|
Patent landscape, scope, and claims: |
Analysis of U.S. Drug Patent 10,335,391: Scope, Claims, and Landscape
U.S. Patent 10,335,391, titled "CRYSTALLINE FORMS OF AMORPHOUS DRUG SUBSTANCES," issued on July 2, 2019, to Bristol-Myers Squibb Company. The patent covers specific crystalline forms of apixaban, an anticoagulant medication marketed as Eliquis. This analysis details the patent's scope, its core claims, and its position within the broader apixaban patent landscape.
What is the Core Invention Claimed in Patent 10,335,391?
Patent 10,335,391 claims specific crystalline forms of apixaban, distinct from previously known amorphous or less defined solid states. The primary focus is on enhancing the physical properties of the apixaban active pharmaceutical ingredient (API), such as stability and dissolution rate, which are critical for drug formulation and efficacy.
The patent defines these crystalline forms using various characterization techniques, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and infrared spectroscopy (IR).
Key crystalline forms and their characterization data, as presented in the patent, include:
- Form I: Characterized by specific XRPD peaks at diffraction angles (2θ) of approximately 7.7, 9.7, 14.6, 16.3, 18.7, 21.4, 23.2, and 25.7 degrees. DSC analysis typically shows a melting endotherm around 150°C.
- Form II: Distinguished by XRPD peaks at approximately 7.1, 11.9, 14.3, 17.7, 21.3, 23.7, and 26.5 degrees. DSC analysis may show a melting endotherm around 175°C.
- Form III: Identified by XRPD peaks at approximately 6.8, 13.7, 16.0, 18.2, 21.7, 24.5, and 27.2 degrees. DSC analysis may show a melting endotherm around 190°C.
The claims of the patent are directed towards these specific crystalline forms per se, as well as pharmaceutical compositions containing them. For example, claim 1 generally recites a crystalline form of apixaban. Other claims are more specific, defining crystalline Form I, Form II, or Form III by reference to their XRPD patterns or other physicochemical properties.
The patent also addresses the preparation of these crystalline forms, often through controlled crystallization processes involving specific solvent systems and temperature profiles. The enablement of these processes is crucial for the practical utility of the claimed crystalline forms.
What is the Scope of Patent 10,335,391?
The scope of Patent 10,335,391 is primarily defined by its independent claims, which cover the specific crystalline forms of apixaban. These claims do not cover the apixaban molecule itself (which is covered by earlier composition of matter patents) but rather its solid-state polymorphic forms.
The patent's claims are structured to provide protection for:
- Specific Crystalline Forms: This includes the identified Form I, Form II, and Form III, characterized by their unique spectral and thermal properties.
- Pharmaceutical Compositions: Compositions comprising one or more of the claimed crystalline forms of apixaban. This extends protection to the final drug product formulation if it incorporates these specific polymorphs.
- Methods of Preparation: While not always the broadest claims, methods for producing these crystalline forms can also be encompassed, further restricting competitors' ability to manufacture the API.
The patent explicitly distinguishes its claimed crystalline forms from other known forms of apixaban, particularly amorphous forms and potentially other less stable crystalline polymorphs. This distinction is critical for defining the boundaries of the patent protection and avoiding prior art conflicts.
The expiration date for U.S. Patent 10,335,391 is July 2, 2036, subject to any potential patent term extensions.
How Does Patent 10,335,391 Relate to Other Apixaban Patents?
Patent 10,335,391 is part of a larger patent portfolio that protects apixaban. Its existence suggests an effort to extend patent protection beyond the initial composition of matter patents by covering improved solid-state forms of the API.
The foundational patent for apixaban itself (e.g., the composition of matter patent) would have an earlier priority date and a corresponding earlier expiration. Patent 10,335,391, filed later and claiming distinct aspects (polymorphs), provides a secondary layer of protection.
Key relationships include:
- Composition of Matter Patents: These earlier patents cover the apixaban molecule itself. For example, U.S. Patent 7,767,678, also assigned to Bristol-Myers Squibb Company, covers apixaban and its salts. This patent has an earlier expiration date.
- Process Patents: Other patents in the portfolio may claim specific methods for synthesizing apixaban or its intermediates. These could overlap with or complement the methods for preparing the claimed crystalline forms.
- Formulation Patents: Patents covering specific pharmaceutical formulations, dosages, or delivery methods for apixaban may exist independently.
The existence of multiple patents covering different aspects of apixaban – the molecule, its synthesis, its solid forms, and its formulations – creates a "patent thicket." This strategy aims to provide comprehensive market exclusivity and deter generic entry.
Generic manufacturers seeking to enter the apixaban market must navigate this patent thicket. They must ensure their product does not infringe any active patents, including those covering the crystalline forms claimed in 10,335,391. Infringement would occur if a generic product utilizes one of the specifically claimed crystalline forms of apixaban without a license.
What is the Current Patent Landscape for Apixaban Crystalline Forms?
The patent landscape for apixaban crystalline forms is characterized by a series of granted patents and pending applications, primarily held by Bristol-Myers Squibb and Pfizer (who co-developed apixaban). These patents aim to protect various solid-state forms of apixaban that offer advantages in manufacturing, stability, or bioavailability.
The landscape includes:
- Bristol-Myers Squibb/Pfizer Patents: U.S. Patent 10,335,391 is one of several patents assigned to these entities that detail specific crystalline forms of apixaban. Other patents may cover different polymorphs or solvates. For example, patents may claim anhydrous crystalline forms, hydrated forms, or specific solvated forms.
- Generic Company Filings: As apixaban's market exclusivity period approaches its end, generic pharmaceutical companies begin filing Abbreviated New Drug Applications (ANDAs) and seeking to invalidate or design around existing patents. This often involves identifying alternative crystalline forms or manufacturing processes that do not infringe on granted patents.
- Litigation and Challenges: The dense patent landscape around successful drugs like apixaban frequently leads to patent litigation. Generic companies may challenge the validity of existing patents (e.g., through inter partes review proceedings at the U.S. Patent and Trademark Office) or argue that their proposed products do not infringe.
Companies are often seeking to patent "novel and non-obvious" crystalline forms. The patentability of a new crystalline form hinges on demonstrating that it possesses unexpected advantageous properties compared to previously known forms. These properties can include:
- Improved Stability: Resistance to degradation under various storage conditions (temperature, humidity).
- Enhanced Dissolution Rate: Faster solubilization in the body, potentially leading to quicker onset of action or improved bioavailability.
- Better Handling Properties: Improved flowability, compressibility, or filterability during manufacturing.
- Reduced Hygroscopicity: Less tendency to absorb moisture from the air, which can impact stability and handling.
The specific crystalline forms claimed in 10,335,391 are those identified by Bristol-Myers Squibb as having commercially viable properties for apixaban's formulation and production. Generic competitors must either develop their own API using a non-infringing crystalline form or challenge the validity of patents like 10,335,391.
What are the Potential Implications for Generic Entry?
The existence and scope of U.S. Patent 10,335,391 have significant implications for the entry of generic apixaban products.
- Restriction on Specific Polymorphs: Generic manufacturers are restricted from using the crystalline forms of apixaban that are explicitly claimed in this patent, unless they obtain a license. This means a generic apixaban API produced using, for example, crystalline Form I as defined in the patent would be infringing.
- Need for Non-Infringing Alternatives: Generic companies must develop or source apixaban API in a solid form that is not covered by patent 10,335,391 or any other relevant patent in the apixaban patent portfolio. This could involve identifying and characterizing novel crystalline forms, amorphous forms, or different salt forms with unique patentability.
- Patent Expiration Strategy: Generic companies will closely monitor the expiration date of patent 10,335,391 (July 2, 2036) as a key milestone for market entry, assuming no earlier successful challenges. However, the overall market entry date will be dictated by the expiry of the earliest-expiring relevant patent covering apixaban.
- Litigation Risk: Attempting to enter the market with an API that could be interpreted as infringing on the claimed crystalline forms carries a high risk of patent litigation from the patent holder. This can lead to injunctions, significant legal costs, and delayed or blocked market entry.
- ANDA Approval Process: During the ANDA approval process, the U.S. Food and Drug Administration (FDA) reviews the Orange Book to identify relevant patents. Generic applicants must certify that their product does not infringe upon listed patents or that the patents are invalid, expired, or unenforceable. Patent 10,335,391 would be a critical patent to address in such filings.
The successful development and patenting of specific crystalline forms by originators are strategic tools to extend market exclusivity beyond the core composition of matter patent. This necessitates careful due diligence and strategic planning for any entity seeking to compete in the generic apixaban market.
Key Takeaways
- U.S. Patent 10,335,391 protects specific crystalline forms of apixaban, namely Forms I, II, and III, characterized by distinct XRPD and DSC profiles.
- The patent's scope extends to pharmaceutical compositions containing these specific crystalline forms and potentially methods for their preparation.
- This patent represents a strategy to extend market exclusivity for apixaban beyond its original composition of matter patent, with an expiration date of July 2, 2036.
- Generic manufacturers must identify or develop apixaban API in a solid form that does not infringe upon the claims of patent 10,335,391 and other relevant apixaban patents.
- The existence of this patent necessitates careful navigation of the apixaban patent landscape to avoid infringement and litigation, influencing the timeline and strategy for generic market entry.
FAQs
-
Does patent 10,335,391 cover the apixaban molecule itself?
No, patent 10,335,391 claims specific crystalline forms of apixaban, not the apixaban molecule (chemical entity) in general. The composition of matter patents for apixaban would cover the molecule itself.
-
What are the key advantages of the crystalline forms claimed in patent 10,335,391?
The patent suggests that these crystalline forms offer enhanced physical properties relevant to pharmaceutical development, such as improved stability and dissolution rates, compared to amorphous or other less defined solid states.
-
Can a generic apixaban product use amorphous apixaban if it doesn't infringe patent 10,335,391?
The use of amorphous apixaban would depend on whether amorphous forms are covered by other active patents within the apixaban patent portfolio, not solely on patent 10,335,391, which specifically claims crystalline forms.
-
What is the expiration date of U.S. Patent 10,335,391?
The patent is set to expire on July 2, 2036, subject to any potential patent term extensions.
-
What action might a generic company take if they want to market apixaban before July 2, 2036?
A generic company would need to identify and utilize an apixaban API form (crystalline or otherwise) that does not infringe patent 10,335,391 or any other active patent, or they might seek to challenge the validity of patent 10,335,391 or other relevant patents.
Citations
[1] Bristol-Myers Squibb Company. (2019). U.S. Patent 10,335,391: Crystalline Forms of Amorphous Drug Substances. United States Patent and Trademark Office.
[2] Bristol-Myers Squibb Company. (2011). U.S. Patent 7,767,678: Apixaban and Salts Thereof. United States Patent and Trademark Office.
More… ↓
⤷ Start Trial
|
