin II’s activity to minimize the negative effect of the activation. ²⁸

On the other hand, NEP inhibitors go through a mechanism of action not involving angiotensin to cause vasodilation and, therefore, to reduce blood vessel constriction. ²⁹ Before the 659 Patent’s earliest priority date, several NEP inhibitors were merely candidates for treating heart failure and hypertension. ³⁰ Among them was sacubitril. ³¹ However, sacubitril had never been administered to humans or tested in an animal model of hypertension and heart failure. ³²

Nevertheless, the 659 Patent asserts that “a combination of valsartan and a NEP inhibitor achieves greater therapeutic effect than the administration of valsartan [] or NEP inhibitors alone.” ³³ The therapeutic effect covers a wide range of hypertension and heart failure. ³⁴

B. Entresto^®

Although Novartis’s PTE application for the 659 Patent alleged that the 659 Patent covers Entresto^®, Entresto^® contains an active ingredient named LCZ696, which is chemically different from the disclosed invention of the 659 Patent. ³⁵ In LCZ696, valsartan and sacubitril are associated as a non-covalently bound complex. ³⁶ Contrarily, the 659 Patent merely describes a physical mixture of valsartan and sacubitril, where no non-covalent bonds exist between valsartan and sacubitril. ³⁷

Novartis’s scientists began experiments on the synthesis of valsartan–sacubitril complexes in March 2005 and finally created LCZ696 in January 2006. ³⁸ LCZ696 was the first complex of valsartan and sacubitril. ³⁹

In 2015, the U.S. Food and Drug Administration (“FDA”) approved Entresto^® for use of treating patients with chronic heart failure and a reduced ejection fraction. ⁴⁰ In 2021, relying on Novartis’s clinical study of Entresto^® involving patients with preserved ejection fractions, FDA approved Entresto^® treatment for patients with chronic heart failure generally. ⁴¹

Novartis’s FY2023 Annual Report published in 2024 showed about $45 billion of total global sales revenue of Entresto^®, including around $3 billion of those sales in the United States. ⁴² However, the report predicted that entry of Entresto^® generics would result in an 85–90% drop in Entresto^®’s sales within three months. ⁴³

A. Undisputed claim construction

In Entresto, claim 1 of the 659 Patent was a representative claim reciting: 1.

A pharmaceutical composition comprising: (i)

the AT 1-antagonist valsartan or a pharmaceutically acceptable salt thereof;

For purposes of claim construction, the Federal Circuit rephrased the “wherein” limitation as “wherein said [valsartan and sacubitril] are administered in combination.” ⁴⁵

At the district court, one group of certain defendants, MSN Pharmaceuticals, Inc., MSN Laboratories Private Ltd., and MSN Life Sciences Private Ltd. (collectively, “MSN”), argued that the “wherein” limitation should be construed merely as the administration of valsartan and sacubitril as two separate components. ⁴⁶ This construction was premised on the fact that MSN’s generic product, like Entresto^®, contains a complex of non-covalently bonded valsartan and sacubitril, specifically crystalline trisodium valsartan sacubitril (“TVS”). ⁴⁷ Had the district court accepted MSN’s interpretation, the district court would have found noninfringement of the 659 Patent. ⁴⁸

However, the district court embraced Novartis’s approach, giving the “wherein” limitation its plain and ordinary meaning. ⁴⁹ The district court reasoned that the specification did not limit the claimed invention solely to a form of separate compounds. ⁵⁰ The district court also relied on Novartis’s PTE application for the 659 Patent, stating that the 659 Patent covers Entresto^®. ⁵¹ Therefore, the “wherein” limitation was interpreted as “wherein said [valsartan and sacubitril] are administered in combination.” ⁵²

On appeal, MSN did not challenge the district court’s claim construction concerning the disputed limitation. ⁵³ Rather, both parties debated about the district court’s invalidity determination including whether the “wherein” limitation satisfied the disclosure requirement. ⁵⁴

B. Issue I: Written description

Regarding the written description issue, since valsartan–sacubitril complexes were unknown on the 659 Patent’s priority date, the district court opined that it was impossible to possess the complexes covered by the “wherein” limitation and, therefore, held that the 659 Patent failed to meet the written description requirement. ⁵⁵ However, the Federal Circuit disagreed. ⁵⁶

The Federal Circuit began with reaffirming that “[a] specification adequately describes an invention when it reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date.” ⁵⁷ The Federal Circuit also followed a traditional notion that “[t]he invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” ⁵⁸

While acknowledging that “the scope of what is claimed (and must be adequately described) is, in turn, determined through claim construction[,]” ⁵⁹ the Federal Circuit directly accepted the district court’s interpretation giving the “wherein” limitation “its plain and ordinary meaning: ‘wherein said [valsartan and sacubitril] are administered in combination.’” ⁶⁰ As a result, the Federal Circuit defined the question here as “whether the [659 Patent] describes what is claimed, viz., a pharmaceutical composition comprising valsartan and sacubitril administered ‘in combination.’” ⁶¹

To resolve the question, the Federal Circuit examined the specification of the 659 Patent. ⁶² The Federal Circuit identified three parts of the specification and found that “[these] disclosures (and more) plainly show that the inventors had possession of a pharmaceutical composition comprising valsartan and sacubitril administered ‘in combination.’” ⁶³ Consequently, the Federal Circuit opined that “[the claimed] invention is plainly described throughout the specification.” ⁶⁴

In addition, the Federal Circuit referred to MSN’s expert testimony admitting that the specification “adequately discloses administration of valsartan and sacubitril in combination as a physical mixture.” ⁶⁵ Therefore, the Federal Circuit held that “the claims are supported by an adequate written description.” ⁶⁶

Furthermore, in supporting its clarification that “[t]he issue is not whether the [659 Patent] describes valsartan–sacubitril complexes[,]” the Federal Circuit explained why the district court’s approach to the written description issue was incorrect in two aspects. ⁶⁷

First, the Federal Circuit reinstated that “[w]ritten description asks whether that which is claimed is adequately described.” ⁶⁸ While recognizing that a complexed form of valsartan and sacubitril had not been discovered until four years after the priority date of the 659 Patent, the Federal Circuit pointed out that the complexed form was not what is claimed. ⁶⁹ Thus, the Federal Circuit held that the omission of valsartan–sacubitril complexes in the specification “does not affect the validity of the patent.” ⁷⁰

Second, the Federal Circuit recalled its precedent, SRI Int’l v. Matsushita Elec. Corp. of Am., which opposed a judicial whim of construing a claim to cover or not cover an infringing product and promoted a procedure of first construing a claim without reference to an accused product and then subjecting that construed claim to infringement analysis. ⁷¹ Relying SRI Int’l, the Federal Circuit criticized the district court’s erroneous conflation of the distinct issues of patentability and infringement “led it astray in evaluating written description.” ⁷²

Therefore, the Federal Circuit concluded that the 659 Patent had “an adequate written description of what is claimed” and that the district court clearly erred in finding the disputed claims invalid for lack of written description. ⁷³

C. Issue II: Enablement

Regarding the enablement issue, the district court disregarded later-existing state of the art as proper evidence in the enablement analysis. ⁷⁴ Because MSN failed to prove that valsartan–sacubitril complexes were known or nascent technology on the 659 Patent’s priority date, the district court found that the disputed claims satisfied the enablement requirement. ⁷⁵

On appeal, the Federal Circuit upheld the district court’s approach to enablement. ⁷⁶ The Federal Circuit again clarified that “a specification must only enable the claimed invention.” ⁷⁷

The Federal Circuit affirmed the district court’s enablement determination in three aspects. ⁷⁸ First, the district court interpreted the claimed invention as “a composition in which valsartan and sacubitril are administered ‘in combination.’” ⁷⁹ Second, valsartan–sacubitril complexes were not what the 659 Patent claims, which was further supported by the fact that Novartis later got two patents disclosing a novel compound comprising non-covalently bound valsartan and sacubitril salts. ⁸⁰

Third, the district court properly found that as compared to the claimed invention, valsartan–sacubitril complexes belonged to a later-existing state of the art not considered in the enablement review. ⁸¹ The Federal Circuit specifically pointed to its predecessor’s opinion, In re Hogan, opposing “utiliz[ing] the patenting or publication of later existing improvements to ‘reach back’ and preclude or invalidate a patent on the underlying invention.” ⁸² By characterizing valsartan–sacubitril complexes as a “later-discovered [technology] which arguably may have improved upon the ‘basic’ or ‘underlying’ invention claimed in the [659 Patent],” the Federal Circuit opined that these complexes “cannot be used to ‘reach back’ and invalidate the asserted claims.” ⁸³

Therefore, since both parties did not debate whether the specification would have enabled the “wherein” limitation, the Federal Circuit agreed with the district court that the disputed claims were not invalid for lack of enablement. ⁸⁴

A. “Administered in combination” as a claim term

In Entresto, the disputed claim term may be precisely identified as “administered in combination” rather than “in combination.” The “wherein” limitation is read as “wherein said valsartan and sacubitril are administered in combination[.]” ⁸⁵ The phrase “in combination” is an adverbial phrase used to modify the passive verb “administered.” That is, a condition that valsartan and sacubitril are “in combination” is meaningful only when these two active ingredients are administered to patients.

“Administered in combination” as a claim term is not new to the Federal Circuit. ⁸⁶ For instance, the disputed claim in Duramed Pharmaceuticals, Inc. v. Watson Laboratories, Inc. (“Duramed claim”) recites:

A method of contraception in a female in need thereof the method comprising administering to the female a dosage comprising a combination of estrogen and progestin for a period of 84 consecutive days, followed by administration of a dosage consisting essentially of estrogen for a period of 7 consecutive days,

The Duramed claim is a method claim reciting a dosage regimen. ⁸⁸ “Dosage regimen” means “the modality of drug administration, including formulation, route of administration, drug dose, dosing interval, and treatment duration.” ⁸⁹ The Duramed claim includes every element of a dosage regimen.

On the other hand, disputed claim 1 of the 659 Patent in Entresto is a product claim which recites a pharmaceutical composition and contains a “dosage regimen” limitation, that is the “wherein” limitation. The “wherein” limitation provides how two active ingredients are administered to patients. However, the dosage regimen described in the “wherein” limitation is merely drug dose in a ratio form.

The “wherein” limitation may be treated as a functional element of a claim. The functional element is a term reciting “intended use.” ⁹⁰ Through the phrase “administered in combination,” the “wherein” limitation expresses how those two main ingredients, valsartan and sacubitril, work together to achieve the objective of the claimed pharmaceutical composition.

Use of “administered in combination” in a pharmaceutical composition claim to import a functional element also can be found in another example, U.S. Patent No. 8,183,295 (“295 Patent”) issued to Novartis, where claim 1 recites:

A pharmaceutical composition consisting of: (i)

150–500 mg aliskiren or a pharmaceutically acceptable salt thereof,

Unlike its counterpart in the 659 Patent, the “wherein” clause in the 295 Patent does not recite a dosage regimen but claims an improved therapeutic effect caused by the claimed combined administration of aliskiren, amlodipine, and hydrochlorothiazide. The “wherein” clause indicates that aliskiren, amlodipine, and hydrochlorothiazide collectively work better than each ingredient does alone.

However, one significant similarity between the 295 Patent and 659 Patent is that the 295 Patent also directs the invention to a kit of parts. ⁹² The disclosed kit comprises a renin inhibitor (e.g., aliskiren), a calcium channel blocker (e.g., amlodipine), and a diuretic (e.g., hydrochlorothiazide). ⁹³

A “kit” is a package containing physically separate items. ⁹⁴ For example, one disputed claim in Norian Corp. v. Stryker Corp. (“Norian claim”) recites:

A kit for preparing a calcium mineral, said kit consisting of:

at least one calcium source and at least one phosphoric acid source free of uncombined water as dry ingredients; and

The Norian claim has dry ingredients and a liquid solution which must be separated. Contrarily, a pharmaceutical composition claim usually comprises at least one active ingredient and several excipients (such as diluents and carriers) which are mixed together in a real drug product. ⁹⁶

Nevertheless, the 295 Patent and 659 Patent together demonstrate a claim drafting strategy allowing a pharmaceutical composition claim to cover a kit. That is, use of “administered in combination” in a wherein clause creates a functional element for binding those separate active ingredients together, so as to transform a kit into a pharmaceutical composition.

Entresto further indicates that a pharmaceutical composition claim based on a kit invention can satisfy the disclosure requirement through use of “administered in combination” as a claim term. Entresto also guides what needs to be stated in a specification.

Let’s assume that a kit comprises two separate active ingredients, L and Q. Under Entresto, several standardized statements are suggested as follows: (1)

The present invention relates to pharmaceutical combinations comprising L and Q and pharmaceutical compositions comprising them. ⁹⁷

B. Patent protection expansion to combination drugs

After Entresto, the district court in 2026 issued a decision barring MSN from adjudicating whether MSN’s generic drug infringed the 659 Patent due to issue preclusion. ¹⁰¹ Thus, Entresto may indicate a pharmaceutical composition claim for a kit-like drug product can utilize “administered in combination” as a claim term to expand the patent protection to later-developed combination drugs, for instance, Entresto^®.

However, the Federal Circuit in Entresto recognized a fact that “the [659 Patent] does not claim valsartan–sacubitril complexes[.]” ¹⁰² So, whether valsartan–sacubitril complexes infringe the 659 Patent remains questionable.

“A determination of infringement generally requires a two-step analysis—the court first determines the scope and meaning of the claims asserted, and then the properly construed claims are compared to the allegedly infringing device (for an apparatus claim) or allegedly infringing act (for a method claim).” ¹⁰³ Step 2 “requires a determination that every claim limitation or its equivalent is found in the accused device [or act].” ¹⁰⁴

In construing a claim, courts consult intrinsic evidence (i.e., the patent claims, specification, and prosecution history) and extrinsic evidence (e.g., expert and inventor testimony, dictionaries, and learned treaties) to give a disputed term its “ordinary and customary meaning.’’ ¹⁰⁵ “[T]he ordinary and customary meaning of a claim term is the meaning that the term would have to a person of ordinary skill in the art in question at the time of the invention, i.e., as of the effective filing date of the patent application.” ¹⁰⁶

As the Federal Circuit in Entresto criticized, “the district court erroneously conflated the distinct issues of patentability and infringement, which led it astray in evaluating written description.” ¹⁰⁷ Thus, step 1 should not ask whether the disputed claims of the 659 Patent cover administration of valsartan–sacubitril complexes. Rather, step 1 may focus on whether the disputed claims are limited to administration of valsartan and sacubitril as separate components as described in the specification.

Since Entresto suggests that the specification of the 659 Patent does not confine the “wherein” limitation to administration of valsartan and sacubitril as separate components, then step 2 asks whether administration of valsartan–sacubitril complexes falls within the “wherein” limitation. However, prior to the step-two analysis, construing the meaning of “said valsartan and sacubitril are administered in combination” may be necessary.

The term “administered in combination” may broadly suggest that the claimed valsartan and sacubitril are administered as a combination of valsartan and sacubitril. Then, the next question is whether a valsartan–sacubitril complex constitutes a combination of valsartan and sacubitril in a 1:1 ratio. The answer is likely yes.

The Federal Circuit’s predecessor in In re Chmiel has learned two definitions of “combination” from Hackh’s Chemical Dictionary of 1950: (1) “the union or mixing of two or more substances; to form a new substance”; (2) “[a] chemical reaction[, usually oxidation or reduction,] in which two elements combine and form a binary compound, or two binary compounds combine and form a complex compound.” ¹⁰⁸

A “valsartan–sacubitril complex” as a combination of valsartan and sacubitril fits the first definition. A valsartan–sacubitril complex comprises valsartan and sacubitril connected together through a non-covalent bonding to form a union thereof. ¹⁰⁹ Because of the non-covalent bonding, the structure of a valsartan–sacubitril complex is different from that of either valsartan or sacubitril, which then transforms the complex into a new substance.

Additionally, in a valsartan–sacubitril complex, two active ingredients are at a 1:1 molar ratio. ¹¹⁰ Therefore, the valsartan–sacubitril complex is a combination of valsartan and sacubitril in a 1:1 ratio. Administration of a valsartan–sacubitril complex is equal to administration of a combination of valsartan and sacubitril.

Because the “wherein” limitation is read on administration of valsartan–sacubitril complexes, the disputed claims of the 659 Patent are literally infringed by valsartan–sacubitril complexes. ¹¹¹ As a result, the 659 Patent offers protection not only on what is invented (i.e., a kit comprising valsartan and sacubitril as separate drugs for administration) but also on what will be invented (i.e., a valsartan–sacubitril complex as a combination drug).