Details for Patent: 11,058,667

Which drugs does patent 11,058,667 protect, and when does it expire?

Patent 11,058,667 protects ENTRESTO and is included in one NDA.

This patent has twenty-seven patent family members in fourteen countries.

Summary for Patent: 11,058,667

Title:	Sacubitril-valsartan dosage regimen for treating heart failure
Abstract:	The present invention relates to sacubitril-valsartan dosage regimens for the treatment of heart failure in a patient.
Inventor(s):	Adel Remond RIZKALA, Victor Chengwei Shi, Fabian CHEN
Assignee:	Novartis Pharmaceuticals Corp
Application Number:	US15/572,399
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 11,058,667
Patent Claim Types: see list of patent claims	Use; Compound;

US Patent 11,058,667: Scope, Claims, Expiration, Litigation and Entresto Patent Landscape

US Patent No. 11,058,667 protects a specific titration regimen for sacubitril/valsartan, marketed by Novartis as Entresto. The patent does not principally protect the molecule, the LCZ696 complex, or the tablet formulation. Its core protection is a method-of-treatment regimen for chronic heart failure with reduced ejection fraction that starts selected patients at 24/26 mg twice daily, increases the dose to 49/51 mg twice daily, and reaches 97/103 mg twice daily after a defined titration period.

The patent is commercially significant because its claims track the FDA-approved Entresto dosing instructions for patients who are not taking an ACE inhibitor or ARB, or who are taking a low dose of either drug. Public patent records identify Novartis AG as the patent owner and February 6, 2036, as the listed patent expiration date for the principal US patent term. The patent is listed in the FDA Orange Book for Entresto-related use protection. [1][2]

What does US Patent 11,058,667 protect?

US 11,058,667 protects a patient-specific dosing sequence rather than broad treatment of heart failure with sacubitril/valsartan.

The central regimen has these elements:

Claim element	Required limitation
Disease	Chronic heart failure with reduced ejection fraction
Patient	Human patient in need of treatment
Active treatment	Sacubitril plus valsartan
Molar relationship	1:1 sacubitril-to-valsartan ratio
Starting dose	50 mg total twice daily, corresponding to 24 mg sacubitril and 26 mg valsartan
Intermediate dose	100 mg total twice daily, corresponding to 49 mg sacubitril and 51 mg valsartan
Target dose	200 mg total twice daily, corresponding to 97 mg sacubitril and 103 mg valsartan
Patient selection	No prior ACE inhibitor or ARB, or low-dose ACE inhibitor/ARB use
Low-dose threshold	Less than 10 mg enalapril-equivalent per day
Titration	Defined intervals before reaching the target dose

The 50 mg, 100 mg and 200 mg figures are the total amounts of the sacubitril/valsartan combination per administration. They correspond to the strengths used in Entresto labeling, not to 50 mg, 100 mg and 200 mg of each individual active ingredient.

How do the claims define the Entresto dose strengths?

The patent uses the same strength convention as the approved product:

Combination strength stated in claim	Sacubitril component	Valsartan component
50 mg twice daily	24 mg	26 mg
100 mg twice daily	49 mg	51 mg
200 mg twice daily	97 mg	103 mg

The patent requires the components to be administered in a 1:1 molar ratio. A product or regimen using materially different amounts, a different ratio, or separate administration that does not preserve the claimed relationship could create noninfringement arguments. Those arguments would depend on claim construction, equivalence, prescribing instructions and the facts of the accused product.

How are independent claims 1 and 7 different?

Claims 1 and 7 are the two principal independent method claims.

Claim 1: three-to-four-week escalation periods

Claim 1 requires:

1. Starting at 50 mg twice daily for approximately three to four weeks.
2. Increasing to 100 mg twice daily for approximately three to four weeks.
3. Increasing thereafter to 200 mg twice daily.

The claim covers two patient categories:

• A patient not previously taking an ACE inhibitor or ARB.
• A patient taking a low dose of an ACE inhibitor or ARB equivalent to less than 10 mg of enalapril per day.

Claim 2 narrows claim 1 to approximately three weeks at each of the first two dose levels.

Claim 7: broader interval ranges with a six-week minimum

Claim 7 requires:

1. 50 mg twice daily for approximately two to four weeks.
2. 100 mg twice daily for approximately two to four weeks.
3. 200 mg twice daily thereafter.
4. A total titration period of at least approximately six weeks.

Claim 8 narrows this sequence to approximately three weeks at each lower dose.

Claim 7 is potentially broader than claim 1 with respect to the individual titration intervals because it expressly allows two-week periods. It is narrower in another respect because it requires the overall titration to last at least about six weeks.

The claim set creates substantial overlap. A regimen involving three weeks at 50 mg, three weeks at 100 mg, and then 200 mg may fall within both claim 1 and claim 7, assuming the other limitations are satisfied.

What patient characteristics are protected?

Claims 4, 5, 6, 9, 10 and 11 add clinical eligibility criteria.

Claim limitation	Threshold
BNP	At least 100 pg/mL, or NT-proBNP at least 400 pg/mL
Alternative BNP criterion	At least 150 pg/mL, or NT-proBNP at least 600 pg/mL
Cardiac function	LVEF of 35% or less

These limitations are dependent claims. The independent claims do not require elevated BNP, elevated NT-proBNP or LVEF of 35% or less unless a dependent claim is asserted.

From an enforcement perspective, the dependent claims are narrower and may be useful where clinical records establish the biomarker or LVEF thresholds. They are less likely to capture every patient receiving the claimed dose escalation.

What is the significance of the 36-hour washout requirement?

Claims 3 and 12 require the patient to stop the ACE inhibitor or ARB at least 36 hours before beginning sacubitril/valsartan treatment.

The ACE-inhibitor washout limitation reflects the safety concern associated with concomitant neprilysin and ACE inhibition, particularly angioedema risk. FDA labeling for Entresto also instructs that the product must not be administered with an ACE inhibitor and requires a 36-hour interval between discontinuation of an ACE inhibitor and initiation of Entresto. [3]

The claim language presents a potential distinction:

• A patient switching from an ACE inhibitor and observing the 36-hour interval may satisfy the limitation.
• A patient switching from an ARB may not necessarily require the same interval under the FDA label, but the patent claim expressly includes an ARB or ACE inhibitor in the washout limitation.
• A regimen that begins Entresto without documenting the required washout could present a defense to infringement of claims 3 or 12, although it would not necessarily avoid claims 1 or 7.

What does claim 18 and claim 19 add?

Claims 18 and 19 specify administration of LCZ696, the compound name historically used for the sacubitril/valsartan combination.

These claims connect the regimen to the trisodium hemipentahydrate complex:

"trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-(pentanoyl{2''-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate] hemipentahydrate."

The practical scope is narrower than claims 1 and 7 because the treatment must be administered as LCZ696. These claims may be easier to map to an Entresto product but less useful against a materially different pharmaceutical presentation that delivers the two active agents separately while preserving the claimed dose ratio.

When does US Patent 11,058,667 lose exclusivity?

The reported patent expiration date is February 6, 2036. [1][2] The relevant term may be affected by patent-term adjustment, terminal-disclaimer provisions, regulatory listing changes or later legal events. The Orange Book listing is the more commercially relevant date for ANDA litigation because it identifies the patent information submitted by the NDA holder for the approved product.

The patent’s 2036 date is separate from earlier composition and formulation patents associated with Entresto. A generic company may face different risk depending on:

• Whether it challenges only the 2036 method patent.
• Whether earlier Entresto patents remain enforceable.
• Whether its proposed label includes the patented titration instructions.
• Whether it seeks a Paragraph IV certification.
• Whether the brand company asserts additional patents after ANDA filing.

What is the Orange Book status of Entresto?

Entresto is approved by FDA under NDA 207620. Novartis Pharmaceuticals Corporation is the listed applicant for the product. The FDA-approved product contains sacubitril and valsartan and is indicated for heart failure treatment, including chronic heart failure with reduced ejection fraction in adults. [3][4]

Public Orange Book records have identified US 11,058,667 among the patents associated with Entresto. The listed patent covers a method of use rather than a basic chemical composition. This distinction affects ANDA strategy:

• A generic applicant can challenge the patent through a Paragraph IV certification.
• A generic applicant can seek a section viii statement that it will omit the patented method from its label, if the remaining label remains legally approvable.
• If the FDA-approved label necessarily directs use of the patented titration regimen, a section viii strategy becomes more difficult.
• A carved-out label may reduce infringement exposure but can also limit the commercial indication and prescribing instructions available to the generic product.

The FDA label itself describes initiation at 24/26 mg twice daily for patients not taking an ACE inhibitor or ARB and for patients previously taking low doses of those drugs. The label recommends doubling the dose every two to four weeks as tolerated to reach 97/103 mg twice daily. [3]

Which earlier patents cover sacubitril/valsartan?

The Entresto patent estate includes multiple categories of protection.

Patent category	Representative US patent	Subject matter
Composition and pharmaceutical product	US 8,877,938	Sacubitril/valsartan pharmaceutical composition and related product protection
Additional product or use protection	US 9,278,096	Entresto-related pharmaceutical and therapeutic claims
Dosing regimen	US 11,058,667	Patient selection and titration to 97/103 mg twice daily
Later continuation or related claims	Additional issued patents and applications	Potentially overlapping use, formulation or administration claims

The earlier patents are generally more important for the chemical product and tablet itself. US 11,058,667 is important because it targets the approved titration protocol and may remain in force after earlier composition patents expire.

Patent-number and expiration-date analysis must distinguish:

• The patent’s nominal expiration.
• Any patent-term adjustment.
• Any terminal disclaimer.
• Orange Book listing status.
• The asserted claims after litigation.
• The approved labeling in effect when an ANDA is filed.

How strong is the patent estate for Entresto?

The estate is strongest where a generic product must use the FDA-approved dosing instructions.

Strengths

The claims contain numerous objective limitations:

• Exact dose levels.
• Exact component amounts.
• A defined molar ratio.
• Defined treatment intervals.
• Specific patient history involving ACE inhibitors and ARBs.
• A target dose that matches the marketed product.
• A six-week minimum in claim 7.

These limitations can make infringement analysis relatively concrete. The commercial product and its label also provide a direct evidentiary framework.

The patent has a strong label-based enforcement profile if the generic label instructs physicians to initiate therapy at 24/26 mg twice daily and titrate to 97/103 mg twice daily over the claimed period.

Weaknesses and defenses

The same specificity creates validity and noninfringement issues.

A challenger may argue that:

• The dosing sequence was obvious in view of clinical development data and the known Entresto dose strengths.
• The claim limitations merely describe routine titration for tolerability.
• The clinical thresholds lack a meaningful therapeutic distinction.
• The phrase "about" makes the scope indefinite or fact-dependent.
• The patient-selection criteria were disclosed in the prior art.
• The accused label does not require every claimed interval.
• Actual physician prescribing does not follow the claimed sequence.
• Separate administration of sacubitril and valsartan does not meet the claimed product limitation in claims 18 and 19.

The patent’s best commercial claims are likely claims 1, 2, 7 and 8 because they map most closely to the standard dosing protocol. Claims 4 through 6 and 9 through 11 have narrower coverage based on biomarkers and LVEF.

What Paragraph IV challenges and litigation affect Entresto?

An ANDA applicant seeking approval before the expiration of an Orange Book patent can submit a Paragraph IV certification asserting that the patent is invalid, unenforceable or not infringed. The certification can trigger a Hatch-Waxman action and a 30-month FDA approval stay under the statutory framework. [5]

Entresto has been the subject of generic competition and patent disputes involving multiple ANDA applicants. Public litigation reporting and court records have identified challenges involving generic manufacturers including Teva, Dr. Reddy’s Laboratories, Mylan/Viatris, Lupin, Zydus, Alembic and related applicants. The asserted patent mix can differ by defendant and filing date. Composition patents, formulation patents and method-of-use patents should not be treated as a single litigation issue.

For US 11,058,667, the key litigation questions are:

1. Whether the ANDA label directs the claimed titration regimen.
2. Whether the applicant uses a section viii carve-out.
3. Whether the generic label includes the low-dose ACE inhibitor/ARB population.
4. Whether the proposed product is the LCZ696 complex or another presentation.
5. Whether Novartis asserts direct, induced or contributory infringement.
6. Whether the defendant challenges validity based on obviousness, anticipation, written description or indefiniteness.

A settlement agreement could permit an earlier generic launch while preserving the patent’s formal expiration date. The existence of a settlement does not by itself establish that the patent claims are valid or infringed. The commercial launch date depends on the settlement terms, FDA approval, pediatric exclusivity, other Orange Book patents and any court injunction.

What formulation patents protect Entresto?

US 11,058,667 is not primarily a formulation patent. Its protection is directed to the therapeutic regimen.

Formulation and product patents in the Entresto estate may address:

• The combined sacubitril/valsartan pharmaceutical composition.
• The LCZ696 salt complex.
• Solid-state or hydrate characteristics.
• Tablet composition.
• Stability and manufacturing parameters.
• The relative amounts of the two active components.

A generic manufacturer can face formulation risk even if it designs around the dosing patent. Conversely, a product that avoids a formulation claim may still infringe a dosing claim if its label directs the patented regimen.

What manufacturing and geographic barriers remain?

The patent is a US right. It does not directly block manufacturing, sale or use outside the United States. International risk depends on corresponding national patents and the local regulatory framework.

The main US barriers are:

• Orange Book-listed composition patents.
• Orange Book-listed method-of-use patents.
• FDA approval timing.
• ANDA certification strategy.
• Clinical-label carve-out constraints.
• Manufacturing ownership or licensing requirements.
• Potential infringement based on the proposed product label.

Manufacturing around US 11,058,667 is more feasible than manufacturing around a composition patent because the patent does not broadly claim the active ingredients or the tablet manufacturing process. The principal barrier is regulatory and label-based, not necessarily chemical synthesis.

How does US 11,058,667 compare with the core Entresto patents?

Issue	US 11,058,667	Earlier composition/formulation patents
Primary protection	Patient selection and titration	Product, composition or formulation
Product-specific	Partly, especially claims 18 and 19	Usually more directly product-specific
Label relevance	Very high	High
Design-around potential	Change dose sequence, intervals or label	More difficult if product requires the claimed composition
Commercial expiration	Reported February 6, 2036	Earlier dates reported for principal patents
Main validity issue	Obviousness of dosing regimen	Novelty, obviousness, composition and formulation scope
Generic strategy	Paragraph IV or section viii	Paragraph IV, formulation design-around or delayed launch

Key Takeaways

• US 11,058,667 is a method-of-treatment patent covering sacubitril/valsartan titration in chronic heart failure with reduced ejection fraction.
• The core regimen progresses from 24/26 mg twice daily to 49/51 mg twice daily and then to 97/103 mg twice daily.
• Claims 1 and 7 are the principal independent claims.
• Claim 1 uses three-to-four-week intervals; claim 7 permits two-to-four-week intervals but requires at least six weeks overall.
• The patent targets patients who are ACE-inhibitor/ARB naïve or taking less than 10 mg enalapril-equivalent per day.
• Claims 3 and 12 add a 36-hour washout requirement.
• Claims 18 and 19 narrow the regimen to LCZ696.
• The reported US expiration date is February 6, 2036.
• The patent is commercially important because its dosing claims track the FDA Entresto label.
• Generic applicants may pursue Paragraph IV litigation, a section viii carve-out, a label modification or a settlement-based launch.
• Earlier composition and formulation patents create separate risks and must be analyzed independently.

FAQs About US Patent 11,058,667 and Entresto Exclusivity

Does US 11,058,667 cover all uses of sacubitril/valsartan?

No. It covers specified dosing regimens for chronic heart failure with reduced ejection fraction and selected patient populations. It does not broadly claim every use of sacubitril/valsartan.

Can a generic avoid US 11,058,667 by using a two-week titration schedule?

Potentially, but not automatically. Claim 7 expressly permits approximately two-to-four-week intervals, subject to the overall six-week minimum. A two-week schedule may still fall within claim 7.

Does the patent cover separate sacubitril and valsartan tablets?

Claims 1 and 7 focus on administering the agents in a 1:1 molar ratio and do not necessarily require the LCZ696 complex. Claims 18 and 19 expressly require LCZ696, making those claims narrower.

Is the 36-hour washout required by every claim?

No. The washout requirement appears in claims 3 and 12. It is not a limitation of independent claims 1 and 7.

Does biosimilar law apply to Entresto?

No. Entresto is a small-molecule drug, not a biologic. Generic competition proceeds through the ANDA pathway rather than the biosimilar pathway under the Public Health Service Act.

References

1. United States Patent and Trademark Office. (2021). US Patent No. 11,058,667, Methods of treating heart failure.
2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. Novartis Pharmaceuticals Corporation. (2024). Entresto (sacubitril and valsartan) prescribing information. U.S. Food and Drug Administration.
4. U.S. Food and Drug Administration. (2015). NDA 207620: Entresto approval letter and prescribing information.
5. United States Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585.

Drugs Protected by US Patent 11,058,667

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Novartis Pharms Corp	ENTRESTO	sacubitril; valsartan	TABLET;ORAL	207620-001	Jul 7, 2015	AB	RX	Yes	No						TREATING CHRONIC HEART FAILURE WITH REDUCED EJECTION FRACTION IN PATIENTS NOT TAKING AN ACE INHIBITOR OR AN ARB OR PREVIOUSLY TAKING LOW DOSES OF THESE AGENTS, BY TITRATING UP FROM HALF THE USUALLY RECOMMENDED STARTING DOSE
Novartis Pharms Corp	ENTRESTO	sacubitril; valsartan	TABLET;ORAL	207620-002	Jul 7, 2015	AB	RX	Yes	No						TREATING CHRONIC HEART FAILURE WITH REDUCED EJECTION FRACTION IN PATIENTS NOT TAKING AN ACE INHIBITOR OR AN ARB OR PREVIOUSLY TAKING LOW DOSES OF THESE AGENTS, BY TITRATING UP FROM HALF THE USUALLY RECOMMENDED STARTING DOSE
Novartis Pharms Corp	ENTRESTO	sacubitril; valsartan	TABLET;ORAL	207620-003	Jul 7, 2015	AB	RX	Yes	Yes						TREATING CHRONIC HEART FAILURE WITH REDUCED EJECTION FRACTION IN PATIENTS NOT TAKING AN ACE INHIBITOR OR AN ARB OR PREVIOUSLY TAKING LOW DOSES OF THESE AGENTS, BY TITRATING UP FROM HALF THE USUALLY RECOMMENDED STARTING DOSE

Foreign Priority and PCT Information for Patent: 11,058,667

PCT Information
PCT Filed	May 09, 2016	PCT Application Number:	PCT/IB2016/052633
PCT Publication Date:	November 17, 2016	PCT Publication Number:	WO2016/181284

International Family Members for US Patent 11,058,667

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Cyprus	1126036
Denmark	3294283
Denmark	4212152