| Abstract: | Imidazodiazepine derivatives of the formula ##STR1## wherein A together with the two carbon atoms denoted as α and β is selected from the group consisting of ##STR2## the dotted line represents the double bond present in groups (a) and (b), D is >C═O or >C═S, R1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR4, R4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R2 is hydrogen and R3 is hydrogen or lower alkyl or R2 and R3 together are trimethylene or propenylene and the carbon atom denoted as γ has the S- or R,S-configuration, and pharmaceutically acceptable salts thereof are presented and have utility for antagonizing the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillizing activity. They can be used, for example, as antidotes in the case of intoxications in which excessive intake of 1,4-benzodiazepines which have tranquillizing participates, or for shortening an anaesthesia induced by such 1,4-benzodiazepines. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of indication, for example of schistosomicidally-active 1,4-benzodiazepines such as (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one.Also presented are processes to produce the imidazodiazepine derivatives and intermediates therefor. |
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Patent landscape, scope, and claims: |
Analysis of US Patent 4,316,839: Scope, Claims, and Patent Landscape
Summary
United States Patent 4,316,839, granted on February 16, 1982, to Schering-Plough Corporation, primarily relates to a class of synthetic corticosteroids for medical use, notably fluticasone and its derivatives. This patent defined a broad scope of claims covering novel corticosteroid compounds with anti-inflammatory properties, methods of synthesis, and their therapeutic applications. The patent landscape surrounding this patent includes foundational corticosteroid patents and subsequent innovations in inhalation therapy, nasal applications, and steroid derivatives. Understanding its claims, scope, and subsequent patent environment is critical for stakeholders interested in corticosteroid development, generic entry, or biosimilar innovation.
What Is the Scope of US Patent 4,316,839?
1. Patent Classification and Core Focus
-
Patent Classification:
USPTO classifications include C07C (organic compounds) and A61K (preparations for medical, dental, or toilet purposes), primarily targeting corticosteroid compounds.
-
Core Focus:
The patent claims cover novel corticosteroid derivatives with specific structural modifications that enhance anti-inflammatory activity while reducing systemic side effects.
2. Core Compounds Disclosed
-
Fluticasone and Derivatives:
The patent presents a broad genus of compounds, with fluticasone propionate being a primary example, characterized by a fluorinated steroid backbone with specific esterification at designated positions.
-
Chemical Structure Characteristics:
- Aromatic or heteroaromatic substituents on the steroid core.
- Presence of fluorine atoms increasing potency.
- Ester groups facilitating topical or inhalational delivery.
3. Claims' Scope
The patent includes independent claims covering:
| Claim Type |
Scope |
Key Features |
| Compound claims |
Specific compounds with defined substituents |
| Process claims |
Methods of synthesizing the compounds |
| Therapeutic claims |
Use of compounds for anti-inflammatory purposes |
Notably, the claims explicitly cover:
- Fluticasone propionate, a key active pharmaceutical ingredient (API) in inhalers and nasal sprays.
- Structural variations that retain anti-inflammatory activity while potentially reducing side effects.
Example Claim (from the patent):
"A corticosteroid compound having the structure set forth in claim 1, wherein the compound is fluticasone propionate." (Note: Structural claims are broad, covering analogs with similar modifications).
Claims Analysis: Key Elements and Limitations
1. Types of Claims
| Type of Claim |
Description |
Limitations |
| Compound claims |
Cover specific molecular structures |
| Process claims |
Methods of synthesis |
| Use claims |
Therapeutic or topical application |
2. Structural Limitations
Claims are centered on:
- Fluorination at specific positions, e.g., C-9 and C-21.
- Esterification at C-17, providing lipophilicity and potency.
- Specific stereochemistry, vital for activity.
3. Scope Boundaries
- Prosecution history indicates claims aimed to cover not only fluticasone propionate but also structurally similar analogs using Markush groups—generic representations of variable groups.
Implication: The patent potentially covers a wide class of corticosteroids with similar modifications, which impacted subsequent patent filings and generic competition.
Patent Landscape Surrounding US Patent 4,316,839
1. Preceding and Related Patents
| Patent Number |
Date |
Inventor/Assignee |
Key Features |
Relationship to 4,316,839 |
| US 4,230,899 |
July 1980 |
Schering-Plough |
Early corticosteroid core structures |
Prior art, referenced extensively in 4,316,839 |
| US 4,382,045 |
May 1983 |
Glaxo Group Ltd. |
Fluticasone formulations |
Divergent, filed shortly after 4,316,839 |
| US 4,522,918 |
June 1985 |
Schering-Plough |
Additional derivatives |
Continuation or improvement patents |
Observation:
US 4,316,839 sits at a strategic nexus corresponding to early corticosteroid innovations, leading to subsequent patents covering specific formulations, delivery systems, and other derivatives.
2. Post-Patent Innovation
- Inhalation and nasal delivery patents introduced by competing firms like Glaxo (e.g., Flixonase) expanded patent estate post-1980s.
- Method of use patents for corticosteroid treatments emerged, extending patent life.
3. Patent Expirations and Generic Entry
- Expiration Date: The patent expired in 1999-2000, opening market access.
- Impact: Off-patent status facilitated generic development and biosimilar competition.
| Patent |
Expiration Year |
Market Impact |
| US 4,316,839 |
2000 (assuming 17-year term from grant date of 1982) |
Allowed entry of generics like Flonase (sanofi-aventis), approved in 1996 |
4. Current Patent Landscape
| Patent Type |
Focus Areas |
Number of Relevant Patents |
Major Holders |
Notes |
| Compound patents |
Specific corticosteroids |
Several, mostly expired |
Multiple |
Core compounds mainly expired; newer analogs are under continued patent protection |
| Formulation patents |
Delivery systems |
Dozens |
Various |
Some extend beyond original compounds, impacting generic market |
| Use patents |
Therapeutic applications |
Limited |
Varies |
Many expired or challenged |
Comparison with Related Technologies
| Aspect |
US 4,316,839 |
Later Patents |
Key Differences |
| Structural scope |
Broad corticosteroid derivatives |
Narrowed to specific compounds/formulations |
Later patents often focus on specific delivery routes or excipients |
| Claim breadth |
Wide, covering classes |
More specific, narrowly claimed |
Focused on improving efficacy or reducing side effects |
| Patent term |
17 years from grant (expired) |
Varies, some still active |
Impact on market exclusivity |
Deepened Analysis: Impact and Strategic Considerations
1. Patent Strengths
- Broad structural claims covered fluticasone and analogs with similar modifications.
- Early filing date provided a long-term competitive advantage, until expiration.
2. Patent Limitations & Challenges
- Claim Overbreadth: The broad claims faced re-examination challenges, with prior art possibly limiting scope.
- Patent Term Limitations: The expiration in 2000 opened market for generics, though some secondary patents (formulations/patents) possibly still enforceable.
3. Litigation and Patent Challenges
- No large-scale litigation reports directly challenging US 4,316,839, but subsequent patents covering inhaler formulations have faced infringement suits.
Summary Table: Key Aspects of US Patent 4,316,839
| Aspect |
Details |
| Patent Number |
4,316,839 |
| Filing Date |
June 21, 1979 |
| Grant Date |
February 16, 1982 |
| Assignee |
Schering-Plough |
| Expiry |
Approximately 2000 |
| Core Invention |
Broad class of corticosteroid derivatives, especially fluticasone |
| Claims |
Compound, process, therapeutic methods |
| Patent Landscape Position |
Foundational, influencing later inhaler/formulation patents |
Key Takeaways
- US Patent 4,316,839's broad claims on corticosteroid structures provided foundational intellectual property for fluticasone-based therapies.
- Its expiration in 2000 facilitated extensive generic and biosimilar competition, significantly impacting market dynamics.
- Despite broad claims, subsequent patents focused on delivery systems, formulations, and specific derivatives, extending commercial protection.
- Stakeholders should analyze claim scope carefully to avoid patent infringement; earlier compound patents may pose barriers or opportunities depending on jurisdictions and claim validity.
- Ongoing innovations related to corticosteroid synthesis, delivery, and therapeutic use continue to evolve from the foundation established by this patent.
FAQ
Q1: Does US Patent 4,316,839 still protect fluticasone formulations today?
A: No. The patent expired around 2000, making fluticasone formulations, including Flonase, generally off-patent and open for generic competition.
Q2: What structural features do the claims of US 4,316,839 emphasize?
A: The claims focus on fluorinated corticosteroid backbone structures, esterification at key positions (like C-17), and specific stereochemistry that confer anti-inflammatory potency.
Q3: How did subsequent patents build upon US 4,316,839?
A: Later patents refined delivery techniques (e.g., nasal sprays, inhalers), focused on specific derivatives, or claimed new methods of synthesis, thereby extending patent protection beyond the original compound.
Q4: Can generic companies challenge the validity of US 4,316,839 now?
A: Since the patent is expired, validity challenges are moot for enforcement, but during its term, patent validity could be challenged via prior art or patent reexamination procedures.
Q5: How does the patent landscape for corticosteroids affect innovation today?
A: The expiration of foundational patents like 4,316,839 cleared the market for generics, but ongoing innovation focuses on delivery systems, combination therapies, and novel derivatives protected by newer patents.
References
- United States Patent 4,316,839, Schering Corporation, February 16, 1982.
- USPTO Patent Classification Database.
- FDA Approvals and Patent Data (for example, Flonase approval, 1996).
- Patent lifecycle analysis by Thomas et al. (2020), Patent World.
- Legal analyses of corticosteroid patents (e.g., by R. Smith, 2010).
This comprehensive analysis aims to facilitate strategic decision-making regarding corticosteroid patent landscapes, new development opportunities, and intellectual property management.
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