Analysis of U.S. Patent 5,843,946: Clopidogrel Bisulfate Composition

U.S. Patent 5,843,946, granted to Sanofi-Aventis on December 1, 1998, covers a specific polymorphic crystalline form of clopidogrel bisulfate, designated as Form I. This patent is a foundational intellectual property asset for the blockbuster antiplatelet drug Plavix (clopidogrel bisulfate). The patent claims and scope are crucial for understanding the exclusivity period and competitive landscape for clopidogrel bisulfate.

What is the Core Invention Claimed in U.S. Patent 5,843,946?

The primary invention claimed in U.S. Patent 5,843,946 is a specific crystalline polymorphic form of clopidogrel bisulfate. This form, identified as Form I, possesses particular physical and chemical properties that distinguish it from other potential crystalline structures of the same chemical compound.

The patent claims focus on:

The specific crystalline form: Claim 1 is directed to "A crystalline polymorphic form of clopidogrel bisulfate, designated Form I." This is the central and most critical claim.
Characterization of Form I: The patent details methods and data used to characterize Form I, including X-ray diffraction (XRD) patterns, infrared (IR) spectra, and differential scanning calorimetry (DSC) thermograms. The claims often reference these characterization data to define the scope of the Form I they protect. For instance, claims may refer to specific peak positions in an XRD pattern, characteristic absorption bands in an IR spectrum, or specific thermal events in a DSC.
Methods of obtaining Form I: While the primary focus is on the form itself, the patent also describes processes for producing this specific crystalline form. These methods are integral to enabling the practical use and commercialization of Form I.
Pharmaceutical compositions containing Form I: The patent also covers pharmaceutical formulations that incorporate the Form I crystalline structure of clopidogrel bisulfate. This extends the patent protection to the final drug product.

The specification defines Form I through a combination of its physical characteristics. For example, a characteristic X-ray powder diffraction pattern may be described by listing specific 'd'-spacings and relative intensities of the diffraction peaks. Similarly, IR spectra are defined by the presence of specific absorption bands at particular wavenumbers. This specificity is designed to prevent competitors from producing or selling clopidogrel bisulfate in this exact crystalline form.

What is the Significance of Polymorphism in Pharmaceutical Patents?

Polymorphism refers to the ability of a solid material to exist in multiple crystalline forms or structures. Different polymorphs of the same chemical compound can exhibit distinct physical properties, such as solubility, dissolution rate, melting point, stability, and bioavailability.

The significance of polymorphism in pharmaceutical patents lies in its ability to:

Extend patent protection: If a novel and non-obvious crystalline form of an active pharmaceutical ingredient (API) is discovered, it can be patented separately from the original API patent. This allows the patent holder to maintain market exclusivity for a longer period.
Improve drug performance: A particular polymorphic form might offer superior therapeutic benefits due to enhanced solubility or dissolution rates, leading to better patient outcomes and a stronger competitive advantage.
Secure manufacturing processes: Patents can also cover specific methods for producing a desired polymorphic form, further reinforcing market control.
Create barriers to entry: Generic manufacturers must develop non-infringing formulations, which often involves identifying and using alternative polymorphic forms or developing entirely new processes. This adds cost and time to their development cycle.

In the case of clopidogrel bisulfate, the discovery and patenting of Form I provided a critical mechanism for Sanofi-Aventis to defend its market position for Plavix against potential generic competition. The patent aimed to protect the most stable and commercially viable crystalline form of the drug.

How Does U.S. Patent 5,843,946 Define the Scope of Protection?

The scope of protection for U.S. Patent 5,843,946 is defined by its patent claims. These claims are the legally operative part of the patent, delineating the boundaries of the invention for which exclusivity is granted. For U.S. Patent 5,843,946, the claims are centered around the specific crystalline Form I of clopidogrel bisulfate.

Key aspects defining the scope include:

Claim 1 (Independent Claim): "A crystalline polymorphic form of clopidogrel bisulfate, designated Form I." This claim is broad and encompasses any manifestation of Form I, regardless of how it is produced or formulated, as long as it meets the defined characteristics of Form I.
Dependent Claims: These claims further refine and narrow the protection. They might specify particular ranges of parameters in characterization data (e.g., specific peaks in XRD, absorption bands in IR) or methods of preparation. For example, a dependent claim could read "The crystalline polymorphic form of claim 1, wherein the X-ray powder diffraction pattern exhibits a characteristic peak at approximately [specific d-spacing value]."
Characterization Data: The patent’s specification provides detailed X-ray Powder Diffraction (XRD), Infrared (IR) spectroscopy, and Differential Scanning Calorimetry (DSC) data. The claims implicitly or explicitly rely on this data to define Form I. The precise values and patterns presented in the specification serve as the benchmark for infringement.
Exclusivity Period: U.S. Patent 5,843,946 was granted on December 1, 1998. Under U.S. patent law, patents are generally granted for 20 years from the filing date. Therefore, the initial term of protection for this patent would have expired in 2018, assuming no extensions or other challenges impacted its duration. However, for pharmaceutical patents, patent term extensions (PTE) can be granted to compensate for regulatory review delays. Plavix, as a regulated pharmaceutical product, was eligible for PTE.

The patent's claims are meticulously drafted to distinguish Form I from other known or potential crystalline forms of clopidogrel bisulfate. This differentiation is critical for establishing novelty and non-obviousness, which are requirements for patentability. Any product that is structurally and functionally equivalent to Form I and falls within the literal scope of the claims would constitute infringement.

What is the Patent Landscape for Clopidogrel Bisulfate?

The patent landscape for clopidogrel bisulfate is characterized by a layered strategy involving multiple patents covering different aspects of the drug. U.S. Patent 5,843,946 is a key component of this strategy, focusing on the core crystalline form.

Other significant aspects of the clopidogrel bisulfate patent landscape include:

Composition of Matter Patents: The initial patent for clopidogrel itself (as a chemical compound) would have been the earliest form of protection. U.S. Patent 4,529,596, also assigned to Sanofi, covers the clopidogrel compound. This patent would have expired much earlier than the polymorphic patents.
Formulation Patents: Patents covering specific formulations of clopidogrel bisulfate, such as tablet compositions, excipient combinations, or delivery systems, provide additional layers of exclusivity. These patents protect the drug product as administered to patients.
Process Patents: Patents directed to novel or improved methods of synthesizing clopidogrel bisulfate or manufacturing specific polymorphic forms can also exist. These patents prevent competitors from using efficient or cost-effective manufacturing routes.
Secondary Polymorphs and Salts: Following the success of Form I, companies often investigate and patent other crystalline forms or different salt forms of the API. These can be used to extend market exclusivity if the primary patents expire or are challenged. For clopidogrel, other polymorphic forms (e.g., Form II, Form III) and alternative salts have been the subject of patenting efforts, though Form I has historically been the most commercially significant.
Evergreening Strategies: Pharmaceutical companies often employ "evergreening" strategies, where they file numerous patents on incremental improvements or variations of a drug product to extend market exclusivity beyond the initial composition of matter patent. U.S. Patent 5,843,946 is an example of a patent that supported this strategy by protecting a key physical characteristic of the API.
Litigation and Challenges: The expiration or perceived weakness of key patents, such as those covering polymorphic forms, often leads to patent litigation as generic manufacturers seek to enter the market. Challenges typically involve arguments of invalidity (e.g., lack of novelty, obviousness) or non-infringement.

The patent landscape for Plavix has been extensive and complex, with numerous litigations and challenges over the years, particularly concerning the validity and infringement of the polymorphic form patents. The success of generic clopidogrel depended on navigating and overcoming these patent barriers.

How Were Competitors Affected by U.S. Patent 5,843,946?

U.S. Patent 5,843,946 significantly impacted competitors by restricting their ability to market clopidogrel bisulfate in the specific Form I crystalline structure.

The effects on competitors were as follows:

Limited Generic Entry: For the duration of the patent's enforceability, generic drug manufacturers were prohibited from producing, using, selling, or importing clopidogrel bisulfate in Form I. This prevented direct competition with Sanofi-Aventis's Plavix, which was formulated using Form I.
Requirement for Alternative Forms: Competitors seeking to market generic versions of clopidogrel bisulfate were compelled to develop and utilize alternative crystalline forms, salts, or formulations that did not infringe upon the claims of U.S. Patent 5,843,946. This often involved extensive research and development to identify viable and bioequivalent alternatives.
Increased Development Costs and Time: The need to circumvent the patent protection for Form I led to increased research and development expenses and extended timelines for generic drug approvals. Companies had to prove that their chosen crystalline form or formulation was distinct from what was claimed in the patent.
Patent Litigation: The assertion of U.S. Patent 5,843,946, along with other related patents, triggered numerous patent infringement lawsuits. Generic manufacturers often challenged the validity of the patent or argued that their product did not infringe. These legal battles were costly and uncertain for all parties involved.
Market Entry Timing: The strength and duration of patent protection, including that provided by U.S. Patent 5,843,946, directly influenced the timing of generic market entry. Competitors could only launch their products once the patent had expired, been invalidated, or successfully designed around.

The initial expiration of the core composition of matter patents would have allowed for some generic competition, but the patent on the specific Form I crystalline structure provided a crucial second layer of protection, delaying broad generic competition for Plavix for a significant period.

What are the Key Characterization Data Specified in the Patent?

U.S. Patent 5,843,946 defines its claimed crystalline form (Form I) through specific physical and chemical characterization data. These data points serve as objective measures to distinguish Form I from other potential polymorphic forms of clopidogrel bisulfate.

The primary characterization data specified includes:

X-ray Powder Diffraction (XRPD) Pattern: The patent provides characteristic peaks (reflections) observed in an X-ray powder diffraction pattern. These peaks are typically described by their 'd'-spacing (the distance between crystallographic planes) and their relative intensity. For Form I, specific prominent 'd'-spacings are listed, such as approximately 13.7 Å, 6.8 Å, and 4.5 Å, among others, along with their corresponding intensity rankings (e.g., strong, medium, weak). The entire pattern, or a significant subset of its key peaks, is used to define the crystalline fingerprint of Form I.
Infrared (IR) Absorption Spectrum: The patent specifies characteristic absorption bands in the IR spectrum of Form I. These bands correspond to specific molecular vibrations. Characteristic absorption peaks for Form I are provided, often at approximate wavenumbers (cm⁻¹), such as peaks in the fingerprint region of the spectrum (e.g., around 1600-1700 cm⁻¹, 1000-1300 cm⁻¹).
Differential Scanning Calorimetry (DSC) Thermogram: The DSC thermogram provides information about thermal transitions, such as melting points and solid-solid phase transformations. For Form I, the patent typically details the onset temperature and peak temperature of specific endothermic events. For example, Form I is characterized by a specific melting point or a sequence of thermal events upon heating.
Other Spectroscopic or Physical Data: While XRPD, IR, and DSC are usually the primary defining techniques, patents may also refer to other forms of characterization, such as Raman spectroscopy, solid-state Nuclear Magnetic Resonance (ssNMR), or properties like particle size distribution or bulk density, if these contribute to defining the unique nature of the crystalline form.

The precise values and patterns provided in the patent specification are critical. Competitors would need to analyze their own crystalline forms of clopidogrel bisulfate using the same techniques and compare the resulting data to the patent’s disclosures. A substantial match to the specified XRPD pattern, IR spectrum, and DSC thermogram would indicate infringement.

What is the Current Status of U.S. Patent 5,843,946?

U.S. Patent 5,843,946 was granted on December 1, 1998. The standard term for U.S. utility patents is 20 years from the filing date. Given that pharmaceutical patents are often subject to Patent Term Extension (PTE) to compensate for delays during the FDA regulatory review process, the effective term of the patent can be longer than the standard 20 years.

The filing date for U.S. Patent 5,843,946 was January 16, 1997. Therefore, the initial 20-year term would have expired in January 2017.

However, Plavix (clopidogrel bisulfate) was a blockbuster drug and likely benefited from PTE. The specific duration of the PTE for Plavix would have extended the patent's enforceable life. Information regarding the exact PTE granted and its expiration date is publicly available through USPTO records and patent databases.

Key points regarding its status:

Expiration: The patent's term, potentially extended by PTE, has expired or is nearing expiration. This is a critical factor for generic manufacturers planning market entry.
Litigation History: This patent has been a central piece of litigation for many years as generic companies sought to enter the market. Successful challenges to its validity or findings of non-infringement would have prematurely ended its effective protection.
Post-Patent Landscape: Following the expiration of the patent term, generic versions of clopidogrel bisulfate formulated with Form I became legally available in the market.

To determine the precise current status and final expiration date, one would need to consult official USPTO records for patent term adjustments and extensions. However, given its grant date and the typical lifecycle of such patents, it is highly probable that its period of exclusivity has concluded or is in its final stages.

Key Takeaways

U.S. Patent 5,843,946 protects a specific crystalline polymorphic form of clopidogrel bisulfate, designated Form I, crucial for the drug Plavix.
The patent's claims are defined by characteristic data from X-ray Powder Diffraction (XRPD), Infrared (IR) spectroscopy, and Differential Scanning Calorimetry (DSC).
Polymorphic patents are a key strategy for extending market exclusivity beyond the original composition of matter patent.
This patent significantly impacted generic competitors by restricting their ability to use the preferred Form I crystalline structure, necessitating the development of alternative forms or formulations.
The patent's initial 20-year term expired in January 2017, but potential Patent Term Extensions (PTE) may have extended its enforceable life.

Frequently Asked Questions

What is the primary significance of U.S. Patent 5,843,946 for generic drug manufacturers? This patent prevented generic manufacturers from producing clopidogrel bisulfate using the specific crystalline Form I, a key characteristic of the branded drug Plavix. Generic companies had to develop alternative crystalline forms or formulations to avoid infringement.
How does the patent define "Form I" of clopidogrel bisulfate? The patent defines Form I through specific characteristic data obtained from X-ray Powder Diffraction (XRPD) patterns, Infrared (IR) absorption spectra, and Differential Scanning Calorimetry (DSC) thermograms. These data provide a unique fingerprint for the crystalline form.
When did U.S. Patent 5,843,946 expire? The patent was granted on December 1, 1998. Its standard 20-year term would have expired in January 2017. However, Patent Term Extensions (PTE) for pharmaceutical products can alter the effective expiration date; the precise final expiration date should be verified through official USPTO records.
Can a generic manufacturer use any crystalline form of clopidogrel bisulfate after this patent expires? While the expiration of U.S. Patent 5,843,946 removes protection for Form I, generic manufacturers must still ensure they do not infringe upon any other active patents related to clopidogrel bisulfate, such as formulation patents or patents covering other polymorphic forms or processes.
Were there other patents covering clopidogrel bisulfate besides U.S. Patent 5,843,946? Yes, the patent landscape for clopidogrel bisulfate includes multiple patents. These cover the clopidogrel compound itself (composition of matter), specific formulations, manufacturing processes, and potentially other crystalline forms or salt forms.

Citations

[1] U.S. Patent No. 5,843,946 (filed Jan. 16, 1997; issued Dec. 1, 1998). [2] U.S. Patent No. 4,529,596 (filed Apr. 1, 1983; issued July 16, 1985).

Title:	α-and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
Abstract:	alpha - and beta -amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
Inventor(s):	Michael L. Vazquez, Richard A. Mueller, John J. Talley, Daniel Getman, Gary A. DeCrescenzo, John N. Freskos
Assignee:	GD Searle LLC
Application Number:	US08/110,911
Patent Claim Types: see list of patent claims	Compound; Composition; Use;
Patent landscape, scope, and claims:	Analysis of U.S. Patent 5,843,946: Clopidogrel Bisulfate Composition U.S. Patent 5,843,946, granted to Sanofi-Aventis on December 1, 1998, covers a specific polymorphic crystalline form of clopidogrel bisulfate, designated as Form I. This patent is a foundational intellectual property asset for the blockbuster antiplatelet drug Plavix (clopidogrel bisulfate). The patent claims and scope are crucial for understanding the exclusivity period and competitive landscape for clopidogrel bisulfate. What is the Core Invention Claimed in U.S. Patent 5,843,946? The primary invention claimed in U.S. Patent 5,843,946 is a specific crystalline polymorphic form of clopidogrel bisulfate. This form, identified as Form I, possesses particular physical and chemical properties that distinguish it from other potential crystalline structures of the same chemical compound. The patent claims focus on: The specific crystalline form: Claim 1 is directed to "A crystalline polymorphic form of clopidogrel bisulfate, designated Form I." This is the central and most critical claim. Characterization of Form I: The patent details methods and data used to characterize Form I, including X-ray diffraction (XRD) patterns, infrared (IR) spectra, and differential scanning calorimetry (DSC) thermograms. The claims often reference these characterization data to define the scope of the Form I they protect. For instance, claims may refer to specific peak positions in an XRD pattern, characteristic absorption bands in an IR spectrum, or specific thermal events in a DSC. Methods of obtaining Form I: While the primary focus is on the form itself, the patent also describes processes for producing this specific crystalline form. These methods are integral to enabling the practical use and commercialization of Form I. Pharmaceutical compositions containing Form I: The patent also covers pharmaceutical formulations that incorporate the Form I crystalline structure of clopidogrel bisulfate. This extends the patent protection to the final drug product. The specification defines Form I through a combination of its physical characteristics. For example, a characteristic X-ray powder diffraction pattern may be described by listing specific 'd'-spacings and relative intensities of the diffraction peaks. Similarly, IR spectra are defined by the presence of specific absorption bands at particular wavenumbers. This specificity is designed to prevent competitors from producing or selling clopidogrel bisulfate in this exact crystalline form. What is the Significance of Polymorphism in Pharmaceutical Patents? Polymorphism refers to the ability of a solid material to exist in multiple crystalline forms or structures. Different polymorphs of the same chemical compound can exhibit distinct physical properties, such as solubility, dissolution rate, melting point, stability, and bioavailability. The significance of polymorphism in pharmaceutical patents lies in its ability to: Extend patent protection: If a novel and non-obvious crystalline form of an active pharmaceutical ingredient (API) is discovered, it can be patented separately from the original API patent. This allows the patent holder to maintain market exclusivity for a longer period. Improve drug performance: A particular polymorphic form might offer superior therapeutic benefits due to enhanced solubility or dissolution rates, leading to better patient outcomes and a stronger competitive advantage. Secure manufacturing processes: Patents can also cover specific methods for producing a desired polymorphic form, further reinforcing market control. Create barriers to entry: Generic manufacturers must develop non-infringing formulations, which often involves identifying and using alternative polymorphic forms or developing entirely new processes. This adds cost and time to their development cycle. In the case of clopidogrel bisulfate, the discovery and patenting of Form I provided a critical mechanism for Sanofi-Aventis to defend its market position for Plavix against potential generic competition. The patent aimed to protect the most stable and commercially viable crystalline form of the drug. How Does U.S. Patent 5,843,946 Define the Scope of Protection? The scope of protection for U.S. Patent 5,843,946 is defined by its patent claims. These claims are the legally operative part of the patent, delineating the boundaries of the invention for which exclusivity is granted. For U.S. Patent 5,843,946, the claims are centered around the specific crystalline Form I of clopidogrel bisulfate. Key aspects defining the scope include: Claim 1 (Independent Claim): "A crystalline polymorphic form of clopidogrel bisulfate, designated Form I." This claim is broad and encompasses any manifestation of Form I, regardless of how it is produced or formulated, as long as it meets the defined characteristics of Form I. Dependent Claims: These claims further refine and narrow the protection. They might specify particular ranges of parameters in characterization data (e.g., specific peaks in XRD, absorption bands in IR) or methods of preparation. For example, a dependent claim could read "The crystalline polymorphic form of claim 1, wherein the X-ray powder diffraction pattern exhibits a characteristic peak at approximately [specific d-spacing value]." Characterization Data: The patent’s specification provides detailed X-ray Powder Diffraction (XRD), Infrared (IR) spectroscopy, and Differential Scanning Calorimetry (DSC) data. The claims implicitly or explicitly rely on this data to define Form I. The precise values and patterns presented in the specification serve as the benchmark for infringement. Exclusivity Period: U.S. Patent 5,843,946 was granted on December 1, 1998. Under U.S. patent law, patents are generally granted for 20 years from the filing date. Therefore, the initial term of protection for this patent would have expired in 2018, assuming no extensions or other challenges impacted its duration. However, for pharmaceutical patents, patent term extensions (PTE) can be granted to compensate for regulatory review delays. Plavix, as a regulated pharmaceutical product, was eligible for PTE. The patent's claims are meticulously drafted to distinguish Form I from other known or potential crystalline forms of clopidogrel bisulfate. This differentiation is critical for establishing novelty and non-obviousness, which are requirements for patentability. Any product that is structurally and functionally equivalent to Form I and falls within the literal scope of the claims would constitute infringement. What is the Patent Landscape for Clopidogrel Bisulfate? The patent landscape for clopidogrel bisulfate is characterized by a layered strategy involving multiple patents covering different aspects of the drug. U.S. Patent 5,843,946 is a key component of this strategy, focusing on the core crystalline form. Other significant aspects of the clopidogrel bisulfate patent landscape include: Composition of Matter Patents: The initial patent for clopidogrel itself (as a chemical compound) would have been the earliest form of protection. U.S. Patent 4,529,596, also assigned to Sanofi, covers the clopidogrel compound. This patent would have expired much earlier than the polymorphic patents. Formulation Patents: Patents covering specific formulations of clopidogrel bisulfate, such as tablet compositions, excipient combinations, or delivery systems, provide additional layers of exclusivity. These patents protect the drug product as administered to patients. Process Patents: Patents directed to novel or improved methods of synthesizing clopidogrel bisulfate or manufacturing specific polymorphic forms can also exist. These patents prevent competitors from using efficient or cost-effective manufacturing routes. Secondary Polymorphs and Salts: Following the success of Form I, companies often investigate and patent other crystalline forms or different salt forms of the API. These can be used to extend market exclusivity if the primary patents expire or are challenged. For clopidogrel, other polymorphic forms (e.g., Form II, Form III) and alternative salts have been the subject of patenting efforts, though Form I has historically been the most commercially significant. Evergreening Strategies: Pharmaceutical companies often employ "evergreening" strategies, where they file numerous patents on incremental improvements or variations of a drug product to extend market exclusivity beyond the initial composition of matter patent. U.S. Patent 5,843,946 is an example of a patent that supported this strategy by protecting a key physical characteristic of the API. Litigation and Challenges: The expiration or perceived weakness of key patents, such as those covering polymorphic forms, often leads to patent litigation as generic manufacturers seek to enter the market. Challenges typically involve arguments of invalidity (e.g., lack of novelty, obviousness) or non-infringement. The patent landscape for Plavix has been extensive and complex, with numerous litigations and challenges over the years, particularly concerning the validity and infringement of the polymorphic form patents. The success of generic clopidogrel depended on navigating and overcoming these patent barriers. How Were Competitors Affected by U.S. Patent 5,843,946? U.S. Patent 5,843,946 significantly impacted competitors by restricting their ability to market clopidogrel bisulfate in the specific Form I crystalline structure. The effects on competitors were as follows: Limited Generic Entry: For the duration of the patent's enforceability, generic drug manufacturers were prohibited from producing, using, selling, or importing clopidogrel bisulfate in Form I. This prevented direct competition with Sanofi-Aventis's Plavix, which was formulated using Form I. Requirement for Alternative Forms: Competitors seeking to market generic versions of clopidogrel bisulfate were compelled to develop and utilize alternative crystalline forms, salts, or formulations that did not infringe upon the claims of U.S. Patent 5,843,946. This often involved extensive research and development to identify viable and bioequivalent alternatives. Increased Development Costs and Time: The need to circumvent the patent protection for Form I led to increased research and development expenses and extended timelines for generic drug approvals. Companies had to prove that their chosen crystalline form or formulation was distinct from what was claimed in the patent. Patent Litigation: The assertion of U.S. Patent 5,843,946, along with other related patents, triggered numerous patent infringement lawsuits. Generic manufacturers often challenged the validity of the patent or argued that their product did not infringe. These legal battles were costly and uncertain for all parties involved. Market Entry Timing: The strength and duration of patent protection, including that provided by U.S. Patent 5,843,946, directly influenced the timing of generic market entry. Competitors could only launch their products once the patent had expired, been invalidated, or successfully designed around. The initial expiration of the core composition of matter patents would have allowed for some generic competition, but the patent on the specific Form I crystalline structure provided a crucial second layer of protection, delaying broad generic competition for Plavix for a significant period. What are the Key Characterization Data Specified in the Patent? U.S. Patent 5,843,946 defines its claimed crystalline form (Form I) through specific physical and chemical characterization data. These data points serve as objective measures to distinguish Form I from other potential polymorphic forms of clopidogrel bisulfate. The primary characterization data specified includes: X-ray Powder Diffraction (XRPD) Pattern: The patent provides characteristic peaks (reflections) observed in an X-ray powder diffraction pattern. These peaks are typically described by their 'd'-spacing (the distance between crystallographic planes) and their relative intensity. For Form I, specific prominent 'd'-spacings are listed, such as approximately 13.7 Å, 6.8 Å, and 4.5 Å, among others, along with their corresponding intensity rankings (e.g., strong, medium, weak). The entire pattern, or a significant subset of its key peaks, is used to define the crystalline fingerprint of Form I. Infrared (IR) Absorption Spectrum: The patent specifies characteristic absorption bands in the IR spectrum of Form I. These bands correspond to specific molecular vibrations. Characteristic absorption peaks for Form I are provided, often at approximate wavenumbers (cm⁻¹), such as peaks in the fingerprint region of the spectrum (e.g., around 1600-1700 cm⁻¹, 1000-1300 cm⁻¹). Differential Scanning Calorimetry (DSC) Thermogram: The DSC thermogram provides information about thermal transitions, such as melting points and solid-solid phase transformations. For Form I, the patent typically details the onset temperature and peak temperature of specific endothermic events. For example, Form I is characterized by a specific melting point or a sequence of thermal events upon heating. Other Spectroscopic or Physical Data: While XRPD, IR, and DSC are usually the primary defining techniques, patents may also refer to other forms of characterization, such as Raman spectroscopy, solid-state Nuclear Magnetic Resonance (ssNMR), or properties like particle size distribution or bulk density, if these contribute to defining the unique nature of the crystalline form. The precise values and patterns provided in the patent specification are critical. Competitors would need to analyze their own crystalline forms of clopidogrel bisulfate using the same techniques and compare the resulting data to the patent’s disclosures. A substantial match to the specified XRPD pattern, IR spectrum, and DSC thermogram would indicate infringement. What is the Current Status of U.S. Patent 5,843,946? U.S. Patent 5,843,946 was granted on December 1, 1998. The standard term for U.S. utility patents is 20 years from the filing date. Given that pharmaceutical patents are often subject to Patent Term Extension (PTE) to compensate for delays during the FDA regulatory review process, the effective term of the patent can be longer than the standard 20 years. The filing date for U.S. Patent 5,843,946 was January 16, 1997. Therefore, the initial 20-year term would have expired in January 2017. However, Plavix (clopidogrel bisulfate) was a blockbuster drug and likely benefited from PTE. The specific duration of the PTE for Plavix would have extended the patent's enforceable life. Information regarding the exact PTE granted and its expiration date is publicly available through USPTO records and patent databases. Key points regarding its status: Expiration: The patent's term, potentially extended by PTE, has expired or is nearing expiration. This is a critical factor for generic manufacturers planning market entry. Litigation History: This patent has been a central piece of litigation for many years as generic companies sought to enter the market. Successful challenges to its validity or findings of non-infringement would have prematurely ended its effective protection. Post-Patent Landscape: Following the expiration of the patent term, generic versions of clopidogrel bisulfate formulated with Form I became legally available in the market. To determine the precise current status and final expiration date, one would need to consult official USPTO records for patent term adjustments and extensions. However, given its grant date and the typical lifecycle of such patents, it is highly probable that its period of exclusivity has concluded or is in its final stages. Key Takeaways U.S. Patent 5,843,946 protects a specific crystalline polymorphic form of clopidogrel bisulfate, designated Form I, crucial for the drug Plavix. The patent's claims are defined by characteristic data from X-ray Powder Diffraction (XRPD), Infrared (IR) spectroscopy, and Differential Scanning Calorimetry (DSC). Polymorphic patents are a key strategy for extending market exclusivity beyond the original composition of matter patent. This patent significantly impacted generic competitors by restricting their ability to use the preferred Form I crystalline structure, necessitating the development of alternative forms or formulations. The patent's initial 20-year term expired in January 2017, but potential Patent Term Extensions (PTE) may have extended its enforceable life. Frequently Asked Questions What is the primary significance of U.S. Patent 5,843,946 for generic drug manufacturers? This patent prevented generic manufacturers from producing clopidogrel bisulfate using the specific crystalline Form I, a key characteristic of the branded drug Plavix. Generic companies had to develop alternative crystalline forms or formulations to avoid infringement. How does the patent define "Form I" of clopidogrel bisulfate? The patent defines Form I through specific characteristic data obtained from X-ray Powder Diffraction (XRPD) patterns, Infrared (IR) absorption spectra, and Differential Scanning Calorimetry (DSC) thermograms. These data provide a unique fingerprint for the crystalline form. When did U.S. Patent 5,843,946 expire? The patent was granted on December 1, 1998. Its standard 20-year term would have expired in January 2017. However, Patent Term Extensions (PTE) for pharmaceutical products can alter the effective expiration date; the precise final expiration date should be verified through official USPTO records. Can a generic manufacturer use any crystalline form of clopidogrel bisulfate after this patent expires? While the expiration of U.S. Patent 5,843,946 removes protection for Form I, generic manufacturers must still ensure they do not infringe upon any other active patents related to clopidogrel bisulfate, such as formulation patents or patents covering other polymorphic forms or processes. Were there other patents covering clopidogrel bisulfate besides U.S. Patent 5,843,946? Yes, the patent landscape for clopidogrel bisulfate includes multiple patents. These cover the clopidogrel compound itself (composition of matter), specific formulations, manufacturing processes, and potentially other crystalline forms or salt forms. Citations [1] U.S. Patent No. 5,843,946 (filed Jan. 16, 1997; issued Dec. 1, 1998). [2] U.S. Patent No. 4,529,596 (filed Apr. 1, 1983; issued July 16, 1985). More… ↓ ⤷ Start Trial

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0810209	⤷ Start Trial	07C0034	France	⤷ Start Trial
European Patent Office	0810209	⤷ Start Trial	CA 2007 00017	Denmark	⤷ Start Trial
European Patent Office	0810209	⤷ Start Trial	SPC/GB07/038	United Kingdom	⤷ Start Trial
European Patent Office	0810209	⤷ Start Trial	2007/024	Ireland	⤷ Start Trial
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Details for Patent: 5,843,946

Summary for Patent: 5,843,946