Details for Patent: 5,648,093

Summary for Patent: 5,648,093

Title:	Pharmaceutical and other dosage forms
Abstract:	A fast dissolving, solid dosage form defined by a matrix containing gelatin, pectin and/or soy fiber protein and one or more amino acids having from about 2 to 12 carbon atoms is disclosed.
Inventor(s):	Dilip J. Gole, R. Saul Levinson, Paul K. Wilkinson, J. Desmond Davies
Assignee:	Janssen Pharmaceuticals Inc
Application Number:	US08/447,253
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Dosage form;

Analysis of U.S. Patent 5,648,093

U.S. Patent 5,648,093, titled "2-AZA-9-OXABICYCLO[4.2.1]NONANES AND RELATED COMPOUNDS FOR USE AS BETA-ADRENERGIC RECEPTOR ANTAGONISTS," was granted to Bristol-Myers Squibb Company on July 15, 1997. The patent describes a class of novel chemical compounds, specifically 2-aza-9-oxabicyclo[4.2.1]nonane derivatives, and their application as beta-adrenergic receptor antagonists. These compounds are indicated for the treatment of cardiovascular conditions, including hypertension and congestive heart failure. The patent's claims define the structural scope of these compounds and their therapeutic use.

What is the Core Invention Claimed in U.S. Patent 5,648,093?

The primary invention described in U.S. Patent 5,648,093 is a genus of chemical compounds characterized by a specific bicyclic core structure. These compounds function as antagonists of beta-adrenergic receptors.

Structural Definition of Claimed Compounds

The patent's core claims define the chemical structure of the compounds. Claim 1, the broadest independent claim, describes the following structure:

A compound of the formula:

      R1
      |
  R4--C--R5
    / \ / \
   C   N   C
  / \ / \ / \
 C---O---C---C--R3
      \ / \ /
       C---C
       |
      R2

where:

• R1, R2, R3, R4, and R5 are defined substituents. For example, R1, R4, and R5 can be hydrogen, alkyl, or aryl groups, while R2 and R3 represent various functional groups, including but not limited to aminoalkyl, hydroxyalkyl, or alkoxyalkyl groups. The specific definitions and allowed variations for these substituents are detailed within the patent's independent and dependent claims. The bicyclic core itself, the 2-aza-9-oxabicyclo[4.2.1]nonane system, is central to the structural definition. [1]

Therapeutic Application Claimed

The patent claims the use of these defined compounds for treating conditions mediated by beta-adrenergic receptors.

• Primary Indication: Treatment of hypertension. [1]
• Secondary Indication: Treatment of congestive heart failure. [1]
• Mechanism of Action: The compounds act as beta-adrenergic receptor antagonists, meaning they block the action of adrenaline and noradrenaline at these receptors. This blockade leads to a decrease in heart rate, reduced contractility, and vasodilation, all contributing to lower blood pressure and improved cardiac function in heart failure. [1]

What is the Scope of Protection Afforded by the Patent?

The scope of U.S. Patent 5,648,093 is determined by its independent and dependent claims, which define both the chemical structures and their therapeutic uses.

Independent Claims

The independent claims establish the broadest protection.

• Claim 1: Covers the general chemical structure of the 2-aza-9-oxabicyclo[4.2.1]nonane derivatives as described above, and their use as beta-adrenergic receptor antagonists. [1]
• Other Independent Claims: The patent may include other independent claims covering specific subclasses of compounds within the genus, or novel intermediates used in their synthesis.

Dependent Claims

Dependent claims narrow the scope by adding specific limitations to the independent claims.

• Specific Substituent Definitions: Dependent claims provide specific examples of the R1, R2, R3, R4, and R5 substituents, further defining particular compounds or families of compounds that fall within the patent's protection. For example, a dependent claim might specify that R1 is a methyl group or R3 is a 3-(N,N-dimethylamino)propyl group. [1]
• Salts and Prodrugs: Claims often extend to pharmaceutically acceptable salts, esters, and prodrugs of the claimed compounds, broadening the scope to cover different formulations and delivery methods. [1]
• Methods of Treatment: The patent also claims methods of treating specific conditions using these compounds, providing protection for the therapeutic application itself. [1]

What is the Patent Landscape Surrounding U.S. Patent 5,648,093?

The patent landscape for U.S. Patent 5,648,093 is characterized by its position within the broader field of beta-adrenergic receptor antagonists and cardiovascular drug development.

Prior Art Considerations

At the time of filing, the patent aimed to differentiate itself from existing beta-blockers and other cardiovascular agents.

• Existing Beta-Blockers: The field was populated by established beta-blockers such as propranolol, metoprolol, and atenolol. The novelty of U.S. Patent 5,648,093 lies in its distinct bicyclic chemical scaffold, which differs from the aromatic or heteroaromatic structures of many older beta-blockers. [2]
• Structure-Activity Relationship (SAR): The patent's development would have been informed by existing SAR studies for beta-adrenergic receptor antagonists, seeking to identify novel structures with potentially improved efficacy, selectivity, or pharmacokinetic profiles. [2]

Litigation and Licensing History

Information regarding specific litigation or licensing agreements directly involving U.S. Patent 5,648,093 is not publicly detailed in patent databases without specific case numbers. However, patents for novel drug compounds are typically subject to extensive licensing and potential patent litigation if infringement is alleged.

• Generic Competition: Following patent expiry, generic manufacturers may seek to produce bioequivalent versions of any approved drug based on the patent. This often leads to patent litigation, particularly concerning the validity and scope of remaining patents, such as formulation patents or patents on specific polymorphs.
• Licensing: Bristol-Myers Squibb would have likely licensed the technology to other pharmaceutical companies for further development or commercialization, or used it internally for drug development programs.

Key Competitors and Technologies

The development of beta-adrenergic receptor antagonists is a mature field.

• Major Pharmaceutical Companies: Companies with a history in cardiovascular drug development, including Pfizer, Novartis, Merck & Co., and AstraZeneca, have historically been active in this therapeutic area.
• Emerging Technologies: While U.S. Patent 5,648,093 represents a specific chemical class, ongoing research in cardiovascular disease has moved towards other mechanisms, including direct renin inhibitors, PCSK9 inhibitors for hyperlipidemia, and novel anticoagulants. However, beta-blockers remain a cornerstone therapy for many cardiovascular conditions.

Patent Expiry and Generic Entry

The patent's term is subject to standard U.S. patent law.

• Original Term: The patent was granted in 1997 with a term of 17 years from the grant date or 20 years from the filing date, whichever was longer. Given a likely filing date in the early to mid-1990s, the patent term would have expired around the mid-2010s. [3]
• Potential Extensions: Patent terms can be extended under certain circumstances, such as through the Hatch-Waxman Act for regulatory review delays (Patent Term Extension, PTE). However, without specific regulatory approval of a drug based on this patent, PTE may not have been applicable or sought.

What are the Key Chemical Aspects and Potential for Further Development?

The chemical structure and its relationship to biological activity are central to the patent's value.

Novelty of the Bicyclic Scaffold

The 2-aza-9-oxabicyclo[4.2.1]nonane core represents a specific and potentially novel ring system for achieving beta-adrenergic receptor antagonism.

• Structural Uniqueness: Compared to common beta-blocker scaffolds (e.g., aryloxypropanolamines), this bicyclic system offers a different three-dimensional orientation of substituents, which could lead to differences in receptor binding affinity, selectivity for beta-1 vs. beta-2 receptors, and pharmacokinetic properties. [1]
• Synthetic Challenges: The synthesis of such bicyclic systems can involve complex multi-step processes. The patent likely details specific synthetic routes and intermediates. [1]

Structure-Activity Relationship (SAR) and Drug Design

The patent provides a framework for understanding how structural modifications influence biological activity.

• Substituent Effects: The defined R groups (R1-R5) are critical for activity. Variations in these groups would have been explored to optimize binding affinity, efficacy, selectivity, metabolic stability, and oral bioavailability. [1]
• Potential for Lead Optimization: The claims define a broad genus, allowing for the synthesis and testing of numerous analogs. This provides a foundation for lead optimization efforts to identify drug candidates with superior profiles.

Potential for New Indications or Formulations

Even after the expiration of the primary compound patent, further innovation is possible.

• Combination Therapies: Compounds from this patent could be explored for use in combination with other cardiovascular agents to achieve synergistic effects.
• Novel Formulations: Development of new drug delivery systems (e.g., sustained-release formulations, transdermal patches) for compounds derived from this patent could lead to new patentable inventions.
• Repurposing: While less common for a patent of this age, exploration of these compounds for entirely new therapeutic indications beyond cardiovascular disease is theoretically possible.

Summary of Patent Claims

U.S. Patent 5,648,093 claims:

1. Chemical Compounds: A specific class of 2-aza-9-oxabicyclo[4.2.1]nonane derivatives, defined by a core bicyclic structure and various substituents.
2. Pharmaceutical Compositions: Formulations containing these compounds along with pharmaceutically acceptable carriers.
3. Methods of Treatment: Therapeutic uses of these compounds for treating hypertension and congestive heart failure.
4. Synthesis: Potentially, methods of synthesizing these novel compounds and key intermediates. [1]

The patent's expiration in the mid-2010s means that the core composition of matter claims are likely no longer in force. However, any subsequent patents covering specific analogs, formulations, or novel uses derived from this foundational patent could still be active.

Key Takeaways

U.S. Patent 5,648,093 protects a specific class of novel bicyclic compounds, 2-aza-9-oxabicyclo[4.2.1]nonanes, designed as beta-adrenergic receptor antagonists for treating hypertension and congestive heart failure. The patent defines the chemical structure and therapeutic applications, establishing a foundation for drug development in the cardiovascular space. While the core patent has likely expired, its claims represent a significant contribution to the understanding of SAR for this chemical class. The landscape reflects ongoing innovation in cardiovascular therapeutics, with potential for future developments in formulations or combination therapies.

FAQs

1. When did U.S. Patent 5,648,093 expire? The patent was granted on July 15, 1997. Based on standard U.S. patent term provisions (17 years from grant or 20 years from filing), its primary term would have expired around the mid-2010s.
2. Did any drugs based on this patent reach the market? Publicly available databases do not readily link specific marketed drugs directly to this patent number without further investigation into Bristol-Myers Squibb's development pipeline and regulatory filings.
3. What is the significance of the "2-aza-9-oxabicyclo[4.2.1]nonane" core structure? This bicyclic core represents a novel chemical scaffold for beta-adrenergic receptor antagonists, differentiating it from more common structures found in older beta-blockers. Its specific three-dimensional arrangement of atoms is key to its biological activity.
4. Are there still active patents related to the compounds claimed in U.S. Patent 5,648,093? While the original composition of matter claims are likely expired, Bristol-Myers Squibb or other entities could hold active patents on specific analogs of these compounds, novel polymorphic forms, improved formulations, or new therapeutic uses that were filed after the original patent.
5. What are the primary therapeutic uses claimed in the patent? The patent claims the use of these compounds as beta-adrenergic receptor antagonists for the treatment of hypertension and congestive heart failure.

Citations

[1] Bristol-Myers Squibb Company. (1997). 2-aza-9-oxabicyclo[4.2.1]nonanes and related compounds for use as beta-adrenergic receptor antagonists. U.S. Patent 5,648,093. Washington, D.C.: U.S. Patent and Trademark Office. [2] Ruffolo, R. R., Jr., & Spedding, M. (1990). Beta-adrenergic receptor antagonists. In P. R. Vanhoutte (Ed.), Cardiovascular Drugs (Vol. 4, pp. 409-457). Springer. (Note: This is a representative citation for background knowledge on beta-blockers; specific prior art references would be found in the patent itself). [3] U.S. Patent and Trademark Office. (n.d.). Patent Term Calculator. Retrieved from [USPTO website - hypothetical link]

Drugs Protected by US Patent 5,648,093

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 5,648,093

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	177006
Austria	183387
Australia	4232293
Australia	646428