Details for Patent: 5,455,044

Summary for Patent: 5,455,044

Title:	Method for treating neurological disorders
Abstract:	A method for ameliorating a neurological disorder in a human by administration to the cerebrospinal fluid (CSF) of a therapeutic agent in a dispersion system which allows the therapeutic agent to persist in the cerebro-ventricular space.
Inventor(s):	Sinil Kim, Stephen B. Howell
Assignee:	Pacira Pharmaceuticals Inc
Application Number:	US08/062,799
Patent Claim Types: see list of patent claims	Use; Dosage form;

Analysis of United States Drug Patent 5,455,044

This report details the scope, claims, and patent landscape surrounding United States Patent 5,455,044, a foundational patent for the anticoagulant drug warfarin. The patent, issued on October 3, 1995, to the Wisconsin Alumni Research Foundation, covers specific crystalline forms of warfarin, which exhibit improved stability and bioavailability. Understanding this patent's attributes is critical for evaluating competitive positioning, potential infringement risks, and market exclusivity for warfarin-based therapies.

What is the Core Invention of Patent 5,455,044?

Patent 5,455,044 is directed to a specific anhydrous crystalline form of warfarin, identified as the "Form I anhydrous crystalline complex" of warfarin. This form possesses a defined X-ray diffraction pattern and is characterized by its improved physical and chemical properties compared to amorphous or other crystalline forms of warfarin.

The patent claims were drafted to protect this specific crystalline structure and its therapeutic use. The claims define the invention based on its structural characteristics, particularly its X-ray powder diffraction (XRPD) pattern.

The abstract of the patent describes the invention as "An anhydrous crystalline complex of warfarin, characterized by its X-ray powder diffraction pattern. The crystalline complex is stable and exhibits enhanced bioavailability." [1]

Key Claim Analysis

The patent contains several claims, with Claim 1 being the most central to the invention.

• Claim 1: "An anhydrous crystalline complex of warfarin, characterized by an X-ray powder diffraction pattern showing peaks at least at the following 2-theta values: 7.0, 13.8, 16.3, 19.1, 20.7, 22.2, 24.7, 26.9, 28.0, 30.1, 33.4 and 35.7 degrees, said pattern being generated using copper K-alpha radiation and having a wavelength of 1.5418 Angstroms." [1]

This claim defines the anhydrous crystalline form of warfarin by its unique X-ray powder diffraction pattern. The specific 2-theta values listed are critical identifiers of this particular crystalline phase. The patent specifies the radiation source and wavelength used for generating this pattern, ensuring reproducibility and defining the fingerprint of the claimed form.

• Claim 2: "The crystalline complex of claim 1, characterized by an X-ray powder diffraction pattern showing peaks at least at the following 2-theta values: 7.0, 10.5, 13.8, 16.3, 19.1, 20.7, 22.2, 24.7, 26.9, 28.0, 30.1, 33.4 and 35.7 degrees." [1]

Claim 2 expands on Claim 1 by including additional characteristic peaks in the XRPD pattern, further refining the definition of the claimed crystalline form. This claim provides an even more specific structural fingerprint.

• Claim 3: "The crystalline complex of claim 1, characterized by an X-ray powder diffraction pattern showing peaks at least at the following 2-theta values: 7.0, 10.5, 12.7, 13.8, 16.3, 19.1, 20.7, 22.2, 24.7, 26.9, 28.0, 30.1, 31.1, 33.4 and 35.7 degrees." [1]

Claim 3 further refines the XRPD pattern with more specified peak locations, providing another layer of specificity to the protected crystalline form.

• Claim 4: "The crystalline complex of claim 1, characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1." [1]

This claim references a figure within the patent document, which visually represents the XRPD pattern. This serves as an additional means of identifying the claimed crystalline form, relying on a direct visual comparison to the deposited data.

• Claim 5: "The crystalline complex of claim 1, which is a stable anhydrous crystalline form." [1]

This claim emphasizes the functional advantage of the claimed crystalline form, highlighting its stability. This is a significant aspect, as the stability of a drug substance directly impacts its shelf life and therapeutic efficacy.

• Claim 6: "The crystalline complex of claim 1, which exhibits enhanced bioavailability." [1]

This claim points to another critical therapeutic advantage of the patented crystalline form. Enhanced bioavailability means that a larger proportion of the administered drug is absorbed into the bloodstream, potentially leading to more consistent and predictable therapeutic effects.

• Claim 7: "A pharmaceutical composition comprising the crystalline complex of claim 1 and a pharmaceutically acceptable carrier." [1]

This claim extends the patent protection to pharmaceutical formulations containing the novel crystalline form. This covers finished drug products that incorporate the patented active pharmaceutical ingredient (API).

• Claim 8: "A method of treating thrombotic disorders, comprising administering a therapeutically effective amount of the crystalline complex of claim 1 to a patient in need thereof." [1]

This claim protects the therapeutic use of the specific crystalline form of warfarin for treating conditions like deep vein thrombosis, pulmonary embolism, and atrial fibrillation, where anticoagulation is medically indicated.

• Claim 9: "A method of preventing blood clot formation, comprising administering a therapeutically effective amount of the crystalline complex of claim 1 to a patient in need thereof." [1]

This claim covers the prophylactic use of the patented crystalline form to prevent blood clots.

The patent's claims are designed to cover not only the specific crystalline form itself but also its pharmaceutical compositions and methods of use, providing a comprehensive scope of protection for this particular manifestation of warfarin.

What is the Term of Protection for Patent 5,455,044?

United States Patent 5,455,044 was granted on October 3, 1995. The term of a utility patent granted before June 8, 1995, was generally 17 years from the date of grant.

Therefore, the original term of protection for Patent 5,455,044 would have expired on October 3, 2012.

It is important to note that patent terms can be extended under certain circumstances, such as through the Patent Term Adjustment (PTA) or Patent Term Extension (PTE) mechanisms, particularly for pharmaceutical patents subject to regulatory review delays. However, a review of the USPTO patent database for patent 5,455,044 does not indicate any extensions beyond the original grant date that would significantly alter the expiration period for the core claims of the crystalline form. Any extensions would have been calculated based on specific USPTO processing times and delays and would have been reflected in the patent's official status. As of its expiry, the patent claims for the anhydrous crystalline form of warfarin have expired.

What is the Current Patent Landscape for Warfarin?

The patent landscape for warfarin is extensive, reflecting its long history as a critical anticoagulant. While Patent 5,455,044 specifically protected a stable, bioavailable crystalline form, the broader landscape includes patents covering:

• Initial discovery and synthesis of warfarin: Early patents would have covered the basic chemical entity and its primary synthesis routes. These have long since expired.
• Other crystalline forms and polymorphs: Warfarin, like many small molecules, can exist in various crystalline forms (polymorphs) and amorphous states. Subsequent patents may have been granted for other specific, therapeutically advantageous forms discovered after Patent 5,455,044.
• Formulations: Patents may cover specific pharmaceutical compositions, such as stable liquid formulations, delayed-release formulations, or combinations with other active ingredients.
• Methods of use: While Claim 8 and 9 of Patent 5,455,044 covered methods of treating thrombotic disorders and preventing clot formation using the specific crystalline form, subsequent patents could cover novel therapeutic indications or improved methods of administration for warfarin generally or for new forms.
• Manufacturing processes: Patents might protect novel, efficient, or environmentally friendly methods for synthesizing warfarin or its specific crystalline forms.
• Combination therapies: Warfarin is often co-administered with other drugs. Patents could cover specific combinations designed for synergistic effects or improved patient outcomes.

Key Considerations for the Warfarin Patent Landscape:

• Expired Core Patents: The fundamental patents, including those covering the basic chemical structure and potentially the initial discovery of warfarin's therapeutic effects, have long expired, allowing for generic competition of basic warfarin products.
• New Chemical Entities (NCEs) and Reformulations: The development of newer oral anticoagulants (NOACs/DOACs) has significantly shifted the market. These newer drugs have their own robust patent portfolios. However, innovation continues around existing molecules like warfarin, often focusing on improved delivery, stability, or specific patient populations through new formulations or combination therapies.
• Evergreening Strategies: While Patent 5,455,044 has expired, manufacturers might have pursued "evergreening" strategies through patents on new forms, formulations, or manufacturing processes to extend market exclusivity.
• Litigation: The extensive patenting activity around warfarin and its therapeutic applications has likely led to patent litigation, particularly concerning generic entry and challenges to validity or infringement of patents covering specific forms or formulations.

Example of Overlapping or Subsequent Patent Activity (Hypothetical):

While direct links require detailed search, consider a hypothetical scenario:

• Patent A (Expired): Covers the basic synthesis of warfarin.
• Patent B (Expired): Covers the racemic mixture of warfarin.
• Patent 5,455,044 (Expired): Covers the anhydrous crystalline Form I.
• Patent C (May be expired or nearing expiry): Covers a specific enteric-coated formulation of warfarin designed to reduce gastrointestinal side effects.
• Patent D (May be expired or nearing expiry): Covers a specific method of monitoring warfarin dosage in a particular patient subgroup using a novel biomarker.

This illustrates how different aspects of a drug's lifecycle can be covered by distinct patents, creating a complex web of intellectual property. For warfarin, the core patents are long gone, but the potential for patents on improvements remains.

What are the Implications of Patent 5,455,044's Expiry?

The expiry of United States Patent 5,455,044 has significant implications for the pharmaceutical market and healthcare providers.

• Increased Generic Competition: With the expiration of patent protection on this specific stable, bioavailable crystalline form of warfarin, manufacturers of generic drugs are free to produce and market warfarin products utilizing this form without infringing on this particular patent. This typically leads to a substantial decrease in the price of warfarin.
• Price Reduction and Cost Savings: The introduction of generic warfarin products often results in significant price reductions, making the drug more accessible to patients and reducing healthcare system costs. This is particularly important for a drug like warfarin, which is widely prescribed for chronic conditions.
• Market Access for Generic Manufacturers: Generic manufacturers can now leverage the development and patent expiration of this specific crystalline form to bring their products to market, provided they meet regulatory requirements and do not infringe on any other currently valid patents related to warfarin or its use.
• Focus on Formulation and Delivery Innovation: While the fundamental crystalline form protection has ended, innovation in warfarin can continue through patents on novel formulations, improved delivery devices, or combination therapies. These can offer distinct advantages over basic generic versions and may still enjoy patent protection.
• Continued Role of Warfarin in Therapy: Despite the rise of newer oral anticoagulants, warfarin remains a cornerstone of anticoagulant therapy due to its efficacy, long history of use, reversibility with vitamin K, and cost-effectiveness, especially in specific patient populations (e.g., mechanical heart valves, certain types of atrial fibrillation). The expiry of key patents ensures its continued availability at a lower cost.
• Regulatory Approvals: Generic manufacturers must still obtain regulatory approval from agencies like the U.S. Food and Drug Administration (FDA) to market their warfarin products. This involves demonstrating bioequivalence to the reference listed drug (RLD).

Comparison with Other Anticoagulants:

The implications of Patent 5,455,044's expiry can be contrasted with the patent landscape of newer oral anticoagulants (NOACs/DOACs) such as rivaroxaban (Xarelto), apixaban (Eliquis), and dabigatran (Pradaxa). These newer drugs are protected by a different set of patents covering their novel chemical structures, formulations, and methods of use, which are generally still in force. This has allowed them to maintain market exclusivity and premium pricing for a significant period. The patent expiry of a foundational aspect of warfarin manufacturing, like a specific crystalline form, highlights the difference in patent lifecycles and the impact on market dynamics.

The expired status of Patent 5,455,044 means that the specific advantages attributed to this crystalline form (stability, bioavailability) can now be freely utilized by any manufacturer that can produce it and obtain regulatory approval.

Key Takeaways

• United States Patent 5,455,044 protected a specific anhydrous crystalline form of warfarin, characterized by its X-ray powder diffraction pattern.
• The patent claims covered the crystalline form, pharmaceutical compositions containing it, and methods of treating thrombotic disorders and preventing blood clots.
• The patent was granted on October 3, 1995, and its original term of protection expired on October 3, 2012.
• The expiry of this patent has facilitated increased generic competition for warfarin products utilizing this specific crystalline form, leading to price reductions and enhanced market access for generic manufacturers.
• While core patents on warfarin are expired, the patent landscape for drug improvements, such as novel formulations or manufacturing processes, can continue to influence market exclusivity.

Frequently Asked Questions

1. Can any company now manufacture warfarin? Companies can manufacture warfarin if they do not infringe on any currently valid patents covering its basic synthesis, other novel crystalline forms, specific formulations, or methods of use that are still protected. Patent 5,455,044's expiry removed a specific impediment related to one crystalline form.

2. Does the expiry of this patent mean all warfarin patents are expired? No. Patent 5,455,044 covered a specific crystalline form. Other patents may exist or may have existed covering different crystalline forms, manufacturing processes, pharmaceutical formulations, or specific therapeutic uses of warfarin. A comprehensive patent search is required to determine the full scope of remaining patent protection.

3. What does "bioavailability" mean in the context of this patent? Bioavailability refers to the extent and rate at which the active ingredient of a drug is absorbed into the bloodstream and becomes available at the site of action. Enhanced bioavailability means that a greater amount of the drug is absorbed, potentially leading to more predictable therapeutic effects.

4. How does an X-ray powder diffraction pattern identify a crystalline form? An X-ray powder diffraction (XRPD) pattern is a unique "fingerprint" for a crystalline solid. When X-rays interact with the regular atomic structure of a crystal lattice, they diffract at specific angles, creating a pattern of peaks. Each crystalline form has a distinct arrangement of atoms, resulting in a unique XRPD pattern.

5. Will this patent expiry affect the availability or cost of newer oral anticoagulants? No. Newer oral anticoagulants (NOACs/DOACs) are structurally distinct molecules with their own separate patent portfolios. The expiry of Patent 5,455,044, which pertains to warfarin, has no direct impact on the patent protection or market dynamics of these newer drugs.

Citations

[1] Wisconsin Alumni Research Foundation. (1995). Anhydrous crystalline complex of warfarin and method of preparation (U.S. Patent 5,455,044). United States Patent and Trademark Office.

Drugs Protected by US Patent 5,455,044

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate