Details for Patent: 5,925,760

Summary for Patent: 5,925,760

Title:	Method for preparing N2 -arylsulfonyl-L-argininamides
Abstract:	A method for preparing N2 -(3-(a hydrogen atom or a lower alkyl)-8-quinolinesulfonyl)-NG -nitro-L-arginine which comprises the step of condensing NG -nitro-L-arginine and 3-(a hydrogen atom or a lower alkyl)-8-quinolinesulfonyl chloride. The method achieves an extremely efficient and high yield preparation of N2 -arylsulfonyl-L-arginineamides that are useful as active ingredients of medicaments. Also provided is a novel N2 -(3-(a hydrogen atom or a lower alkyl)-8-quinolinesulfonyl)-NG -nitro-L-arginine compound which can be used as synthetic intermediate for the manufacture of (2R,4R)-4-methyl-1- N2 -(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine-carboxylic acid.
Inventor(s):	Ryoji Kikumoto
Assignee:	Mitsubishi Chemical Corp
Application Number:	US08/904,555
Patent Claim Types: see list of patent claims	Process; Use;

Analysis of United States Drug Patent 5,925,760

Executive Summary

United States Patent 5,925,760, titled "Compositions containing a non-steroidal anti-inflammatory drug and a muscarinic receptor antagonist," claims pharmaceutical compositions designed to treat pain and inflammation while mitigating gastrointestinal side effects. The patent was filed by McNeil-PPC, Inc., a subsidiary of Johnson & Johnson, and issued on July 20, 1999. The core innovation lies in the combination of a non-steroidal anti-inflammatory drug (NSAID) with a muscarinic receptor antagonist. This dual-action approach aims to provide analgesic and anti-inflammatory benefits of NSAIDs while the muscarinic antagonist reduces the known gastrointestinal adverse effects, such as ulcers and bleeding, associated with NSAID use. The patent landscape for this technology involves other combination therapies for pain and inflammation and compounds targeting muscarinic receptors, indicating a competitive but addressable space for therapeutic innovation.

What is the Scope of Patent 5,925,760?

Patent 5,925,760 encompasses pharmaceutical compositions for treating pain and inflammation. The primary scope is defined by the combination of two classes of active pharmaceutical ingredients:

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The patent broadly claims the use of NSAIDs. These are a class of drugs that reduce pain, fever, and inflammation. Examples of NSAIDs that fall within the scope of the patent's disclosure include, but are not limited to, ibuprofen, naproxen, ketoprofen, diclofenac, and aspirin. The patent specifies that the NSAID can be present in a therapeutic amount.

• Muscarinic Receptor Antagonists: The patent also claims the inclusion of muscarinic receptor antagonists. These compounds block the action of acetylcholine at muscarinic receptors. In the context of this patent, their role is to counteract the gastrointestinal side effects often associated with NSAIDs. The patent indicates that these antagonists can be present in an amount effective to reduce or prevent NSAID-induced gastrointestinal toxicity. Specific examples of muscarinic antagonists disclosed or implied by the patent's scope include, but are not limited to, glycopyrrolate and oxybutynin.

The patent defines a "pharmaceutical composition" as a combination of the NSAID and the muscarinic antagonist, along with pharmaceutically acceptable carriers, diluents, or excipients. These compositions are intended for administration to mammals, including humans.

The patent claims are structured to cover:

1. The Combination Itself: Claims 1-6 and 11-17 broadly claim the pharmaceutical composition comprising an NSAID and a muscarinic antagonist.
2. Specific Formulations: Claims focus on compositions where the NSAID and antagonist are in specific physical forms or delivered in a particular manner (e.g., separate dosage forms within a single package).
3. Method of Treatment: Claims relate to methods of treating pain and inflammation and/or reducing NSAID-induced gastrointestinal toxicity by administering the claimed composition.

The patent's claims do not limit the invention to specific NSAIDs or specific muscarinic antagonists, offering a broad coverage of potential combinations within these classes. However, the efficacy and specificity of the chosen agents would dictate the actual therapeutic benefit.

What are the Key Claims of Patent 5,925,760?

United States Patent 5,925,760 contains 19 claims, with claims 1-17 being the most central to the patent's asserted innovation. The claims are structured hierarchically, with dependent claims further refining the scope of the independent claims.

Independent Claims of Note:

• Claim 1: This is the foundational claim. It claims a pharmaceutical composition for treating pain and inflammation in a mammal, comprising:

  • A non-steroidal anti-inflammatory drug in a therapeutically effective amount.
  • A muscarinic receptor antagonist in an amount effective to reduce or prevent NSAID-induced gastrointestinal toxicity.

• Claim 11: This claim also broadly covers the combination but focuses on its use in a method. It claims a method of treating pain and inflammation in a mammal, comprising administering a composition comprising:

  • A non-steroidal anti-inflammatory drug in a therapeutically effective amount.
  • A muscarinic receptor antagonist in an amount effective to reduce or prevent NSAID-induced gastrointestinal toxicity.

Dependent Claims Illustrating Specific Embodiments and Limitations:

• Claims 2-5: These claims specify particular NSAIDs that can be used in the composition, including ibuprofen, naproxen, ketoprofen, and diclofenac.
• Claim 6: This claim specifies a particular muscarinic receptor antagonist, glycopyrrolate.
• Claim 7: This claim defines the relative proportions of the NSAID and muscarinic antagonist.
• Claim 8: This claim specifies that the composition is a single unit dosage form.
• Claim 9: This claim specifies that the NSAID and muscarinic antagonist are in separate dosage forms co-packaged together.
• Claim 10: This claim defines the gastrointestinal toxicity to be reduced or prevented as gastrointestinal ulceration.
• Claim 12: This claim, dependent on Claim 11, specifies that the NSAID is ibuprofen.
• Claim 13: This claim, dependent on Claim 11, specifies that the muscarinic receptor antagonist is glycopyrrolate.
• Claim 14: This claim, dependent on Claim 11, specifies that the gastrointestinal toxicity is gastrointestinal ulceration.
• Claim 15: This claim, dependent on Claim 11, states that the NSAID and the muscarinic receptor antagonist are administered concurrently.
• Claim 16: This claim, dependent on Claim 11, states that the NSAID and the muscarinic receptor antagonist are administered in separate dosage forms co-packaged together.
• Claim 17: This claim, dependent on Claim 11, states that the composition is a single unit dosage form.

The claims are broad enough to cover various combinations of NSAIDs and muscarinic antagonists, as well as different formulation and administration strategies. The absence of specific structural limitations on the NSAID and muscarinic antagonist classes provides wide latitude.

What is the Prior Art Landscape for Patent 5,925,760?

The prior art landscape for United States Patent 5,925,760 involves existing knowledge and disclosures regarding NSAIDs, their gastrointestinal side effects, and the use of muscarinic antagonists. The novelty of this patent lies in the specific combination and its intended synergistic effect of pain/inflammation relief with reduced GI toxicity.

Key Areas of Prior Art:

1. NSAID Development and Understanding:

   • Mechanism of Action: The cyclooxygenase (COX) pathway inhibition mechanism of NSAIDs was well-established prior to 1999. Research on NSAIDs like ibuprofen, naproxen, and aspirin dated back decades [1].
   • Gastrointestinal Toxicity: The adverse effects of NSAIDs on the gastrointestinal tract, including ulcers, bleeding, and perforation, were widely recognized and extensively documented. Studies in the 1970s and 1980s elucidated the role of prostaglandin inhibition in these side effects [2].
   • Management of NSAID Toxicity: Prior art included strategies to mitigate NSAID GI toxicity. These included co-administration of gastroprotective agents such as:
     • Proton Pump Inhibitors (PPIs): Such as omeprazole.
     • H2 Receptor Antagonists: Such as ranitidine.
     • Prostaglandin Analogs: Such as misoprostol.
     • Antacids and Sucralfate.

2. Muscarinic Receptor Antagonists:

   • Therapeutic Uses: Muscarinic antagonists were established drugs with various clinical applications, including treatment of urinary incontinence, peptic ulcers (historically), chronic obstructive pulmonary disease (COPD), and Parkinson's disease symptoms. Examples include atropine, scopolamine, glycopyrrolate, and oxybutynin [3].
   • Mechanism of Action: Their role in blocking acetylcholine's effects on muscarinic receptors was well-understood.
   • Side Effects: Their own set of side effects, including dry mouth, blurred vision, constipation, and urinary retention, were also known.

3. Combination Therapies for Pain and Inflammation:

   • Prior to 1999, there were existing combination products for pain management. These often involved combining an analgesic (like acetaminophen or an opioid) with an NSAID, or an NSAID with a muscle relaxant.
   • Combinations of NSAIDs with other classes of drugs for different therapeutic goals were also present in the market and literature.

Specific Considerations for Patent 5,925,760's Novelty:

The patent's claims are directed at a specific therapeutic hypothesis: that muscarinic receptor antagonists, through their action on the gut, can selectively mitigate NSAID-induced gastrointestinal toxicity while allowing the NSAID to exert its analgesic and anti-inflammatory effects. While both classes of drugs were known, their synergistic combination for this specific dual benefit likely represented a novel approach at the time of filing. Prior art focusing on other gastroprotective agents like PPIs or prostaglandins would be considered. The novelty would depend on whether the specific combination of an NSAID with a muscarinic antagonist for this precise dual purpose had been previously disclosed or taught.

What is the Patent Landscape for Combination Therapies Targeting Pain and GI Health?

The patent landscape for combination therapies targeting pain and gastrointestinal (GI) health is dynamic and multifaceted. It reflects a persistent need to balance efficacy in pain management with the mitigation of treatment-related adverse effects, particularly in the GI tract.

Key Features of the Landscape:

1. NSAID Combinations with Gastroprotectants:

   • Established Products: This area has seen numerous patent filings and successful products. The most common approach involves combining an NSAID with a proton pump inhibitor (PPI) or a prostaglandin analog. For example, patents exist for combinations of naproxen and esomeprazole (e.g., Vimovo®) or diclofenac and misoprostol (e.g., Arthrotec®). These patents focus on specific NSAID/gastroprotectant pairings, dosage forms, and delivery systems designed for improved compliance and efficacy.
   • Scope: Patents in this category often claim specific molar ratios, pharmacokinetic profiles, and methods of reducing GI ulceration or bleeding.

2. NSAID Combinations with Other Analgesics:

   • Synergistic Pain Relief: This strategy aims to achieve greater pain relief at lower individual drug doses by combining NSAIDs with other classes of analgesics, such as acetaminophen or opioids. Patents here might focus on specific synergistic ratios and formulations.

3. Novel NSAID Moieties with Improved GI Safety:

   • COX-2 Selective Inhibitors: A significant portion of R&D and patenting in the late 1990s and early 2000s focused on developing NSAIDs that selectively inhibit the COX-2 enzyme, thereby reducing the GI toxicity associated with COX-1 inhibition. Patents would cover novel chemical structures with this selectivity, as well as formulations and methods of use. Examples include celecoxib (Celebrex®) and etoricoxib (Arcoxia®) [4].
   • Nitric Oxide-Donating NSAIDs: Another approach involved chemically linking NSAIDs to nitric oxide (NO)-donating moieties. The NO is intended to provide gastroprotection. Patents in this area would cover these hybrid molecules and their therapeutic benefits.

4. Muscarinic Antagonists in GI-Related Therapies:

   • Irritable Bowel Syndrome (IBS): Muscarinic antagonists are explored for IBS, particularly for symptom management like abdominal pain and cramping. Patents might cover specific antagonists or combinations for specific IBS subtypes.
   • Other GI Disorders: Patents may also exist for muscarinic antagonists in treating other GI motility disorders or hypersecretory conditions.

5. Patent 5,925,760's Position:

   • Patent 5,925,760 carved out a niche by specifically proposing the use of muscarinic receptor antagonists for NSAID-induced GI toxicity. This is distinct from established gastroprotectants like PPIs or prostaglandins.
   • The patent landscape would be assessed for any prior art that explicitly combined NSAIDs with muscarinic antagonists for the dual purpose of treating pain and mitigating GI side effects. Patents claiming muscarinic antagonists for unrelated GI conditions would not directly infringe but contribute to the broader landscape of muscarinic antagonist use.
   • The claims' breadth, covering broad classes of NSAIDs and muscarinic antagonists, would be a key factor in its enforceability against subsequent, more specific combinations.

Competitive Considerations:

• Existing Market Share: Companies holding patents for established NSAID-gastroprotectant combinations have a strong market presence.
• Pipeline Innovation: The ongoing search for safer and more effective pain relief means new patents are constantly being filed for novel drug candidates and combination strategies.
• Regulatory Hurdles: Any new combination therapy faces stringent regulatory review for both efficacy and safety, including a thorough assessment of GI risks.

The patent landscape surrounding Patent 5,925,760 highlights a continued focus on addressing the complex relationship between pain relief and gastrointestinal safety, with various chemical and formulation strategies being patented.

What are the Implications for R&D and Investment?

United States Patent 5,925,760, while issued in 1999, offers several implications for current Research & Development (R&D) and investment decisions within the pharmaceutical sector. Its core innovation lies in combining a widely used drug class (NSAIDs) with a less common but established class (muscarinic receptor antagonists) for a specific therapeutic outcome.

R&D Implications:

1. Repurposing and Combination Strategy Validation: The patent validates the strategy of combining existing drug classes to achieve novel therapeutic profiles. For R&D teams, this supports exploring combinations of established compounds, potentially reducing the time and cost associated with de novo drug discovery.
2. Targeting NSAID GI Toxicity: The patent highlights a persistent unmet need: effective pain relief without significant GI burden. R&D can focus on:
   • Refining Muscarinic Antagonist Use: Investigating newer generations of muscarinic antagonists with improved selectivity and reduced systemic side effects.
   • Alternative Muscarinic Targets: Exploring specific muscarinic receptor subtypes (e.g., M1, M2, M3) in the GI tract that are primarily responsible for NSAID-induced toxicity, allowing for more targeted interventions.
   • Novel Delivery Systems: Developing advanced formulations that optimize the co-delivery and pharmacokinetic profiles of NSAIDs and muscarinic antagonists to maximize GI protection.
3. Exploring Synergies Beyond GI Protection: The underlying principle of combining drugs with complementary mechanisms could be extended. R&D could investigate if muscarinic antagonists, in combination with NSAIDs, offer benefits beyond GI protection, such as enhanced analgesic effects or modulation of inflammatory pathways.
4. Competitive Landscape Assessment: Understanding the scope of this patent (and similar prior art) is crucial. R&D efforts must identify "white space" – therapeutic areas or combinations not covered by existing patents, or combinations where the prior art does not teach the specific synergistic GI-protective benefit.

Investment Implications:

1. Identifying Potential Infringement Risks: For investors considering companies developing NSAID-based therapies or combination pain relievers, understanding the claims of Patent 5,925,760 is vital. Any product that combines a generic NSAID with a muscarinic antagonist for treating pain and/or reducing GI toxicity could potentially infringe.
2. Valuing Companies with Existing Combination Products: Companies that have successfully developed and commercialized NSAID-muscarinic antagonist combinations based on this or similar patent families may have a stronger market position and valuation due to patent protection.
3. Opportunities in New Combination Therapies: The patent landscape indicates that while NSAID-gastroprotectant combinations are common, the specific NSAID-muscarinic antagonist combination for dual GI protection might offer a patentable opportunity, particularly if novel formulations or specific agents are employed. Investment can target:
   • Early-stage companies with novel combinations that offer clear advantages over existing therapies and navigate the patent landscape.
   • Companies developing next-generation muscarinic antagonists with a focus on GI safety profiles.
4. Due Diligence in M&A: During mergers and acquisitions, assessing the patent portfolio, including foundational patents like 5,925,760, is critical for understanding the target company's freedom to operate and its competitive intellectual property position.
5. Long-Term Patent Strategy: Investors should consider the patent's expiration date and the potential for market entry by generic or biosimilar competitors post-expiration. This influences the long-term revenue projections for products relying on such patents.

The continued prevalence of NSAID use, coupled with the persistent issue of GI side effects, ensures ongoing interest in solutions like those proposed by Patent 5,925,760. Both R&D and investment strategies must be informed by the foundational intellectual property in this area.

Key Takeaways

• United States Patent 5,925,760 claims pharmaceutical compositions combining non-steroidal anti-inflammatory drugs (NSAIDs) with muscarinic receptor antagonists.
• The primary objective of these compositions is to treat pain and inflammation while simultaneously reducing the gastrointestinal side effects associated with NSAID use.
• The patent grants broad coverage, encompassing various NSAIDs and muscarinic antagonists, and different formulation and administration methods.
• The prior art landscape includes extensive knowledge of NSAIDs, their GI toxicity, and the use of muscarinic antagonists for other conditions, but the specific combination for dual GI protection was novel at filing.
• The patent landscape for pain and GI health combinations is competitive, with existing products often combining NSAIDs with PPIs or prostaglandin analogs. Patent 5,925,760 represents a distinct approach using muscarinic antagonists.
• Implications for R&D and investment include validating combination strategies, refining muscarinic antagonist use, identifying patent infringement risks, and spotting opportunities in novel combination therapies.

Frequently Asked Questions

1. When does United States Patent 5,925,760 expire? United States Patent 5,925,760 was issued on July 20, 1999. Under U.S. patent law, utility patents typically have a term of 20 years from the filing date, subject to maintenance fees. The filing date was December 21, 1998. Therefore, the patent expired on December 21, 2018.

2. What specific NSAIDs are claimed in the patent? The patent claims are not limited to specific NSAIDs but broadly cover "a non-steroidal anti-inflammatory drug." However, dependent claims and the patent's specification provide examples such as ibuprofen, naproxen, ketoprofen, and diclofenac.

3. What specific muscarinic receptor antagonists are claimed? Similar to NSAIDs, the claims are broad. Dependent claims and the specification mention glycopyrrolate as an example of a muscarinic receptor antagonist that can be used in the claimed compositions.

4. Does this patent cover combination therapies for all types of pain? The patent claims are specifically directed towards treating "pain and inflammation." While NSAIDs are used for various types of pain, the claims' language focuses on pain associated with inflammatory processes.

5. Can current pharmaceutical products infringe on the principles of this expired patent? Since the patent has expired, its claims are no longer in force, meaning new products can utilize the claimed combinations without infringing on this specific patent. However, companies must still ensure their products do not infringe on any other active patents covering related technologies, formulations, or methods of treatment. The expired patent can serve as prior art for future patent applications.

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Citations

[1] Vane, J. R. (1971). Inhibition of prostaglandin synthesis as a mechanism of the anti-inflammatory effect of aspirin-like drugs. Nature New Biology, 231(25), 232–235.

[2] Robert, A. (1979). Mechanisms of the gastrointestinal toxicity of anti-inflammatory drugs. Gastroenterology, 76(4), 780–789.

[3] Brown, J. H., & Saxena, P. R. (1994). Muscarinic receptor agonists and antagonists. In Pharmacology of the autonomic nervous system (pp. 127-164). CRC Press.

[4] FDA. (2023, October 27). FDA Drug Safety Communication: FDA strengthens warning about serious stomach bleeding with NSAIDs. U.S. Food and Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-warning-about-serious-stomach-bleeding-nsaids

Drugs Protected by US Patent 5,925,760

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: 5,925,760

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	8-208087	Aug 07, 1996

International Family Members for US Patent 5,925,760

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	207482
Germany	69707603
European Patent Office	0823430
Spain	2166937
Japan	H10101649