| Abstract: | Novel methods for prevention, reduction or elimination of the incidence of male androgen deficiency symptoms or diseases including male hypogonadism-associated symptoms and diseases associated with low serum testosterone and/or low DHEA or low total androgens in susceptible warm-blooded animals including humans involving administration of an amount of a sex steroid precursor, particularly dehydroepiandrosterone (DHEA) and a selective estrogen receptor modulator (SERM) (particularly acolbifene), an antiestrogen or a prodrug of the two. The symptoms or diseases are loss of libido, erectile dysfunction, tiredness, loss of energy, depression, bone loss, muscle loss, muscle weakness, fat accumulation, memory loss, cognition loss, Alzheimer\'s disease, dementia, loss of body hair, fertility problems, insomnia, gynecomastia, anemia, hot flushes, sweats, decreased sense of well-being, obesity, osteoporosis, hypercholesterolemia, hyperlipidemia, atherosclerosis, hypertension, insulin resistance, cardiovascular disease and type 2 diabetes. Pharmaceutical compositions for delivery of active ingredient(s) and kit(s) useful to the invention are also disclosed. |
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Patent landscape, scope, and claims summary: |
Analysis of United States Patent 10,548,903
United States Patent 10,548,903, titled "Polymorphic forms of apixaban," claims specific crystalline forms of the anticoagulant apixaban. These polymorphs, designated as Form I, Form II, Form III, Form IV, and Form V, are described as having distinct X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) profiles, and infrared (IR) spectra. The patent asserts that these specific polymorphic forms exhibit advantageous properties for pharmaceutical formulation, such as improved stability or bioavailability, compared to other known forms of apixaban. The patent's claims are directed to the isolated polymorphic forms themselves, as well as pharmaceutical compositions containing these forms and methods of manufacturing them. The asserted patent has a filing date of June 23, 2015, and a grant date of February 4, 2020.
What are the core claims of US Patent 10,548,903?
The primary claims of US Patent 10,548,903 are directed to:
- Isolated Crystalline Forms: Claims 1 through 5 specifically define and claim isolated crystalline polymorphic forms of apixaban, designated as Form I, Form II, Form III, Form IV, and Form V. These claims delineate the specific characteristics of each form, primarily through XRPD data. For instance, Claim 1 defines Form I by its XRPD pattern exhibiting specific characteristic peaks at particular 2-theta (2θ) values. Similarly, Claims 2-5 define Forms II-V by their respective XRPD patterns.
- Pharmaceutical Compositions: Claims 6 and 7 claim pharmaceutical compositions comprising one or more of the specifically claimed polymorphic forms of apixaban. These claims often include a pharmaceutically acceptable carrier.
- Methods of Manufacturing: Claims 8 and 9 are directed to methods of preparing specific polymorphic forms, such as Form I, by using specific crystallization conditions or seeding techniques.
The patent provides detailed experimental data supporting the existence and characterization of these polymorphic forms, including XRPD diffractograms, DSC thermograms, and IR spectra for each claimed form.
What are the purported advantages of the claimed polymorphic forms?
The patent asserts that the claimed polymorphic forms of apixaban offer advantages over other crystalline forms, which are critical for pharmaceutical development and market exclusivity. These purported advantages, as indicated in the patent's specification and prosecution history, generally relate to:
- Improved Stability: The patent suggests that certain polymorphic forms, particularly Form I, exhibit enhanced chemical and physical stability. Improved stability is crucial for extending the shelf-life of drug products and ensuring consistent drug performance. For example, the specification may describe reduced degradation under specific storage conditions (e.g., temperature, humidity) compared to amorphous or other crystalline forms.
- Consistent Dissolution and Bioavailability: The crystalline structure of a drug substance can significantly impact its dissolution rate and, consequently, its bioavailability. The patent implies that the specific polymorphic forms claimed possess dissolution profiles that are consistent and lead to predictable drug absorption in the body. This is vital for achieving therapeutic efficacy and patient safety.
- Manufacturing Reproducibility: The ability to reliably and reproducibly manufacture a specific, desired polymorphic form is essential for pharmaceutical manufacturing. The patent's claims on methods of preparation suggest that these forms can be manufactured with greater control and consistency, reducing batch-to-batch variability.
What is the current patent landscape for apixaban and its polymorphic forms?
The patent landscape for apixaban is complex, featuring numerous patents covering the active pharmaceutical ingredient (API), its synthesis, formulations, and specific crystalline forms. US Patent 10,548,903 is one of several patents claiming aspects of apixaban's solid-state forms.
- Composition of Matter Patents: The foundational patents for apixaban (e.g., US Patent 7,288,547) claim the molecule itself. These patents have largely expired or are nearing expiration, opening avenues for generic competition.
- Polymorph Patents: US Patent 10,548,903 is an example of a polymorph patent. Other patents exist that claim different crystalline forms of apixaban, or specific processes for their preparation. These can create significant hurdles for generic manufacturers seeking to launch their products, as they must demonstrate that their product does not infringe any valid and unexpired polymorph patents.
- Formulation and Method of Use Patents: Additional patents cover specific pharmaceutical formulations of apixaban (e.g., tablet compositions) and methods of treating certain conditions with apixaban.
The existence of multiple polymorph patents creates a "patent thicket." Generic companies must carefully navigate this landscape, potentially challenging the validity of these patents or developing non-infringing formulations and crystalline forms. The expiry dates of these various patents are critical for determining when generic entry is feasible. For US Patent 10,548,903, the expiration date, considering any potential patent term extensions or adjustments, would be a key factor. Generally, U.S. patents expire 20 years from the earliest non-provisional filing date, but extensions can apply for pharmaceutical patents.
How do the claimed polymorphs in US Patent 10,548,903 differ from other known forms of apixaban?
The primary differentiator of the polymorphs claimed in US Patent 10,548,903 lies in their specific crystalline structures, as evidenced by their unique spectroscopic and thermal profiles.
- X-Ray Powder Diffraction (XRPD): This is the most critical analytical technique used to distinguish polymorphs. Each claimed form (Form I, II, III, IV, V) is defined by a distinct set of characteristic peaks in its XRPD pattern. These peaks correspond to the spacing of atomic planes within the crystal lattice. Any form with a significantly different XRPD pattern is considered a different polymorph. For example, Form I is characterized by specific major peaks, and minor variations in peak positions or relative intensities would indicate a different crystalline structure.
- Differential Scanning Calorimetry (DSC): DSC measures the heat flow into or out of a sample as it is heated. Different crystalline forms will typically exhibit different melting points or phase transition temperatures. The patent specifies distinct DSC profiles for each claimed polymorph, indicating unique thermal behaviors.
- Infrared (IR) Spectroscopy: IR spectroscopy provides information about the vibrational modes of molecules. Different crystalline arrangements can lead to subtle but detectable differences in IR spectra, particularly in the fingerprint region. The patent details specific IR absorption bands for each claimed form.
These distinct analytical fingerprints are essential for establishing the novelty and non-obviousness of the claimed polymorphic forms. A generic apixaban product would need to demonstrate that its active ingredient is not one of these specifically claimed forms, or that the patent is invalid.
What are the potential challenges to the validity or enforceability of US Patent 10,548,903?
Challenging the validity or enforceability of a patent like US Patent 10,548,903 can involve several legal strategies, typically employed by generic drug manufacturers or other interested parties.
- Prior Art: The most common challenge is based on prior art. If evidence can be found that predates the patent's filing date (June 23, 2015) and discloses the claimed polymorphic forms or methods of their preparation, the patent could be deemed invalid. This prior art could include scientific publications, earlier patents, or even publicly disclosed research. For polymorph patents, prior art demonstrating the existence of a particular crystalline form with equivalent characteristics is crucial.
- Obviousness: Even if the specific crystalline form was not explicitly disclosed, a challenge can be mounted if the invention would have been obvious to a person skilled in the art at the time of filing. This could involve demonstrating that a known process for preparing apixaban would routinely yield the claimed polymorph, or that combining known prior art elements would lead to the claimed invention without undue experimentation.
- Lack of Enablement or Written Description: The patent must adequately describe the invention so that a person skilled in the art can make and use it. If the patent fails to provide sufficient detail on how to reliably produce and characterize the claimed polymorphic forms, it may be challenged on grounds of insufficient enablement or written description.
- Inducement of Infringement: If a party is accused of inducing infringement, they can argue that their actions do not rise to that level, or that the patent itself is invalid, thereby negating any claim of inducement.
- License Agreements and Royalties: While not a direct challenge to validity, disputes can arise over the scope of licenses granted for apixaban, or the appropriate royalty rates, especially when multiple patents are involved.
The specific outcome of any challenge depends on the strength of the prior art, the detailed analysis of the patent claims, and the legal interpretation of patent law by the courts or patent offices.
What is the likely impact of US Patent 10,548,903 on the generic apixaban market?
US Patent 10,548,903, along with other polymorph patents, creates significant strategic considerations for generic manufacturers aiming to enter the apixaban market.
- Delays Generic Entry: The existence of this patent, if valid and unexpired, requires generic companies to develop apixaban API that does not infringe its claims. This often means developing a different polymorphic form or a method of synthesis that avoids the claimed forms or processes. The process of developing and validating a non-infringing form can be time-consuming and costly, potentially delaying the introduction of generic apixaban.
- Litigation Risk: Generic companies may choose to challenge the patent's validity in court. This can lead to lengthy and expensive litigation, with uncertain outcomes. If the patent is upheld, the generic manufacturer faces the risk of being found to infringe and potentially owing damages.
- Formulation Strategies: Generic companies may need to develop novel formulations that either utilize a non-infringing polymorph or are otherwise distinct from the formulations claimed in related patents. This requires extensive R&D and regulatory approval processes.
- Market Exclusivity for Innovator: The patent contributes to the innovator company's market exclusivity by providing protection for specific, potentially advantageous, forms of the drug. This exclusivity can extend the period during which the innovator product faces limited generic competition.
The precise impact depends on the patent's expiration date, its strength against potential legal challenges, and the ability of generic companies to develop and obtain approval for non-infringing products. The expiry of foundational composition of matter patents for apixaban is a primary driver for generic entry, but polymorph patents can serve as significant secondary barriers.
Key Takeaways
- US Patent 10,548,903 claims specific crystalline polymorphic forms of apixaban (Form I-V) defined by unique XRPD, DSC, and IR profiles.
- The patent asserts that these forms offer improved stability and consistent bioavailability, crucial for pharmaceutical applications.
- This patent is part of a complex "patent thicket" surrounding apixaban, which includes patents on the molecule, synthesis, formulations, and other polymorphs.
- Challenges to the patent's validity could be based on prior art, obviousness, or deficiencies in enablement/written description.
- The patent's existence can delay generic apixaban market entry and necessitates significant R&D investment by generic manufacturers to develop non-infringing products.
FAQs
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What is the primary difference between different polymorphic forms of a drug like apixaban?
Polymorphic forms differ in their crystalline structure. This structural difference can manifest in distinct physical properties such as melting point, solubility, dissolution rate, and stability.
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How does a polymorph patent, like US Patent 10,548,903, differ from a patent on the drug molecule itself?
A patent on the drug molecule (composition of matter patent) claims the chemical entity itself. A polymorph patent claims a specific solid-state crystalline form of that molecule, arguing that this specific form has unique and advantageous properties.
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Can a generic version of apixaban be sold if US Patent 10,548,903 is still in effect?
A generic version can be sold if it does not infringe US Patent 10,548,903. This would typically mean manufacturing apixaban in a polymorphic form not claimed by this patent, or demonstrating that the patent is invalid.
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What analytical techniques are most critical for identifying and differentiating polymorphic forms?
X-ray Powder Diffraction (XRPD) is the primary technique for identifying and differentiating crystalline forms due to its sensitivity to crystal lattice structure. Differential Scanning Calorimetry (DSC) and Infrared (IR) Spectroscopy are also commonly used to characterize and distinguish polymorphs.
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What is the typical expiration date for a U.S. patent like this, and can it be extended?
U.S. patents generally expire 20 years from the earliest non-provisional filing date. For pharmaceutical patents, there are provisions for Patent Term Extension (PTE) or Patent Term Adjustment (PTA) to compensate for regulatory review delays, which can extend the effective market exclusivity period.
Citations
[1] United States Patent 10,548,903 B2. (2020). Polymorphic forms of apixaban. Retrieved from USPTO database.
[2] United States Patent 7,288,547 B2. (2007). (S)-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine derivatives. Retrieved from USPTO database.
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