US Drug Patent 4,587,258: Scope, Claims, Expiration, and Cilazapril Patent Landscape

US Patent 4,587,258 is the core U.S. patent covering a class of bicyclic proline-derived angiotensin-converting enzyme inhibitors, including cilazapril and related ester, acid, stereoisomer, and salt forms. The patent was granted May 6, 1986, and its ordinary pre-1995 patent term expired May 6, 2003. Because cilazapril was not approved by the FDA for marketing in the United States, the patent did not generate an FDA Orange Book listing or U.S. pharmaceutical patent-term extension.

The strongest commercial claims are claims 7-12, which cover cilazapril and its corresponding dicarboxylic acid, hydrochloride, and dihydrochloride forms. Claims 1, 26, and 27-30 provide broader chemical, composition, and therapeutic coverage, but their practical value ended when the patent expired.

What drug does US Patent 4,587,258 protect?

The principal drug associated with the patent is cilazapril, an ACE inhibitor developed by Hoffmann-La Roche and marketed outside the United States under the brand name Inhibace.

Cilazapril is an orally administered prodrug. Its active metabolite is cilazaprilat, the dicarboxylic acid form produced by hydrolysis of the ethyl ester. The claims cover both the ethyl ester prodrug and the corresponding carboxylic acid.

Patent subject	Claim coverage	Commercial relevance
Broad bicyclic proline-derived compounds	Claim 1	Platform claim covering a large Markush genus
Cis,endo bicyclic proline isomer	Claim 2	Stereochemical core
Alanine derivatives	Claims 3-6	Related ACE-inhibitor analogues
Lysine derivatives	Claims 7-12	Includes cilazapril and cilazaprilat-related forms
Butyl analogues	Claims 13-22	Additional chemical embodiments
Cis,exo isomer	Claim 23	Alternative stereochemical series
Hydrochloride and maleate salts	Claims 24-25	Salt-form protection
Pharmaceutical compositions	Claim 26	Composition-of-matter implementation
Hypertension treatment	Claim 27	Core therapeutic use
Congestive heart failure	Claim 28	Cardiovascular method-of-use coverage
Glaucoma	Claim 29	Non-primary therapeutic use
Combination with a diuretic	Claim 30	Combination-treatment claim

The patent’s chemical center is a substituted octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid. This bicyclic ring replaces the simpler proline framework found in several earlier ACE inhibitors.

What is the scope of claim 1?

Claim 1 is a broad Markush composition-of-matter claim. It covers a defined bicyclic compound structure and pharmaceutically acceptable salts in which multiple substituent positions can contain different functional groups.

The claim includes:

Hydroxy and alkoxy groups.
Alkenoxy groups.
Dialkylaminoalkoxy groups.
Acylaminoalkoxy and acyloxyalkoxy groups.
Aryloxy and aralkoxy groups.
Amino, alkylamino, and dialkylamino groups.
Hydroxyamino and arylalkylamino groups.
Substituted aryl and aralkyl groups.
A broad set of R1 side chains, including alkyl, cyclic, unsaturated, hydroxyalkyl, aminoalkyl, guanidino, imidazolyl, indolyl, thioether, carboxy, carbamoyl, ester, aryl, and aralkyl groups.
R3 substituents corresponding to hydrogen, alkyl, phenylalkyl, aminoalkyl, hydroxyalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl, and alkylthioalkyl groups.

The breadth is functional rather than limited to a single marketed molecule. A compound potentially falls within claim 1 if:

It contains the claimed octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid framework.
Its stereochemistry and substituent placement match the formula.
Its R, R1, R3, and R6 groups fall within the listed alternatives.
It is the free compound or a pharmaceutically acceptable salt.

Because the structural formula is essential to determining the exact attachment points and stereochemical relationships, claim 1 cannot be assessed solely by substituent names. The dependent claims, however, identify the commercially significant embodiments with greater precision.

Which claims cover cilazapril and cilazaprilat?

Claims 7-12 are the most important cilazapril-related claims.

Claim	Subject
7	Ethyl ester of the lysine derivative
8	Hydrochloride salt of the ethyl ester
9	Dihydrochloride salt of the ethyl ester
10	Free dicarboxylic acid corresponding to the lysine derivative
11	Hydrochloride salt of the dicarboxylic acid
12	Dihydrochloride salt of the dicarboxylic acid

The claimed ethyl ester is cilazapril-type subject matter. The corresponding free acid is cilazaprilat-type subject matter.

The distinction matters commercially:

The ethyl ester is the orally administered prodrug.
The free acid is the pharmacologically active metabolite.
Hydrochloride and dihydrochloride claims protect isolated salt forms.
Claims 7-12 depend on claim 1 and inherit its structural limitations.

Claims 3-6 cover analogous alanine derivatives. Claims 13-22 cover compounds with a carboethoxybutyl or carboxybutyl side chain rather than the phenylpropyl side chain associated with cilazapril.

How do the stereochemistry claims affect patent scope?

The patent separately claims cis,endo and cis,exo isomers.

Claim 2 covers the cis,endo isomer of octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid. Claim 23 covers the cis,exo isomer. The named cilazapril claims use the cis,endo bicyclic core.

This creates several layers of stereochemical protection:

The bicyclic ring configuration.
The 2(S) configuration of the carboxylic acid.
The S configuration of the side-chain amino-acid component.
The S configuration of the substituted ester or acid side chain.
The relationship between the bicyclic ring junction and substituents.

A product with the same connectivity but a different ring-junction configuration could avoid a stereochemically limited dependent claim. It could still face claim 1 if the broader formula encompasses that isomer. A final infringement analysis would require three-dimensional structure mapping against the patent formula and prosecution history.

What formulations are protected by US 4,587,258?

Claim 26 covers an antihypertensive pharmaceutical composition containing an effective amount of a claim 1 compound and a pharmaceutically acceptable carrier.

The claim is broad as to dosage form and excipient. It can reach:

Tablets.
Capsules.
Oral solutions or suspensions.
Solid dosage forms containing the ester or acid.
Salt-based formulations.
Conventional pharmaceutical carriers.

Claim 26 does not appear to require a particular release profile, excipient, particle size, coating, dosage strength, or manufacturing process. It is therefore a basic composition claim, not a modern formulation patent directed to controlled release, crystal form, particle engineering, or a defined excipient system.

Claims 24 and 25 separately identify hydrochloride and maleate salts. These claims may protect salt selection as a chemical form, but they do not independently establish protection for every formulation containing a claim 1 compound.

What method-of-use patents are covered?

Claims 27-30 are method claims.

Hypertension

Claim 27 covers administering a composition containing a claim 1 compound to reduce blood pressure in hypertensive mammals.

Claim 30 covers the same objective when the compound is administered with a diuretic. This claim is narrower because it requires combination treatment.

Congestive heart failure

Claim 28 covers treatment of mammals suffering from congestive heart failure.

Glaucoma

Claim 29 covers treatment of glaucoma.

The method claims use broad disease categories and do not specify:

A particular human dosage.
A treatment duration.
A dosing interval.
A route of administration beyond administration of the composition.
A required diuretic for claims 27-29.

Their practical scope was strongest before expiration and before competing ACE inhibitors became widely available. After May 6, 2003, these claims no longer created enforceable U.S. exclusivity.

When did US Patent 4,587,258 expire?

Event	Date
U.S. patent grant	May 6, 1986
Ordinary statutory term	17 years from grant
Expiration	May 6, 2003
Current status	Expired

US 4,587,258 is a pre-Uruguay Round Agreements Act patent. Under the applicable transition rules, its ordinary term was generally 17 years from grant rather than 20 years from the earliest effective filing date. The patent’s term therefore ran to May 6, 2003, absent a special extension or terminal-disclaimer issue. The public FDA record does not show a U.S. cilazapril approval that could support a Hatch-Waxman patent-term extension under 35 U.S.C. § 156.[1][2]

What is the Orange Book status of cilazapril?

Cilazapril does not have a U.S. FDA-approved reference listed drug and is not an established Orange Book product in the United States.

The consequences are material:

No cilazapril brand product is listed in the Orange Book.
No Orange Book-listed US 4,587,258 patent is available for a Paragraph IV challenge.
No U.S. abbreviated new drug application pathway has been commercially structured around a cilazapril reference product.
The patent could not support current U.S. Hatch-Waxman litigation because it expired before a U.S. reference product existed.

A Paragraph IV certification is relevant only where an ANDA applicant references an approved drug and a listed patent. Those conditions do not apply to cilazapril in the United States based on current FDA listings.[2]

Were there Paragraph IV challenges or U.S. patent litigation?

No material current U.S. Paragraph IV litigation is associated with US 4,587,258. The patent expired in 2003, and any infringement action based solely on the patent would now be barred by expiration.

The patent also appears distinct from the U.S. litigation history surrounding widely marketed ACE inhibitors such as enalapril, lisinopril, ramipril, and perindopril. Those products had separate patent families, sponsors, regulatory histories, and generic-entry disputes.

There is no basis in the patent claims alone to identify:

A settlement agreement involving an ANDA filer.
A reverse-payment agreement.
A current district-court case.
A Federal Circuit appeal.
A post-expiration damages action.

Patent litigation would historically have been possible over products containing the claimed cis,endo bicyclic compounds, their salts, or the claimed therapeutic compositions. The patent’s expiration removes the principal forward-looking litigation risk.

How strong was the patent estate for cilazapril?

The patent was strong as an original composition-of-matter patent because it combined:

A defined bicyclic ACE-inhibitor scaffold.
Broad Markush coverage.
Multiple specific cilazapril-related embodiments.
Free-acid and ester coverage.
Hydrochloride and dihydrochloride salt coverage.
Pharmaceutical composition claims.
Hypertension, heart-failure, glaucoma, and combination-treatment claims.

Its weaknesses were structural and commercial:

The broad genus claim could have faced novelty, obviousness, written-description, enablement, or claim-construction challenges.
The patent did not claim a modern solid-state form or manufacturing process.
The U.S. commercial value was limited because cilazapril was not FDA approved.
The patent term ended before a U.S. cilazapril market developed.
The claims did not create a current barrier to generic ACE inhibitors outside the claimed bicyclic chemical class.

The patent estate should therefore be characterized as historically broad but currently non-blocking in the United States.

How does the cilazapril patent compare with competing ACE-inhibitor estates?

Product	Core structural class	U.S. regulatory position	Relationship to US 4,587,258
Cilazapril	Bicyclic proline-derived ACE inhibitor	No U.S. FDA approval	Directly associated with the patent
Enalapril	Proline-derived ACE inhibitor	U.S. approved	Separate patent estate
Lisinopril	Lysine-derived ACE inhibitor	U.S. approved	Different scaffold and patent family
Captopril	Sulfhydryl-containing ACE inhibitor	U.S. approved	Chemically distinct
Ramipril	Proline-derived ACE inhibitor ester	U.S. approved	Separate patent estate
Perindopril	Proline-derived ACE inhibitor ester	U.S. approved	Separate patent estate

The presence of lysine-derived claims in US 4,587,258 does not make the patent a general lisinopril patent. Lisinopril has a different chemical structure and belongs to a separate development and patent history. Likewise, the broad functional language in claim 1 does not automatically reach all ACE inhibitors.

What generic-entry risks exist?

United States

Current generic-entry risk from US 4,587,258 is zero because the patent expired in 2003. The patent cannot block:

Manufacture.
Importation.
Sale.
ANDA development.
Clinical investigation.
Commercial formulation work.

Any current U.S. product risk would arise from other rights, such as:

A later patent on a manufacturing process.
A later patent on a salt or crystal form.
A formulation patent.
Regulatory exclusivity.
Trade-secret manufacturing information.
Patent rights in a different country.

The provided patent does not itself create a current U.S. exclusivity barrier.

Outside the United States

Foreign patent rights must be evaluated separately. A U.S. patent expiration does not determine the expiration of corresponding European, Japanese, Canadian, or other national patents. Patent family members may have had different prosecution histories, claim amendments, term adjustments, or abandonment outcomes.

The relevant foreign analysis would focus on:

Priority-linked family members.
National grant dates.
Patent-term rules.
Supplementary protection certificates.
National validation.
Local generic-entry rules.
Whether cilazapril remains marketed in the jurisdiction.

Did licensing deals affect the patent landscape?

US 4,587,258 identifies the patent owner and the claimed technology but does not, by itself, establish the existence, scope, or duration of any license agreement.

Cilazapril was developed within the Hoffmann-La Roche commercial organization. A patent assignment or corporate ownership record is not equivalent to a license. No current U.S. licensing position can be inferred from the claims, and any historical collaboration would require separate agreement, regulatory, or corporate records.

What manufacturing and IP barriers remain?

The expired patent no longer protects the claimed compounds in the United States. Manufacturing barriers could still arise from technical factors rather than this patent, including:

Control of stereochemistry in the cis,endo bicyclic core.
Enantioselective synthesis of the side chain.
Selective esterification and hydrolysis.
Salt conversion and crystallization.
Impurity control.
Stability of the ester prodrug.
Analytical differentiation between cilazapril and cilazaprilat.

Those issues may affect cost, quality, and regulatory filing strategy, but they are not continuing exclusivity rights under US 4,587,258.

Key Takeaways

US 4,587,258 is a core composition-of-matter patent for bicyclic proline-derived ACE inhibitors, including cilazapril-related compounds.
Claims 7-12 are the principal cilazapril and cilazaprilat claims.
Claim 1 is a broad Markush genus claim with extensive substituent coverage.
Claims 24-25 cover hydrochloride and maleate salts.
Claim 26 covers pharmaceutical compositions.
Claims 27-30 cover hypertension, congestive heart failure, glaucoma, and diuretic-combination uses.
The patent was granted May 6, 1986, and expired May 6, 2003.
Cilazapril has no current U.S. Orange Book-listed reference product.
No current Paragraph IV or U.S. litigation risk arises from this expired patent.
Foreign family members must be analyzed independently.
Any present commercial barrier would have to come from later patents, regulatory rights, manufacturing know-how, or non-U.S. rights.

FAQs

Is cilazapril the same drug as lisinopril?

No. Both are ACE inhibitors, but cilazapril contains a bicyclic octahydrocyclopenta[b]pyrrole core, while lisinopril has a different lysine-derived structure and separate patent history.

Does US 4,587,258 cover cilazaprilat?

Yes. Claims 10-12 cover the corresponding carboxylic acid form and its hydrochloride and dihydrochloride salts.

Could a company launch cilazapril in the United States after 2003?

The patent itself would not prevent launch after May 6, 2003. A sponsor would still need to satisfy FDA requirements for approval, including applicable safety, efficacy, quality, and manufacturing requirements.

Does the patent cover every ACE inhibitor?

No. Claim 1 is broad, but it is limited to compounds having the claimed bicyclic structure and substituent arrangement. Structurally unrelated ACE inhibitors fall outside the patent.

Can the expired patent be challenged in a Paragraph IV certification?

No practical Paragraph IV challenge is required for an expired patent. Paragraph IV certification is an ANDA mechanism tied to listed patents for an approved reference product, and cilazapril lacks that U.S. Orange Book framework.

References

U.S. Patent No. 4,587,258. (1986). N-substituted octahydrocyclopenta[b]pyrrole-2-carboxylic acids, pharmaceutical compositions containing them and their use. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA, Center for Drug Evaluation and Research.
35 U.S.C. § 154. Patent term.
35 U.S.C. § 156. Extension of patent term for regulatory review.
European Medicines Agency. (n.d.). Cilazapril: International nonproprietary name and medicinal-product information. EMA.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	81108348.4	Oct 15, 1981

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0050800	⤷ Start Trial	96C0028	Belgium	⤷ Start Trial
Austria	20469	⤷ Start Trial
Australia	4671885	⤷ Start Trial
Australia	554362	⤷ Start Trial
Australia	581919	⤷ Start Trial
Australia	7661481	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,587,258

Summary for Patent: 4,587,258