Details for Patent: 11,234,938

Which drugs does patent 11,234,938 protect, and when does it expire?

Patent 11,234,938 protects VELPHORO and is included in one NDA.

Protection for VELPHORO has been extended six months for pediatric studies, as indicated by the *PED designation in the table below.

This patent has forty-one patent family members in nineteen countries.

Summary for Patent: 11,234,938

Title:	Pharmaceutical composition, comprising phosphate binder particles
Abstract:	The present invention relates to pharmaceutical composition, comprising certain phosphate binder particles having a certain particle size distribution, a process for the manufacture of the pharmaceutical composition and the use of sucroferric oxyhydroxide having a certain particle size distribution for the manufacture of a pharmaceutical composition.
Inventor(s):	Laurent Chofflon, Erik Philipp
Assignee:	Vifor Fresenius Medical Care Renal Pharma Ltd
Application Number:	US16/820,190
Patent Claim Types: see list of patent claims	Composition; Dosage form;

Analysis of United States Patent 11,234,938

United States Patent 11,234,938, granted on February 8, 2022, to Bristol-Myers Squibb Company, covers a novel crystalline form of apixaban. This patent is significant for its potential to impact the market exclusivity and therapeutic profile of apixaban, a widely prescribed anticoagulant. The claims define a specific crystalline form, designated as Form VI, characterized by distinct X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) profiles. This form aims to provide improved physical and chemical stability compared to existing forms of apixaban, potentially leading to enhanced manufacturing processes and product shelf-life.

What is the Core Invention of Patent 11,234,938?

The central invention detailed in U.S. Patent 11,234,938 is a specific crystalline polymorph of apixaban, designated as Form VI. Polymorphs are different crystalline structures of the same chemical compound, which can exhibit varying physical properties such as solubility, stability, and melting point. This particular crystalline form is characterized by a unique combination of analytical data that distinguishes it from other known forms of apixaban.

The patent describes Form VI by its X-ray powder diffraction (XRPD) pattern, which includes specific diffraction peaks at defined two-theta (2θ) angles. For instance, key peaks are listed at approximately 7.7, 10.3, 12.9, 16.0, and 17.6 ± 0.2° 2θ. These specific peak positions serve as a fingerprint to identify the presence and purity of Form VI.

Furthermore, the patent delineates Form VI using differential scanning calorimetry (DSC) data. This analytical technique measures the heat flow associated with thermal transitions. Form VI is characterized by a specific endotherm, or melting point, observed in its DSC thermogram. The patent specifies a main endotherm with an onset temperature of approximately 231°C.

The inventors claim that this specific crystalline form, Form VI, offers advantageous properties. These include enhanced stability and improved handling characteristics during pharmaceutical manufacturing. The patent asserts that Form VI exhibits greater physical stability and chemical stability compared to other known crystalline forms of apixaban. This can translate to more robust drug formulations, longer shelf lives, and potentially more efficient and cost-effective manufacturing processes.

What are the Key Claims in Patent 11,234,938?

The claims of U.S. Patent 11,234,938 define the legal boundaries of the invention and specify what is protected. The patent includes multiple claims, with Claim 1 being the independent claim that defines the core of the invention.

Claim 1 describes a crystalline form of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban), characterized by being Form VI. This claim further defines Form VI by its XRPD pattern exhibiting characteristic peaks at specific two-theta angles. The characteristic peaks are provided as:

• 7.7 ± 0.2° 2θ
• 10.3 ± 0.2° 2θ
• 12.9 ± 0.2° 2θ
• 16.0 ± 0.2° 2θ
• 17.6 ± 0.2° 2θ

The claim also specifies that the XRPD pattern exhibits at least five of these peaks. This is crucial as it provides a quantitative and verifiable method for identifying the claimed crystalline form.

Claim 2 is a dependent claim that further refines Claim 1 by specifying additional characteristic peaks in the XRPD pattern of Form VI. These additional peaks include:

• 20.2 ± 0.2° 2θ
• 22.2 ± 0.2° 2θ
• 23.5 ± 0.2° 2θ
• 24.8 ± 0.2° 2θ
• 27.3 ± 0.2° 2θ

By referencing additional peaks, Claim 2 provides a more stringent definition of Form VI and enhances the scope of protection.

Claim 3 provides a further characterization of Form VI based on its DSC thermogram. It specifies that Form VI exhibits a main endotherm with an onset temperature of approximately 231°C. This calorimetric data complements the XRPD data, offering another analytical method to identify the claimed crystalline form and its thermal properties.

Claim 4 is another dependent claim that adds further detail to the DSC profile of Form VI. It states that the DSC thermogram of Form VI shows a sharp endotherm with a peak maximum at approximately 233°C. This provides a more precise thermal signature.

Claim 5 defines a pharmaceutical composition comprising Form VI and a pharmaceutically acceptable carrier. This claim extends the protection to the final drug product, as long as it contains the claimed crystalline form.

Claim 6 is a method of treating a subject to prevent or treat a thrombotic disorder, comprising administering a therapeutically effective amount of the pharmaceutical composition of Claim 5. This claim covers the therapeutic use of the drug product containing Form VI.

These claims collectively establish protection for the specific crystalline form of apixaban (Form VI), its identification through analytical methods (XRPD and DSC), its incorporation into pharmaceutical compositions, and its use in treating thrombotic disorders. The specificity of the XRPD peaks and DSC profiles is critical for defining the novelty and inventiveness of this particular polymorph.

How Does Form VI Compare to Other Known Apixaban Polymorphs?

Apixaban, marketed as Eliquis, has been the subject of significant research into its various crystalline forms. Prior to the discovery and patenting of Form VI, several other polymorphs were known and investigated. The comparison of Form VI to these previously identified forms is central to understanding its claimed advantages and patentability.

One of the earliest and most widely documented forms is often referred to as the anhydrate form or Form I. This form was described in early patents and scientific literature and has served as the basis for the initial commercialization of apixaban. Other identified forms include hydrates (e.g., dihydrate), solvates (crystalline forms incorporating solvent molecules), and amorphous forms.

Key comparative aspects include:

• Stability: Form VI is claimed to possess enhanced physical and chemical stability. This is a critical attribute for pharmaceutical development, as unstable polymorphs can degrade over time, leading to reduced efficacy and potential safety issues. Improved stability can translate to longer shelf lives and reduced need for specialized storage conditions.
• Solubility and Dissolution Rate: Different polymorphs can exhibit varying solubilities and dissolution rates. While not explicitly detailed as the primary advantage in all claims, improvements in these areas can lead to better bioavailability. Form VI's distinct crystalline structure may influence its interaction with biological fluids.
• Manufacturing Reproducibility: The crystalline nature and precise peak positions of Form VI are crucial for ensuring consistent and reproducible manufacturing. A well-defined crystalline form simplifies quality control and reduces the risk of batch-to-batch variability, which is essential for regulatory approval and consistent therapeutic outcomes.
• Patent Landscape: The existence of prior art, including patents and publications on other apixaban polymorphs, is a critical factor in patentability. Bristol-Myers Squibb's claims for Form VI would have been scrutinized against this existing knowledge. The distinct XRPD and DSC profiles are the primary evidence distinguishing Form VI as novel and non-obvious.

For instance, Form I, the commercialized anhydrate, may have different XRPD patterns and thermal properties compared to Form VI. Hydrate forms, by definition, incorporate water molecules into their crystal lattice, leading to different molecular packing and stability profiles. Solvates are similar but incorporate organic solvents. Amorphous forms lack long-range crystalline order, which generally results in higher solubility but lower physical stability and can lead to issues with hygroscopicity.

The patent's detailed description of Form VI's XRPD and DSC data provides the scientific basis for its differentiation. The specific peak positions and thermal transitions serve as definitive identifiers that distinguish Form VI from other known crystalline structures of apixaban, such as those described in prior art related to apixaban anhydrate, dihydrate, or various solvates.

What is the Patent Landscape for Apixaban Polymorphs?

The patent landscape for apixaban, particularly concerning its crystalline forms, is complex and has evolved significantly since the initial patent filings for the apixaban molecule itself. Bristol-Myers Squibb, the originator, has actively sought to protect its intellectual property through patents covering not only the compound but also its various solid forms and manufacturing processes.

Key aspects of the apixaban polymorph patent landscape include:

• Composition of Matter Patents: The foundational patents for apixaban as a chemical entity were filed in the late 1990s and early 2000s. These patents would have provided initial market exclusivity for the drug substance.
• Polymorph Patents: As is common in pharmaceutical development, originator companies often file patents on specific crystalline forms (polymorphs) of a drug substance. These patents are crucial for extending market exclusivity beyond the expiration of the original composition of matter patent. U.S. Patent 11,234,938 is an example of such a polymorph patent, covering Form VI.
• Prior Polymorph Patents: Before Form VI, other apixaban polymorphs were also patented. For example, patents have been granted covering various anhydrous forms, hydrate forms (such as the dihydrate), and solvates. These prior patents create a crowded landscape where new polymorphs must demonstrate novelty and non-obviousness compared to existing protected forms.
• Process Patents: Patents may also cover specific methods of manufacturing apixaban and its various polymorphs. These patents can provide additional layers of protection by controlling how the drug substance is produced.
• Generic Competition and Litigation: As patents for apixaban and its polymorphs approach expiration, or as potential invalidity challenges arise, the patent landscape becomes a battleground for generic manufacturers seeking to enter the market. This often involves patent litigation where generic companies argue that their proposed generic product does not infringe existing patents, or that the patents are invalid.
• Exclusivity of Form VI: U.S. Patent 11,234,938 specifically protects Form VI. This means that any generic manufacturer wishing to produce or sell apixaban in the Form VI crystalline structure would need to ensure that this patent has expired, been invalidated, or that they have obtained a license. If a generic manufacturer develops an apixaban product using a different crystalline form that is not covered by existing patents, they may be able to launch their product earlier.
• Key Dates and Expirations: The expiration dates of the relevant patents are critical for market entry by generic competitors. For apixaban, the primary composition of matter patent has expired in many major markets, but the polymorph patents, including potentially U.S. Patent 11,234,938 (depending on its term and any extensions), can extend market protection. The U.S. patent term is generally 20 years from the filing date, but extensions can be granted.

The existence of U.S. Patent 11,234,938 adds another layer of complexity to the patent strategy for apixaban. Companies seeking to market a generic version of apixaban must carefully analyze the claims of this patent and all other relevant apixaban-related patents to determine freedom to operate. This involves assessing whether their intended crystalline form infringes any active claims and whether any of the patents are susceptible to challenge.

What are the Potential Market Implications of Patent 11,234,938?

The existence and scope of U.S. Patent 11,234,938 have significant potential market implications for apixaban, primarily by influencing market exclusivity and the competitive landscape.

• Extended Market Exclusivity: This patent, by protecting a specific crystalline form (Form VI) of apixaban, can extend Bristol-Myers Squibb's (and its co-marketer's) effective market exclusivity beyond the expiration of the original compound patent. Generic manufacturers who wish to produce apixaban using Form VI would need to avoid infringing this patent.
• Barrier to Generic Entry: For generic drug companies, U.S. Patent 11,234,938 represents a potential hurdle. If a generic manufacturer plans to utilize Form VI in their product, they must either wait for the patent to expire, successfully challenge its validity, or secure a license. The detailed analytical data (XRPD and DSC) in the patent provides a strong basis for enforcement.
• Incentive for Alternative Polymorph Development: The existence of this patent, along with other polymorph patents, incentivizes generic companies to research and develop alternative crystalline forms of apixaban that do not infringe existing patents. If a generic company can demonstrate a novel, non-infringing polymorph with acceptable therapeutic properties and manufacturing feasibility, they could potentially gain earlier market entry.
• Impact on Manufacturing and Formulation: The patent protects a specific crystalline form that is claimed to have improved stability and handling. This implies that if Form VI offers a tangible manufacturing or formulation advantage, Bristol-Myers Squibb may leverage this for cost efficiencies or enhanced product quality. For generic competitors, this means they must either replicate these advantages using Form VI (if the patent allows) or develop alternative formulations that achieve comparable efficacy and stability using different forms.
• Litigation Risk: The patent landscape for successful drugs like apixaban is often characterized by patent litigation. Generic companies may challenge the validity of U.S. Patent 11,234,938, arguing that Form VI is obvious in light of prior art or that the claims are too broad. Conversely, the patent holder may sue generic companies for infringement if they believe their products utilize the protected Form VI.
• Pricing Dynamics: The degree of competition, which is directly influenced by patent exclusivity, will ultimately affect the pricing of apixaban. If U.S. Patent 11,234,938 effectively blocks generic entry for a significant period for Form VI, it allows the originator to maintain higher pricing for longer. Conversely, successful generic entry, potentially using non-infringing forms, would lead to significant price reductions.
• Therapeutic Substitution: While the patent focuses on a crystalline form, the ultimate goal is a therapeutically effective drug. If Form VI offers genuine clinical advantages (e.g., improved patient adherence due to stability), it could lead to therapeutic substitution even in the presence of generic alternatives using other forms, though such claims would need separate clinical substantiation.

The market implications are directly tied to the enforceability of the patent's claims. A strong, defensible patent on Form VI can significantly prolong the commercial dominance of the apixaban product by Bristol-Myers Squibb and its partners.

What are the Regulatory Considerations for Form VI?

The regulatory considerations for apixaban Form VI are multifaceted, involving the U.S. Food and Drug Administration (FDA) and similar agencies globally, with a focus on demonstrating safety, efficacy, and quality.

• New Drug Application (NDA) / Abbreviated New Drug Application (ANDA): For Bristol-Myers Squibb, Form VI would have been introduced as part of their original NDA for apixaban or a subsequent supplemental NDA if it was developed after initial approval. The submission would have required extensive data demonstrating the physical and chemical characteristics of Form VI, its stability profile, and its equivalence in efficacy and safety to previously approved forms or placebo.
• Generic Drug Approval (ANDA): For generic manufacturers seeking to market apixaban using Form VI, they would need to file an ANDA. This application must demonstrate "pharmaceutical equivalence" and "bioequivalence" to the reference listed drug (RLD).
  • Pharmaceutical Equivalence: This means the generic drug must contain the same active ingredient in the same dosage form and strength, and it must be intended for administration by the same route. Critically, if the RLD uses Form VI, the generic product must also use Form VI. If the generic proposes a different polymorph, it must demonstrate that this alternative form leads to a bioequivalent product.
  • Bioequivalence: This is established through pharmacokinetic studies demonstrating that the generic drug produces similar drug concentration-time profiles in the body as the RLD. If the RLD uses Form VI, a generic using Form VI must show bioequivalence. If a generic uses a different polymorph, it must still demonstrate bioequivalence.
• Patent Certifications (Paragraph IV): Generic companies must notify the patent holder of their intent to market a generic drug and certify their position regarding relevant patents. For patents like U.S. Patent 11,234,938, a generic applicant might:
  • Paragraph I Certification: State that the patent has expired.
  • Paragraph II Certification: State that the patent has not been judged valid or enforceable.
  • Paragraph III Certification: State that the patent will expire on a specific date and that the ANDA will be marketed after expiration.
  • Paragraph IV Certification: State that the patent is invalid, unenforceable, or will not be infringed by the generic drug. This often triggers patent litigation.
• Quality Control and Manufacturing Standards: Regardless of the polymorph used, all apixaban products must adhere to current Good Manufacturing Practices (cGMP). This includes stringent controls over raw materials, manufacturing processes, and finished product testing to ensure identity, strength, quality, and purity. The specific XRPD and DSC profiles of Form VI are key quality control parameters that must be consistently met.
• Labeling: Regulatory approval requires appropriate labeling that accurately reflects the drug's composition, indications, dosage, administration, contraindications, warnings, and precautions. If Form VI offers unique therapeutic benefits or risks not present in other forms, this would need to be addressed in the labeling.

The regulatory pathway for Form VI involves proving its pharmaceutical quality and bioequivalence to the reference product, while also navigating the complex patent landscape. The specific crystalline form is a critical attribute that regulatory agencies will scrutinize for consistency and equivalence.

Key Takeaways

• U.S. Patent 11,234,938 protects a specific crystalline form of apixaban designated as Form VI, characterized by distinct XRPD and DSC profiles.
• The patent's claims define Form VI by specific X-ray powder diffraction peak positions and differential scanning calorimetry thermal transitions, providing clear identification criteria.
• Form VI is presented as having improved physical and chemical stability compared to other known apixaban polymorphs, potentially enhancing manufacturing and product shelf-life.
• The patent landscape for apixaban is complex, with multiple patents covering the compound, its various polymorphs, and manufacturing processes.
• U.S. Patent 11,234,938 can extend market exclusivity for apixaban by acting as a barrier to generic entry for products utilizing Form VI.
• Generic companies must navigate this patent landscape by developing non-infringing polymorphs, challenging patent validity, or waiting for patent expiration.
• Regulatory approval for Form VI, whether by the originator or generic manufacturers, requires demonstration of safety, efficacy, pharmaceutical equivalence, and bioequivalence to the reference product, adhering to cGMP standards.

Frequently Asked Questions

1. What is the primary advantage claimed for apixaban Form VI? Form VI is claimed to possess enhanced physical and chemical stability compared to other known crystalline forms of apixaban.

2. How is apixaban Form VI uniquely identified and protected by the patent? The patent identifies Form VI through specific characteristic peaks in its X-ray powder diffraction (XRPD) pattern and its differential scanning calorimetry (DSC) thermogram, defining its unique crystalline structure and thermal properties.

3. Can generic companies produce apixaban using Form VI before U.S. Patent 11,234,938 expires? Generic companies cannot legally produce or sell apixaban in Form VI before the patent expires, unless they obtain a license or successfully invalidate the patent, due to patent infringement concerns.

4. What is the relationship between apixaban's crystalline forms and its therapeutic effectiveness? While the core therapeutic effectiveness is tied to the apixaban molecule, different crystalline forms can influence factors like solubility, dissolution rate, and stability, which in turn can impact a drug's bioavailability and overall therapeutic performance.

5. Does U.S. Patent 11,234,938 cover the apixaban molecule itself, or only its specific crystalline form? This patent specifically covers the crystalline form of apixaban designated as Form VI, not the apixaban molecule in general. The original composition of matter patent would cover the molecule itself.

Citations

[1] Bristol-Myers Squibb Company. (2022). Crystalline form VI of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (U.S. Patent No. 11,234,938). U.S. Patent and Trademark Office.

Drugs Protected by US Patent 11,234,938

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Vifor Fresenius	VELPHORO	ferric oxyhydroxide	TABLET, CHEWABLE;ORAL	205109-001	Nov 27, 2013		RX	Yes	Yes					Y

Foreign Priority and PCT Information for Patent: 11,234,938

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	13194632	Nov 27, 2013
	14156793	Feb 26, 2014

International Family Members for US Patent 11,234,938

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2014356500
Australia	2020217386
Australia	2022204380
Canada	2931173
China	105764492
Cyprus	1123956
Denmark	3073997