US Patent 11,135,192: Scope, Claims, Expiration, and Entresto Patent Landscape
US Patent 11,135,192 protects a method of treating heart failure with preserved ejection fraction, or HFpEF, using sacubitril/valsartan, the active combination in Entresto. Its central limitations are the specific drug combination, a 1:1 molar ratio, twice-daily dosing for at least 36 weeks, and dose levels corresponding to 50 mg, 100 mg, or 200 mg of the combination. Claim 1 requires improvement in left atrial structural measurements; claim 4 omits that outcome requirement and is therefore the broader independent claim.
The patent is a method-of-use patent rather than the principal composition-of-matter patent for sacubitril/valsartan. It is relevant to generic Entresto launch strategy, but it does not by itself prevent development of other HFpEF treatments, including SGLT2 inhibitors, mineralocorticoid receptor antagonists, or alternative renin-angiotensin system regimens.
What drug does US Patent 11,135,192 protect?
The compound identified in the claims is sacubitril, also known as AHU-377 or LBQ657 after conversion to its active metabolite. The claimed combination is sacubitril plus valsartan, marketed by Novartis as Entresto.
| Claim element |
Patent requirement |
Commercial interpretation |
| Active ingredient 1 |
Sacubitril or a pharmaceutically acceptable salt |
Neprilysin-inhibitor component |
| Active ingredient 2 |
Valsartan or a pharmaceutically acceptable salt |
Angiotensin II receptor blocker |
| Ratio |
1:1 molar ratio |
Matches the sacubitril/valsartan combination used in Entresto |
| Dose |
50 mg, 100 mg, or 200 mg |
Corresponds to total combination strengths |
| Administration |
Twice daily |
Entresto's standard dosing schedule |
| Treatment duration |
At least 36 weeks |
A long-term treatment limitation |
| Disease |
HF-PEF or HFpEF |
Heart failure with preserved ejection fraction |
| Claim 1 outcome |
Reduced left atrial volume, LAVI, or left atrial dimension |
Structural cardiac remodeling limitation |
| Claim 4 outcome |
No express reduction requirement |
Broader treatment claim |
The commercial strengths are generally labeled as 24/26 mg, 49/51 mg, and 97/103 mg of sacubitril/valsartan. Those strengths contain approximately 50 mg, 100 mg, and 200 mg of total active substances, respectively. The patent's dose language therefore maps closely to the labeled Entresto strength convention.
What are the independent claims in US Patent 11,135,192?
Claim 1: HFpEF treatment with a cardiac structural outcome
Claim 1 requires all of the following:
- A human patient in need of treatment.
- HFpEF, described in the patent as HF-PEF.
- Administration of sacubitril or a salt of sacubitril.
- Administration of valsartan or a salt of valsartan.
- A 1:1 molar ratio between the two components.
- A dose of 50 mg, 100 mg, or 200 mg.
- Twice-daily administration.
- Treatment for at least 36 weeks.
- Reduction in left atrial volume, left atrial volume index, or left atrial dimension.
The final limitation materially narrows claim 1. A party could administer the claimed combination to an HFpEF patient for the stated duration and dose, yet avoid literal infringement of claim 1 if the claimed left atrial measurement does not decrease. The outcome must be tied to the treatment method and supported by clinical or patient-specific evidence.
Claim 4: Broader HFpEF treatment claim
Claim 4 contains the same drug, dose, ratio, frequency, duration, and disease limitations but does not require reduction in left atrial volume, LAVI, or left atrial dimension.
Claim 4 is the principal commercial claim. A generic product label that directs use of sacubitril/valsartan in HFpEF at the claimed strengths and schedule could create a direct infringement theory even where the label does not expressly promise a reduction in atrial measurements.
The absence of an express biomarker or structural outcome limitation makes claim 4 more difficult to design around than claim 1. A product administered for less than 36 weeks, at a nonclaimed ratio, or for a disease population outside the claim may present a different analysis.
How do claims 2, 3, 5, and 6 affect patent scope?
Claims 2, 3, 5, and 6 are dependent claims directed to clinical outcomes.
| Claim |
Added limitation |
Scope effect |
| 2 |
Reduced plasma NT-proBNP concentration |
Narrows claim 1 |
| 3 |
Improved, stabilized, or delayed worsening of NYHA classification |
Narrows claim 1 |
| 5 |
Reduced plasma NT-proBNP concentration |
Narrows claim 4 |
| 6 |
Improved, stabilized, or delayed worsening of NYHA classification |
Narrows claim 4 |
These claims may be important in litigation because they provide narrower positions if a court limits the independent claims. NT-proBNP is a recognized heart-failure biomarker. NYHA classification is a clinical functional-status system, generally ranging from Class I to Class IV.
The dependent claims do not require a specific numerical biomarker reduction, a defined NYHA class transition, or a particular time point beyond the 36-week limitation inherited from the independent claim. That creates potential claim-construction issues concerning baseline measurements, statistical significance, and whether stabilization qualifies without measurable improvement.
What dose and formulation are protected by US Patent 11,135,192?
The patent protects use of the combination at total active-substance amounts of 50 mg, 100 mg, or 200 mg administered twice daily. It does not claim a particular tablet shape, excipient system, coating, dissolution profile, particle size, or manufacturing process in the claims provided.
The 1:1 molar-ratio limitation is central. Sacubitril and valsartan do not have identical molecular weights, so a 1:1 molar ratio is not the same as an equal-milligram ratio. The commercial 24/26 mg, 49/51 mg, and 97/103 mg presentations reflect the relevant molar relationship.
The claims cover:
- Immediate-release or other dosage forms if they deliver the claimed combination and meet the method limitations.
- Sacubitril and valsartan salts.
- Co-packaged or single-unit products, provided the administration meets the claim.
- Use of the combination at any of the three claimed total dose levels.
The claims do not expressly require:
- A tablet.
- The brand Entresto.
- A particular excipient.
- A specific dissolution profile.
- A specific treatment setting.
- Concomitant use of a diuretic or beta blocker.
- A particular ejection-fraction cutoff.
- A particular diagnostic test for HFpEF.
When does US Patent 11,135,192 expire?
US Patent 11,135,192 issued on October 5, 2021. Public patent records identify a priority date in December 2013 and an expiration date in December 2033, subject to any applicable patent-term adjustment or other statutory calculation. The patent is therefore positioned as a later-expiring use patent relative to older sacubitril/valsartan composition and formulation rights. (U.S. Patent No. 11,135,192, 2021; USPTO, n.d.)
| Event |
Date |
| Earliest reported priority |
December 20, 2013 |
| Patent issued |
October 5, 2021 |
| Reported expiration |
December 20, 2033 |
| Patent type |
Therapeutic method of use |
| Primary commercial product |
Entresto |
The 2033 date does not replace the earlier expiration of core composition patents. Generic entry depends on the full Orange Book and litigation profile, not on this patent alone.
What is the Orange Book status of US Patent 11,135,192?
US Patent 11,135,192 has been associated with the Entresto patent estate and is listed in FDA patent data for the product. The Orange Book separates patents covering the drug substance, drug product, and approved methods of use. Method-of-use listings can impose a regulatory obstacle even when a generic applicant seeks approval for a nonprotected indication through a section viii statement. (FDA, 2024a)
The practical effect depends on the generic applicant's proposed labeling:
- A Paragraph IV certification challenges the listed patent's validity, enforceability, or infringement.
- A section viii statement seeks approval with the patented use carved out.
- A full-label ANDA that includes the relevant HFpEF indication creates greater exposure under a method-of-use patent.
- A carved-out label may reduce risk if the remaining labeling does not encourage the patented use.
For method patents, the critical issue is whether the approved generic label will instruct physicians to administer sacubitril/valsartan for HFpEF using the claimed dose, ratio, frequency, and duration.
What Paragraph IV challenges affect Entresto?
Entresto has attracted generic competition because its core exclusivity depends on a combination of drug-substance, formulation, and method-of-use patents. Generic applicants have pursued ANDA strategies directed at sacubitril/valsartan tablets, and Novartis has used patent litigation to defend the product's remaining listed rights.
A Paragraph IV challenge to US Patent 11,135,192 would likely focus on:
- Obviousness of treating HFpEF with sacubitril/valsartan.
- Written description and enablement for the claimed 36-week treatment regimen.
- Whether the clinical data support the claimed atrial-volume and biomarker outcomes.
- Whether the dose language corresponds to the claimed molar ratio.
- Whether the proposed generic label induces infringement.
- Whether the patent claims an approved method sufficiently distinct from earlier heart-failure treatment disclosures.
A generic applicant may also argue that an ANDA label omits the patented method or that the label does not require administration for at least 36 weeks. Novartis would likely rely on the label, prescribing information, physician instructions, and foreseeable use to establish induced infringement.
The existence of an ANDA or Paragraph IV notice does not establish that the patent is invalid or that generic entry will occur. Litigation outcome and settlement terms determine the commercial launch date.
What patent litigation affects Entresto generic entry?
Entresto litigation has involved several Novartis patents, including patents directed to the sacubitril/valsartan combination, pharmaceutical compositions, and approved methods of use. The relevant litigation risk is cumulative because a generic applicant must overcome every enforceable patent that covers its proposed product or labeled use.
| Patent category |
Typical issue for generic entry |
| Composition patents |
Whether the active combination remains protected |
| Formulation patents |
Whether the proposed tablet infringes the claimed dosage form |
| Method-of-use patents |
Whether the label instructs the protected HFpEF treatment |
| Manufacturing patents |
Whether the generic process uses a protected route |
| Regulatory exclusivity |
Whether FDA approval is blocked independently of patent validity |
US Patent 11,135,192 is more important for full-label HFpEF approval than for a product approved only for other indications. A generic company pursuing a narrow indication may attempt a section viii carve-out. That strategy can fail if the FDA label still encourages the patented use or if the generic product is marketed with promotional materials that direct HFpEF treatment.
How strong is the patent estate for Entresto?
The Entresto estate is stronger as a portfolio than as a single-patent position. US Patent 11,135,192 has commercially relevant claim breadth because claim 4 omits the left-atrial outcome limitation. Its weaknesses are the narrow patient population, the defined 36-week duration, and the need to prove that the proposed labeling or conduct satisfies the HFpEF method.
| Strength factor |
Assessment |
| Product identification |
Strong; the claims map directly to sacubitril/valsartan |
| Dose coverage |
Strong for the three specified strengths |
| Ratio limitation |
Strong if the commercial product uses the claimed 1:1 molar ratio |
| Duration limitation |
Potential design-around and proof issue |
| Disease limitation |
Narrows exposure to HFpEF |
| Claim 4 |
Broadest and commercially most significant |
| Claim 1 |
Narrower due to left-atrial outcome requirement |
| Biomarker claims |
Useful fallback claims, but evidence-intensive |
| Formulation coverage |
Not provided by these claims |
| Manufacturing coverage |
Not provided by these claims |
The patent is more vulnerable to an abbreviated-label strategy than to a simple formulation substitution. Changing excipients or tablet coating would not necessarily avoid the method claims if the same combination is administered for the same indication, dose, ratio, frequency, and duration.
What generic launch scenarios exist for sacubitril/valsartan?
Full-label launch
A generic applicant seeks approval for HFpEF and other Entresto indications. This strategy creates the highest exposure to US Patent 11,135,192 and may lead to Paragraph IV litigation.
Section viii carve-out
The applicant removes the patented HFpEF use from its label while retaining nonprotected indications. This can reduce method-of-use risk but may limit market access and create induced-infringement disputes if the label or marketing materials still direct HFpEF use.
Post-expiration launch
The applicant waits until the relevant enforceable patents expire. This reduces litigation exposure but sacrifices earlier market entry.
Settlement-based launch
Novartis and a generic applicant agree to a licensed or otherwise authorized entry date. The economic value depends on the settlement date, exclusivity arrangements, supply terms, and whether the agreement covers all relevant Entresto patents.
Is there biosimilar risk for Entresto?
There is no biosimilar pathway for Entresto. Sacubitril/valsartan is a chemically defined small-molecule combination regulated through the ANDA pathway under section 505(j) of the Federal Food, Drug, and Cosmetic Act. Competitive risk comes from generic tablets, not biosimilars. (FDA, 2024b)
The principal regulatory questions are bioequivalence, pharmaceutical equivalence, labeling, patent certification, and any applicable exclusivity. A generic applicant does not need to reproduce Entresto's clinical efficacy trials in the manner required for a biosimilar to a biologic.
How does US Patent 11,135,192 compare with other Entresto patents?
US Patent 11,135,192 is narrower in subject matter than an original composition patent but later in time than many foundational rights.
| Patent type |
Main protection |
Relevance to 11,135,192 |
| Core combination patent |
Sacubitril plus valsartan |
Earlier, foundational product protection |
| Formulation patent |
Tablet composition or dosage form |
Separate infringement analysis |
| HFpEF method patent |
Treatment of preserved-EF heart failure |
Direct overlap with 11,135,192 |
| Biomarker or remodeling claim |
NT-proBNP or atrial-structure outcomes |
Narrower fallback protection |
| Manufacturing patent |
Preparation or processing method |
Relevant to API or tablet production |
A design-around that changes the formulation will not necessarily avoid US Patent 11,135,192. Conversely, a generic product that avoids the claimed HFpEF indication may avoid this patent while remaining exposed to composition or formulation patents.
What revenue exposure does the patent create?
The commercial exposure is tied to Entresto's large installed base in heart failure and to the growing use of sacubitril/valsartan in patients with preserved or mildly reduced ejection fraction. The patent does not block all heart-failure use. Its direct value is concentrated in the HFpEF segment and in the ability to keep a full-label generic competitor from entering that indication before the reported 2033 expiry date.
The most material business consequences are:
- Preserving branded HFpEF labeling.
- Limiting full-label generic substitution.
- Supporting settlement leverage in ANDA litigation.
- Extending portfolio protection beyond earlier composition rights.
- Maintaining differentiation against non-ARNI competitors through a patented remodeling and biomarker-based treatment method.
Key Takeaways
- US Patent 11,135,192 covers treatment of HFpEF with sacubitril/valsartan.
- The claimed regimen is 50 mg, 100 mg, or 200 mg twice daily for at least 36 weeks.
- The sacubitril and valsartan components must be administered in a 1:1 molar ratio.
- Claim 4 is the broadest independent claim because it does not require reduced left atrial volume or another structural outcome.
- Claim 1 requires reduction in left atrial volume, LAVI, or left atrial dimension.
- Claims 2, 3, 5, and 6 add NT-proBNP or NYHA outcomes.
- The patent is a method-of-use patent, not the foundational composition patent for Entresto.
- Public records identify an October 5, 2021 issue date and a reported December 20, 2033 expiration date.
- Generic risk is primarily an ANDA and Paragraph IV issue, not a biosimilar issue.
- A section viii carve-out may reduce exposure if the generic label omits the patented HFpEF use.
- The patent's commercial strength comes from claim 4 and its direct alignment with Entresto dosing.
FAQs About US Patent 11,135,192 and Entresto
Does US Patent 11,135,192 cover all uses of Entresto?
No. It covers a specified HFpEF treatment regimen. Other Entresto uses may be covered by separate patents or may fall outside this patent's disease, dose, duration, or method limitations.
Does reducing the dose below 36 weeks avoid the patent?
It may avoid literal infringement of the express duration limitation, but the complete label, actual use, and inducement theory must be assessed. The patent requires treatment for at least 36 weeks.
Is the 50 mg dose the same as Entresto 50 mg?
The patent's 50 mg, 100 mg, and 200 mg language refers to the total combination amount. Entresto is commonly labeled as 24/26 mg, 49/51 mg, and 97/103 mg, reflecting the sacubitril and valsartan component amounts.
Can a generic company market sacubitril/valsartan without infringing this patent?
Potentially, if its approved labeling and conduct avoid the claimed HFpEF method or another valid design-around applies. Separate composition, formulation, and manufacturing patents may still restrict launch.
Does US Patent 11,135,192 protect reduced NT-proBNP as a standalone treatment?
No. The NT-proBNP limitations appear in dependent claims and require the underlying HFpEF regimen of claims 1 or 4. They do not create an independent treatment claim detached from the sacubitril/valsartan dosing limitations.
References
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Food and Drug Administration. (2024a). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services. https://www.accessdata.fda.gov/scripts/cder/ob/
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Food and Drug Administration. (2024b). Abbreviated new drug application (ANDA): Generics. U.S. Department of Health and Human Services. https://www.fda.gov/drugs/types-applications/abbreviated-new-drug-application-anda
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Food and Drug Administration. (2024c). Entresto prescribing information. Novartis Pharmaceuticals Corporation. https://www.accessdata.fda.gov/drugsatfda_docs/label/
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U.S. Patent No. 11,135,192. (2021). Methods of treating heart failure with preserved ejection fraction. U.S. Patent and Trademark Office. https://patents.google.com/patent/US11135192B2
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U.S. Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation resources. https://www.uspto.gov/patents/laws/patent-term-adjustment-patent-term-extension and
