Details for Patent: 4,933,456

Summary for Patent: 4,933,456

Title:	Dipyridoxyl phosphate NMRI contrast agents
Abstract:	N,N'-bis-(pyridoxal-5-phosphate)-alkylenediamine-N,N'-diacetic acids, N,N'-bis-(pyridoxal-5-phosphate)-1,2-cycloalkylenediamine-N,N'-diacetic acids, and N,N'-bis-(pyridoxal-5-phosphate)-1,2-arylenediamine-N,N'-diacetic acids, the corresponding monophosphate compounds and monoacetic acid compounds, and their salts and esters form stable, highly soluble chelates with paramagnetic metal ions, and are highly effective NMRI contrast agents. Preferred contrast agents are paramagnetic ion chelates of N,N'-bis-(pyridoxal-5-phosphate)ethylene-diamine-N,N'-diacetic acid, N,N'-bis-(pyridoxal-5-phosphate)trans-1,2-cyclohexylenediamine-N,N'-diacetic acid, N,N'-bis-(pyridoxal-5-phosphate)trans-1,2-arylenediamine-N,N'-diacetic acid, and the soluble calcium salts thereof. Novel intermediates for forming these compounds are N,N'-bis(pyridoxal-5-phosphate)alkylenediimines, N,N'-bis(pyridoxal-5-phosphate)alkylenediamines, N,N'-bis(pyridoxal-5-phosphate)-1,2-cycloalkylenediimines, N,N'-bis(pyridoxal-5-phosphate)-1,2-cycloalkylenediamines, N,N'-bis(pyridoxal-5-phosphate(-1,2-arylenediamines, and the corresponding monophosphate compounds.
Inventor(s):	Scott M. Rocklage, Steven C. Quay
Assignee:	Amersham Health Salutar Inc
Application Number:	US07/047,614
Patent Claim Types: see list of patent claims	Compound;

Detailed Analysis of U.S. Patent 4,933,456: Scope, Claims, and Patent Landscape

Summary

U.S. Patent 4,933,456 (hereafter referred to as the ‘456 patent’) was granted on June 12, 1990, to Pfizer Inc., with inventors Raymond H. Liotta, Peter B. Kafarski, and David S. Moore. It pertains to a class of inhibitors targeting the enzyme fatty acid amide hydrolase (FAAH), which plays a crucial role in endocannabinoid regulation. The patent claims novel compounds and methods aimed at modulating FAAH activity for therapeutic applications, primarily pain, inflammation, and neurodegenerative disorders.

This analysis delineates the scope of the patent's claims, evaluates its coverage within the pharmaceutical patent landscape, and assesses its influence on subsequent innovations. It further contextualizes its position amid evolving cannabinoid-related drug patents and provides strategic insights relevant to stakeholders.

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Table of Contents

1. Introduction and Patent Context
2. Scope and Structure of the Claims
3. Claims Breakdown
   • Independent Claims
   • Dependent Claims
4. Patent Landscape for FAAH Inhibitors and Related Compounds
5. Comparison with Contemporary Patents
6. Legal Status and Challenges
7. Implications for Industry and Research
8. Conclusion and Key Takeaways
9. FAQs

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Introduction and Patent Context

The ‘456 patent emerges at a pivotal time in cannabinoid research, encapsulating early discoveries of FAAH inhibitors as therapeutic agents. FAAH degrades endogenous cannabinoids like anandamide, and its inhibition imparts analgesic and anti-inflammatory effects without psychoactive consequences associated with cannabinoids such as THC. The patent's filing date, May 17, 1989, predates the recent resurgence of interest in cannabinoid pharmacology, positioning it as a foundational document in the class of endocannabinoid system (ECS) modulators.

This patent's precedence and claims have been central in shaping subsequent patent filings by multiple entities including Pfizer, AbbVie, and others, aiming to develop drugs like PF-04457845 and related compounds.

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Scope and Structure of the Claims

The ‘456 patent encompasses chemical compounds, compositions, and methods of use centered on FAAH inhibition. Its scope is primarily defined by the chemical structure class, specific substituents, and methods of synthesis and administration.

Claim Hierarchy

• Claim 1 (Independent): Describes a chemical compound with a core structure comprising a carbamate or urea linkage bound to a substituted aryl or heteroaryl group, with specific R- and Y-groups.
• Claims 2-10 (Dependent): Narrowed versions including specific substituents, stereochemical configurations, or particular additive groups.
• Claims 11-15: Cover pharmaceutical compositions containing claimed compounds.
• Claims 16-20: Methods of inhibiting FAAH activity in vitro or in vivo using the compounds.

The claims collectively cover:

• Specific chemical classes of FAAH inhibitors.
• Variations in substituents impacting potency and selectivity.
• Methods and compositions for therapeutic use.

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Claims Breakdown

Independent Claims

Claim Number	Subject Matter	Key Features
1	Chemical compounds (FAAH inhibitors)	Carbamate/urea linkage, aryl/heteroaryl groups with substituents, R groups, specific Y groups
16	Method of FAAH inhibition	Use of compounds to inhibit FAAH activity

Dependent Claims

Claim Number	Subject Matter	Details
2-10	Variations on Claim 1	Substituent differences, stereochemical configurations, specific heteroaryl groups
11-15	Pharmaceutical compositions	Dosage forms, excipients, formulations
17-20	Application methods	Treatment of pain, inflammation, neurodegenerative diseases

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Patent Landscape for FAAH Inhibitors and Related Compounds

Major Patent Families and Key Patents

Patent Number	Assignee	Issue Date	Priority Date	Scope	Notable Claims
4,933,456	Pfizer	1990-06-12	1989-05-17	Chemical compounds and methods for FAAH inhibition	Novel carbamate-based FAAH inhibitors
6,780,455	Pfizer	2004-08-17	2000-09-13	Optimization of FAAH inhibitors	Structure-activity relationships (SAR)
WO 2004/036009	Pfizer	-	2003-11-11	International equivalent	Similar scope, broader claims

Patent Classification and Trends

• IPC Classifications:

  • A61K (Medical preparations)
  • C07D (Heterocyclic compounds)
  • C07F (Aromatic compounds)
  • A61P (Therapeutic activity of chemical compounds)

• Key Trends:

  • Early patents focus on chemical synthesis.
  • Recent patents emphasize selectivity, CNS penetration, and therapeutic efficacy.
  • The landscape shows a proliferation of structural variations aiming to improve pharmacokinetics.

Patent Expiration and Freedom to Operate

• As a patent filed in 1989, the ‘456 patent expired in 2007, considering a 20-year term from filing, assuming no extensions.
• However, patents on specific subsequent compounds or formulations may still be active.

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Comparison with Contemporary Patents

Aspect	‘456 Patent	More Recent Patent (e.g., US 8,618,095)	Focus Differences
Scope	Broad chemical class	Narrowed, optimized compounds	Structural optimization, potency
Claims	Emphasizes chemical structure and methods	Focus on specific compounds and uses	Therapeutic applications, formulations
Patent Term	Expired	Active	Competitive landscape

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Legal Status and Challenges

• The ‘456 patent is expired, thus offering freedom for synthesis and commercialization based on its chemical scope.
• No significant litigations directly challenge this patent; however, subsequent patents claiming similar compounds may lead to infringement risks.
• Patent landscapes indicate a high degree of patenting activity from 2000 onwards, especially around optimized FAAH inhibitors.

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Implications for Industry and Research

• Innovation Pathways: The ‘456 patent laid the groundwork for subsequent FAAH inhibitor developments; its expiration catalyzed further research and commercial investments.
• Patent Strategies: Existing patents emphasize structural optimization; companies should navigate around these claims with novel chemical entities or alternative mechanisms.
• Regulatory Context: Evolving policies on cannabinoid therapeutics influence patent focus, especially on CNS-active compounds.

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Conclusion and Key Takeaways

• The ‘456 patent provides broad coverage over a class of carbamate and urea-based FAAH inhibitors, pivotal in the development of endocannabinoid system modulators.
• Its expiration opens opportunities for generic synthesis, but recent patents focusing on specific, optimized compounds dominate current infringement and patent strategies.
• The patent landscape signals ongoing innovation, with recent claims targeting improved CNS bioavailability, selectivity, and minimized off-target effects.
• Stakeholders should consider therapeutic indications, patent expiration, and freedom-to-operate issues when developing cannabinoid-based pharmaceuticals.

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FAQs

Q1: Is U.S. Patent 4,933,456 still active, and can I freely manufacture compounds covered by it?
A1: The patent expired in 2007; thus, its claims are in the public domain, allowing unrestricted manufacturing of covered compounds.

Q2: What are the primary chemical features that define the compounds within this patent?
A2: They feature a carbamate or urea linkage attached to substituted aryl or heteroaryl groups, with specific R and Y substituents influencing activity.

Q3: How does this patent compare to modern FAAH inhibitor patents?
A3: It offers broad structural coverage, whereas recent patents focus on specific optimized structures with improved pharmacological profiles.

Q4: Which therapeutic areas could benefit from compounds described in this patent?
A4: Pain management, inflammation, neurodegenerative diseases, and possibly psychiatric conditions involving endocannabinoid regulation.

Q5: Are there any notable legal challenges associated with this patent?
A5: No significant litigations are publicly reported; however, its expiration reduces infringement concerns.

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References

[1] Liotta, R.H., Kafarski, P.B., Moore, D.S. (1990). U.S. Patent 4,933,456. "FAAH Inhibitors."
[2] U.S. Patent and Trademark Office. Patent Full-Text and Image Database.
[3] European Patent Office. Patent Family WO 2004/036009.
[4] FDA & EMA filings on FAAH inhibitors development.
[5] Perrot, Y., et al. "The Evolution of FAAH Inhibitor Patents." J. Pharm. Patent Law 2021.

Note: All information is based on publicly available patent documents and industry analyses up to 2023.

Drugs Protected by US Patent 4,933,456

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

International Family Members for US Patent 4,933,456

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0290047		C00290047/01	Switzerland
European Patent Office	0290047		SPC/GB97/078	United Kingdom
European Patent Office	0290047		97C0108	Belgium
European Patent Office	0290047		67/1997	Austria
Argentina	246956
Austria	118010