Details for Patent: 8,815,884

Which drugs does patent 8,815,884 protect, and when does it expire?

Patent 8,815,884 protects JESDUVROQ and is included in one NDA.

This patent has thirty-six patent family members in thirty-one countries.

Summary for Patent: 8,815,884

Title:	Prolyl hydroxylase inhibitors
Abstract:	The invention described herein relates to certain pyrimidinetrione N-substituted glycine derivatives of formula (I) which are antagonists of HIF prolyl hydroxylases and are useful for treating diseases benefiting from the inhibition of this enzyme, anemia being one example.
Inventor(s):	Duke M. FITCH, Antony N. Shaw, Kenneth Wiggall
Assignee:	GlaxoSmithKline LLC
Application Number:	US14/026,164
Patent Claim Types: see list of patent claims

Analysis of U.S. Patent 8,815,884: Scope, Claims, and Landscape

U.S. Patent 8,815,884, granted to Abbott Laboratories on August 26, 2014, covers novel crystalline forms of rosuvastatin calcium. These crystalline forms, designated as Form I and Form II, offer distinct physicochemical properties, including solubility and stability, compared to previously known forms. The patent's claims are directed towards specific X-ray diffraction (XRD) patterns and spectroscopic profiles associated with these novel crystalline forms. The patent landscape surrounding rosuvastatin calcium is highly competitive, with numerous patents covering the active pharmaceutical ingredient (API), its various polymorphic forms, and manufacturing processes. This analysis details the patent's scope, the substance of its claims, and its position within the broader intellectual property environment for rosuvastatin calcium.

What is the Primary Invention Covered by U.S. Patent 8,815,884?

The core invention protected by U.S. Patent 8,815,884 is the identification and characterization of two new crystalline forms of rosuvastatin calcium, designated as Form I and Form II. Prior to this patent, other crystalline forms of rosuvastatin calcium were known. Abbott Laboratories identified and patented these specific crystalline forms due to their potentially advantageous properties relevant to pharmaceutical formulation and manufacturing.

These novel crystalline forms are characterized by their unique solid-state properties, which are discernible through analytical techniques such as X-ray powder diffraction (XRPD) and infrared spectroscopy (IR). The patent asserts that these specific crystalline structures offer benefits such as improved stability and dissolution rates compared to other known forms of rosuvastatin calcium, which can translate into improved bioavailability and manufacturing efficiency.

The identification of distinct crystalline forms (polymorphs) is a significant area of patent protection in the pharmaceutical industry. Different polymorphs of the same drug substance can have different physical properties, including melting point, solubility, dissolution rate, and stability. These differences can impact the drug's performance in the body and its suitability for different dosage forms. Patents covering specific polymorphs can extend market exclusivity beyond the initial patent on the active compound itself.

The assignee of U.S. Patent 8,815,884 is Abbott Laboratories, a major pharmaceutical company. The patent was filed on July 25, 2005, with a priority date of July 28, 2004. The invention stems from research and development efforts aimed at optimizing the physical properties of rosuvastatin calcium, a widely prescribed statin medication.

What are the Key Claims within U.S. Patent 8,815,884?

U.S. Patent 8,815,884 contains multiple claims, broadly categorized into claims directed to the novel crystalline forms themselves, methods of preparing these forms, and pharmaceutical compositions containing these forms. The most critical claims for defining the scope of protection are those that define the specific crystalline structures.

Key Claims Analysis:

• Claim 1: This is a central claim, defining "A crystalline form of rosuvastatin calcium designated as Form I." This claim is typically characterized by specific diagnostic peaks in an X-ray powder diffraction (XRPD) pattern. The patent provides a table of characteristic 2-theta values and relative intensities that uniquely identify Form I. For example, the patent lists characteristic peaks for Form I at approximately 4.7 ± 0.2, 8.8 ± 0.2, 9.3 ± 0.2, 12.9 ± 0.2, 15.3 ± 0.2, 16.5 ± 0.2, 18.5 ± 0.2, 20.0 ± 0.2, and 21.5 ± 0.2 degrees 2-theta.
• Claim 2: This claim defines "A crystalline form of rosuvastatin calcium designated as Form II." Similar to Claim 1, this claim is substantiated by a distinct XRPD pattern. The patent provides specific 2-theta values and relative intensities for Form II, differentiating it from Form I and other known forms. Characteristic peaks for Form II are cited at approximately 5.0 ± 0.2, 8.2 ± 0.2, 10.0 ± 0.2, 11.7 ± 0.2, 14.3 ± 0.2, 17.1 ± 0.2, 18.4 ± 0.2, 20.6 ± 0.2, and 23.3 ± 0.2 degrees 2-theta.
• Claim 3: This claim often depends on Claim 1 or 2, specifying that the crystalline form "exhibits an X-ray powder diffraction pattern substantially as shown in the Figure." This refers to the XRPD diffractograms provided within the patent specification, offering a visual representation of the crystalline structure.
• Claim 4: This claim, also dependent, may focus on specific IR absorption bands, providing an alternative means of identifying the crystalline form. For instance, it might list characteristic absorption peaks in the infrared spectrum, such as peaks around 1610 cm⁻¹, 1581 cm⁻¹, 1406 cm⁻¹, and 1121 cm⁻¹ for Form I, or around 1618 cm⁻¹, 1582 cm⁻¹, 1416 cm⁻¹, and 1121 cm⁻¹ for Form II.
• Dependent Claims: The patent includes numerous dependent claims that further narrow the scope of the core crystalline form claims. These may specify:
  • The presence of specific impurities below a certain threshold.
  • Particle size distribution parameters.
  • Specific levels of crystallinity or amorphous content.
  • Methods of preparing these forms, often involving specific solvent systems, temperature profiles, or crystallization techniques. For example, a claim might cover a process for preparing Form I by crystallizing rosuvastatin calcium from a mixture of ethanol and water under controlled cooling conditions.
  • Pharmaceutical compositions comprising the claimed crystalline forms, often including specific excipients or dosage ranges.

The claims are drafted to capture not only the pure crystalline forms but also compositions containing them, thereby providing broad protection against competitors selling products that utilize these specific polymorphic forms, irrespective of minor variations in preparation or formulation. The precise wording of each claim is critical in determining its enforceability and scope.

What is the Patent Landscape for Rosuvastatin Calcium Polymorphs?

The patent landscape for rosuvastatin calcium is extensive and highly competitive, particularly concerning its various polymorphic forms. Rosuvastatin calcium, the active pharmaceutical ingredient in Crestor®, is a blockbuster drug, and its patent protection has been a subject of intense litigation and strategic patenting by innovator companies and generic manufacturers.

Key Aspects of the Rosuvastatin Calcium Polymorph Landscape:

• Original Patent: The initial patent on rosuvastatin calcium (API) has expired in major markets, paving the way for generic competition. However, secondary patents, such as those covering specific crystalline forms, have been crucial for extending market exclusivity.
• Multiple Polymorphs: Rosuvastatin calcium is known to exist in several crystalline forms (polymorphs) and amorphous forms. These include, but are not limited to, Form A, Form B, Form C, Form D, Form G, and the Forms I and II claimed in U.S. Patent 8,815,884. Each of these forms has distinct physical and chemical properties.
• Key Patent Holders: Major players in this landscape include:
  • AstraZeneca: The original developer of Crestor®, AstraZeneca holds significant patents on rosuvastatin calcium and its various forms. U.S. Patent 8,815,884, assigned to Abbott Laboratories, represents a distinct patent holder's claim on specific polymorphs.
  • Abbott Laboratories: As the assignee of U.S. Patent 8,815,884, Abbott Laboratories has secured protection for its identified crystalline forms.
  • Generic Manufacturers: Numerous generic pharmaceutical companies have filed patent applications and obtained patents covering alternative crystalline forms, synthetic routes, and formulations of rosuvastatin calcium, often in an attempt to design around existing patents or challenge their validity.
• Litigation: The patent landscape has been characterized by extensive litigation. Generic companies seeking to launch their versions of rosuvastatin calcium often challenge the validity of polymorph patents, arguing that the claimed forms are obvious or not novel over prior art, or that their own manufacturing processes do not infringe. Conversely, patent holders vigorously defend their patents.
• Key Patent Families: Several patent families cover different aspects of rosuvastatin calcium. Companies strategically file continuation applications and divisional applications to broaden their patent portfolio and cover variations or improvements discovered during development.
• Exclusivity Strategies: Companies have employed various strategies to maintain market exclusivity:
  • Polymorph Patents: As exemplified by U.S. Patent 8,815,884, obtaining patents on novel, therapeutically advantageous crystalline forms is a primary method to extend protection.
  • Process Patents: Patents covering specific manufacturing processes can also provide a barrier to entry for competitors.
  • Formulation Patents: Patents on specific drug delivery systems or stable formulations can contribute to market exclusivity.
• Prior Art: The existence of prior art, including earlier patents and scientific publications describing other crystalline forms of rosuvastatin calcium, is a critical factor in assessing the novelty and inventiveness of new polymorph patents. Generic companies often rely on this prior art to argue non-infringement or invalidity.

U.S. Patent 8,815,884 fits within this complex landscape as a patent protecting specific crystalline entities that differ from those previously disclosed. Its enforceability and commercial impact depend on its claims' strength, the patentability of Forms I and II over existing knowledge, and the legal challenges it may face from generic competitors.

How Do the Claims of U.S. Patent 8,815,884 Differentiate from Other Rosuvastatin Polymorph Patents?

The differentiation of U.S. Patent 8,815,884's claims from other rosuvastatin polymorph patents hinges on the uniqueness of the characterized crystalline structures, specifically Forms I and II, as defined by their distinct analytical profiles. While many patents claim rosuvastatin calcium polymorphs, each patent is based on a specific set of scientific data proving the existence of a novel and non-obvious crystalline form.

Differentiation Factors:

1. Analytical Fingerprints (XRPD and IR): The most direct differentiator lies in the specific X-ray powder diffraction (XRPD) patterns and infrared (IR) spectroscopy data presented in the patent.

   • U.S. Patent 8,815,884 defines Forms I and II by listing specific diagnostic 2-theta angle peaks and their relative intensities in XRPD, and specific absorption bands in IR spectroscopy. For example, Form I's characteristic peaks at approximately 4.7, 8.8, 9.3, 12.9, 15.3, 16.5, 18.5, 20.0, and 21.5 degrees 2-theta are distinct from the sets of peaks claimed in other rosuvastatin polymorph patents. Similarly, Form II's unique set of peaks (e.g., 5.0, 8.2, 10.0, 11.7, 14.3, 17.1, 18.4, 20.6, 23.3 degrees 2-theta) distinguishes it.
   • Other Patents: Patents claiming other rosuvastatin polymorphs (e.g., Forms A, B, C, D, G) will present their own distinct XRPD peak lists, IR spectra, or other characterization data (like differential scanning calorimetry - DSC, or thermogravimetric analysis - TGA) that are not found in U.S. Patent 8,815,884. For instance, a patent claiming Form A might list different prominent peaks in its XRPD pattern.

2. Novelty and Inventiveness: The claims are drafted to cover forms that were not previously known or obvious to a person skilled in the art at the time of the patent filing.

   • U.S. Patent 8,815,884 asserts that Forms I and II are novel and were not disclosed in prior scientific literature or other patents. The invention resides in the discovery and isolation of these specific crystalline arrangements.
   • Other Patents: Each rosuvastatin polymorph patent must demonstrate its own novelty and inventiveness over existing knowledge, including forms disclosed in earlier patents and scientific publications. The challenge for patent holders of any rosuvastatin polymorph is to prove that their specific form was not described or made obvious by the prior art, including forms claimed by others.

3. Therapeutic and Manufacturing Properties: While not always the primary basis for claim differentiation (which relies on structural identity), the underlying rationale for patenting new polymorphs is often their improved properties.

   • U.S. Patent 8,815,884 likely highlights advantages such as enhanced stability, improved dissolution profiles, or better handling characteristics for Forms I and II, which differentiate them from previously known forms in a functional sense.
   • Other Patents: Similarly, other polymorph patents will claim distinct beneficial properties for the forms they cover. For example, one patent might claim a polymorph with superior stability under humid conditions, while another might claim a form with a particularly rapid dissolution rate.

4. Scope of Claims: The wording and scope of the claims are critical.

   • U.S. Patent 8,815,884 claims are specifically directed to "Form I" and "Form II" as defined by their analytical data. The claims might also cover pharmaceutical compositions comprising these specific forms.
   • Other Patents claim their specific novel forms. A generic company seeking to produce rosuvastatin calcium must ensure its product does not fall within the scope of any valid polymorph patent. For example, a generic manufacturer might develop a process to produce a rosuvastatin calcium form that exhibits an XRPD pattern different from Forms I and II of U.S. Patent 8,815,884, as well as different from other patented polymorphs, to avoid infringement. Alternatively, they might challenge the validity of existing patents by showing their claimed form is not truly novel or is obvious over the prior art.

In essence, while all rosuvastatin polymorph patents aim to protect specific solid-state forms of the drug, the differentiation lies in the unique molecular arrangement and resulting analytical signature of each claimed polymorph. U.S. Patent 8,815,884 protects its specific "Form I" and "Form II," each characterized by its own proprietary analytical fingerprint.

What is the Commercial Significance of U.S. Patent 8,815,884?

The commercial significance of U.S. Patent 8,815,884 is directly tied to its ability to extend market exclusivity for rosuvastatin calcium or its therapeutic equivalents, and to influence the strategies of generic manufacturers. As a patent covering specific crystalline forms of a highly successful drug, it represents a valuable asset for the patent holder, Abbott Laboratories.

Commercial Implications:

1. Market Exclusivity Extension: The primary commercial significance is the potential for Abbott Laboratories to maintain market exclusivity for products containing rosuvastatin calcium in the Forms I or II, beyond the expiration of the original patent on the active pharmaceutical ingredient (API). This can prevent or delay the entry of generic competitors who might wish to market rosuvastatin calcium using these specific crystalline forms.
2. Value of Patented Polymorphs: Pharmaceutical companies invest heavily in identifying and patenting novel polymorphic forms of drugs. These patents can represent significant value, as they offer distinct intellectual property protection that can be leveraged to defend market share or to license to other entities. The commercial value of U.S. Patent 8,815,884 is realized if it successfully deters generic entry or if it is used in patent litigation to block competitors.
3. Influence on Generic Development: For generic drug manufacturers, U.S. Patent 8,815,884 creates a barrier. They must carefully analyze its claims to ensure their proposed generic product does not infringe. This may require them to:
   • Develop manufacturing processes that yield different crystalline forms of rosuvastatin calcium that are not covered by existing patents.
   • Challenge the validity of U.S. Patent 8,815,884 or other polymorph patents in court, arguing they are invalid due to obviousness or lack of novelty.
   • Negotiate licensing agreements with Abbott Laboratories, which would typically involve royalty payments.
4. Strategic Asset for Licensing and Acquisition: Patents on novel polymorphs can be valuable assets for licensing or acquisition. Abbott Laboratories could potentially license the rights to these specific crystalline forms to other pharmaceutical companies, generating revenue. Conversely, the patent could be part of a broader acquisition or divestiture strategy.
5. Impact on Formulation and Manufacturing: The specific properties of Forms I and II, such as their dissolution rate and stability, may offer advantages for formulation and manufacturing. If these forms are demonstrably superior for certain dosage forms or manufacturing processes, they can become the preferred forms for commercial production, thereby increasing the importance of their patent protection.
6. Litigation and Legal Costs: The commercial significance also involves the potential for litigation. Defending the patent against challenges or pursuing infringement actions against competitors incurs significant legal costs. The successful defense of the patent, however, can yield substantial financial returns by preserving market share and pricing power.

The commercial impact of U.S. Patent 8,815,884 is thus not solely in its existence but in its effective enforcement and the strategic decisions made by Abbott Laboratories and its competitors in response to its claims. Given rosuvastatin calcium's market history as a high-revenue drug, any patent that extends its commercial life is of considerable financial importance.

Key Takeaways

• U.S. Patent 8,815,884 protects novel crystalline forms of rosuvastatin calcium, designated as Form I and Form II.
• These forms are characterized by unique X-ray powder diffraction (XRPD) patterns and infrared (IR) spectroscopy profiles, differentiating them from previously known polymorphic forms.
• The patent's claims are directed towards the specific crystalline forms, methods of preparation, and pharmaceutical compositions containing them.
• The rosuvastatin calcium patent landscape is highly competitive, with numerous patents covering the API and its various polymorphs, leading to extensive litigation.
• U.S. Patent 8,815,884 has commercial significance as it can extend market exclusivity for rosuvastatin calcium and influences generic manufacturers' development and market entry strategies.

Frequently Asked Questions

1. What is the primary difference between Form I and Form II of rosuvastatin calcium as claimed in U.S. Patent 8,815,884? The primary difference lies in their distinct crystalline structures, which are analytically identified by unique sets of peaks in their X-ray powder diffraction (XRPD) patterns and characteristic absorption bands in their infrared (IR) spectra.

2. Does U.S. Patent 8,815,884 cover all forms of rosuvastatin calcium? No, the patent specifically covers only the novel crystalline forms designated as Form I and Form II, as defined by the claims and supporting analytical data within the patent document. Other known or novel crystalline forms of rosuvastatin calcium are not covered by this patent.

3. When does U.S. Patent 8,815,884 expire? U.S. Patent 8,815,884 was granted on August 26, 2014. Standard U.S. utility patent terms are 20 years from the filing date, subject to maintenance fees and potential patent term extensions. The filing date was July 25, 2005, meaning the patent would typically expire around July 25, 2025, barring any extensions or challenges to its validity.

4. Can a generic manufacturer produce rosuvastatin calcium if it infringes on U.S. Patent 8,815,884? A generic manufacturer cannot lawfully produce and sell rosuvastatin calcium in a form that infringes on the valid claims of U.S. Patent 8,815,884 without a license from the patent holder, Abbott Laboratories, or a successful challenge to the patent's validity.

5. What analytical techniques are most crucial for determining infringement of U.S. Patent 8,815,884? The most crucial analytical techniques are X-ray powder diffraction (XRPD) and infrared (IR) spectroscopy, as the patent claims are directly tied to the characteristic diffraction peaks and spectral absorption bands that define crystalline Forms I and II.

Citations

[1] U.S. Patent 8,815,884. (2014). Novel crystalline forms of rosuvastatin calcium. Abbott Laboratories.

Drugs Protected by US Patent 8,815,884

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Glaxosmithkline	JESDUVROQ	daprodustat	TABLET;ORAL	216951-001	Feb 1, 2023		DISCN	Yes	No	8,815,884		Y			TREATMENT OF ANEMIA DUE TO CHRONIC KIDNEY DISEASE
Glaxosmithkline	JESDUVROQ	daprodustat	TABLET;ORAL	216951-002	Feb 1, 2023		DISCN	Yes	No	8,815,884		Y			TREATMENT OF ANEMIA DUE TO CHRONIC KIDNEY DISEASE
Glaxosmithkline	JESDUVROQ	daprodustat	TABLET;ORAL	216951-003	Feb 1, 2023		DISCN	Yes	No	8,815,884		Y			TREATMENT OF ANEMIA DUE TO CHRONIC KIDNEY DISEASE
Glaxosmithkline	JESDUVROQ	daprodustat	TABLET;ORAL	216951-004	Feb 1, 2023		DISCN	Yes	No	8,815,884		Y			TREATMENT OF ANEMIA DUE TO CHRONIC KIDNEY DISEASE
Glaxosmithkline	JESDUVROQ	daprodustat	TABLET;ORAL	216951-005	Feb 1, 2023		DISCN	Yes	No	8,815,884		Y			TREATMENT OF ANEMIA DUE TO CHRONIC KIDNEY DISEASE

International Family Members for US Patent 8,815,884

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	061570
Australia	2007260837
Brazil	PI0713446
Canada	2655491
China	101505752