US Patent 5,403,856: Scope, Claims, Expiration, and Perindopril Patent Landscape

US Patent 5,403,856 protects the use of stereochemically pure perindopril and closely defined related compounds for treating cardiac insufficiency, including administration at a sub-antihypertensive dose. The patent is expired and no longer blocks generic perindopril development or marketing. Its principal commercial significance was as a method-of-use patent layered on top of earlier composition-of-matter and process protection for perindopril.

What does US Patent 5,403,856 cover?

US 5,403,856 covers a method of treating cardiac insufficiency by administering a defined angiotensin-converting enzyme inhibitor, or a pharmaceutically acceptable salt, to a mammal in recognized need of treatment.[1]

The patent's technical scope is centered on:

A substituted amino-acid ACE inhibitor of Formula I.
An octahydrocyclopenta[b]pyrrole ring system.
A phenyl-containing side chain.
Specified stereochemistry, with all chiral centers in the S configuration.
A product substantially free of other isomers.
Use for cardiac insufficiency rather than merely hypertension.
Oral or parenteral administration.
Administration with an excipient or other pharmaceutical carrier.
Administration at a sub-anti-hypertensive dose.

The claimed compounds correspond principally to perindopril and perindoprilat.

What compounds are identified in the claims?

Claim	Compound or limitation	Commercial relevance
1	Formula I ACE inhibitors with the specified substituents and all-S stereochemistry	Genus claim covering perindopril-type compounds
2	N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid or salt	Perindopril, generally administered as a salt such as perindopril erbumine
3	N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid or salt	Perindoprilat, the active diacid metabolite
4	Oral or parenteral administration	Covers tablets, capsules, solutions, injections, and similar routes
5	Administration with an excipient or pharmaceutically acceptable organic or inorganic substance	Covers conventional pharmaceutical compositions
6	Administration in a sub-anti-hypertensive dose	Targets cardiac-insufficiency treatment without requiring a blood-pressure-lowering dose

The claim text contains OCR-style formatting errors, including the representation of the bicyclic ring as "2-azabicyclo[3.3.0]octane." The chemical identity is clear from the structure and nomenclature.

How should claim 1 be construed?

Claim 1 is a combination of chemical-structure and method-of-treatment limitations. A practicing product would need to satisfy both categories.

Chemical limitations

The claimed inhibitor must have:

The specified Formula I framework.
A phenyl group at R.
Methyl substitution at R1.
Hydrogen, methyl, ethyl, or benzyl at R2.
Hydrogen at R3.
A fused octahydrocyclopenta[b]pyrrole ring system formed by R4 and R5.
All chiral centers in the S configuration.
Substantial freedom from other isomers.

These limitations exclude many otherwise related ACE inhibitors. Enalapril, ramipril, lisinopril, captopril, and quinapril do not fall within the claim merely because they are ACE inhibitors used in cardiovascular disease. They have materially different structures or stereochemical arrangements.

Therapeutic limitations

The compound must be administered:

To a mammal.
To a patient in recognized need of treatment.
For the purpose of treating cardiac insufficiency.
In an amount effective for that treatment.

The claim therefore does not read on every administration of perindopril. Administration for hypertension alone would not satisfy the express cardiac-insufficiency purpose limitation, although a product label or promotional materials could create inducement issues during the patent term if they encouraged the claimed use.

What do claims 2 and 3 protect?

Claim 2: perindopril

Claim 2 narrows claim 1 to the ethyl ester form of the compound. This is perindopril, commonly formulated as perindopril erbumine in the US product Aceon.

The claim requires the specified S stereochemistry and does not cover a racemic or materially contaminated isomeric preparation. A perindopril salt can still fall within the claim because the claim expressly includes pharmaceutically acceptable salts.

Claim 3: perindoprilat

Claim 3 covers the corresponding carboxylic acid, perindoprilat. Perindopril is an ester prodrug that is hydrolyzed in vivo to perindoprilat, the pharmacologically active ACE-inhibiting species.

This claim is narrower than claim 1 in compound identity but has practical importance because it reaches administration of perindoprilat itself, whether as the free acid or a pharmaceutically acceptable salt.

Does the patent cover perindopril arginine?

The claims expressly cover pharmaceutically acceptable salts of the claimed compound. Perindopril arginine would require separate analysis of the specific salt, product composition, and claim construction. The broad salt language creates a strong basis for treating an eligible perindopril salt as within claims 1 or 2, subject to the expired status of the patent.

What is the significance of the "substantially free of other isomers" limitation?

The isomer-purity language is a central limitation. It distinguishes the claimed products from racemic mixtures and preparations containing substantial quantities of unwanted stereoisomers.

The phrase does not necessarily require absolute stereochemical purity. "Substantially free" generally creates a factual issue concerning the amount and identity of contaminating isomers. Relevant evidence would include:

Chiral HPLC results.
Enantiomeric or diastereomeric purity specifications.
Manufacturing batch records.
Certificate-of-analysis data.
The analytical method used to quantify stereoisomers.
Regulatory specifications for the finished product and active ingredient.

For generic manufacturers, this limitation would have been commercially significant before expiration because modern perindopril manufacturing ordinarily seeks high stereochemical purity. After expiration, it remains a quality and regulatory issue but no longer creates prospective patent exclusion.

What does claim 6 add?

Claim 6 requires administration at a "sub-anti-hypertensive dose." This limitation narrows the method to treatment intended to address cardiac insufficiency without necessarily producing the dose-dependent blood-pressure reduction associated with conventional antihypertensive therapy.

The limitation has two consequences:

It narrows literal infringement to a dosage regimen below the level considered antihypertensive.
It creates proof issues concerning dosage, patient response, treatment objective, and prescribing instructions.

A label that recommends only standard antihypertensive dosing would present a weaker claim 6 risk than a label expressly recommending low-dose therapy for heart failure or cardiac insufficiency. The claim does not, however, require a fixed milligram amount. Its scope depends on the relationship between dose, patient, and antihypertensive effect.

When did US Patent 5,403,856 expire?

US Patent 5,403,856 issued on April 4, 1995.[1] It is a pre-URAA patent subject to the former 17-year term measured from grant, absent a later effective terminal disclaimer or patent-term adjustment.

Event	Date
Patent issued	April 4, 1995
Ordinary 17-year term from grant	April 4, 2012
Current status	Expired
Current enforcement risk	No prospective infringement injunction based on this patent

The patent therefore cannot block a new generic launch today. Any historical damages theory would require proof of infringing conduct occurring before expiration and would be subject to the applicable statutory, equitable, and litigation limitations.

The patent's expiration is separate from the expiration of earlier perindopril composition-of-matter patents and later patents directed to salts, formulations, manufacturing processes, or other uses.

What was the relationship between this patent and earlier perindopril patents?

US 5,403,856 appears to be a use patent layered over earlier perindopril compound protection. A key earlier US patent associated with perindopril-type compounds is US 4,914,214, which covers octahydroindole carboxylic acid derivatives and related ACE-inhibitor chemistry.[2]

The patent estate can be divided into several layers:

Protection layer	Typical subject matter	Relevance to US 5,403,856
Composition of matter	Perindopril and related ACE inhibitors	Earlier protection for the active molecule
Stereochemistry	Specific enantiomers and diastereomers	Supports purity and product identity
Processes	Synthesis, resolution, purification, and salt formation	Manufacturing barriers
Formulations	Tablets, dosage forms, stability, or selected salts	Potential later barriers
Method of use	Cardiac insufficiency and low-dose treatment	Direct subject of US 5,403,856
Regulatory exclusivity	FDA approval-related exclusivity	Separate from patent term

The use patent did not extend the underlying composition patent's term. It created a separate cause of action for practicing the claimed cardiac-insufficiency method during its enforceable period.

What was the Orange Book status of US Patent 5,403,856?

The patent's Orange Book significance was limited by the approved indication for the US perindopril product. Aceon was approved by the FDA for treatment of hypertension, while US 5,403,856 claims cardiac-insufficiency treatment.[3]

A method-of-use patent is generally most relevant to the Orange Book when it covers an approved method of use and is properly submitted for listing. A patent claiming an indication absent from the approved label is less likely to create a conventional FDA regulatory block to an ANDA for the labeled use.

The relevant regulatory distinctions were:

The patent was not a current Orange Book barrier after its 2012 expiration.
A cardiac-insufficiency claim would not automatically block an ANDA directed to hypertension.
A generic applicant could use a section viii statement to carve out a patented method of use where the FDA-approved labeling and patent listing permitted that approach.
Patent expiry and regulatory exclusivity are separate issues.

The Orange Book should be checked by historical edition to determine whether the patent was ever listed against the relevant product. Current Orange Book status cannot revive an expired patent.[4]

Were there Paragraph IV challenges to this patent?

A Paragraph IV certification would have been relevant only while the patent was unexpired and listed against the applicable reference product. Because US 5,403,856 expired in 2012, a new Paragraph IV challenge directed solely to this patent no longer creates a meaningful entry dispute.

Publicly available FDA and patent records do not establish that this particular patent produced a current, live Paragraph IV litigation barrier. Generic perindopril competition has instead been driven primarily by the expiry of compound protection, FDA approval of abbreviated applications, and the availability of non-infringing labels.

A Paragraph IV challenge to a separate perindopril patent would not necessarily resolve the claims of US 5,403,856. Patent-by-patent analysis is required.

Which companies challenged or commercialized generic perindopril?

Perindopril is a small-molecule product, not a biologic. The relevant competitive field includes generic manufacturers and branded or licensed commercial parties rather than biosimilar sponsors.

Known market participants in the broader perindopril category have included:

Servier and its affiliated entities, associated with the originator product.
Solvay Pharmaceuticals, historically associated with US commercialization of Aceon.
Teva and other large generic manufacturers active in ACE-inhibitor products.
Regional generic manufacturers marketing perindopril or perindopril combinations outside the US.

The existence of a generic product does not alone establish that a company challenged US 5,403,856 through Paragraph IV litigation. ANDA filing, patent certification, FDA approval, and commercial launch are separate events. After April 4, 2012, this patent ceased to provide a viable basis for blocking generic entry.

What formulation and manufacturing barriers remained after expiration?

The patent does not claim a specific tablet formulation, release profile, coating, particle-size distribution, or manufacturing process. Claims 4 and 5 are broad administration and excipient limitations, not detailed formulation claims.

Potential residual barriers could have included:

A separate patent on perindopril arginine.
A salt-selection patent.
A stability or solid-state patent.
A process patent covering stereochemical resolution.
A specific fixed-dose combination.
A controlled-release formulation.
Regulatory requirements for impurity and stereoisomer control.

Those rights must be analyzed separately. US 5,403,856 itself does not preserve manufacturing exclusivity after expiration.

How strong was the patent estate?

The patent was moderately strong as a pre-expiration method-of-use patent but weaker as a standalone barrier to generic perindopril.

Factor	Assessment
Claim clarity	Moderate; chemical identity is clear, but Formula I and OCR issues require prosecution-history review
Product coverage	Strong for stereochemically pure perindopril and perindoprilat
Use coverage	Narrower; limited to cardiac insufficiency
Dose coverage	Claim 6 is narrower and fact-sensitive
Orange Book impact	Potentially limited because the approved US indication was hypertension
Design-around potential	Available through non-covered indications, labeling, or different compounds
Current enforceability	None; patent expired
Biosimilar relevance	None; perindopril is a synthetic small molecule
Manufacturing barrier	Limited under this patent
Litigation value today	Historical only

The most commercially important claim was claim 2, because it directly identifies perindopril. Its practical enforcement value depended on proving that the accused product was prescribed, promoted, or administered for cardiac insufficiency during the patent term.

What generic launch risks exist today?

A new generic perindopril launch does not face a live infringement risk from US 5,403,856. Current risk analysis should focus on:

Other unexpired US patents.
FDA labeling and exclusivity status.
Product-specific formulation or combination patents.
ANDA litigation involving separate patents.
Manufacturing patents in the supply chain.
State substitution and contracting requirements.
Market access and pricing pressure from existing suppliers.

The expired patent remains relevant for historical freedom-to-operate reviews, litigation due diligence, and reconstruction of the originator's exclusivity strategy. It is not a current barrier to US entry.

How does this patent compare with competing ACE-inhibitor patents?

US 5,403,856 is narrower than many composition-of-matter patents for ACE inhibitors because it requires both a particular chemical class and a particular therapeutic use.

Drug	Relationship to US 5,403,856
Perindopril	Directly implicated by claims 1 and 2
Perindoprilat	Directly implicated by claim 3
Enalapril	Different structure; not covered merely as an ACE inhibitor
Ramipril	Different ring and side-chain structure
Lisinopril	Different molecular structure and substituents
Captopril	Different sulfhydryl-containing structure
Quinapril	Different bicyclic framework and substituents

The patent is therefore not a platform patent over ACE inhibitors generally. It is a compound-specific method patent covering the use of one defined stereochemical family for cardiac insufficiency.

Key Takeaways

US 5,403,856 covers treatment of cardiac insufficiency with stereochemically pure perindopril-type ACE inhibitors.
Claim 2 is directed to perindopril; claim 3 is directed to perindoprilat.
Claim 6 narrows the method to a sub-anti-hypertensive dose.
The patent does not broadly cover enalapril, ramipril, lisinopril, captopril, or other ACE inhibitors.
The patent issued April 4, 1995, and expired April 4, 2012.
It is no longer a current US patent barrier to generic perindopril.
The patent's Orange Book value was constrained by its cardiac-insufficiency indication compared with the hypertension indication for Aceon.
Biosimilar analysis is irrelevant because perindopril is a synthetic small molecule.
Any current freedom-to-operate review must examine separate compound, salt, formulation, process, combination, and method patents.

FAQs About US Patent 5,403,856

Does US Patent 5,403,856 cover perindopril erbumine?

Yes. Claim 2 covers perindopril and expressly includes pharmaceutically acceptable salts. Perindopril erbumine is a salt form of perindopril.

Does the patent cover perindopril used for hypertension?

Not on the claim language provided. The claims require treatment of cardiac insufficiency. Hypertension-only use does not satisfy that express therapeutic limitation.

Is US 5,403,856 still enforceable?

No. The patent expired in 2012 and cannot support a prospective injunction against current generic activity.

Is perindopril a biosimilar product?

No. Perindopril is a chemically synthesized small-molecule ACE inhibitor. Generic approval is generally pursued through the ANDA pathway, not the biosimilar pathway.

Could a generic company avoid the patent by using a different stereoisomer?

Before expiration, a product containing a different stereochemical configuration could potentially avoid the literal compound limitations, but it would require separate analysis of efficacy, regulatory approval, other patents, and possible equivalents. After expiration, the patent no longer requires a design-around.

References

United States Patent and Trademark Office. (1995). US Patent No. 5,403,856, Treatment of cardiac insufficiency with an angiotensin-converting enzyme inhibitor.
United States Patent and Trademark Office. (1990). US Patent No. 4,914,214, Octahydro-1H-indole-2-carboxylic acid derivatives, process for preparing them and their use as medicaments.
U.S. Food and Drug Administration. (1998). Aceon (perindopril erbumine) prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	34 13 710.6	Apr 12, 1984

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	171376	⤷ Start Trial
Austria	98128	⤷ Start Trial
Australia	4104885	⤷ Start Trial
Australia	585502	⤷ Start Trial
Canada	1246457	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,403,856

Summary for Patent: 5,403,856