United States Drug Patent 4,508,729: Scope, Claims, Expiration, and Perindopril Patent Landscape

United States Patent No. 4,508,729 is the foundational U.S. patent covering perindopril, an orally active angiotensin-converting enzyme inhibitor. The patent issued on March 5, 1985, and, under the pre-Uruguay Round patent-term rules applicable to the application, expired on March 5, 2002. Its claims cover the active compound, stereochemical forms, pharmaceutically acceptable salts, pharmaceutical compositions, and antihypertensive treatment methods. It no longer presents a live U.S. patent barrier to generic perindopril.

What drug does U.S. Patent 4,508,729 protect?

The claimed compound is perindopril and related stereochemical or salt forms.

Perindopril is an ethyl ester prodrug that is converted in vivo to perindoprilat, the active ACE-inhibiting metabolite. The compound was marketed in the United States primarily as perindopril erbumine under the brand name Aceon.

The chemical subject matter corresponds to an N-acylated octahydroindole carboxylic acid bearing an ethoxycarbonylbutyl substituent. Claim 3 identifies the principal commercial compound as:

(2S)-1-{N-[(1RS)-1-ethoxycarbonylbutyl]-(S)-alanyl}-2-carboxyperhydroindole;
its S-isomer; and
the sodium salt of those compounds.

The claim language is consistent with the perindopril chemical family, including stereochemical variants and pharmaceutically acceptable salts.

Core chemical limitations

Claim element	Limitation
Core scaffold	Perhydroindole or octahydroindole carboxylic-acid structure
N-substituent	Alanyl group connected to an ethoxycarbonylbutyl moiety
R1	Lower alkyl containing one to four carbon atoms
R2	Hydrogen or lower alkyl containing one to four carbon atoms
R3	n-Propyl group, represented as -CH2CH2CH3
Stereochemistry	Racemate or optical isomer
Salt forms	Pharmaceutically acceptable inorganic or organic acid or base salts
Therapeutic use	Treatment of hypertension

The claim is a closed Markush claim because it uses the phrase “selected from the group consisting of.” That language generally limits claim 1 to compounds falling within the listed structural alternatives rather than extending to unrelated analogues.

How broad is claim 1 of U.S. Patent 4,508,729?

Claim 1 is the principal composition-of-matter claim. It covers a defined family of iminodiacid compounds rather than only one named molecule.

Its principal breadth comes from four features:

R1 may be any lower alkyl group from methyl through butyl.
R2 may be hydrogen or a lower alkyl group from methyl through butyl.
The compounds may exist as racemates or optical isomers.
The compounds may be converted into pharmaceutically acceptable acid or base salts.

The claim is narrower than a general ACE-inhibitor genus claim because it fixes R3 as n-propyl and requires the specific perhydroindole-alanyl-ethoxycarbonylbutyl architecture. It is broader than a claim limited solely to commercial perindopril because it covers additional alkyl substitutions and stereochemical forms.

Claim 1 versus claim 3

Claim 3 narrows the invention to a specifically identified compound and stereochemical configuration. It is important commercially because a generic product structurally identical to perindopril would fall within the type of species claim represented by claim 3, subject to claim construction and any validity defenses.

Claim 3 also expressly identifies the sodium salt. Claim 1 has broader salt language and would potentially reach other pharmaceutically acceptable salts, including salts formed with organic or inorganic bases. The commercial product, perindopril erbumine, is an addition salt with tert-butylamine. The broader salt language in claim 1 is therefore more commercially relevant to the marketed product than the sodium-salt limitation in claim 3.

What do claims 2 through 7 cover?

Claim 2: methyl-substituted compounds

Claim 2 limits claim 1 to compounds in which R1 is methyl. It is a narrower chemical claim directed to a defined subset of the Markush genus.

Claim 3: named perindopril species

Claim 3 covers the specified perhydroindole compound, its S-isomer, and sodium salt forms. It is the key species claim for the perindopril structure identified in the patent.

Claims 4 and 5: pharmaceutical compositions

Claims 4 and 5 cover pharmaceutical compositions containing at least one claimed compound together with an inert, nontoxic, pharmaceutically acceptable carrier or excipient.

These claims reach finished dosage forms, including tablets, capsules, and other oral dosage forms, when the active ingredient is a compound within claims 1 or 3. They do not require a particular excipient, release profile, dosage strength, tablet design, or manufacturing process.

The formulation claims are therefore broad but conventional. They do not provide the type of differentiated protection typically associated with a narrow controlled-release formulation, fixed-dose combination, particle-size limitation, polymorph, or specific dissolution profile.

Claims 6 and 7: antihypertensive treatment methods

Claims 6 and 7 cover administering a therapeutically effective dose to a patient suffering from hypertension.

These claims are method-of-treatment claims, not compound claims. They would historically have been relevant to branded labeling and physician use, but they expired with the patent. Their practical enforcement value was also narrower than the composition-of-matter claims because liability generally depends on conduct involving the claimed therapeutic method.

When did U.S. Patent 4,508,729 expire?

U.S. Patent 4,508,729 issued on March 5, 1985. Its term was governed by the pre-1995 rule providing 17 years from issuance. The patent therefore expired on March 5, 2002, absent an earlier terminal disclaimer or other unusual event. Public U.S. patent records identify the patent as expired [1].

Event	Date
U.S. patent grant	March 5, 1985
Original statutory term	17 years from grant
Expiration	March 5, 2002
Current status	Expired
Current blocking effect	None in the United States

The patent predates the Hatch-Waxman patent-term system, so its expiration was not calculated as 20 years from the earliest effective U.S. filing date. Patent term adjustment and patent term extension provisions associated with later-issued patents do not revive this expired patent.

What is the Orange Book status of perindopril and Aceon?

Aceon was approved by the FDA as perindopril erbumine, a small-molecule ACE inhibitor. The relevant regulatory pathway was an NDA, not a biologics license application.

A patent listed for an approved drug can remain relevant to an ANDA applicant through Paragraph IV certification while the patent is unexpired. Once the listed patent expires, it no longer prevents approval or commercial launch on patent-term grounds.

The principal U.S. regulatory implications are:

Perindopril is a small molecule, so biosimilar regulations do not apply.
An ANDA applicant would generally seek approval through the generic-drug pathway.
The expired ’729 patent cannot support a current Paragraph IV litigation threat.
Any current regulatory barrier would have to arise from a separate unexpired patent, regulatory exclusivity, labeling issue, pharmaceutical equivalence issue, or other FDA requirement.
The ’729 patent itself no longer creates an Orange Book exclusivity period.

FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, commonly called the Orange Book, is the controlling source for current patent and exclusivity listings associated with approved drug products [2]. FDA labeling identifies Aceon as perindopril erbumine and describes its use for hypertension [3].

Did U.S. Patent 4,508,729 create formulation protection?

The patent contains composition claims, but it does not appear from the supplied claims to contain a narrow, technology-specific formulation estate.

Claims 4 and 5 require only:

a claimed perindopril compound; and
an inert, nontoxic, pharmaceutically acceptable carrier or excipient.

They do not require:

a particular tablet coating;
a modified-release matrix;
a defined particle-size distribution;
a particular polymorph;
a specified impurity profile;
a fixed-dose combination;
a selected dissolution range; or
a manufacturing sequence.

The claims could therefore reach a conventional pharmaceutical composition containing the claimed active ingredient, but they would not independently distinguish one generic formulation from another where the active ingredient and ordinary excipient use are otherwise lawful. Since all such claims expired in 2002, they have no present U.S. blocking effect.

What patent protection exists for perindopril salts and stereoisomers?

The patent’s salt language is materially important. Claim 1 covers pharmaceutically acceptable salts formed with inorganic or organic acids and bases. This can encompass salt forms beyond the sodium salt expressly recited in claim 3.

The patent also covers racemic and optical-isomer forms. That broadens the historical scope to stereoisomeric variants of the defined scaffold. For perindopril, stereochemistry is commercially significant because activity, pharmacokinetics, and impurity control depend on the configuration of the amino-acid and substituted-carbon centers.

The scope does not necessarily extend to every later-developed crystalline form or solid-state form as a separate property right. A later patent could claim a particular polymorph, hydrate, solvate, particle size, or manufacturing process if it met novelty and non-obviousness requirements. Such a later patent would be distinct from the expired composition claims in ’729.

What manufacturing and process barriers did the patent create?

The supplied claims do not claim a process for making perindopril. They claim compounds, compositions, and methods of treatment.

As a result, the patent did not directly block an alternative synthetic route after expiration. A generic manufacturer could use a different process, provided that the process did not infringe a separate unexpired process patent and produced a product meeting FDA quality requirements.

Commercial manufacturing barriers for perindopril are more likely to involve:

control of multiple stereochemical centers;
separation or control of diastereomeric impurities;
production of the desired salt form;
stability of the ester prodrug;
residual solvent and genotoxic impurity controls; and
demonstration of bioequivalence.

These are regulatory and technical barriers rather than surviving rights under U.S. Patent 4,508,729.

Which companies challenged the perindopril patent?

The supplied record does not identify a specific ANDA filer, Paragraph IV notice, or federal litigation docket. The expired status of the ’729 patent means that any historical Paragraph IV challenge is no longer commercially material to present U.S. entry.

A Paragraph IV certification would have been relevant only while the patent remained listed and unexpired. Under the Hatch-Waxman framework, a Paragraph IV notice can trigger patent litigation and a 30-month stay of FDA approval under specified conditions [4]. That mechanism does not extend the life of an expired patent.

No biosimilar challenge applies because perindopril is not a biologic. The competitive challenge is a conventional generic-drug challenge involving pharmaceutical equivalence and bioequivalence.

How strong is the patent estate for perindopril?

Historical strength

The estate was strong during its enforceable term because claim 1 was a composition-of-matter claim directed to the active chemical family. Composition claims generally provide greater leverage than formulation or method claims because they can reach manufacture, sale, and use of the active compound regardless of the dosage form.

Claim 3 strengthened the estate by identifying a commercially relevant species and stereochemical form. Claims 4 and 5 extended coverage into drug products, while claims 6 and 7 covered antihypertensive treatment.

Current strength

The estate has no remaining U.S. patent-term strength under ’729. The patent is expired, and its claims cannot support current exclusionary rights.

Protection category	Covered by ’729	Current status
Active compound	Yes	Expired
Stereoisomers	Yes	Expired
Pharmaceutically acceptable salts	Yes	Expired
Sodium salt	Yes	Expired
Pharmaceutical compositions	Yes	Expired
Hypertension treatment	Yes	Expired
Specific polymorph	Not shown in supplied claims	Separate analysis required
Controlled-release formulation	Not shown in supplied claims	Separate patent issue
Manufacturing process	Not shown in supplied claims	Separate patent issue
Biosimilar protection	No	Not applicable

What generic launch risks exist for perindopril?

The ’729 patent presents no current launch risk. A generic perindopril product would not need to wait for this patent’s expiration because the expiration occurred in 2002.

The relevant launch risks are instead:

FDA approval and therapeutic-equivalence requirements.
Bioequivalence to the reference listed drug.
Correct salt and strength selection, particularly for perindopril erbumine.
Product labeling and use-related regulatory requirements.
Any separate later patent covering a formulation, process, combination, or specific use.
Commercial competition from existing generic suppliers.

A generic launch would not create a biosimilar interchangeability issue. It would proceed through the ANDA framework applicable to small-molecule drugs.

What revenue exposure did the patent create?

The patent historically protected the commercial franchise around Aceon and perindopril before expiration. Its commercial value was highest before March 2002 because the composition-of-matter claims could restrict competing products containing perindopril.

After expiration, revenue exposure shifted from patent exclusivity to:

brand loyalty;
physician prescribing;
formulary position;
generic price erosion;
supply reliability; and
any separate product differentiation.

The patent itself does not support a current royalty or exclusionary revenue claim in the United States.

Key Takeaways

U.S. Patent 4,508,729 is the core historical U.S. patent for perindopril-related compounds.
Claim 1 is a Markush composition claim covering defined iminodiacid derivatives, stereoisomers, and pharmaceutically acceptable salts.
Claim 3 narrows the scope to the commercially relevant perindopril species and specified salt forms.
Claims 4 and 5 cover pharmaceutical compositions; claims 6 and 7 cover hypertension treatment methods.
The patent issued on March 5, 1985, and expired on March 5, 2002.
The patent is no longer a U.S. barrier to generic perindopril.
Perindopril is a small molecule, so biosimilar provisions do not apply.
The supplied claims do not establish separate protection for a polymorph, controlled-release formulation, manufacturing process, or fixed-dose combination.
Current market risk depends on FDA requirements and any later unexpired patents, not on ’729.

FAQs

Is perindopril protected by an active U.S. composition-of-matter patent?

No. The core U.S. patent identified here, U.S. 4,508,729, expired on March 5, 2002.

Does the patent cover perindopril erbumine?

Claim 1’s broad pharmaceutically acceptable salt language is capable of covering organic-base salts such as perindopril erbumine, subject to the structural limitations of the claim. That protection expired with the patent.

Can a generic manufacturer use a different perindopril synthesis?

Yes, with respect to ’729, because the supplied claims do not claim a manufacturing process and the patent has expired. A separate process patent would require independent analysis.

Is a Paragraph IV certification still relevant to U.S. Patent 4,508,729?

No. Paragraph IV certification is relevant to an unexpired listed patent. The ’729 patent expired in 2002.

Does perindopril require a biosimilar application?

No. Perindopril is a chemically synthesized small-molecule drug. A qualifying generic product would use the ANDA pathway rather than the biosimilar pathway.

References

United States Patent and Trademark Office. (1985). United States Patent No. 4,508,729.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations.
U.S. Food and Drug Administration. (n.d.). Aceon (perindopril erbumine) prescribing information.
United States Code, 21 U.S.C. § 355(j). (2024). Abbreviated new drug applications and patent certifications.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
France	80 21095	Oct 02, 1980
France	81 06916	Apr 07, 1981

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0049658	⤷ Start Trial	SPC/GB93/141	United Kingdom	⤷ Start Trial
Argentina	242949	⤷ Start Trial
Austria	7910	⤷ Start Trial
Australia	539414	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,508,729

Summary for Patent: 4,508,729