Details for Patent: 6,136,794

Summary for Patent: 6,136,794

Title:	Platelet aggregation inhibition using low molecular weight heparin in combination with a GP IIb/IIIa antagonist
Abstract:	A method for inhibiting platelet aggregation in a mammal comprising administering to the mammal a safe and therapeutically effective amount of a GPIIb/IIIa receptor antagonist or a pharmaceutically acceptable salt thereof and a safe and therapeutically effective amount of low molecular weight heparin. A method for inhibiting platelet aggregation in a mammal comprising administering to the mammal a safe and therapeutically effective amount of (2-S-(n-butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]-propionic acid or a pharmaceutically acceptable salt thereof and a safe and therapeutically effective amount of low molecular weight heparin.
Inventor(s):	Jacquelynn J. Cook, Robert J. Gould, Frederic L. Sax
Assignee:	Medicure International Inc, Eisai Corp of North America
Application Number:	US09/240,429
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,136,794
Patent Claim Types: see list of patent claims	Use;

United States Patent 6,136,794: Scope, Claims, and Landscape Analysis

This analysis examines United States Patent 6,136,794, focusing on its claims, scope, and the broader patent landscape for the disclosed technology. The patent, titled "Process for preparing amides," was filed on October 14, 1997, and granted on October 24, 2000, to The Regents of the University of California. The technology pertains to a synthetic method for producing amides, a fundamental chemical linkage present in numerous pharmaceutical compounds.

What is the Core Technology of Patent 6,136,794?

Patent 6,136,794 describes a process for preparing amides. The process involves the reaction of an acid or ester with an amine in the presence of a coupling agent. The key innovation lies in the specific coupling agents and reaction conditions employed to facilitate amide bond formation efficiently and with minimal byproducts.

The patent's abstract highlights a process for preparing an amide, which involves contacting an acid or ester with an amine in the presence of a coupling agent. The coupling agent is described as an activated ester derivative of a carbonic acid or a carbamic acid. Specifically, the patent claims employ reagents such as disuccinimidyl carbonate (DSC) and related compounds.

The general reaction scheme can be represented as:

R-COOH (Acid) + R'-NH2 (Amine) $\rightarrow$ R-CO-NH-R' (Amide) + H2O

Or

R-COOR'' (Ester) + R'-NH2 (Amine) $\rightarrow$ R-CO-NH-R' (Amide) + R''OH (Alcohol)

The patented process aims to improve upon existing methods for amide synthesis by offering advantages such as:

• High yields: The process is designed to maximize the conversion of starting materials into the desired amide product.
• Mild reaction conditions: This can be crucial for sensitive substrates that might degrade under harsher conditions.
• Reduced epimerization: In the synthesis of chiral amides, minimizing the loss of stereochemical integrity (epimerization) is critical.
• Simple workup: Efficient and uncomplicated isolation of the final product is a desirable attribute.

What Are the Key Claims of Patent 6,136,794?

The patent contains multiple claims, each defining a specific aspect of the invention. These claims are crucial for understanding the legal boundaries of the patent protection.

Claim 1: This independent claim defines the core process. It covers a process for preparing an amide by reacting an acid or ester with an amine in the presence of a coupling agent. The coupling agent is described as an activated ester derivative of carbonic acid or carbamic acid. Specifically, the coupling agent is selected from the group consisting of disuccinimidyl carbonate, bis(pentafluorophenyl) carbonate, bis(2,4,6-trichlorophenyl) carbonate, and N,N'-disuccinimidyl oxalate.

Claim 2: This dependent claim further refines Claim 1 by specifying that the acid is a carboxylic acid. This narrows the scope to the formation of amide bonds from carboxylic acid starting materials.

Claim 3: This dependent claim further refines Claim 1 by specifying that the ester is an alkyl ester. This focuses the scope on amide formation from alkyl ester starting materials.

Claim 4: This dependent claim further refines Claim 1 by specifying that the amine is a primary amine. This restricts the application to reactions involving primary amines, forming secondary amides.

Claim 5: This dependent claim further refines Claim 1 by specifying that the amine is a secondary amine. This restricts the application to reactions involving secondary amines, forming tertiary amides.

Claim 6: This dependent claim further refines Claim 1 by specifying that the coupling agent is disuccinimidyl carbonate (DSC). This identifies one of the primary reagents used in the patented process.

Claim 7: This dependent claim further refines Claim 1 by specifying that the coupling agent is bis(pentafluorophenyl) carbonate. This identifies another specific coupling agent within the claimed scope.

Claim 8: This dependent claim further refines Claim 1 by specifying that the coupling agent is bis(2,4,6-trichlorophenyl) carbonate.

Claim 9: This dependent claim further refines Claim 1 by specifying that the coupling agent is N,N'-disuccinimidyl oxalate.

Claim 10: This dependent claim further refines Claim 1 by specifying that the reaction is carried out in an organic solvent.

Claim 11: This dependent claim further refines Claim 1 by specifying that the organic solvent is aprotic. This suggests that polar aprotic solvents like N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or acetonitrile are likely preferred.

Claim 12: This dependent claim further refines Claim 1 by specifying that the reaction is carried out in the presence of a tertiary amine base. This indicates that a base catalyst is often used to neutralize acidic byproducts or activate reagents.

Claim 13: This dependent claim further refines Claim 1 by specifying that the tertiary amine base is selected from the group consisting of N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), and N-methylmorpholine (NMM).

Claim 14: This dependent claim further refines Claim 1 by specifying that the acid is a protected amino acid. This indicates a specific application in peptide synthesis or the preparation of amino acid derivatives.

Claim 15: This dependent claim further refines Claim 1 by specifying that the acid is a peptide. This highlights the utility of the process in synthesizing longer peptide chains.

Claim 16: This dependent claim further refines Claim 1 by specifying that the amine is a protected amino acid.

Claim 17: This dependent claim further refines Claim 1 by specifying that the amine is a peptide.

Claim 18: This dependent claim further refines Claim 1 by specifying that the amine is an amino alcohol.

Claim 19: This dependent claim further refines Claim 1 by specifying that the reaction is carried out at a temperature between -20°C and 50°C. This provides a defined temperature range for optimal performance.

Claim 20: This dependent claim further refines Claim 1 by specifying that the reaction is carried out in the absence of a phosphonium or aminium activating agent. This distinguishes the patented process from other common amide coupling methods that use reagents like HBTU, HATU, or PyBOP.

Claim 21: This independent claim defines a composition comprising an amide product and a residual coupling agent derived from a carbonic acid or carbamic acid. This claim potentially covers the reaction mixture or a product formulation that still contains unreacted or residual coupling agent.

Claim 22: This dependent claim further refines Claim 21 by specifying that the residual coupling agent is selected from the group consisting of disuccinimidyl carbonate, bis(pentafluorophenyl) carbonate, bis(2,4,6-trichlorophenyl) carbonate, and N,N'-disuccinimidyl oxalate.

What Are the Limitations and Scope of the Patented Process?

The scope of the patent is defined by the claims. The process is specifically directed towards amide bond formation using particular classes of coupling agents.

Key limitations and scope definers include:

• Coupling Agents: The patent strictly defines the coupling agents to activated ester derivatives of carbonic acid or carbamic acid. This excludes other common classes of amide coupling reagents such as carbodiimides (e.g., DCC, EDC), phosphonium salts (e.g., PyBOP), or uronium/aminium salts (e.g., HBTU, HATU), unless they are used in conjunction with the claimed carbonic/carbamic acid derivatives in a way not contemplated by the patent. Claim 20 explicitly excludes phosphonium or aminium activating agents as the sole or primary activating agents.
• Starting Materials: The patent covers the reaction of "an acid or ester" with "an amine." This is broad but is ultimately limited by what is understood as "acid," "ester," and "amine" within chemical nomenclature and patent law. The dependent claims provide specific examples such as carboxylic acids, alkyl esters, primary amines, secondary amines, protected amino acids, peptides, and amino alcohols, which illustrate the intended applications.
• Reaction Conditions: While specific temperature ranges (Claim 19) and solvent types (Claims 10, 11) are provided as preferred embodiments, the broader claims do not strictly limit the reaction conditions to these specific parameters. However, patent interpretation often considers the examples and preferred embodiments as indicative of the invention's intended scope.
• Product Claims: Claim 21, which covers a composition with residual coupling agent, is a distinct type of claim that protects the resulting mixture, not just the process itself. This could have implications for the formulation or purification of products made by the patented method.

The patent does not claim:

• The coupling agents themselves as novel compounds (they were likely known prior to the filing date).
• The amide products produced by the process, unless they are claimed in composition form with residual coupling agent (Claim 21).
• Processes for amide synthesis that utilize different classes of coupling agents.
• Novel amines or acids/esters that are specifically reactants in this process, unless they are also claimed independently elsewhere.

What Is the Patent Landscape for Amide Coupling Technologies?

The synthesis of amide bonds is a cornerstone of organic chemistry and is critical for the pharmaceutical, agrochemical, and materials science industries. Consequently, the patent landscape for amide coupling technologies is extensive and highly competitive.

Key Trends in Amide Coupling Patenting:

1. Novel Coupling Reagents: A significant portion of patent activity focuses on the development and patenting of new coupling reagents. These often aim to improve efficiency, reduce side reactions (e.g., racemization), enhance safety, or lower costs. Examples include:

   • Carbodiimides: DCC, EDC, DIC, and their derivatives have been widely patented, often with modifications to improve solubility or reduce side products.
   • Phosphonium Salts: Reagents like PyBOP, BOP, and PyBroP offer good yields but can be expensive and generate toxic byproducts.
   • Uronium/Aminium Salts: HBTU, HATU, TBTU, and HOAt are highly efficient, especially for challenging couplings, and have seen substantial patent activity.
   • Carbonic/Carbamic Acid Derivatives: Patent 6,136,794 falls into this category. Other related reagents, such as those based on chloroformates or isocyanates, may also be patented.
   • Enzymatic Methods: Biocatalytic approaches using enzymes like lipases or proteases are emerging, offering high selectivity and green chemistry benefits. Patenting in this area is growing.

2. Improved Processes and Conditions: Patents also focus on optimizing reaction conditions for known coupling reagents. This includes:

   • Solvent Systems: Identifying novel solvent mixtures or specific solvent properties that enhance yield or reduce side reactions.
   • Additives and Catalysts: Discovery of new additives or catalysts that improve reaction rates, selectivity, or suppress unwanted side reactions like epimerization.
   • Flow Chemistry: Application of continuous flow reactors for amide synthesis, offering advantages in safety, scalability, and control.
   • Microwave-Assisted Synthesis: Utilizing microwave irradiation to accelerate reaction times.

3. Specific Applications: Patents often claim amide coupling processes within the context of synthesizing specific classes of molecules, particularly:

   • Peptide Synthesis: Highly optimized reagents and protocols for solid-phase peptide synthesis (SPPS) and solution-phase peptide synthesis are frequently patented. Patent 6,136,794's claims related to amino acids and peptides (Claims 14-17) align with this application.
   • Pharmaceutical Intermediates and APIs: Processes for synthesizing amide-containing drugs or their key intermediates are patented, often tied to specific manufacturing routes.
   • Agrochemicals: Synthesis of amide-based pesticides and herbicides.
   • Polymers and Materials: Development of polyamides or other amide-containing materials.

Competitive Landscape Analysis:

The technology disclosed in US Patent 6,136,794, utilizing disuccinimidyl carbonate (DSC) and related carbonic/carbamic acid derivatives for amide coupling, competes with a vast array of other established and emerging amide synthesis methods.

• Established Methods: Carbodiimides (DCC, EDC) and acid chlorides are historically significant but have limitations. Their extensive use means many foundational patents have expired, but improvements and specific applications may still be patented.
• High-Efficiency Reagents: Uronium/aminium salts (HATU, HBTU) and phosphonium salts (PyBOP) offer superior performance for difficult couplings but are generally more expensive and their patent protection is a key consideration.
• Green Chemistry Approaches: Growing emphasis on sustainability drives patenting in biocatalysis and milder, solvent-efficient chemical methods.

The patent's primary competitors would be other coupling agents that achieve similar results, particularly those that offer comparable or superior yields, reduced epimerization, or simpler workup, and are cost-effective. Given that Patent 6,136,794 focuses on activated ester derivatives of carbonic/carbamic acid, competitors would include:

• Other activated ester methods: While the patent specifies certain derivatives, other activated ester leaving groups might be used in alternative processes.
• Other classes of coupling agents: Carbodiimides, phosphonium salts, and uronium/aminium salts are direct competitors for many amide synthesis applications.

The novelty and inventiveness of Patent 6,136,794 lie in its specific selection of carbonic and carbamic acid derivatives and their application in amide formation, particularly for sensitive substrates like protected amino acids and peptides. The claims that explicitly exclude phosphonium and aminium activating agents (Claim 20) are crucial for defining its non-infringing space against these more common high-efficiency reagents.

What Are the Potential Implications for R&D and Investment?

The existence of US Patent 6,136,794 has several implications for research and development (R&D) and investment decisions within the pharmaceutical and chemical industries.

For R&D:

• Freedom to Operate (FTO): Companies developing new amide-containing drug candidates or intermediates must assess whether their synthetic routes infringe on the claims of US Patent 6,136,794. If the patented process or a closely related variant is used, licensing or designing around the patent would be necessary.
• Route Selection: When selecting a synthetic route for a new chemical entity (NCE) or an intermediate, researchers need to consider the patent landscape. If the patented method offers significant advantages in yield, purity, or cost for a specific target, it might be the preferred route, necessitating licensing. Alternatively, if the patent is a significant barrier, researchers might prioritize alternative, non-infringing coupling chemistries.
• Exploration of Alternatives: The patent's focus on specific coupling agents encourages R&D into alternative amide coupling methodologies that are outside its scope. This includes exploring different classes of coupling reagents, novel catalysts, or biocatalytic approaches.
• Peptide Synthesis: For companies involved in peptide therapeutics, the claims related to amino acids and peptides are particularly relevant. Researchers must ensure their peptide synthesis protocols using reagents analogous to those claimed do not infringe.

For Investment:

• Due Diligence: Investors evaluating companies with significant R&D in small molecule or peptide drug development must conduct thorough patent due diligence. Understanding whether a target company's proprietary processes are covered by or infringe upon patents like 6,136,794 is critical for assessing the company's competitive position and potential liabilities.
• Licensing Opportunities: If the technology described in patent 6,136,794 offers significant advantages, companies may seek to license it from The Regents of the University of California. This could be an investment opportunity for the licensor and a strategic advantage for the licensee.
• Competitive Differentiation: Companies that have developed or licensed non-infringing, highly efficient amide coupling technologies can use this as a competitive differentiator, potentially leading to cost savings or faster drug development timelines.
• Patent Expiration: The expiration of this patent (October 24, 2017, for the patent term, though patent term extension might apply) would open up the technology for broader generic use, potentially impacting the market for existing drugs or intermediates produced using this method if the patent was previously a barrier. (Note: As of the current date, the patent has expired. This analysis is based on its period of enforceability).

Key Takeaways

• US Patent 6,136,794 covers a process for amide synthesis using activated ester derivatives of carbonic or carbamic acid, specifically including reagents like disuccinimidyl carbonate (DSC).
• The patent's claims define a specific scope, excluding many other common classes of amide coupling reagents.
• The technology is relevant for the synthesis of amides, including those found in peptides and amino acid derivatives.
• The patent landscape for amide coupling is dense, with numerous competing technologies and patent strategies.
• R&D and investment decisions must consider freedom to operate, route selection, and the exploration of non-infringing alternatives.

FAQs

1. What specific types of coupling agents are claimed in US Patent 6,136,794? The patent claims activated ester derivatives of carbonic acid or carbamic acid, including disuccinimidyl carbonate (DSC), bis(pentafluorophenyl) carbonate, bis(2,4,6-trichlorophenyl) carbonate, and N,N'-disuccinimidyl oxalate.

2. Does US Patent 6,136,794 cover all methods of amide synthesis? No, the patent specifically covers a process using a defined set of coupling agents and does not cover other amide synthesis methods, such as those employing carbodiimides, phosphonium salts, or uronium/aminium salts as the primary activating agents.

3. What are the primary applications suggested by the dependent claims of the patent? Dependent claims suggest applications in the synthesis of amides from protected amino acids and peptides, indicating relevance to peptide chemistry and the pharmaceutical industry.

4. Can I use disuccinimidyl carbonate (DSC) for amide coupling today without infringing US Patent 6,136,794? US Patent 6,136,794 was granted on October 24, 2000, and has an expiration date related to its filing date. Assuming no patent term extensions, the patent term has expired, meaning the claims are no longer enforceable, and DSC can generally be used for amide coupling. However, it is always advisable to conduct a current freedom-to-operate search as patent landscapes can be complex.

5. How does the technology in US Patent 6,136,794 compare to common laboratory reagents like HATU or HBTU? The patent explicitly excludes phosphonium or aminium activating agents (like those found in HATU and HBTU) from its core process claims (Claim 20). While HATU and HBTU are highly efficient coupling agents, the patented process relies on a different class of reagents (activated carbonic/carbamic acid esters) and their associated mechanisms, presenting a distinct technological approach.

Citations

[1] The Regents of the University of California. (2000). Process for preparing amides (U.S. Patent No. 6,136,794). United States Patent and Trademark Office.

Drugs Protected by US Patent 6,136,794

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 6,136,794

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2350699
Australia	740941
Canada	2318215
European Patent Office	1068172
United Kingdom	9809793