United States Drug Patent 4,703,038: Scope, Claims, Expiration, and Patent Landscape

U.S. Patent No. 4,703,038 covers pharmaceutical combinations of an angiotensin-converting enzyme inhibitor, or ACE inhibitor, with a 1,4-dihydropyridine calcium-channel blocker. The patent issued on October 27, 1987, and, as a pre-URAA patent, expired no later than October 27, 2004, absent an unusual term adjustment or terminal-disclaimer event. Its claims no longer create an enforceable U.S. patent barrier.

The commercial concept was a combination of compounds such as enalapril or lisinopril with felodipine, nicardipine, nisoldipine, or nitrendipine. Claim 15 specifically targets enalapril with nitrendipine. Claim 14 covers combinations involving enalapril or lisinopril and four dihydropyridines.

What does U.S. Patent 4,703,038 protect?

The patent protects four related subject-matter categories:

Chemical combinations containing an ACE inhibitor and a dihydropyridine calcium antagonist.
Specific weight ratios of the two active ingredients.
Therapeutic use for circulatory disease and hypertension.
Medicaments and a solvent-based preparation process for producing the combination.

The patent does not claim a single active ingredient in isolation. Infringement of the central combination claims would require the presence of both:

A qualifying compound within formula I; and
A qualifying dihydropyridine within formula II.

The claims also require the claimed combination to satisfy the structural definitions, selected species, or weight ratios stated in the applicable claim.

Patent identification

Item	Data
Patent	U.S. Patent No. 4,703,038
Issue date	October 27, 1987
Technology	ACE inhibitor and dihydropyridine calcium-channel blocker combinations
Principal claim types	Composition, method of treatment, medicament, preparation process
Key ACE-inhibitor species	Enalapril-type compound and lisinopril-type compound
Key calcium-channel blocker species	Nitrendipine, nisoldipine, nicardipine, felodipine
U.S. statutory status	Expired
Maximum ordinary pre-URAA term	17 years from issue
Earliest ordinary expiration date	October 27, 2004

Source: U.S. Patent No. 4,703,038.

What compounds fall within formula I?

Formula I is drafted as a broad Markush genus. It covers substituted peptide-like ACE inhibitors with extensive variation at multiple positions.

The specification and dependent claims identify two commercially important members:

N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, commonly recognized as enalapril or the enalapril free-acid ester structure, with its maleate salt.
N-alpha-(1-(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline, corresponding to lisinopril.

Claim 1 reaches a much broader group than those two compounds. It permits variation in:

The groups designated R and R6;
Alkyl, alkenyl, aralkyl, heteroaralkyl, aminoalkyl and substituted aromatic groups;
Amino-acid-derived side chains;
Hydroxyl, alkoxy, amino, guanidino, imidazolyl, indolyl, mercapto and carboxyl-containing substituents;
Ring systems formed by linking R4 and R5.

The claim also covers pharmaceutically acceptable salts.

Claim 3 and the proline-related structures

Claim 3 narrows the formula I compound by requiring:

R to be hydroxyl or C1-C4 alkoxy;
R6 to be hydroxyl;
R2 and R7 to be hydrogen;
R3 to be methyl or amino-C1-C6 alkyl;
R4 and R5 to form proline, 4-thiaproline or 4-methoxyproline-related structures.

This claim is commercially significant because it directs the scope toward enalapril-like and lisinopril-like ACE-inhibitor structures rather than the entire genus in claim 1.

The supplied claim text contains apparent transcription errors, including inconsistent references to R3 and R7, duplicated alternatives, and typographical defects. The authoritative construction must use the issued patent images and prosecution history, not an OCR transcription alone.

What calcium-channel blockers fall within formula II?

Formula II is directed to substituted 1,4-dihydropyridines. Claim 5 identifies the principal permitted substituents:

X: 2-nitro, 3-nitro, 2-chloro, 2,3-dichloro, or the specified ring system;
R1: methyl, ethyl, propyl or propyloxyethyl;
R2: methyl, ethyl, propyl, butyl, propyloxyethyl, methoxyethyl, decyl, trifluoromethylmethyl or N-benzyl-N-methylaminoethyl derivatives;
R3: methyl, hydroxymethyl or cyano.

Claim 6 expressly names:

Nisoldipine;
Nicardipine;
Felodipine.

Claim 14 adds nitrendipine to the specifically claimed combination group. This creates an internal drafting asymmetry: claim 6 lists three named dihydropyridines, while claim 14 lists four. Claim 14 should be read as a separate, narrower combination claim and not as a correction of claim 6.

How broad is claim 1?

Claim 1 is broad in chemical scope but narrow in functional combination structure.

It is broad because it covers a large Markush genus for formula I and multiple structural classes for formula II. It also covers salts and a wide range of substituents.

It is narrow because the accused product must contain both claimed compound classes. A product containing only felodipine, only enalapril, or an unrelated antihypertensive would not meet the combination limitation.

The claim also requires a “combination of compounds.” That language could cover a single dosage form containing both ingredients, a kit, or a pharmaceutical composition in which the ingredients are intended for combined administration, depending on the claim construction and factual record. The claim does not clearly require a fixed-dose tablet in every case.

Claim-by-claim scope

Claim	Subject matter	Commercial relevance
1	Broad combination of formula I ACE inhibitors and formula II dihydropyridines	Principal genus claim
2	Narrower formula I definitions and cyclic amino-acid structures	Intermediate genus
3	Further narrowed ACE-inhibitor structures, including proline-related compounds	Enalapril/lisinopril-focused scope
4	Enalapril-type and lisinopril-type compounds with formula II	Key species-oriented claim
5	Narrowed formula II substituent definitions	Dihydropyridine subgenus
6	Formula II compounds selected from nisoldipine, nicardipine and felodipine	Named calcium-channel blockers
7	1:1 to 1:10 weight ratio	Broad ratio limitation
8	1:1 to 1:3 weight ratio	Narrower ratio
9	1:3 weight ratio	Specific ratio
10	Treatment of circulatory diseases	Method-of-use claim
11	Treatment of hypertension	Core therapeutic-use claim
12	Medicament containing the combination	Composition/product claim
13	Solvent dissolution, evaporation and mixing process	Manufacturing claim
14	Enalapril or lisinopril with nitrendipine, nisoldipine, nicardipine or felodipine	Narrow named-species combination
15	Enalapril with nitrendipine	Most specific composition claim
16	Hypertension treatment using the named ACE inhibitor and dihydropyridine combinations	Specific method claim
17	Hypertension treatment using enalapril and nitrendipine	Narrowest treatment claim

What patent expiration date applies to U.S. Patent 4,703,038?

The patent issued in 1987, before the Uruguay Round Agreements Act changed the ordinary U.S. patent term to 20 years from the earliest effective nonprovisional filing date. The ordinary term for this patent was therefore 17 years from issuance.

On that basis, the patent expired on October 27, 2004. The patent is not a current exclusionary right.

The expiration applies to all claim categories, including:

Combination compositions;
Enalapril-dihydropyridine combinations;
Lisinopril-dihydropyridine combinations;
The 1:1 to 1:10 ratios;
Hypertension treatment methods;
The claimed manufacturing process.

Later patents could have protected particular formulations, extended-release systems, salts, dosage regimens or commercial products. Those later rights would not extend the term of U.S. Patent 4,703,038.

What is the Orange Book status of U.S. Patent 4,703,038?

U.S. Patent 4,703,038 is not a current Orange Book barrier. The patent expired before the current commercial patent disputes involving many fixed-dose antihypertensive products.

The patent’s combination concept is relevant to the historical development of products containing enalapril and felodipine. A prominent example is Lexxel, a combination of enalapril maleate and extended-release felodipine. Lexxel received FDA approval in the 1990s, after the patent issued and before its expiration. The product’s later regulatory and patent position depended on its approved formulation and separately listed patents, not solely on U.S. Patent 4,703,038.

An Orange Book listing does not itself extend patent life. Once the patent expired, an ANDA applicant could no longer face a viable Paragraph IV challenge directed to this patent.

FDA and regulatory relevance

Ingredient or combination	FDA position relevant to the patent landscape
Enalapril	FDA-approved ACE inhibitor; marketed as enalapril maleate
Lisinopril	FDA-approved ACE inhibitor
Nicardipine	FDA-approved calcium-channel blocker
Felodipine	FDA-approved calcium-channel blocker, including extended-release products
Nisoldipine	FDA-approved calcium-channel blocker
Nitrendipine	Not historically a major U.S. commercial product; availability has been jurisdiction-dependent
Enalapril/felodipine	FDA-approved fixed-dose combination marketed as Lexxel

FDA approval of the individual ingredients does not establish approval of every combination covered by the patent.

Were there Paragraph IV challenges to this patent?

A current Paragraph IV challenge is not legally relevant because the patent expired in 2004. Paragraph IV certification is used against listed patents that remain unexpired or otherwise affect approval timing. An ANDA applicant would not need to certify that it would infringe an expired patent.

No meaningful current generic-entry risk attaches to U.S. Patent 4,703,038. Any historical Paragraph IV activity would have occurred before expiration and would need to be evaluated from the relevant NDA, Orange Book editions, ANDA records and litigation docket. The patent’s present status is not dependent on such a challenge.

The practical distinction is:

Before October 27, 2004: a listed patent could have delayed approval or generated Hatch-Waxman litigation.
After October 27, 2004: the patent could no longer block generic approval or commercial sale.

What formulation patents are separate from U.S. 4,703,038?

The patent is principally a combination patent. It does not provide a detailed modern controlled-release formulation platform.

A later product such as enalapril/felodipine extended release could raise separate issues involving:

Extended-release felodipine matrices;
Tablet architecture;
Release-rate control;
Particle size and polymorph selection;
Salt form and stability;
Bilayer or multilayer dosage forms;
Coating systems;
Manufacturing processes;
Fixed-dose dosing schedules.

Those features may be protected by later formulation or process patents. They are not automatically covered by the claims of U.S. 4,703,038.

Claim 13 is limited to a preparation process in which the formula I and formula II compounds are dissolved in inert solvents, the solvent is evaporated, and the resulting combination is mixed with auxiliaries if appropriate. This claim could be relevant to a particular manufacturing route, but it does not automatically cover every tablet or capsule containing the two ingredients.

How strong is the patent estate for enalapril and felodipine combinations?

As a live estate, it is weak because U.S. 4,703,038 has expired. As a historical blocking patent, it was more important for the combination concept than for a particular commercial formulation.

Strengths

Claim 1 covers a broad ACE-inhibitor and dihydropyridine combination concept.
Claims 4, 14, 15, 16 and 17 identify commercially recognizable species.
Claims 7 through 9 create defined ratio positions.
Claims 10 and 11 provide method-of-use coverage for hypertension.

Weaknesses

The broad Markush language creates potential written-description and enablement issues across the full genus.
The claim text contains apparent drafting and transcription inconsistencies.
The claims require a combination, limiting their application to single-agent products.
The patent does not by itself establish protection for extended-release technology.
The patent term ended before current combination-product competition developed.
Some named compounds, particularly nitrendipine, had limited U.S. commercial relevance.

The strongest historical claims were likely the narrow species claims, particularly claims 14, 15 and 17. The broadest claim, claim 1, was more exposed to validity and construction disputes because it covered a wide chemical space.

What generic launch risks exist today?

There is no current U.S. generic launch risk from this patent. Generic or authorized-generic products can enter without waiting for the expiration of U.S. 4,703,038.

Potential barriers could arise only from separate rights, such as:

Later patents covering an extended-release formulation;
Patents on a specific fixed-dose dosage form;
Patents on a new dosing regimen;
Manufacturing patents;
Regulatory exclusivity attached to a later-approved product;
Trade-secret manufacturing controls.

Those rights would need to be assessed independently. U.S. 4,703,038 cannot support a present injunction against a generic manufacturer.

Which companies and products are most relevant?

The original patent landscape centered on companies developing ACE inhibitors and calcium-channel blockers. The commercially relevant products included:

Product or ingredient	Relevance
Enalapril maleate	Formula I species; principal ACE-inhibitor component
Lisinopril	Formula I species; named in claims 4, 14 and 16
Felodipine	Formula II species; important to later fixed-dose combination products
Nicardipine	Named formula II species
Nisoldipine	Named formula II species
Nitrendipine	Specifically claimed with enalapril in claim 15
Lexxel	Historical enalapril/felodipine combination product

The patent does not create a current competitive advantage for any one manufacturer. Competition is now determined by ingredient availability, formulation patents, FDA approval status, manufacturing economics and market demand.

How does this patent compare with patents on individual drugs?

U.S. 4,703,038 differs from basic compound patents in three ways.

First, it does not claim enalapril, lisinopril or felodipine as standalone molecules. Second, it requires a therapeutic or pharmaceutical combination. Third, its value depended on simultaneous use of two drug classes.

Patent type	Typical protected subject matter	Relation to U.S. 4,703,038
Basic compound patent	New ACE inhibitor or calcium-channel blocker molecule	Separate and usually earlier
Salt or polymorph patent	Specific crystalline or salt form	Separate
Formulation patent	Extended release, bilayer, coating or stability	Separate
Method-of-use patent	Treatment of hypertension or another indication	Partly overlapping in concept
Combination patent	Two active ingredients used together	Core subject of U.S. 4,703,038
Manufacturing patent	Synthesis or dosage-form production method	Claim 13-type subject matter

Does biosimilar risk apply?

No. Biosimilar law is not relevant to this patent because the claimed products are small-molecule drugs, not biologics.

The appropriate regulatory pathway for a generic version of an approved small-molecule product is generally an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act. A fixed-dose combination can require demonstration of pharmaceutical equivalence and bioequivalence for the approved product, but it is not a biosimilar application.

Key Takeaways

U.S. Patent 4,703,038 covers combinations of ACE inhibitors and 1,4-dihydropyridine calcium-channel blockers.
The principal ACE-inhibitor species are enalapril-type and lisinopril-type compounds.
The principal dihydropyridine species are nitrendipine, nisoldipine, nicardipine and felodipine.
Claim 15 specifically covers enalapril with nitrendipine.
Claims 10, 11, 16 and 17 cover hypertension-treatment methods.
Claim 13 covers a solvent-dissolution and evaporation preparation process.
The patent issued on October 27, 1987, and expired no later than October 27, 2004, under the ordinary pre-URAA term.
It is not a current U.S. Orange Book or Paragraph IV barrier.
Any present commercial risk must come from later formulation, dosage-form, manufacturing or regulatory rights.
The patent has no biosimilar relevance.

FAQs About U.S. Patent 4,703,038

Does U.S. Patent 4,703,038 still block enalapril and felodipine products?

No. The patent expired in 2004 and cannot presently block manufacture, approval or sale based on its claims.

Did U.S. Patent 4,703,038 cover Lexxel?

The patent’s claimed combination concept is relevant to an enalapril/felodipine product such as Lexxel. Lexxel’s complete patent position also depended on later product, formulation and regulatory rights.

Is nitrendipine specifically covered by the patent?

Yes. Claim 15 specifically recites a combination of the enalapril-type ACE inhibitor and nitrendipine. Claims 14 and 16 also include nitrendipine among named combination options.

Can a company challenge this patent under Paragraph IV today?

No practical Paragraph IV challenge is required against an expired patent. The applicant can proceed without treating the expired patent as a current approval-blocking right.

Are fixed-dose ACE-inhibitor and calcium-channel-blocker tablets covered by this patent?

They could fall within the composition claims if they contain qualifying formula I and formula II compounds. A particular extended-release or multilayer product may also require analysis of later formulation patents.

References

U.S. Patent No. 4,703,038. (1987). Combinations of an angiotensin-converting enzyme inhibitor and a dihydropyridine calcium antagonist. U.S. Patent and Trademark Office.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
U.S. Food and Drug Administration. (1997). Lexxel: Enalapril maleate and felodipine extended-release tablets prescribing information. FDA.
U.S. Patent and Trademark Office. (2024). Patent term adjustment and patent term examination guidance. USPTO.
U.S. Food and Drug Administration. (2024). Abbreviated new drug application regulations and patent certifications under the Hatch-Waxman Act. FDA.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	3437917	Oct 17, 1984

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	44650	⤷ Start Trial
Australia	4840085	⤷ Start Trial
Canada	1251733	⤷ Start Trial
German Democratic Republic	239525	⤷ Start Trial
Germany	3437917	⤷ Start Trial
Germany	3571550	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,703,038

Summary for Patent: 4,703,038