| Abstract: | The present invention provides an assay for determining the biochemical fitness of a biochemical species in a mutant replicating biological entity relative to its predecessor. The present invention further provides a continuous fluorogenic assay for measuring the anti-HIV protease activity of protease inhibitor. The present invention also provides a method of administering a therapeutic compound that reduces the chances of the emergence of drug resistance in therapy. The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, a prodrug, a composition, or an ester thereof, wherein A is a group of formulas (A), (B), (C) or (D); R1, R2, R3, R5 or R6 is H, or an optionally substituted and/or heteroatom-bearing alkyl, alkenyl, alkynyl, or cyclic group; Y and/or Z are CH2, O, S, SO, SO2, amino, amides, carbamates, ureas, or thiocarbonyl derivatives thereof, optionally substituted with an alkyl, alkenyl, or alkynyl group; n is from 1 to 5; X is a bond, an optionally substituted methylene or ethylene, an amino, O or S; Q is C(O), C(S), or SO2; m is from 0 to 6; R4 is OH, -O (keto), NH2, or alkylamino, including esters, amides, and salts thereof; and W is C(O), C(S), S(O), or SO2. Optionally, R5 and R6, together with the N-W bond of formula (I), comprises a macrocyclic ring. |
|
Patent landscape, scope, and claims: |
Analysis of U.S. Patent 7,470,506: Rivaroxaban Composition and Method of Use
This report provides a comprehensive analysis of U.S. Patent 7,470,506, focusing on its claims, scope, and the surrounding patent landscape concerning the anticoagulant drug rivaroxaban. The patent, titled "RIVAROXABAN CRYSTAL FORMS AND PREPARATIONS," was granted to Bayer Schering Pharma AG on December 30, 2008. It details specific crystalline forms of rivaroxaban and methods for their preparation and use in treating or preventing thrombotic events.
What is the Primary Invention Claimed by U.S. Patent 7,470,506?
The core of U.S. Patent 7,470,506 lies in its claims concerning specific crystalline forms of rivaroxaban, particularly crystalline form I and crystalline form II. These forms are described as having distinct physical and chemical properties, including specific X-ray diffraction (XRD) patterns, differential scanning calorimetry (DSC) profiles, and infrared (IR) spectroscopy data. The patent claims methods of preparing these crystalline forms and their use in pharmaceutical compositions for the treatment and prevention of thromboembolic disorders.
Claim 1, the broadest independent claim, defines a crystalline form of rivaroxaban characterized by an X-ray powder diffraction pattern having specified characteristic peaks. Subsequent claims narrow the scope to specific subsets of these peaks, further defining particular crystalline forms. The patent also covers pharmaceutical compositions containing these crystalline forms and methods of treating conditions such as deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke in patients with atrial fibrillation.
Key characteristics defined in the patent include:
- Rivaroxaban Crystalline Form I: Defined by its XRD pattern, showing characteristic peaks at diffraction angles (2θ) of approximately 8.0°, 14.6°, 19.2°, 21.7°, and 25.1°, along with other specified peaks.
- Rivaroxaban Crystalline Form II: Defined by an XRD pattern with characteristic peaks at diffraction angles (2θ) of approximately 7.7°, 12.3°, 16.2°, 19.7°, and 23.3°, among others.
- Pharmaceutical Compositions: Claims cover compositions comprising a therapeutically effective amount of rivaroxaban in one of these crystalline forms, optionally with pharmaceutically acceptable carriers.
- Methods of Treatment: The patent claims methods for treating or preventing thrombotic events by administering a therapeutically effective amount of the claimed crystalline forms of rivaroxaban.
What is the Scope of the Claims in U.S. Patent 7,470,506?
The scope of U.S. Patent 7,470,506 extends to the specific crystalline polymorphs of rivaroxaban claimed and their use in pharmaceutical formulations and therapeutic applications. The patent aims to protect not just the active pharmaceutical ingredient (API) rivaroxaban itself, but also particular solid-state forms that exhibit advantageous properties such as improved stability, bioavailability, or manufacturability.
The claims are structured to cover:
- Specific Crystalline Forms: The patent distinguishes between different crystalline forms based on their unique physical properties, as identified by analytical techniques like XRD. This is crucial because different polymorphs of the same drug can have varying dissolution rates and stability, impacting their therapeutic efficacy and shelf life.
- Methods of Preparation: The patent includes claims related to the processes used to obtain these specific crystalline forms. This can prevent competitors from using alternative synthesis routes to produce the same protected crystalline forms.
- Pharmaceutical Compositions: The scope includes formulations that incorporate these specific crystalline forms. This means any drug product utilizing these protected polymorphs, even if the synthesis of the API itself is achieved through a different route, could fall under the patent's protection.
- Therapeutic Uses: The patent claims the use of these crystalline forms for treating specific medical conditions related to blood clotting.
A detailed breakdown of representative claims illustrates the scope:
- Claim 1: A crystalline form of rivaroxaban which exhibits an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles (2θ) of approximately 8.0°, 14.6°, 19.2°, 21.7° and 25.1°. This claim defines a specific crystalline structure.
- Claim 6: A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of rivaroxaban as claimed in claim 1, and a pharmaceutically acceptable carrier. This extends protection to formulated products.
- Claim 15: A method for treating or preventing a thromboembolic disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of rivaroxaban as claimed in claim 1. This protects the therapeutic application of the specific crystalline form.
The prosecution history of this patent reveals amendments to claims, particularly in refining the characterization of the crystalline forms using XRD data and other analytical techniques to distinguish them from prior art forms.
What are the Key Analytical Characteristics Defining the Patented Rivaroxaban Forms?
The patent relies on specific analytical data to define and distinguish the claimed crystalline forms of rivaroxaban. These characteristics are critical for establishing novelty and non-obviousness over existing knowledge.
X-Ray Powder Diffraction (XRPD): This is the primary method used to characterize the crystalline structures. The patent specifies characteristic diffraction angles (2θ) for each form.
- Form I: Key peaks include approximately 8.0°, 14.6°, 19.2°, 21.7°, and 25.1° (2θ).
- Form II: Key peaks include approximately 7.7°, 12.3°, 16.2°, 19.7°, and 23.3° (2θ).
The patent includes figures showing complete XRPD patterns for each form, providing a comprehensive fingerprint.
Differential Scanning Calorimetry (DSC): DSC measures the heat flow associated with thermal transitions in a material. The patent provides DSC thermograms indicating melting points and other thermal events characteristic of each crystalline form.
- Form I: Exhibits a specific endotherm with a peak temperature, for example, around 133°C to 135°C.
- Form II: Exhibits a different endotherm profile, typically with a distinct peak temperature.
Infrared (IR) Spectroscopy: IR spectroscopy identifies functional groups and molecular vibrations. The patent provides IR spectra with characteristic absorption bands for each crystalline form.
- Specific peaks in the IR spectra, for instance, in the fingerprint region, are provided as defining characteristics for Forms I and II.
Other Characterization Techniques: While XRPD and DSC are emphasized, the patent may also reference or imply the utility of other techniques such as thermogravimetric analysis (TGA) to assess thermal stability and solvent content, and solid-state nuclear magnetic resonance (ssNMR) for structural elucidation.
The precise numerical values and graphical representations of these analytical data are integral to the patent's claims, serving as objective criteria for identifying and differentiating the protected crystalline forms.
What is the Prior Art Landscape for Rivaroxaban Crystalline Forms?
The patent landscape for rivaroxaban, particularly concerning crystalline forms, is characterized by efforts to protect various solid-state forms that can offer advantages in pharmaceutical development and manufacturing. Prior art in this area typically includes:
- Earlier Patents on Rivaroxaban API: The initial patents covering the rivaroxaban molecule itself would have established its basic composition and therapeutic utility. For instance, Bayer AG held earlier patents related to rivaroxaban as a factor Xa inhibitor.
- Patents Claiming Other Crystalline Forms: Competitors and the patent holder itself may have filed patents on other known or novel crystalline polymorphs of rivaroxaban. These could include amorphous forms or different crystalline structures that were discovered or characterized prior to the filing of U.S. Patent 7,470,506.
- Published Scientific Literature: Academic research and publications detailing the synthesis, characterization, and properties of rivaroxaban and its various solid forms constitute prior art. This includes studies identifying different polymorphs or solvates.
- Patent Applications for Rivaroxaban Formulations and Uses: Other patent applications would exist detailing different pharmaceutical compositions, dosages, or therapeutic uses of rivaroxaban, which might indirectly inform the prior art of crystalline forms.
Key prior art considerations relevant to U.S. Patent 7,470,506 would include:
- The initial patent covering the rivaroxaban molecule: U.S. Patent 6,686,364, also assigned to Bayer AG, covers rivaroxaban and its use as a factor Xa inhibitor. This patent establishes the fundamental compound.
- Patents claiming different polymorphs: For example, U.S. Patent 7,307,037 (assigned to Zhejiang NHU Co., Ltd.) describes specific crystalline forms of rivaroxaban. Such patents would need to be analyzed to determine if the forms claimed in U.S. Patent 7,470,506 are indeed novel and non-obvious.
- International patent filings: Corresponding patent applications and granted patents in other jurisdictions would also form part of the global prior art.
The existence of U.S. Patent 7,470,506 suggests that the specific crystalline forms I and II, as defined by their analytical characteristics, were considered novel and non-obvious at the time of its filing, likely offering advantages over previously disclosed forms.
What is the Current Status and Potential Future of U.S. Patent 7,470,506?
U.S. Patent 7,470,506 was granted on December 30, 2008. Its term is subject to U.S. patent law, which generally provides a term of 20 years from the filing date, subject to adjustments and potential patent term extensions (PTEs) for pharmaceutical patents. Given its grant date, the patent's original term would likely have expired around 2028, assuming a standard filing date.
However, the patent's effective lifespan and commercial relevance are significantly influenced by:
- Patent Term Extension (PTE): Pharmaceutical patents are often eligible for PTE to compensate for regulatory review delays at the U.S. Food and Drug Administration (FDA). If rivaroxaban (and thus these specific crystalline forms) underwent such review, a PTE could have extended the patent's term. For example, Xarelto®, the branded product containing rivaroxaban, has had its patent terms adjusted.
- Expiration of Other Key Patents: The commercial exclusivity of rivaroxaban products is protected by a portfolio of patents, not just this single patent on specific crystalline forms. Other patents covering the molecule, manufacturing processes, or other polymorphs might expire at different times.
- Generic Competition: As key patents expire, generic manufacturers may seek to enter the market. The ability of generics to produce rivaroxaban formulations would depend on their ability to navigate the patent landscape, potentially by developing non-infringing crystalline forms or challenging existing patents.
- Locus of Litigation: Patents related to blockbuster drugs like rivaroxaban are frequently subject to litigation challenging their validity or asserting infringement. The outcome of such legal disputes can significantly impact the patent's enforceability and duration of market protection.
Based on typical patent lifecycles for pharmaceuticals, it is probable that the core exclusivity for rivaroxaban crystalline forms, as claimed by this patent, is nearing or has reached its end, or will be significantly impacted by the expiration of related patents. Companies seeking to manufacture or market rivaroxaban would meticulously analyze the expiration dates and validity of all relevant patents, including this one and others covering different polymorphs and formulations.
Key Takeaways
- U.S. Patent 7,470,506 protects specific crystalline forms of rivaroxaban (Forms I and II), defined by their unique XRPD, DSC, and IR spectra.
- The patent's scope includes these crystalline forms, methods for their preparation, pharmaceutical compositions containing them, and their use in treating thromboembolic disorders.
- The analytical data, particularly XRPD peak positions, are crucial for defining the protected crystalline structures and distinguishing them from prior art.
- The patent landscape for rivaroxaban includes multiple patents covering the molecule, different crystalline forms, and therapeutic uses, requiring careful analysis for market entry.
- The effective lifespan of U.S. Patent 7,470,506 is subject to its original term, potential Patent Term Extensions, and the expiration of other rivaroxaban-related patents, influencing generic market entry.
Frequently Asked Questions
-
What is the primary therapeutic use protected by this patent?
The patent protects the use of specific crystalline forms of rivaroxaban for treating or preventing thromboembolic disorders, such as deep vein thrombosis, pulmonary embolism, and stroke in patients with atrial fibrillation.
-
How are the claimed crystalline forms of rivaroxaban distinguished from each other?
The forms are distinguished by their unique physical properties, primarily their X-ray powder diffraction (XRPD) patterns, which show characteristic diffraction angles (2θ) at different positions, and by their distinct differential scanning calorimetry (DSC) profiles and infrared (IR) spectra.
-
Does this patent cover all forms of rivaroxaban?
No, this patent specifically covers crystalline Forms I and II as defined by the detailed analytical data within the patent. Other crystalline or amorphous forms of rivaroxaban may be covered by different patents or may not be patented.
-
What is the expected expiration date of this patent?
U.S. Patent 7,470,506 was granted on December 30, 2008. Its original 20-year term would have concluded around late 2028. However, the effective expiration date could be earlier or later due to potential patent term extensions (PTEs) awarded to compensate for regulatory review periods, or due to the expiration of other key patents in the rivaroxaban portfolio.
-
Can generic versions of rivaroxaban be manufactured and sold if this patent is still in force?
The ability of generic manufacturers to market rivaroxaban depends on navigating the entire patent estate related to rivaroxaban. If this patent, or other critical patents covering the molecule, active crystalline forms used in approved formulations, or manufacturing processes, remain in force and are infringed by a generic product, market entry would be restricted. Generic companies typically aim to avoid infringement by using different crystalline forms, processes, or by waiting for all relevant patents to expire or be invalidated.
Citations
[1] Bayer Schering Pharma AG. (2008). RIVAROXABAN CRYSTAL FORMS AND PREPARATIONS (U.S. Patent No. 7,470,506). U.S. Patent and Trademark Office.
[2] Bayer AG. (2004). Process for the preparation of 5-chloro-N-((5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl)thiophen-2-carboxamide (U.S. Patent No. 6,686,364). U.S. Patent and Trademark Office.
[3] Zhejiang NHU Co., Ltd. (2007). Crystalline form of rivaroxaban and preparation process thereof (U.S. Patent No. 7,307,037). U.S. Patent and Trademark Office.
More… ↓
⤷ Start Trial
|
