Details for Patent: 10,154,987

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Which drugs does patent 10,154,987 protect, and when does it expire?

Patent 10,154,987 protects EPANED and is included in one NDA.

This patent has three patent family members in three countries.

Summary for Patent: 10,154,987

Title:	Enalapril formulations
Abstract:	Provided herein are stable enalapril oral liquid formulations. Also provided herein are methods of using enalapril oral liquid formulations for the treatment of certain diseases including hypertension, heart failure and asymptomatic left ventricular dysfunction.
Inventor(s):	Gerold L. Mosher, David W. Miles
Assignee:	Azurity Pharmaceuticals Inc
Application Number:	US16/003,994
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,154,987
Patent Claim Types: see list of patent claims	Use; Formulation;

US Patent 10,154,987: Enalapril Oral Liquid Formulation Scope, Expiration, and Patent Landscape

US Patent 10,154,987 protects specified methods of treating hypertension, heart failure, and left ventricular dysfunction with a refrigerated, stable oral liquid enalapril formulation. The core formulation requires enalapril, citric acid, sodium citrate, sodium benzoate, water, and defined stability performance. Optional claim features include sucralose, pH of about 3.0 to 3.5, a pH of about 3.3, exclusion of mannitol and silicon dioxide, and storage stability for up to 24 months.

The patent is formulation-specific and method-of-treatment-based. It does not broadly cover every enalapril oral solution, every enalapril product, or the active ingredient itself. A competing product would face the greatest literal infringement risk if it uses the claimed excipient system, falls within the concentration ranges, and is marketed for one of the claimed cardiovascular indications.

What does US Patent 10,154,987 cover?

The patent covers four independent method claims:

Independent claim	Disease or condition	Formulation basis
Claim 1	Hypertension	Concentration-based formulation
Claim 13	Hypertension	Weight-percent-of-solids formulation
Claim 18	Heart failure	Concentration-based formulation
Claim 25	Left ventricular dysfunction	Concentration-based formulation

Each independent claim requires administration of a therapeutically effective amount of a stable oral liquid formulation. The formulation must contain:

• Enalapril or a pharmaceutically acceptable salt or solvate
• Citric acid
• Sodium citrate
• Sodium benzoate
• Water
• At least 95% of the initial enalapril amount after storage
• No more than 5% total impurities or related substances after storage

The required storage condition is approximately 5 ± 3° C., corresponding to refrigerated storage. The minimum stability period is 12 months in the independent claims, with dependent claims extending the requirement to 18 or 24 months.

The claims therefore combine composition limitations, analytical stability limitations, storage conditions, and therapeutic-use limitations. A formulation that matches the excipient ranges but is not administered to treat a claimed condition would not literally satisfy the method claims.

What are the key formulation limitations in US 10,154,987?

Concentration ranges in claims 1, 18, and 25

The core concentration-based formulation requires the following ranges:

Component	Claimed range
Enalapril or salt/solvate	About 0.6 to about 1.2 mg/mL
Citric acid	About 0.8 to about 3.5 mg/mL
Sodium citrate	About 0.1 to about 0.8 mg/mL
Sodium benzoate	About 0.7 to about 1.2 mg/mL
Water	Required
Enalapril remaining after storage	At least about 95%
Total impurities or related substances	No more than about 5%

The ranges are expressed using “about,” which creates potential interpretation issues at the boundaries. Courts generally assess the intrinsic evidence, prosecution history, specification, and technical meaning of the term. A formulation slightly outside a numerical range may still raise an infringement issue under the doctrine of equivalents, although prosecution history estoppel can limit that argument.

Weight-percent-of-solids ranges in claims 13 and 14

Claim 13 provides an alternative concentration framework:

Component	Claimed amount as weight percent of solids
Enalapril or salt/solvate	About 10% to about 25%
Citric acid	About 17% to about 47%
Sodium citrate	About 1% to about 11%
Sodium benzoate	About 3% to about 25%
Water	Required
Enalapril remaining after storage	At least about 95%
Total impurities or related substances	No more than about 5%

Claim 14 adds sucralose at about 8% to about 18% of solids.

These claims may capture formulations that satisfy the relative solids composition even if the final liquid concentration differs from a particular commercial presentation. The meaning of “solids” is commercially important. It may require exclusion of water and may create disputes regarding whether the calculation includes the active ingredient, buffer components, preservative, sweetener, or other dissolved materials.

Which dependent claims add the most commercial risk?

The most commercially significant dependent limitations are sucralose, pH, stability duration, and excipient exclusions.

Claim group	Added limitation	Commercial significance
2, 14, 19, 26	Sucralose	Captures a palatable pediatric or geriatric formulation profile
3, 15, 20, 27	No mannitol or silicon dioxide	Narrows the formulation and may distinguish earlier formulations
4, 16, 21, 28	pH about 3.0 to 3.5	Limits the acid-buffer system
5, 22, 29	pH about 3.3	Creates a narrower formulation target
6	At least 18 months refrigerated stability	Raises the performance burden
7, 17, 23, 30	At least 24 months refrigerated stability	Potentially significant for commercial shelf life
8, 9	Primary or secondary hypertension	Expands the hypertension indication
10	Blood pressure at least 140/90 mm Hg	Adds a patient-selection limitation
11	Elderly or child	Targets populations likely to use oral liquid dosage forms
12	Combination with specified antihypertensive classes	Broadens treatment setting
24	Congestive heart failure	Narrows the heart-failure claim
30	24-month stability for left ventricular dysfunction	Combines indication and long-term stability

The child and elderly limitations have practical relevance because oral liquids are often used when tablets are difficult to swallow or when pediatric dose flexibility is required. The claims, however, do not appear limited to a particular dose, container, measuring device, flavor, or administration volume.

How strong is the patent estate for enalapril oral liquid formulations?

The patent has meaningful formulation protection but a narrower scope than a composition-of-matter patent.

Strengths

1. The independent claims require a defined combination of active ingredient, buffer, preservative, water, and stability performance.
2. The claims cover three clinically relevant uses: hypertension, heart failure, and left ventricular dysfunction.
3. The claims include both absolute concentration ranges and relative solids ranges.
4. The 24-month stability claims may be difficult to avoid if a competitor uses essentially the same formulation and seeks a comparable refrigerated shelf life.
5. The claims expressly cover enalapril salts and solvates, potentially including enalapril maleate if supported by the specification.

Limitations

1. The claims do not cover enalapril generally.
2. They do not appear to cover tablets, capsules, powders, or dry suspensions that are reconstituted only immediately before use unless the resulting product satisfies the claimed liquid formulation and stability requirements.
3. They require a specific citric acid/sodium citrate buffer system.
4. They require sodium benzoate within a relatively narrow range.
5. They require refrigerated stability and specified impurity performance.
6. They are method claims, so infringement requires the claimed administration and therapeutic-use context.
7. A formulation using another preservative, another buffer, a different pH, or a materially different enalapril concentration may avoid literal infringement.

The estate is strongest against a directly substitutable commercial oral solution that uses the same excipient architecture. It is weaker against alternative dosage forms and alternative liquid formulations.

What formulations are protected by US 10,154,987?

A formulation is most likely within the literal scope if it has all of the following characteristics:

• Enalapril, enalapril maleate, or another covered salt or solvate
• Liquid dosage form for oral administration
• Citric acid and sodium citrate together
• Sodium benzoate
• Water
• Enalapril concentration between about 0.6 and 1.2 mg/mL, or the claimed solids percentages
• Refrigerated stability at approximately 5 ± 3° C.
• At least 95% enalapril remaining after the claimed storage period
• No more than 5% total impurities or related substances
• Treatment of hypertension, heart failure, or left ventricular dysfunction

The following features are optional under the dependent claims rather than mandatory under every claim:

• Sucralose
• pH of about 3.0 to 3.5
• pH of about 3.3
• Exclusion of mannitol
• Exclusion of silicon dioxide
• 18- or 24-month stability
• Pediatric or elderly use
• Combination therapy

A product can therefore infringe an independent claim without containing sucralose or having a pH of 3.3, provided the other limitations are met.

Does the patent cover enalapril maleate?

The claims cover “enalapril or a pharmaceutically acceptable salt or solvate thereof.” Enalapril maleate is the commercially established salt form of enalapril and would ordinarily be a principal candidate for coverage under that language, subject to the patent specification and claim-construction record.

The salt limitation does not eliminate the other requirements. Enalapril maleate in a tablet, a dry powder, or a liquid with a different preservative system would not automatically fall within the claims.

What is the likely patent expiration date?

US Patent 10,154,987 was issued on December 18, 2018. Its term is governed principally by the 20-year term measured from the earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers, and any patent-term extension. The patent appears to originate from a mid-2010s priority chain, placing the ordinary statutory expiration in the mid-2030s absent an earlier terminal disclaimer or other limiting event. The controlling expiration date should be taken from the USPTO Patent Center record and any Orange Book entry rather than calculated solely from the grant date. [1]

A grant date of 2018 does not mean the patent expires in 2038. US utility patents generally run from the effective filing date, not 20 years from issuance. [2]

What is the Orange Book status of US Patent 10,154,987?

The relevant FDA product context is enalapril maleate oral solution, including EPANED, an oral solution indicated for hypertension and certain cardiovascular uses. FDA Orange Book relevance depends on whether the patent was submitted for listing against the applicable approved drug product and whether FDA accepted the listing. [3]

The patent’s method claims correspond closely to approved-use categories associated with enalapril, but claim language alone does not establish that the patent is currently listed in the Orange Book. A listing may include an FDA use code narrower than the full scope of the patent claims. Orange Book analysis should distinguish:

• Patent ownership from Orange Book listing
• Patent expiration from regulatory exclusivity
• A listed method-of-use patent from a formulation patent
• The full claim scope from the use code submitted to FDA

The patent does not create new chemical-entity exclusivity for enalapril. Enalapril is an established ACE inhibitor, and any regulatory protection associated with a later oral solution would arise from the approved product, formulation, labeling, and listed patents rather than from the original active ingredient.

When does enalapril oral solution lose exclusivity?

Enalapril oral solution loses meaningful market exclusivity when all relevant regulatory exclusivities expire and a competing applicant can lawfully launch without infringing enforceable patents.

The principal barriers are:

Barrier	Relevance
FDA approval exclusivity	Depends on the approved product and regulatory pathway
Listed formulation or method patents	Can delay approval or launch through Hatch-Waxman procedures
Patent-term adjustment	May extend the nominal patent term
Paragraph IV litigation	Can trigger a 30-month stay under specified conditions
Pediatric exclusivity	May add six months to qualifying exclusivity or patent protection
Commercial formulation know-how	May delay a practical launch even after legal expiry

A generic oral solution applicant would typically evaluate whether its product is therapeutically equivalent to the reference listed drug and whether it must certify against Orange Book patents. A Paragraph IV certification alleges that a listed patent is invalid, unenforceable, or not infringed. If the patent holder brings suit within the statutory period, FDA approval may be stayed for up to 30 months, subject to statutory exceptions and court developments. [4]

What Paragraph IV challenges could target this patent?

A Paragraph IV challenge could attack the patent on several grounds.

Anticipation

A challenger could argue that a single prior-art reference discloses every element of an independent claim, including:

• The enalapril concentration
• Citric acid and sodium citrate amounts
• Sodium benzoate
• Water
• The oral liquid dosage form
• The claimed stability period
• The impurity threshold
• The claimed therapeutic use

The stability limitation may make anticipation more difficult if the prior art does not disclose the same storage condition and analytical result.

Obviousness

Obviousness would likely be the principal vulnerability. A challenger could combine prior art on:

• Enalapril oral liquids
• Citrate buffering
• Sodium benzoate preservation
• Acidic pH adjustment
• Sucralose sweetening
• Refrigerated storage
• Pediatric or geriatric liquid medicines

The patent holder would likely rely on the claimed stability profile, impurity control, excipient exclusions, and any unexpected results. Stability data can materially affect the obviousness analysis when the prior art does not reasonably predict the claimed performance.

Indefiniteness and written description

Potential issues include:

• The meaning of “about”
• The definition of “solids”
• The measurement method for total impurity or related substances
• The meaning of “stable”
• Whether the specification supports all combinations across the claimed ranges
• Whether all salts and solvates are adequately described

These issues are fact-dependent and require review of the full patent specification, prosecution history, and cited stability methods.

Which companies are most likely to challenge the patent?

Potential challengers would include manufacturers developing generic enalapril oral solution products, specialty pharmaceutical companies targeting pediatric cardiovascular medicines, and companies seeking an alternative to the reference oral solution.

The commercial incentive is greater for a competitor whose formulation is close to the patented product. A company using a materially different buffer, preservative, concentration, or dosage form may prefer a noninfringement strategy rather than a Paragraph IV validity challenge.

No specific active Paragraph IV litigation, settlement agreement, or district-court case can be established from the claim text alone. Such determinations require current USPTO, FDA, PACER, and Orange Book records. The patent should not be treated as litigated or settled without documentary confirmation.

What generic launch scenarios exist?

Scenario 1: Same formulation, same indication

This is the highest-risk scenario. A generic applicant using enalapril, citrate buffer, sodium benzoate, water, and the claimed concentration and stability parameters could face both patent-listing and infringement exposure.

Scenario 2: Same active ingredient, different preservative

Replacing sodium benzoate with another preservative may avoid literal infringement if sodium benzoate is absent. The alternative must still satisfy regulatory quality, microbial, palatability, and stability requirements.

Scenario 3: Same excipients, different concentration

A formulation outside the claimed enalapril, buffer, or preservative ranges may avoid literal infringement. The risk would depend on the degree of deviation, the prosecution history, and the availability of a doctrine-of-equivalents argument.

Scenario 4: Non-refrigerated or shorter-life product

A product that does not maintain the claimed stability at 5 ± 3° C. for at least 12 months may avoid the stability limitation. This strategy may create regulatory and commercial disadvantages if the reference product has a longer labeled shelf life.

Scenario 5: Tablet, capsule, or reconstituted product

A solid oral dosage form is outside the apparent formulation scope. A reconstituted suspension or powder product may also avoid the claims if it does not meet the claimed stable liquid formulation and storage requirements.

Scenario 6: Different therapeutic labeling

Because the claims are method claims, a product labeled only for an indication outside hypertension, heart failure, or left ventricular dysfunction may reduce inducement risk. This strategy is constrained if the FDA-approved labeling or physician use supports the patented indication.

How does this patent compare with broad enalapril patents?

US Patent 10,154,987 is narrower than an active-ingredient or broad composition patent. Enalapril’s basic pharmaceutical protection is long expired. The commercial value of this patent instead lies in a particular liquid formulation and its stability profile.

Patent type	Scope	Relevance to US 10,154,987
Active-ingredient patent	Enalapril molecule or broad salt coverage	Generally expired and not the focus here
Broad formulation patent	Broad oral liquid or excipient class	Potential prior art or blocking right
US 10,154,987	Specific enalapril liquid, buffer, preservative, stability, and use	Narrower but directly relevant to oral solution products
Method-of-use patent	Treatment of a specified disease or population	Integrated into every independent claim
Manufacturing patent	Process, mixing, filling, packaging, or preservation	Could create separate freedom-to-operate risk

A complete freedom-to-operate review must therefore examine related continuation, divisional, foreign, and family members, as well as independent patents covering the manufacturing process, container-closure system, and approved labeling.

What manufacturing and IP barriers remain after patent expiry?

The principal non-patent barriers include:

• Demonstrating chemical and microbiological stability
• Controlling enalapril degradation products
• Maintaining pH during shelf life
• Preserving the formulation without unacceptable toxicity or taste
• Establishing container compatibility
• Validating dosing accuracy for pediatric and geriatric patients
• Meeting FDA requirements for oral solution sameness or therapeutic equivalence
• Reproducing the reference product’s quality attributes
• Avoiding separate patents covering filling, packaging, or manufacturing

The absence of mannitol and silicon dioxide in certain dependent claims may reflect formulation-development choices rather than a complete manufacturing limitation. A competitor should not assume that omitting those excipients avoids the independent claims.

What is the patent’s overall strength?

The patent has moderate strength against close copies of the claimed refrigerated enalapril oral solution. Its strongest features are the combined excipient system and the defined stability and impurity requirements. Its scope is constrained by the need to prove the formulation, storage performance, and therapeutic administration.

The principal design-around opportunities are:

1. Use a different preservative.
2. Replace the citric acid/sodium citrate buffer.
3. Select a concentration outside the claimed ranges.
4. Use a solid dosage form or a differently constituted liquid.
5. Develop a formulation that does not satisfy the claimed stability parameters.
6. Pursue a therapeutic labeling strategy outside the claimed uses, where legally and regulatorily available.

The most important diligence items are the complete patent family, prosecution history, terminal disclaimer status, current patent term, Orange Book listing, FDA use code, and any active litigation or settlement.

Key Takeaways

• US Patent 10,154,987 is a formulation and method-of-treatment patent for stable oral liquid enalapril.
• Its four independent claims cover hypertension, heart failure, and left ventricular dysfunction.
• The core formulation requires enalapril, citric acid, sodium citrate, sodium benzoate, and water.
• The formulation must retain at least 95% enalapril and contain no more than 5% total impurities after refrigerated storage.
• Dependent claims add sucralose, pH limits, exclusion of mannitol and silicon dioxide, pediatric or elderly use, combination therapy, and 18- or 24-month stability.
• The patent is narrower than an active-ingredient patent but potentially important for a directly substitutable enalapril oral solution.
• The ordinary patent term appears to extend into the mid-2030s, subject to the official USPTO term calculation and any terminal disclaimer or adjustment.
• A generic using a different buffer, preservative, concentration, or dosage form may have meaningful design-around options.
• Orange Book listing, Paragraph IV activity, litigation, and settlement status must be verified from current FDA, USPTO, and court records.

Frequently Asked Questions

Does US Patent 10,154,987 cover all enalapril oral solutions?

No. It covers oral liquid formulations meeting the claimed ingredient ranges, stability requirements, and therapeutic-use limitations.

Is enalapril maleate likely covered by the patent?

Yes, enalapril maleate is a leading candidate for the claimed “pharmaceutically acceptable salt” language, provided the remaining formulation and method limitations are satisfied.

Can a generic avoid the patent by removing sucralose?

Usually, removal of sucralose would avoid only the sucralose-dependent claims. It would not avoid the independent claims if all independent-claim limitations remain present.

Does a 24-month shelf life automatically infringe the patent?

No. Shelf life alone is insufficient. The product must also satisfy the active, buffer, preservative, water, stability, impurity, and therapeutic-use limitations.

Is this patent a patent on EPANED itself?

The patent appears directed to the formulation and use of stable enalapril oral liquid, not to every aspect of the EPANED product. Product-specific regulatory and Orange Book status must be assessed separately from the patent claims.

References

1. United States Patent and Trademark Office. (2018). U.S. Patent No. 10,154,987, Stable liquid formulations of enalapril.
2. 35 U.S.C. § 154. Patent term.
3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. 21 U.S.C. § 355(j). Abbreviated applications and patent certifications.

Drugs Protected by US Patent 10,154,987

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Azurity	EPANED	enalapril maleate	SOLUTION;ORAL	208686-001	Sep 20, 2016	AB	RX	Yes	Yes						TREATMENT OF HYPERTENSION
Azurity	EPANED	enalapril maleate	SOLUTION;ORAL	208686-001	Sep 20, 2016	AB	RX	Yes	Yes						METHOD OF TREATING LEFT VENTRICULAR DYSFUNCTION
Azurity	EPANED	enalapril maleate	SOLUTION;ORAL	208686-001	Sep 20, 2016	AB	RX	Yes	Yes						METHOD OF TREATING HYPERTENSION
Azurity	EPANED	enalapril maleate	SOLUTION;ORAL	208686-001	Sep 20, 2016	AB	RX	Yes	Yes						METHOD OF TREATMENT OF HEART FAILURE
Azurity	EPANED	enalapril maleate	SOLUTION;ORAL	208686-001	Sep 20, 2016	AB	RX	Yes	Yes						TREATMENT OF HEART FAILURE

International Family Members for US Patent 10,154,987

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Brazil	112018068960
European Patent Office	3429581
World Intellectual Property Organization (WIPO)	2017161339