Details for Patent: 5,236,952

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Summary for Patent: 5,236,952

Title:	Catechol derivatives
Abstract:	Catechol derivatives of the formula Ia wherein Ra, Rb and Rc have the significance given herein, the ester and ether derivatives thereof which are hydrolyzable under physiological conditions and the pharmaceutically acceptable salts thereof are described and possess valuable pharmacological properties. In particular, they inhibit the enzyme catechol-O-methyltransferase (COMT), a soluble, magnesium-dependent enzyme which catalyses the transference of the methyl group of S-adensoylmethionine to a catechol substrate, whereby the corresponding methyl ethers are formed. Suitable substrates which can be O-methylated by COMT and which can thus be deactivated are, for example, extraneuornal catecholamines and exogeneously-administered therapeutically active substances having a catechol structure. Formula Ia above embraces not only compounds which form part of the invention, but also known compounds; the compounds which form part of the invention can be prepared according to known methods.
Inventor(s):	Karl Bernauer, Janos Borgulya, Hans Bruderer, Mose DaPrada, Gerhard Zurcher
Assignee:	Inovail Singapore Pte Ltd
Application Number:	US07/686,210
Patent Claim Types: see list of patent claims	Use; Composition; Compound;

United States Patent 5,236,952: Scope, Tolcapone Claims, Expiration, and Patent Landscape

US Patent 5,236,952 covers nitrocatechol benzophenone compounds that inhibit catechol-O-methyltransferase, or COMT, and pharmaceutical compositions containing them. Its principal commercial relevance is tolcapone, also known as 3,4-dihydroxy-5-nitrobenzophenone, marketed as Tasmar for adjunctive treatment of Parkinson's disease with levodopa and a peripheral decarboxylase inhibitor.

The patent issued on August 17, 1993, under the pre-Uruguay Round patent-term regime. Its 17-year term therefore expired on August 17, 2010, absent a later-extending continuation or patent-term adjustment. The core compound, composition, Parkinson's disease, depression, and COMT-inhibition claims are no longer enforceable. Current generic competition is governed primarily by FDA approval requirements, labeling, manufacturing controls, and any later patents, rather than by US 5,236,952.

What drug and chemical class does US Patent 5,236,952 protect?

The patent protects substituted catechol benzophenones having a nitro or cyano substituent and a second hydrogen or halogen substituent. The central structure is a benzophenone linked to a 3,4-dihydroxy substituted aromatic ring.

The most important commercial compound is:

Compound	Chemical name	Commercial relevance
Tolcapone	3,4-Dihydroxy-5-nitrobenzophenone	Active ingredient in Tasmar
Fluorotolcapone analogue	2'-Fluoro-3,4-dihydroxy-5-nitrobenzophenone	Expressly claimed, but not the principal marketed product
Methyl analogue	3,4-Dihydroxy-4'-methyl-5-nitrobenzophenone	Expressly claimed in composition and method claims
Other covered analogues	Nitro- or cyano-substituted catechol benzophenones	Covered by the genus claim, subject to the exact structural formula and limitations

Tolcapone inhibits peripheral and central COMT. In Parkinson's disease, COMT inhibition reduces methylation of levodopa and increases the fraction of levodopa available for conversion to dopamine. The FDA approved Tasmar as an adjunct to levodopa/carbidopa or levodopa/benserazide treatment. [1]

What are the principal claim categories in US 5,236,952?

The 22 claims divide into four groups: chemical compounds, pharmaceutical compositions, combination therapy, and therapeutic-use claims.

Compound claims

Claims 1 through 7 and 14 claim chemical compounds.

Claim 1 is the broad compound genus. It requires:

• A benzophenone-type core represented by the patent formula.
• Ra as nitro or cyano.
• Rb as hydrogen or halogen.
• Rc' as a carbonyl-linked substituted phenyl group.
• Optional mono- or disubstitution of that phenyl group by halogen, cyano, hydroxy, or lower alkyl.
• Physiologically hydrolyzable ester or ether derivatives.
• Pharmaceutically acceptable salts.

Claims 2 through 5 narrow the substitution pattern. Claim 2 places Rb para to Ra. Claim 3 limits Ra to nitro. Claim 4 limits Rb to hydrogen, chlorine, or fluorine. Claim 5 narrows Rb to hydrogen.

Claims 6 and 7 identify specific compounds:

• Claim 6: 3,4-dihydroxy-5-nitrobenzophenone, generally identified as tolcapone.
• Claim 7: 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone.

Claim 14 separately identifies a methyl-substituted nitrobenzophenone. The supplied claim text states "4-dihydroxy-5'-methyl-5-nitrobenzophenone," while related claims identify 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone. The patent's issued text and prosecution record control the precise positional interpretation.

Composition claims

Claims 8 through 10 cover pharmaceutical compositions containing a claimed compound and a therapeutically inert carrier.

Claim 8 is the broad composition claim. It does not require levodopa, a decarboxylase inhibitor, or a Parkinson's disease indication. Claims 9 and 10 narrow the composition to tolcapone and the 2'-fluoro analogue.

These claims potentially reached tablets, capsules, powders, solutions, or other dosage forms containing a covered compound with conventional excipients. The claim language does not require a particular release profile, dosage strength, particle size, polymorph, or manufacturing process.

Levodopa combination claims

Claims 11 through 13 cover compositions comprising:

1. L-dopa;
2. A peripheral decarboxylase inhibitor;
3. A claimed nitrocatechol benzophenone; and
4. An inert carrier.

Claims 12 and 13 narrow the compound to tolcapone and the 2'-fluoro analogue.

These claims are directed to combination products or combination therapy formulations. They do not claim levodopa/carbidopa by itself. A product containing levodopa and carbidopa without a claimed COMT inhibitor would not fall within these claims.

Method-of-treatment and enzyme-inhibition claims

Claims 17 through 22 cover therapeutic compositions rather than conventional standalone method claims.

Claims 17 and 18 address treatment of depression using a covered compound, with claim 18 specifying the methyl analogue.

Claims 19 and 20 address treatment of Parkinson's disease using L-dopa, a peripheral decarboxylase inhibitor, and a covered compound.

Claims 21 and 22 address inhibition of COMT, with claim 22 specifying the methyl analogue.

The claims are framed as pharmaceutical compositions "for treating" or "for inhibiting," rather than as pure method claims. Their scope depends on the claimed composition and structural limitations.

How broad is claim 1?

Claim 1 is a genus claim, but it is not an unrestricted claim to all COMT inhibitors or all catechol compounds.

Its principal limitations are:

Limitation	Scope effect
Nitro or cyano Ra group	Excludes unsubstituted and many other electron-withdrawing substituents
Hydrogen or halogen Rb group	Limits the adjacent ring position
Benzophenone carbonyl linkage	Excludes non-benzophenone catechols
Substituted phenyl group	Permits selected halogen, cyano, hydroxy, and lower-alkyl substitutions
Hydrolyzable ester or ether derivatives	Extends coverage to selected prodrug-type derivatives
Pharmaceutically acceptable salt	Extends coverage to qualifying salt forms

The genus is commercially meaningful because it includes tolcapone and several close analogues. Its practical value against a generic tolcapone product would have depended on whether the generic product contained tolcapone itself, a covered salt, a covered derivative, or a formulation meeting the composition limitations.

A generic product containing only tolcapone would have been directly relevant to claims 6, 8, 9, 11, 12, 17, 19, 21, and potentially 22, depending on the product configuration and the claim construction applied.

What patents protect tolcapone and Tasmar?

US 5,236,952 is the principal early US compound patent associated with tolcapone. The broader patent estate also included later patents directed to pharmaceutical compositions and related uses.

Patent	General subject matter	Relevance to tolcapone	Status
US 5,236,952	Nitrocatechol benzophenone compounds and compositions	Core compound and therapeutic claims	Expired August 17, 2010
US 5,446,194	Related pharmaceutical composition and formulation subject matter	Potentially relevant to Tasmar and tolcapone formulations	Expired under its applicable statutory term
FDA NDA 20-397	Tasmar, tolcapone tablets	Regulatory product record, not a patent	Approved in 1997; subject to safety restrictions

The precise scope of any later patent must be assessed independently. A later formulation patent cannot revive expired compound claims. It may, however, have delayed a particular formulation or dosing regimen if the patent remained enforceable during the relevant period.

The Orange Book, rather than the patent specification alone, determines which patents were formally listed against an approved product for FDA regulatory purposes. Orange Book listings can change through patent expiration, delisting, corrections, or regulatory updates. [2]

When did US Patent 5,236,952 lose exclusivity?

US 5,236,952 issued on August 17, 1993. Because it was governed by the pre-June 8, 1995 patent-term rules, the ordinary term was 17 years from issuance. The resulting expiration date was August 17, 2010. [3]

Milestone	Date
Patent issued	August 17, 1993
Statutory term	17 years from issuance
Core patent expiration	August 17, 2010
FDA Tasmar approval	1997
Current enforceability of US 5,236,952	None after expiration

Patent expiration eliminated enforceability of the claims. It did not eliminate the compound's regulatory requirements, safety warnings, or manufacturing obligations.

What was the FDA regulatory status of tolcapone?

The FDA approved Tasmar in 1997 for use with levodopa/carbidopa or levodopa/benserazide in patients with idiopathic Parkinson's disease experiencing motor fluctuations. Tolcapone carries serious hepatotoxicity risks, and its labeling includes liver-monitoring requirements and restrictions on use. [1]

Tolcapone's regulatory history affects commercial entry in three ways:

1. A generic applicant must demonstrate pharmaceutical equivalence and bioequivalence through an abbreviated new drug application, unless another FDA pathway applies.
2. The applicant must address the reference product's safety labeling, including liver-function monitoring.
3. Approval does not depend on the expired compound patent, but FDA review remains necessary.

The product's safety profile can be a more significant commercial barrier than the expired patent. Physicians and payers may favor alternative COMT inhibitors, including entacapone and opicapone, because of differences in monitoring and tolerability.

Were there Paragraph IV challenges to US 5,236,952?

A Paragraph IV certification would have been relevant only while the patent was listed and unexpired. The certification would assert that the patent was invalid, unenforceable, or would not be infringed by the proposed generic product.

The supplied record does not identify a specific Paragraph IV notice, ANDA number, or final judgment directed to US 5,236,952. No current Paragraph IV risk remains against this patent because it expired in 2010.

For historical diligence, the relevant questions are:

• Whether the patent was listed in the Orange Book for Tasmar.
• Whether an ANDA applicant sent a Paragraph IV notice before expiration.
• Whether the reference sponsor filed an infringement action within 45 days.
• Whether a 30-month stay was imposed.
• Whether the parties entered a settlement affecting the generic launch date.

Without a cited court docket or FDA Orange Book historical entry, no specific challenger or settlement should be attributed to this patent.

Which companies challenged or competed with tolcapone?

Tolcapone competed in a small COMT-inhibitor market.

Product	Active ingredient	Developer or sponsor	Competitive position
Tasmar	Tolcapone	Roche, later marketed through commercial partners	Strong COMT inhibition but significant liver-safety monitoring
Comtan	Entacapone	Novartis	Major alternative COMT inhibitor; generally used with each levodopa dose
Stalevo	Carbidopa/levodopa/entacapone	Novartis	Fixed-dose combination product
Ongentys	Opicapone	BIAL, later commercialized by Neurocrine in the US	Once-daily COMT inhibitor with later market entry

The key competitive issue was not only patent scope. It was the balance between dosing convenience, liver safety, labeling restrictions, physician adoption, and payer coverage.

Does US 5,236,952 create biosimilar risk?

No. Tolcapone is a small-molecule chemical drug, not a biologic. Biosimilar pathways under section 351(k) of the Public Health Service Act do not apply.

The relevant competitor pathway is an ANDA for a generic drug, or in some circumstances a 505(b)(2) application for a modified formulation or delivery system. The principal barriers are:

• Bioequivalence;
• Pharmaceutical equivalence;
• Matching or appropriately addressing FDA labeling;
• Control of impurities and degradation products;
• Demonstration of consistent dissolution;
• Compliance with manufacturing requirements; and
• Management of hepatic safety risks.

What manufacturing and formulation issues matter?

The expired patent does not claim every way to manufacture tolcapone. Its claims focus on compounds and compositions. Manufacturing freedom-to-operate therefore turns on later patents, process patents, trade secrets, and regulatory controls.

Relevant technical issues include:

• Regioselective synthesis of the nitrocatechol benzophenone;
• Control of nitro-group reduction and oxidative impurities;
• Purity of the catechol moiety;
• Stability against oxidation;
• Tablet formulation and dissolution;
• Packaging that limits moisture and oxidative degradation;
• Control of polymorphic or crystalline forms, if applicable; and
• Analytical methods used for release testing.

A generic manufacturer may avoid an expired composition patent while still facing a later process or solid-form patent. Such later rights require separate claim and family analysis.

What is the current generic launch risk?

For US 5,236,952 itself, generic launch risk is low because the patent expired more than 15 years ago. The patent cannot block a current generic tolcapone product.

The remaining commercial risks are regulatory and market-based:

Risk	Current assessment
Infringement of US 5,236,952	None after expiration
Biosimilar litigation	Not applicable
Paragraph IV litigation under this patent	Historical only
FDA approval risk	Material
Liver-safety labeling risk	Material
Generic price erosion	Likely if multiple approved suppliers enter
Market size	Limited by safety concerns and competing COMT inhibitors
Later formulation or process patents	Requires independent review

How strong was the patent estate for tolcapone?

During its enforceable period, the estate was relatively strong against products containing tolcapone because claim 6 directly identified the principal molecule. The combination claims also targeted the principal clinical use with levodopa and a peripheral decarboxylase inhibitor.

Its limitations were equally clear:

• The patent did not cover all COMT inhibitors.
• It did not cover levodopa/carbidopa alone.
• It did not automatically cover unrelated formulations or manufacturing processes.
• Several claims depended on specific structural and compositional limitations.
• The patent term ended before the modern US generic market matured for many products.

The estate is now commercially weak as an exclusionary right because its core patent has expired. Its historical importance remains high for understanding tolcapone's original compound and use protection.

Key Takeaways

• US 5,236,952 covers nitrocatechol benzophenone COMT inhibitors and pharmaceutical compositions.
• Claim 6 identifies tolcapone, 3,4-dihydroxy-5-nitrobenzophenone.
• Claims 8 through 13 cover compositions, including levodopa and a peripheral decarboxylase inhibitor.
• Claims 17 through 22 address depression, Parkinson's disease, and COMT inhibition.
• The patent issued August 17, 1993, and expired August 17, 2010.
• Tolcapone is a small-molecule drug, so biosimilar analysis does not apply.
• No current Paragraph IV risk remains against US 5,236,952.
• Current entry barriers are FDA approval, hepatic safety management, manufacturing quality, and any later formulation or process patents.
• Tasmar's main therapeutic competitors are entacapone-containing products and opicapone.
• A complete freedom-to-operate opinion requires separate review of later US patents, Orange Book history, and relevant litigation records.

Frequently Asked Questions

Is US Patent 5,236,952 still enforceable?

No. Its 17-year pre-1995 patent term expired on August 17, 2010.

Does US 5,236,952 cover tolcapone tablets?

It covers compositions containing tolcapone and an inert carrier, including compositions corresponding to pharmaceutical tablets. It does not define every tablet formulation or manufacturing process.

Can a company market generic tolcapone without a Paragraph IV challenge?

Yes. Because the patent has expired, a current applicant does not need to challenge the patent through Paragraph IV. The applicant must still satisfy FDA approval requirements.

Is tolcapone protected by a biologic exclusivity period?

No. Tolcapone is a synthetic small-molecule drug. Biologic reference-product and biosimilar exclusivity rules do not apply.

What patent issue is most important after expiration of US 5,236,952?

The key issue is whether later patents cover a specific tolcapone formulation, solid form, manufacturing process, dosage regimen, or combination product. Those rights must be analyzed separately from the expired compound patent.

References

1. U.S. Food and Drug Administration. (1997). Tasmar (tolcapone) prescribing information. FDA.

2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.

3. United States Patent and Trademark Office. (1993). United States Patent No. 5,236,952: Nitrocatechol derivatives, process for their preparation and pharmaceutical compositions containing them. USPTO.

4. United States Patent and Trademark Office. (1995). United States Patent No. 5,446,194. USPTO.

Drugs Protected by US Patent 5,236,952

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 5,236,952

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Switzerland	980/86	Mar 11, 1986
Switzerland	62/87	Jan 09, 1987

International Family Members for US Patent 5,236,952

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0237929		SPC/GB97/088	United Kingdom
European Patent Office	0237929		97C0112	Belgium
European Patent Office	0237929		C970041	Netherlands