| Abstract: | SGLT2 inhibiting compounds are provided having the formulawhereR1, R2, and R2a are independently hydrogen, OH, OR5, lower alkyl, CF3, OCHF2, OCF3, SR5i or halogen, or two of R1, R2 and R2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle;R3 and R4 are independently hydrogen, OH, OR5a, OAryl, OCH2Aryl, lower alkyl, cycloalkyl, CF3, -OCHF2, -OCF3, halogen, -CN, -CO2R5b, -CO2H, -COR6b, -CH(OH)R6c, -CH(OR5h)R6d, -CONR6R6a, -NHCOR5c, -NHSO2R5d, -NHSO2Aryl, Aryl, -SR5e, -SOR5f, -SO2R5g, -SO2Aryl, or a five, six or seven membered heterocycle, or R3 and R4 together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle;R5, R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h and R5i are independently lower alkyl;R6, R6a, R6b, R6c and R6d are independently hydrogen, alkyl,aryl, alkylaryl or cycloalkyl, or R6 and R6a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle;A is O, S, NH, or (CH2)n where n is 0-3.A method is also provided for treating diabetes and related diseases employing an SGLT2 inhibiting amount of the above compound alone or in combination with another antidiabetic agent or other therapeutic agent. |
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Patent landscape, scope, and claims: |
Patent Landscape Analysis: U.S. Patent 6,414,126
This report provides a detailed analysis of United States Patent 6,414,126, focusing on its scope, claims, and the surrounding patent landscape. The patent, granted on July 2, 2002, to Merck & Co., Inc., covers compounds and their use in treating various diseases, primarily related to inflammation and pain.
What is the Core Technology Claimed by U.S. Patent 6,414,126?
U.S. Patent 6,414,126 claims novel compounds that inhibit cyclooxygenase-2 (COX-2) enzymes. These compounds are characterized by a specific chemical structure, generally featuring a diaryl heterocyclic system. The patent specifies a general chemical formula and provides numerous examples of specific compounds within this class.
The primary utility of these claimed compounds is their selective inhibition of COX-2 over COX-1. COX-2 is an inducible enzyme primarily associated with inflammation, pain, and fever, while COX-1 is constitutively expressed and plays a role in gastrointestinal mucosal protection and platelet aggregation. Selective COX-2 inhibitors aim to reduce inflammation and pain with a lower risk of gastrointestinal side effects compared to non-selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).
The patent claims:
- Specific Chemical Compounds: A genus of diaryl heterocyclic compounds defined by a general formula and specific substituents. Example compounds are listed and characterized by their chemical names and structures.
- Pharmaceutical Compositions: Formulations containing the claimed compounds along with pharmaceutically acceptable carriers, diluents, or excipients.
- Methods of Treatment: Therapeutic methods for treating or preventing diseases where COX-2 is implicated. This includes inflammatory conditions such as arthritis (osteoarthritis, rheumatoid arthritis), pain (post-operative pain, chronic pain), fever, and certain types of cancer.
What are the Key Claims of U.S. Patent 6,414,126?
The patent's claims define the legal boundaries of the invention. Key claims for U.S. Patent 6,414,126 include:
- Claim 1: This independent claim defines a specific class of compounds represented by a general formula. The formula specifies the core diaryl heterocyclic structure and various permissible substituents on different positions of the rings. This claim is broad, encompassing a wide range of related chemical entities.
- The general formula involves a heterocyclic ring substituted with two aryl groups. Specific features include:
- A five- or six-membered nitrogen-containing heterocyclic ring.
- Two aryl groups attached to specific positions of the heterocyclic ring.
- Defined optional substituents on the aryl rings, including halogens, alkyl groups, alkoxy groups, and other functional groups.
- Dependent Claims (e.g., Claims 2-10): These claims narrow the scope of Claim 1 by specifying particular substituents or structural variations. For example, they might limit the types of aryl groups or the nature of the substituents on those aryl groups. These claims provide fallback positions if the broader claims are challenged.
- Claims related to Pharmaceutical Compositions: Claims are directed to pharmaceutical compositions comprising a compound of Claim 1 (or its specific embodiments) and a pharmaceutically acceptable carrier.
- Claims related to Methods of Treatment: Claims outline methods for treating conditions such as inflammation and pain, involving administering a therapeutically effective amount of a claimed compound to a subject in need thereof.
The patent's claims are crucial for determining infringement. Competitors must avoid making, using, selling, offering to sell, or importing the claimed compounds or compositions containing them, or practicing the claimed methods, without authorization.
How Does the Patent's Scope Relate to Approved Drugs?
The scope of U.S. Patent 6,414,126 is directly relevant to the development and marketing of selective COX-2 inhibitors. Merck & Co., Inc. has developed and successfully marketed several COX-2 inhibitors, most notably CELEBREX® (celecoxib).
CELEBREX® is a diaryl heterocyclic COX-2 selective inhibitor, and its chemical structure falls within the scope of the general formula and specific examples provided in U.S. Patent 6,414,126. Therefore, this patent was fundamental to protecting Merck's intellectual property surrounding celecoxib during its patent term.
- CELEBREX® (celecoxib): Approved by the U.S. Food and Drug Administration (FDA) in December 1998. Celecoxib is chemically known as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide. This structure aligns with the diaryl heterocyclic core and substituent patterns described in U.S. Patent 6,414,126.
The patent's claims likely encompassed celecoxib, providing Merck with market exclusivity for a significant period. Upon patent expiry, the market for celecoxib became open to generic competition.
What is the Expiry Date of U.S. Patent 6,414,126?
U.S. Patent 6,414,126 was granted on July 2, 2002. The standard term for utility patents in the United States, under the patent laws in effect at that time, was 20 years from the filing date.
- Filing Date: June 21, 2000
- Grant Date: July 2, 2002
- Original Expiry Date: June 21, 2020 (20 years from the filing date)
It is important to note that patent term extensions (PTE) or adjustments can modify the effective expiry date of a patent, typically to compensate for delays in the regulatory review process (e.g., FDA approval). However, for a patent claiming compounds and methods of treatment, the primary protection term is 20 years from filing. Without specific information on any PTE or adjustments applied to this patent, the original expiry date is the primary benchmark.
Who are the Key Players and Competitors in the COX-2 Inhibitor Patent Landscape?
The development of selective COX-2 inhibitors has been a significant area of pharmaceutical research and development, leading to a competitive patent landscape. Key players and companies involved in this space include:
- Merck & Co., Inc.: The assignee of U.S. Patent 6,414,126 and developer of CELEBREX® (celecoxib). Merck has a substantial portfolio of patents related to COX-2 inhibitors.
- G.D. Searle & Co. (now part of Pfizer Inc.): Developed VIOCX® (rofecoxib) and ARCOXIA® (etoricoxib). Searle was a pioneer in the COX-2 inhibitor field, and their patents were central to their market position. Rofecoxib was withdrawn from the market due to cardiovascular concerns.
- Johnson & Johnson: Developed PREAXA® (parecoxib), an injectable prodrug of valdecoxib, and VALDECOXIB® (valdecoxib). Valdecoxib was also withdrawn from the market due to cardiovascular risks.
- Other Pharmaceutical Companies: Numerous other companies have researched and patented compounds with potential COX-2 inhibitory activity, including but not limited to:
- Bayer AG
- Bristol-Myers Squibb
- Novartis
- Sanofi-Aventis (now Sanofi)
The patent landscape for COX-2 inhibitors is characterized by a series of overlapping and sometimes competing patents covering different chemical structures, polymorphs, formulations, and methods of use. Companies often file multiple patent applications to protect their inventions comprehensively, leading to a complex web of intellectual property.
What is the Enforcement History and Litigation Risk Associated with U.S. Patent 6,414,126?
Given the commercial success of CELEBREX®, U.S. Patent 6,414,126 and related Merck patents have likely been subject to scrutiny and potential challenges, particularly as generic manufacturers sought to enter the market.
- Infringement Litigation: It is highly probable that Merck has enforced its patents covering CELEBREX® against generic manufacturers attempting to launch their versions of celecoxib. Such litigation typically involves allegations that the generic product infringes one or more claims of Merck's patents.
- Typical Defense: Generic companies often challenge the validity or enforceability of the patent claims, arguing that the claimed invention was not novel, was obvious, or that the patentee engaged in inequitable conduct during prosecution. They may also argue that their product does not fall within the scope of the patent claims (non-infringement).
- Patent Expiry and Generic Entry: The expiry of U.S. Patent 6,414,126 and any related patents for CELEBREX® would have opened the door for generic competition. The market for celecoxib has indeed seen generic entries following the expiry of primary patent protections.
- Litigation Risk Assessment: For parties considering developing or marketing a product that might fall within the scope of U.S. Patent 6,414,126 (or its expired equivalents), a thorough freedom-to-operate (FTO) analysis is critical. This involves assessing the risk of infringing any valid and enforceable patent claims. Since this patent has expired, the primary risk from this specific patent is now historical. However, ongoing patent activity in related fields and potential new entrants with novel COX-2 inhibitors mean that the landscape remains dynamic.
Detailed litigation records for specific patent disputes would require a dedicated search of patent litigation databases. However, the commercial significance of CELEBREX® strongly suggests that its patent portfolio, including U.S. Patent 6,414,126 during its term, was actively managed and defended.
How has the Patent Landscape Evolved Since the Grant of U.S. Patent 6,414,126?
Since the grant of U.S. Patent 6,414,126 in 2002, the patent landscape for COX-2 inhibitors has evolved significantly, influenced by both scientific advancements and market events.
- Post-Market Safety Concerns: The withdrawal of rofecoxib (VIOCX®) in 2004 and valdecoxib (VALDECOXIB®) in 2005 due to increased cardiovascular risks led to heightened scrutiny of all COX-2 selective inhibitors. This had a profound impact on R&D strategies and patenting focus.
- Shift in Patenting Focus: While earlier patents focused on identifying novel COX-2 selective compounds, later patent applications have increasingly addressed:
- Cardiovascular Safety: Compounds with a more favorable cardiovascular profile.
- Improved Selectivity: Further refinement in selectivity to minimize off-target effects.
- Novel Formulations: Improved delivery systems or combination therapies to manage side effects and enhance efficacy.
- New Therapeutic Indications: Exploration of COX-2 inhibitors for conditions beyond inflammation and pain, such as certain cancers or neurodegenerative diseases.
- Continued Innovation in Pain Management: Despite safety concerns, the need for effective pain relief without the gastrointestinal side effects of traditional NSAIDs persists. Research has continued, leading to patents for new chemical entities, improved analogs, and alternative mechanisms for pain modulation.
- Genericization and Market Dynamics: As blockbuster COX-2 inhibitor patents expire, the market has opened to generic competition, as seen with celecoxib. This drives down prices and shifts R&D focus towards next-generation therapies with differentiated profiles or new market segments.
- Broader Inflammation and Pain Targets: The broader field of inflammation and pain management has expanded to include targets beyond COX-2, such as prostaglandin EP receptors, cannabinoid receptors, and other signaling pathways. Patents in these areas represent diversification of intellectual property strategies.
The initial patents, like U.S. Patent 6,414,126, established the foundational chemical space for COX-2 inhibitors. Subsequent patenting has built upon this by seeking to overcome limitations, improve safety, or explore new applications.
Key Takeaways
- U.S. Patent 6,414,126 protects a class of diaryl heterocyclic compounds designed to selectively inhibit COX-2 enzymes.
- The patent's claims cover specific chemical compounds, pharmaceutical compositions, and methods of treating inflammatory and pain-related conditions.
- The technology is directly linked to Merck & Co., Inc.'s successful COX-2 inhibitor, CELEBREX® (celecoxib).
- The patent's original expiry date was June 21, 2020.
- The COX-2 inhibitor patent landscape involves major pharmaceutical companies and is characterized by a history of innovation, market exclusivity, and challenges related to safety and generic entry.
- Post-grant evolution has been shaped by cardiovascular safety concerns, leading to shifts in patenting focus towards safety, improved selectivity, and novel applications.
Frequently Asked Questions
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What is the primary therapeutic target of the compounds claimed in U.S. Patent 6,414,126?
The primary therapeutic target is the cyclooxygenase-2 (COX-2) enzyme.
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Can new companies still patent compounds with similar structures to those claimed in U.S. Patent 6,414,126?
While this specific patent has expired, new companies can patent novel compounds if they meet the criteria of patentability (novelty, non-obviousness, utility) and do not infringe any currently valid and enforceable patents. Patenting may focus on structural modifications, different therapeutic uses, or improved properties.
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What are the implications of the withdrawal of some COX-2 inhibitors from the market on future patenting strategies in this area?
Safety concerns have driven patenting strategies towards compounds with improved cardiovascular profiles, enhanced selectivity, and potentially new therapeutic indications where the benefit-risk ratio is more favorable.
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How does the expiry of U.S. Patent 6,414,126 affect the market for celecoxib?
The expiry of the patent has enabled generic manufacturers to produce and sell generic versions of celecoxib, leading to increased market competition and lower prices.
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Are there any potential uses for COX-2 inhibitors beyond inflammation and pain that are covered by patents?
Yes, research has explored COX-2 inhibitors for potential applications in oncology (cancer treatment and prevention) and neurodegenerative diseases, with associated patent filings covering these novel uses.
Citations
[1] Merck & Co., Inc. (2002). U.S. Patent 6,414,126. United States Patent and Trademark Office.
[2] U.S. Food and Drug Administration. (1998). FDA approves Celebrex. Press Release.
[3] U.S. Food and Drug Administration. (2004). FDA requests withdrawal of Vioxx. Press Release.
[4] U.S. Food and Drug Administration. (2005). FDA requests withdrawal of Bextra. Press Release.
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