United States Patent 4,051,141: Claim Scope, Ticlopidine Coverage, Expiration, and Patent Landscape

U.S. Patent 4,051,141 covers a class of substituted tetrahydrothienopyridines, including 5-(2-chlorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine, the compound later known as ticlopidine. The patent issued on September 27, 1977, and its ordinary U.S. patent term expired in September 1994. It no longer presents an enforceable U.S. patent barrier to ticlopidine manufacture, formulation, or sale.

The patent is significant historically because it claims the core ticlopidine chemical entity. Its claims do not cover clopidogrel, prasugrel, ticagrelor, finished pharmaceutical formulations, manufacturing processes in general, or methods of treating patients.

What drug does U.S. Patent 4,051,141 protect?

U.S. Patent 4,051,141 protects substituted 4,5,6,7-tetrahydro-thieno[3,2-c]pyridines and pharmaceutically acceptable acid-addition salts. The principal commercial compound within the patent is ticlopidine.

Patent and product identification

Item	Information
U.S. patent	4,051,141
Patent title	Tetrahydrothienopyridine derivatives
Core chemical class	Substituted tetrahydrothieno[3,2-c]pyridines
Commercial compound	Ticlopidine
Ticlopidine chemical name	5-(2-chlorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine
Common marketed form	Ticlopidine hydrochloride
Original commercial brand	Ticlid
Original U.S. sponsor	Sanofi-related entities
Patent issue date	September 27, 1977
Ordinary patent expiration	September 27, 1994
Current enforceability	Expired

The patent’s principal commercial species is claim 2:

5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine and its pharmaceutically acceptable acid addition salts.

Ticlopidine is an oral antiplatelet drug that inhibits platelet aggregation through irreversible inhibition of the platelet P2Y12 ADP receptor pathway. The FDA approved Ticlid tablets for reduction of thrombotic stroke risk in certain patients and for maintaining coronary artery stent patency, subject to significant hematologic safety warnings (FDA, 2011).

What does claim 1 of U.S. Patent 4,051,141 cover?

Claim 1 is a Markush claim covering a broad chemical genus. It is broader than the individual compounds recited in claims 2 through 6.

The claim requires:

A tetrahydro-thienopyridine derivative with sulfur in the fused heterocyclic system.
A substituent represented by the claimed R, R1, R2, and n variables.
R groups selected from specified phenyl, substituted phenyl, benzoyl, and substituted benzoyl groups.
R1 substituents selected from hydrogen, halogen, hydroxy, and C1-C6 alkyl.
R2 selected from hydrogen and halogen.
n equal to 1 or 2.
A pharmaceutically acceptable acid-addition salt where the claimed compound is converted into such a salt.

Claim 1 structural scope

The R group options include:

Unsubstituted phenyl.
Phenyl substituted with one or two halogens.
Phenyl substituted with C1-C6 alkyl.
Phenyl substituted with C1-C6 alkoxy.
Hydroxy-substituted phenyl.
Nitro-substituted phenyl.
Benzoyl.
Chloro- or fluoro-substituted benzoyl.
Alkyl-substituted benzoyl.
Alkoxy-substituted benzoyl.
Mono- or dihydroxy-substituted benzoyl.
Nitro-substituted benzoyl.

The claim also allows variation in the carbon chain connecting the aromatic or benzoyl group to the thienopyridine nitrogen framework. Where n is 2, the R1 variables may have different meanings at each methylene or substituted methylene position.

This drafting approach gives claim 1 substantial genus coverage, while claims 2 through 6 identify specific compounds within that genus.

How do claims 2 through 6 differ?

Claims 2 through 6 are narrower species claims. Each covers one named benzyl-substituted tetrahydrothienopyridine and its pharmaceutically acceptable acid-addition salts.

Claim	Named compound	Principal substituent
2	5-(2-chlorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine	2-chlorobenzyl
3	5-(4-methoxybenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine	4-methoxybenzyl
4	5-(3,4,5-trimethoxybenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine	3,4,5-trimethoxybenzyl
5	5-(4-chlorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine	4-chlorobenzyl
6	5-(2-fluorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine	2-fluorobenzyl

Claim 2 is the commercially important claim because it specifically covers ticlopidine and ticlopidine salts, including ticlopidine hydrochloride.

Claims 3 through 6 cover analogues that were part of the disclosed chemical program but did not become the principal U.S. marketed product.

What salts are covered by the patent?

The claims extend to pharmaceutically acceptable acid-addition salts of the claimed bases. For ticlopidine, the principal commercial salt is ticlopidine hydrochloride.

The salt language does not create a separate claim to every pharmaceutical composition containing the compound. It covers the claimed chemical compound in salt form. A salt must remain within the scope of the claimed base and must qualify as a pharmaceutically acceptable acid-addition salt.

Potentially relevant salt categories include salts formed with pharmaceutically acceptable inorganic or organic acids. The commercial significance is concentrated in hydrochloride salt formulations.

The patent does not expressly claim:

Tablets as dosage forms.
Specific excipients.
Coated tablets.
Extended-release formulations.
Specific dissolution profiles.
Specific particle sizes.
Manufacturing equipment.
Packaging.
Patient treatment regimens.

What is the patent expiration date for U.S. Patent 4,051,141?

U.S. Patent 4,051,141 issued on September 27, 1977. Under the pre-Uruguay Round U.S. patent-term framework applicable to the patent, the ordinary term was 17 years from issuance. The patent therefore expired in September 1994.

Milestone	Date
U.S. application and priority period	Early 1970s
Patent issued	September 27, 1977
Ordinary 17-year expiration	September 27, 1994
Current status	Expired
Enforceable patent term remaining	None

The patent predates the modern 20-year term measured from the earliest effective nonprovisional filing date. The transition rules for older patents did not extend the patent beyond its applicable term in a commercially meaningful way.

There is no current patent-term-extension issue associated with U.S. Patent 4,051,141. Any regulatory exclusivity associated with the later Ticlid approval would have been separate from the expired compound patent and would not revive the patent.

What is the Orange Book status of ticlopidine?

Ticlopidine was approved in the United States as Ticlid tablets under NDA 19-979. The FDA labeling identifies ticlopidine hydrochloride as the active ingredient and describes its antiplatelet indications and boxed hematologic warnings (FDA, 2011).

The original compound patent expired before the principal generic-entry period. The current commercial issue is therefore regulatory and commercial rather than patent-based.

Orange Book implications

The relevant Orange Book conclusions are:

U.S. Patent 4,051,141 is expired.
The patent cannot support a current Paragraph IV litigation strategy.
No enforceable compound patent remains from the 1970s patent family.
Any historic Orange Book listing for the product would have ceased to block approval after expiration.
A current abbreviated new drug application would generally address ticlopidine hydrochloride equivalence, labeling, quality, and manufacturing requirements rather than the expired compound patent.

FDA regulatory approval does not by itself establish freedom from every possible patent claim. However, for the specific expired patent analyzed here, there is no remaining U.S. exclusionary right.

When did ticlopidine lose exclusivity?

Ticlopidine lost compound-patent exclusivity no later than September 1994 when U.S. Patent 4,051,141 expired. Regulatory exclusivity associated with FDA approval would have been shorter and would not extend the compound patent.

Ticlopidine also lost commercial exclusivity through the availability of generic ticlopidine hydrochloride tablets. The product’s commercial position declined because clopidogrel offered a more favorable safety and prescribing profile, especially after ticlopidine became associated with neutropenia, agranulocytosis, thrombotic thrombocytopenic purpura, and aplastic anemia risks.

The commercial lifecycle was therefore shaped by two separate events:

Patent expiry in 1994.
Clinical displacement by clopidogrel and subsequent generic competition.

Which companies challenged or competed with the ticlopidine patent?

The principal competitive activity involved generic manufacturers seeking approval for ticlopidine hydrochloride tablets after patent and regulatory barriers ceased to block entry.

Publicly relevant generic manufacturers have included companies such as:

Apotex.
Mylan.
Teva-related entities.
Other ANDA sponsors supplying or having supplied ticlopidine hydrochloride.

The available commercial record does not support treating U.S. Patent 4,051,141 as the basis for an active modern Paragraph IV dispute. Any ANDA challenge directed to this patent would have been rendered commercially ineffective by expiration.

Paragraph IV status

A Paragraph IV certification asserts that a listed patent is invalid, unenforceable, or will not be infringed. Because U.S. Patent 4,051,141 expired in 1994:

It cannot generate a current 30-month stay.
It cannot support a current infringement action against an ANDA applicant.
It cannot provide a current first-filer litigation advantage.
It has no remaining blocking value for ticlopidine generic entry.

What other patents are relevant to ticlopidine?

The ticlopidine patent estate included later patents and applications directed to related subject matter, including pharmaceutical compositions, crystalline or salt forms, preparation methods, and dosage-form technology.

A commonly cited later U.S. patent in the ticlopidine landscape is U.S. Patent 4,591,592. That patent is associated with later ticlopidine-related subject matter and had a term extending beyond U.S. Patent 4,051,141. Its expiration did not create a current barrier because it also expired.

Relevant patent categories

Patent category	Relevance to ticlopidine	Current status
Core compound patent	Covers ticlopidine chemical entity	Expired
Salt patent	May cover ticlopidine hydrochloride or related salt subject matter	Expired
Formulation patent	May cover tablet composition or dosage form	Expired
Process patent	May cover preparation or purification	Expired or commercially obsolete
Method-of-use patent	May cover antiplatelet indications	Expired or limited by statutory term
Manufacturing know-how	Process efficiency, impurity control, scale-up	May remain confidential, but not a patent barrier

The commercial distinction is important. A process patent could have been relevant to a particular manufacturing route without preventing production through a different route. A formulation patent could have covered a specific composition without covering the active ingredient itself. Neither category changes the expired status of claim 2 of U.S. Patent 4,051,141.

What formulations are protected by U.S. Patent 4,051,141?

The patent does not claim a specific formulation. Its claims are compound claims and salt claims.

A ticlopidine hydrochloride tablet could fall within claim 2 because it contains the claimed salt, but the patent’s legal coverage would arise from the chemical compound rather than from tablet architecture. The claim does not require:

A specified tablet weight.
A defined concentration.
A particular excipient.
A coating.
A dissolution rate.
A release profile.
A manufacturing method.

The formulation itself could have been subject to separate patents, but those rights would require independent claim analysis. They cannot be inferred from the compound claims.

Does U.S. Patent 4,051,141 cover clopidogrel or prasugrel?

No. U.S. Patent 4,051,141 does not provide a current patent basis for clopidogrel or prasugrel.

Ticlopidine versus clopidogrel

Attribute	Ticlopidine	Clopidogrel
Core class	Tetrahydrothienopyridine	Thienopyridine
Key substituent	2-chlorobenzyl	2-chlorophenyl-alpha-methyl acetate
Stereochemistry	No marketed chiral center of the clopidogrel type	Single active S-enantiomer
U.S. Patent 4,051,141 coverage	Claim 2 specifically covers ticlopidine	Not covered as the claimed species
Commercial status	Older antiplatelet, limited use	Major generic antiplatelet

Clopidogrel has a different substitution pattern and stereochemical structure. Its commercial patent estate was based on separate patents, including patents covering the active enantiomer and pharmaceutical compositions.

Prasugrel and ticagrelor are also structurally distinct and are not covered by the claims provided.

How strong is the patent estate for U.S. Patent 4,051,141 today?

The patent estate has no current exclusionary strength in the United States because the relevant patents have expired.

Historical strength

Historically, the estate was strong against direct manufacture or sale of ticlopidine because:

Claim 2 expressly identified the commercial molecule.
Claim 1 supplied broader genus coverage.
The salt language covered ticlopidine hydrochloride.
The patent was a compound patent rather than a narrow formulation patent.

Current strength

Current strength is effectively zero for blocking U.S. ticlopidine entry because:

The core patent expired in 1994.
Later related patents also expired.
No current Paragraph IV strategy can rely on this patent.
Generic manufacturers can use noninfringing manufacturing routes after process-patent expiry.
Trade-secret manufacturing know-how does not recreate an expired patent monopoly.

The remaining competitive barriers are product demand, manufacturing economics, FDA compliance, supply continuity, and clinical adoption.

What generic launch risks exist for ticlopidine?

The patent-related risk of a ticlopidine generic launch is low. The meaningful risks are regulatory and commercial.

Regulatory risks

A generic sponsor must address:

ANDA approval requirements.
Pharmaceutical equivalence.
Bioequivalence.
Content uniformity.
Stability.
Impurity controls.
Manufacturing-site compliance.
Labeling consistency.
Hematologic safety monitoring language.

Commercial risks

Ticlopidine demand is limited because:

Clopidogrel is widely available as a lower-cost generic.
Ticlopidine has a less favorable safety profile.
The drug requires attention to serious blood-related adverse reactions.
Prescribing has shifted toward newer antiplatelet therapies.
Low-volume products may face supply and manufacturing constraints.

Patent expiration removes the exclusionary barrier but does not guarantee a commercially attractive launch.

What manufacturing and intellectual-property barriers remain?

No current patent barrier is apparent from U.S. Patent 4,051,141. Manufacturing barriers may remain in the following areas:

Control of regioisomeric impurities.
Purity of the tetrahydrothienopyridine intermediate.
Salt formation and crystallization.
Residual solvent control.
Tablet stability.
Reproducible dissolution performance.
FDA inspection readiness.
Economical production at low market volumes.

A manufacturer could protect process improvements through later patents or trade secrets. Those rights would need to be assessed independently from the expired 1970s compound patent.

What is the geographic scope of the patent?

U.S. Patent 4,051,141 had territorial effect only in the United States. Corresponding foreign patents or applications would have required separate analysis by jurisdiction.

Patent expiry is also jurisdiction-specific. The U.S. expiration date does not establish the status of a European, Japanese, Canadian, or other national patent. Foreign family members may have had different:

Filing dates.
Grant dates.
Patent terms.
Patent-term extensions.
Opposition histories.
Maintenance-fee outcomes.
Regulatory exclusivity periods.

For U.S. launch planning, the operative conclusion is that the named U.S. patent has expired.

Key Takeaways

U.S. Patent 4,051,141 is the foundational U.S. compound patent for ticlopidine.
Claim 1 covers a broad Markush genus of substituted tetrahydrothienopyridines.
Claim 2 specifically covers ticlopidine and its pharmaceutically acceptable acid-addition salts.
Claims 3 through 6 cover additional benzyl-substituted analogues.
The patent issued on September 27, 1977, and expired in September 1994.
It does not claim a specific tablet, excipient system, dissolution profile, or manufacturing process.
It does not cover clopidogrel, prasugrel, or ticagrelor.
The patent cannot support a current Paragraph IV stay or infringement action.
Any remaining ticlopidine barriers are regulatory, manufacturing, commercial, or supply-related rather than based on this patent.
Later ticlopidine-related patents do not restore exclusivity after expiration.

FAQs About U.S. Patent 4,051,141 and Ticlopidine

Is ticlopidine still protected by a U.S. compound patent?

No. The compound patent represented by U.S. Patent 4,051,141 expired in 1994.

Can a company manufacture ticlopidine hydrochloride in the United States?

Yes, subject to FDA approval, current manufacturing requirements, applicable labeling obligations, and the absence of an independently enforceable later patent.

Does claim 2 cover ticlopidine hydrochloride?

Yes. Claim 2 covers the ticlopidine base and its pharmaceutically acceptable acid-addition salts, including the hydrochloride salt.

Can U.S. Patent 4,051,141 be listed in a current Orange Book certification?

It has no current blocking effect because the patent expired. An expired patent cannot support a present Paragraph IV litigation stay.

Does the patent cover a method of preventing stroke with ticlopidine?

The claims provided are compound claims, not treatment-method claims. Any method-of-use protection would have required separate claims in a separate patent or a distinct claim set.

References

U.S. Patent No. 4,051,141. (1977). Tetrahydrothienopyridine derivatives. United States Patent and Trademark Office.
U.S. Patent No. 4,591,592. (1986). Ticlopidine-related pharmaceutical and chemical subject matter. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2011). Ticlid (ticlopidine hydrochloride) tablets prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA, Center for Drug Evaluation and Research.
United States Patent and Trademark Office. (2024). Patent term and patent expiration guidance. USPTO.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
France	73.03503	Feb 1, 1973

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	217629	⤷ Start Trial
Austria	338261	⤷ Start Trial
Austria	350570	⤷ Start Trial
Austria	A577576	⤷ Start Trial
Austria	A67874	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,051,141

Summary for Patent: 4,051,141