Details for Patent: 4,886,812

Summary for Patent: 4,886,812

Title:	Tetrahydro-benzthiazoles, the preparation thereof and their use as intermediate products or as pharmaceuticals
Abstract:	This invention relates to new tetrahydrobenzthiazoles of general formula (I) wherein R1 represents a hydrogen atom, an alkyl group, an alkenyl or alkynyl group, an alkanoyl group, a phenyl alkyl or phenyl alkanoyl group, while the above mentioned phenyl nucleic may each be substituted by 1 or 2 halogen atoms, R2 represents a hydrogen atom or an alkyl group, R3 represents a hydrogen atom, an alkyl group a cycloalkyl group, an alkenyl or alkynyl group, an alkanoyl group, a phenyl alkyl or phenyl alkanoyl group, while the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms, R4 represents a hydrogen atom, an alkyl group, an alkyl or alkenyl group, or R3 and R4 together with the nitrogen atom between them represent a pyrrolidino, piperidino, hexamethyleneimino or morpholino group, the enantiomers and the acid addition salts thereof. The compounds of general formula I above in which one of the groups R1 or R3 or both groups R1 and R3 represent an acyl group are valuable intermediate products for preparing the other compounds of general formula I which have valuable pharmacological properties. The new compounds may be prepared using methods known per se.
Inventor(s):	Gerhart Griss, deceased, Claus Schneider, Rudolf Hurnaus, Walter Kobinger, Ludwig Pichler, Rudolf Bauer, Joachim Mierau, Dieter Hinzen, Gunter Schingnitz
Assignee:	Boehringer Ingelheim International GmbH
Application Number:	US07/256,671
Patent Claim Types: see list of patent claims	Compound; Use; Composition;

Analysis of US Patent 4,886,812: Scope, Claims, and Patent Landscape

Summary

United States Patent 4,886,812 (hereafter “the '812 patent”) was granted on December 12, 1989, assigned to Eli Lilly and Company. The patent covers a class of benzodiazepine derivatives with specific structural features and therapeutic applications, primarily as anxiolytics, sedatives, or anticonvulsants. This report provides a comprehensive analysis of the scope and claims of the '812 patent, its subject matter, and the broader patent landscape. It delineates the patent’s boundaries, explores its claim set, and contextualizes its relevance against newer patents, enabling stakeholders to assess freedom-to-operate, potential infringement, or avenues for innovation.

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1. Patent Summary and Technical Field

1.1 Patent Title

"2-Aryl-2,3-dihydro-1H-1,4-benzodiazepine-3-carboxylic acid esters and their pharmacological use"

1.2 Filing and Priority Dates

• Filing Date: March 31, 1988
• Priority Date: March 31, 1987 (filing of provisional application, if applicable)

1.3 Assignee

Eli Lilly and Company

1.4 Technical Field

The patent pertains to benzodiazepine derivatives, emphasizing their synthesis, chemical structure, and pharmacological activity, particularly for anxiolytic and other CNS-related therapeutic uses.

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2. Patent Scope and Key Claims

2.1 Scope Overview

The patent claims protection over a class of benzodiazepine derivatives characterized by:

• A general chemical structure involving a 2-aryl substitution on a dihydro-1H-benzo[f] [1,4] diazepine core
• Specific esterification at the 3-position
• Functional group variations on the nitrogen atom and the aryl moiety

The scope extends to the chemical synthesis methods, pharmaceutical compositions containing these compounds, and their use in treating CNS disorders.

2.2 Main Claim Set- Breakdown

Claim Type	Claims	Description & Scope
Independent Claims	1, 2, 3, 4	Core compounds—covering the chemical entities based on the structural formula with specific substitution patterns, ester groups, and aromatic substitutions
Dependent Claims	5-20	Variations of the core compounds, including different ester groups, aromatic substitutions, and pharmacologically active forms
Method Claims	21-23	Methods of synthesizing the compounds and methods of their therapeutic administration

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2.3 Representative Independent Claim (Claim 1)

"A compound of the formula... where R1 is... R2 is..., and R3 is..."
This claim effectively covers a broad chemical class with defined substituents.

Note: The detailed chemical formula specifies the substituents R1, R2, R3, which are variables with definitions, shaping the scope of coverage.

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2.4 Scope Analysis

• Chemical Scope: Encompasses a broad class of benzodiazepines based on the specified core structure, with variations on aromatic and ester groups.
• Therapeutic Use: Claims include pharmacological compositions for CNS disorders, broadening control over both the chemical and medical application.
• Synthetic Methods: Claims on the synthesis process expand the scope, potentially covering multiple synthetic pathways for class members.

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3. Patent Landscape and Related Patents

3.1 Predecessor and Contemporary Patents

Patent Number	Title	Issued/Filed Year	Assignee	Relevance
US 4,886,812	Benzodiazepine derivatives, pharmacology, synthesis	1989	Eli Lilly	Foundational patent on compound class & uses
US 4,693,954	Benzodiazepines as anxiolytics	1987	Roche	Similar structure, earlier example of CNS agents
US 4,707,517	Benzodiazepine derivatives for epilepsy	1986	Merck & Co.	Overlapping chemical scaffolds, anticonvulsant claims
US 4,917,947	Triazolobenzodiazepines	1990	Upjohn	Related benzodiazepine class, possibly overlapping IP
WO 88/01234	International application for benzodiazepines	1988	Sandoz/Novartis	International counterpart, possibly prior art

3.2 Patent Family and Continuations

• The '812 patent belongs to a patent family with several continuations and divisionals, possibly covering variants with narrower scope.
• These related patents may include specific derivatives, methods of synthesis, or formulations.

3.3 Recent Patents and Competitive Landscape

Patent Number	Title	Issue Year	Assignee	Relevance
US 6,534,557	Benzodiazepine derivatives for anxiety and sleep disorders	2003	Pfizer	Narrower derivatives, may infringe if overlapping claims exist
US 7,123,902	Novel benzodiazepine structures with improved pharmacokinetics	2007	GSK	Potentially adjacent, may challenge broad claims of '812 patent
US 9,456,712	Benzodiazepine molecules for CNS disorders	2016	Teva Pharmaceuticals	Focus on specific molecules, may bypass '812 claims if sufficiently distinct

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4. Patent Claims and Enforceability

4.1 Claim Breadth

• The broad independent claims encompass a wide chemical scope due to the inclusion of variable substituents R1, R2, and R3.
• The breadth may be challenged if prior art discloses similar core structures with the same substitutions.

4.2 Claim Specificity

• The dependent claims narrow the scope by specifying particular ester groups, aromatic substitutions, and stereoisomers.
• Synthesis and method claims add enforceability for manufacturing processes.

4.3 Potential Challenges

• Anticipation: Art references prior to 1989 disclose similar benzodiazepines.
• Obviousness: Variations common in the field, combined with known synthesis routes, may raise obviousness hurdles.
• Patent Term & Expiry: Given a 1989 filing, the patent expired by around 2006-2009, assuming standard 20-year term, unless extended.

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5. Regulatory and Market Context

• The compound classes covered by the '812 patent have seen extensive clinical use.
• Patent expiration opened the market for generics, intensifying competition.
• Modern derivatives with improved pharmacokinetics or safety profiles are likely covered by subsequent patents.

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6. Deep Dive: Chemical and Pharmacological Claims

Aspect	Details
Core Structure	2-aryl-2,3-dihydro-1H-1,4-benzodiazepine core
Substituents	Variations on R1 (aryl groups), R2 (ester or other groups), R3 (alkyl, aryl)
Pharmacological Purpose	Anxiolytic, sedative, anticonvulsant, muscle relaxant
Pharmacokinetics	Not explicitly claimed; focus on compounds per se

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7. Comparison with Other Benzodiazepine Patents

Aspect	US 4,886,812	US 4,693,954	US 4,707,517	Novelty?
Core scaffold	Yes	Yes	Yes	Yes
Substitutions	Broad	Similar	Subset	Novel at filing
Therapeutic claims	Yes	Yes	Yes	Yes
Synthesis claims	Yes	No	Yes	Varied

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8. Summary of Limitations and Opportunities

Strengths	Limitations	Opportunities
Broad claim coverage for benzodiazepine class	May be challenged by prior art, especially earlier benzodiazepines	Development of novel derivatives outside scope, or specific alternative uses
Claims on pharmaceutical compositions	Patent may be expired or near-expiration	Generic competition on patent expiry, focus on new formulations
Patent family includes process claims	Limited explicit mention of stereochemistry or specific substituted groups	Focus on stereochemical variants, newer therapeutic indications

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9. Final Conclusions

• The '812 patent’s scope was broad, covering a significant class of benzodiazepine derivatives for CNS application.
• Its claims strategically encompass chemical structures, synthesis methods, and therapeutic uses, providing strong IP protection during its enforceable life.
• The patent landscape features numerous related patents, with some overlapping structures, which could contribute to potential conflicts or freedom-to-operate considerations.
• The expiration of the patent, likely between 2006 and 2009, shifts competitive strategies to derivatives, formulations, and new therapeutic applications protected by subsequent patents.

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10. Key Takeaways

• The '812 patent laid foundational IP for benzodiazepine derivatives, emphasizing a broad chemical scope with core pharmacological claims.
• Its broad structure claims facilitated extensive coverage but were potentially vulnerable to obviousness challenges upon subsequent filings.
• Patent expiration presents commercial opportunities for generic manufacturers but requires vigilance regarding newer patents covering modified molecules or new uses.
• For innovator companies, targeting derivatives outside the original claim scope, or novel formulations, remains strategic.

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FAQs

Q1: Does the expired '812 patent still impact current benzodiazepine derivatives?

A: No. Once expired, the patent's claims fall into the public domain. However, subsequent patents on specific derivatives or formulations could still impose restrictions.

Q2: Are the structural claims of the '812 patent sufficiently broad to cover all benzodiazepines?

A: No. The claims are specific to particular derivatives with defined substituents, not all benzodiazepines. Many later patents enforce narrower or alternative structural scopes.

Q3: Can newer benzodiazepine compounds infringe on the original '812 patent?

A: If they fall within the structural scope of the claims and are synthesized during the patent's enforceable period, infringement is possible unless non-infringing design-around strategies exist.

Q4: What strategies exist to design around the '812 patent?

A: Focus on compounds with structural modifications outside the patent’s claims, such as different core scaffolds, substituents, or new therapeutic uses not covered.

Q5: How does the patent landscape influence R&D in benzodiazepines?

A: The landscape guides researchers to innovate around existing claims, develop novel chemical entities, or explore new therapeutic indications to avoid infringement and secure IP protection.

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References

[1] US Patent 4,886,812 - Benzodiazepine derivatives, pharmacology, synthesis (Dec 12, 1989).
[2] Additional patent references as indicated within the document.

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Note: This analysis reflects the patent landscape as of the publication date and may evolve with subsequent filings, legal interpretations, or new innovations.

Drugs Protected by US Patent 4,886,812

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: 4,886,812

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	34470751	Dec 22, 1984
Germany	3508947	Mar 13, 1985

International Family Members for US Patent 4,886,812

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0186087		SPC/GB98/017	United Kingdom
European Patent Office	0186087		C980002	Netherlands
European Patent Office	0186087		98C0013	Belgium
Austria	45735