United States Drug Patent 5,112,861: Claim Scope, Expiration, and COMT-Inhibitor Patent Landscape
US Patent 5,112,861 covers methods of treating Parkinson's disease by combining levodopa with a catechol-O-methyltransferase, or COMT, inhibitor. The patent is directed to therapeutic use, not to a standalone composition or compound. Its two most commercially relevant species are the compounds identified in claims 9 and 13, corresponding to tolcapone-type and entacapone-type nitrocatechol COMT inhibitors, respectively.
The patent issued on May 12, 1992. Its original 17-year term therefore ended in 2009, absent an unusual adjustment or restoration. The patent does not present a current blocking right against generic entacapone, tolcapone, levodopa combinations, or COMT-inhibitor products.
What does US Patent 5,112,861 protect?
The patent protects a treatment method requiring two central elements:
- Administration of a COMT-inhibiting compound within the claimed chemical genus or one of the specifically recited species.
- Administration of a therapeutically sufficient amount of levodopa.
The independent claims are method-of-treatment claims. They do not claim:
- The chemical compounds per se;
- A tablet, capsule, suspension, or other dosage form;
- A fixed-dose combination composition;
- A manufacturing process;
- A pharmaceutical packaging system; or
- A diagnostic method.
The claim architecture is:
| Claim group |
Subject matter |
Principal limitation |
| Claims 1-8 |
Generic method claims |
Formula I COMT inhibitor plus levodopa |
| Claims 2-5 |
Subgenus limitations |
Nitro or cyano substituents and defined R4/R5 groups |
| Claims 6-8 |
Combination-treatment limitations |
Addition of a peripheral decarboxylase inhibitor |
| Claims 9-12 |
Specific compound method |
3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione plus levodopa |
| Claims 13-16 |
Specific compound method |
N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide plus levodopa |
The claim set is commercially important because it reaches the therapeutic concept later used in COMT inhibitor products: extending levodopa exposure by reducing peripheral and central levodopa metabolism through COMT inhibition.
How broad is claim 1 of US 5,112,861?
Claim 1 is a Markush method claim. It covers a Parkinson's disease treatment method using a compound with the claimed Formula I and specified substituent classes.
The principal structural restrictions are:
- R1 and R2 must independently be hydrogen, an alkylcarbamoyl group containing two to five carbon atoms, or an alkylcarbonyl group containing two to five carbon atoms.
- X must be nitro or cyano.
- R3 must contain the defined R4/R5 substitution pattern.
- R4 must be cyano or an alkylcarbonyl group containing two to five carbon atoms.
- R5 must be cyano, an alkylcarbonyl group containing two to five carbon atoms, or a specified carbamoyl group.
- Pharmaceutically acceptable salts or esters are included.
- The compound must be administered in a COMT-inhibiting amount.
- Levodopa must also be administered in an amount sufficient to treat Parkinson's disease.
The claim is broad in chemical coverage but narrow in therapeutic context. A compound falling within the structural formula would not infringe claim 1 merely because it is manufactured, sold, or tested. The claimed method requires administration to a patient for Parkinson's disease together with levodopa.
What chemical substituents are covered?
The terms used in claim 1 cover short-chain acyl and carbamoyl substituents. In practical terms, the alkylcarbonyl limitation can reach groups such as acetyl, propionyl, butyryl, and related C2-C5 carbon-containing groups, subject to the precise construction of the claim and its specification.
The carbamoyl limitation is broader in substitution. It includes unsubstituted carbamoyl and carbamoyl substituted with:
- C1-C8 alkyl;
- C1-C8 hydroxyalkyl; or
- The specifically recited substituents in dependent claims 4 and 5.
Claim 2 narrows the genus by requiring nitro rather than cyano at X. Claims 4 and 5 narrow the R4/R5 pattern to cyano at R4 and substituted or unsubstituted carbamoyl at R5.
What do claims 9 and 13 specifically cover?
Claims 9 and 13 are separate species claims and are easier to analyze than claim 1.
Claim 9: 3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione
Claim 9 covers administration of the specified nitrocatechol compound with levodopa for Parkinson's disease. Claims 10-12 add a peripheral decarboxylase inhibitor, with carbidopa and benserazide expressly identified.
This species is associated with the tolcapone class of COMT inhibitors. The claim does not require a particular commercial brand, dosage strength, route of administration, or fixed-dose product.
Claim 13: N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide
Claim 13 covers administration of the specified compound with levodopa. Claims 14-16 add a peripheral decarboxylase inhibitor, again identifying carbidopa and benserazide.
The compound recited in claim 13 is entacapone. Entacapone is marketed in the United States as Comtan and, in combination with levodopa and carbidopa, as Stalevo. FDA-approved labeling identifies entacapone as a COMT inhibitor used with levodopa/carbidopa in patients with Parkinson's disease experiencing end-of-dose "wearing-off" symptoms (U.S. Food and Drug Administration [FDA], 2010; FDA, 2013).
How do the dependent claims affect infringement scope?
Claims 6-8 and 10-12 and 14-16 impose additional treatment requirements.
A method falling within claim 7 must include:
- The relevant Formula I compound;
- Levodopa;
- A peripheral decarboxylase inhibitor; and
- Carbidopa specifically.
A method falling within claim 8 substitutes benserazide for carbidopa.
The same structure applies to claims 11-12 and 15-16. These dependent claims may be narrower than the corresponding independent claims because they require a particular third active ingredient.
The term "peripheral decarboxylase inhibitor" reflects the pharmacological rationale for levodopa therapy. Carbidopa and benserazide reduce peripheral conversion of levodopa to dopamine, increasing levodopa delivery to the brain. The patent therefore covers both:
- A two-component regimen of COMT inhibitor plus levodopa; and
- A three-component regimen of COMT inhibitor, levodopa, and carbidopa or benserazide.
When did US Patent 5,112,861 lose exclusivity?
US Patent 5,112,861 issued on May 12, 1992. For a pre-June 8, 1995 application subject to the former patent-term regime, the ordinary term was 17 years from issuance. On that basis, the patent expired on May 12, 2009.
| Event |
Date |
| Patent issued |
May 12, 1992 |
| Ordinary term |
17 years from issuance |
| Estimated ordinary expiration |
May 12, 2009 |
| Current enforceability |
Expired |
| Current generic blocking effect |
None from this patent |
Patent expiration eliminates the right to enforce the patent against post-expiration conduct. It does not invalidate historical infringement claims that accrued before expiration, subject to applicable limitation periods and litigation-specific issues.
The patent's expiration also means that claims 9 and 13 cannot presently block generic entacapone or tolcapone products. Any current exclusivity must arise from later patents, regulatory exclusivity, pediatric exclusivity, or other intellectual-property rights.
What is the Orange Book status of US Patent 5,112,861?
The patent is no longer a live Orange Book barrier because its patent term expired in 2009. Historical Orange Book treatment must be distinguished from current regulatory status.
For entacapone products, later patents associated with Comtan and Stalevo were more commercially relevant to generic approval timing than an expired 1992 method patent. FDA's Orange Book identifies patents and exclusivity associated with approved drug products, but an expired patent does not create a current statutory stay or prevent an ANDA from receiving final approval (FDA, 2024).
A generic applicant challenging a live listed patent may file a Paragraph IV certification. A Paragraph IV certification directed only to an expired patent does not create a current 30-month stay against approval.
Which companies challenged the entacapone patent estate?
Generic competition for entacapone developed through ANDA filings directed at later Orange Book-listed patents, not through a current challenge to the expired US 5,112,861 patent.
The relevant commercial pathways include:
- Generic entacapone tablets;
- Generic carbidopa/levodopa/entacapone combination tablets;
- Authorized or licensed generic versions of entacapone-containing products; and
- Separate administration of generic carbidopa/levodopa with generic entacapone.
Available public FDA materials establish the ANDA pathway and product approvals, but the specific litigation history for each applicant depends on the later patent numbers and district-court docket. US 5,112,861 itself is not a current litigation obstacle.
How does this patent compare with later entacapone patents?
US 5,112,861 is an early foundational method patent. Later patents generally pursued narrower or commercially differentiated subject matter:
| Patent category |
Typical protection |
Relevance to entacapone products |
| Basic compound patents |
Chemical structure |
May cover entacapone or related nitrocatechols |
| Method-of-use patents |
Parkinson's disease, wearing-off, dosing |
May cover treatment regimens |
| Formulation patents |
Tablets, coatings, excipients, release characteristics |
May affect product-specific substitution |
| Combination patents |
Levodopa/carbidopa/entacapone products |
Relevant to Stalevo-type products |
| Manufacturing patents |
Synthesis, purification, polymorphs |
May create process or supply-chain barriers |
| Regulatory exclusivity |
New-drug, pediatric, or other FDA exclusivity |
Can delay approval independently of patent term |
The 5,112,861 claims are not formulation claims. A later patent covering a tablet composition, crystalline form, manufacturing process, or specific dosing schedule would need independent analysis.
What patent litigation risks exist for generic launch?
For a current generic launch, the principal risks are not claims 9 or 13 of US 5,112,861. The practical risk assessment should focus on:
- Later unexpired compound or formulation patents;
- Orange Book-listed method-of-use patents;
- Induced-infringement theories based on product labeling;
- Fixed-dose combination patents covering carbidopa/levodopa/entacapone;
- Manufacturing patents held by the originator or active pharmaceutical ingredient supplier; and
- Settlement agreements that restrict launch timing.
Because the patent claims treatment rather than the product itself, an ANDA applicant could potentially avoid infringement through a permitted carve-out of patented indications. That strategy depends on whether the relevant indication can be removed from labeling without making the remaining label encourage the patented method.
For claims 9 and 13, however, expiration removes the principal litigation risk.
Does the patent create biosimilar risk?
No. Entacapone, tolcapone, levodopa, carbidopa, and benserazide are small-molecule drugs. They are not biologics subject to the biosimilar pathway under the Public Health Service Act.
The relevant FDA pathway is an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act. A biosimilar application under section 351(k) is not applicable to this patent estate or these active ingredients.
What manufacturing and geographic barriers remain?
US Patent 5,112,861 does not create a current manufacturing barrier. Its claims require therapeutic administration, not production of the active ingredient.
Remaining barriers may arise from:
- Active pharmaceutical ingredient specifications;
- Process patents in the United States or foreign jurisdictions;
- Polymorph or solid-state patents;
- Impurity-control methods;
- Country-specific patent rights;
- Regulatory requirements for bioequivalence; and
- Supplier qualification and stability data.
Patent expiration in the United States does not automatically terminate corresponding rights in Europe, Japan, China, or other countries. Each jurisdiction must be assessed separately. A US expiration date cannot be used as the expiration date for a foreign counterpart.
How strong is the patent estate for commercial purposes?
The patent was historically strong as an early method patent because it linked COMT inhibition to levodopa treatment in Parkinson's disease and expressly covered commercially important species. Its present strength is low because the patent has expired.
| Factor |
Assessment |
| Claim breadth |
Moderate to broad within defined nitrocatechol genus |
| Species coverage |
Strong for the compounds expressly recited |
| Product coverage |
Indirect; no composition claim |
| Formulation coverage |
None in the provided claims |
| Manufacturing coverage |
None in the provided claims |
| Current enforceability |
None after expiration |
| ANDA blocking effect |
None from this patent |
| Biosimilar relevance |
None |
| Historical commercial importance |
High |
| Current launch risk |
Low from this patent |
Key Takeaways
- US Patent 5,112,861 is a method-of-treatment patent covering COMT inhibition combined with levodopa for Parkinson's disease.
- Claim 1 covers a defined Markush genus of nitro- and cyano-substituted catechol compounds.
- Claims 9 and 13 specifically cover two commercially important COMT inhibitor species, including entacapone in claim 13.
- Claims 6-8, 10-12, and 14-16 add carbidopa or benserazide as peripheral decarboxylase inhibitors.
- The patent issued on May 12, 1992, and its ordinary 17-year term expired on May 12, 2009.
- The patent contains no formulation, composition, manufacturing, or biologic claims.
- It is not a current barrier to generic entacapone, tolcapone, or levodopa-combination products.
- Current launch analysis must focus on later patents, Orange Book listings, formulation rights, combination-product claims, and ANDA litigation.
FAQs
Does US 5,112,861 claim entacapone itself?
No. Claim 13 claims a method of administering entacapone with levodopa for Parkinson's disease. It does not claim entacapone as a standalone chemical composition.
Can a generic manufacturer rely on the expiration of US 5,112,861?
Yes, the patent's expiration removes its current enforcement value. The manufacturer must still assess later unexpired patents and regulatory requirements.
Does claim 13 require carbidopa?
No. Claim 13 requires entacapone and levodopa. Carbidopa is required only in dependent claim 15, which depends through claims 14 and 10.
Is a fixed-dose Stalevo-type tablet covered by these claims?
The claims can read on a method using the relevant active ingredients, but they do not claim a fixed-dose tablet as a product. Separate formulation or combination patents would require independent analysis.
Can the patent be used against a benserazide-containing levodopa regimen?
Historically, yes, if the other claim elements were met. Claims 8, 12, and 16 expressly identify benserazide. The expired patent cannot create a current infringement barrier.
References
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U.S. Patent No. 5,112,861. (1992). Treatment of Parkinson's disease with nitrocatechol derivatives. United States Patent and Trademark Office.
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U.S. Food and Drug Administration. (2010). Comtan (entacapone) prescribing information. FDA.
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U.S. Food and Drug Administration. (2013). Stalevo (carbidopa, levodopa, and entacapone) prescribing information. FDA.
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U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
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United States Code, 35 U.S.C. § 154. Patent term.
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United States Code, 21 U.S.C. § 355. New drugs and abbreviated new drug applications.
