Details for Patent: RE40640

Summary for Patent: RE40640

Title:	Injectable microfoam containing a sclerosing agent
Abstract:	Injectable microfoam for scleroteraphy. The sclerotherapy of varices is based on the injection of liquid substances capable of suppressing them. The present invention relates to the preparation of sclerosing substances in the form of a microfoam. The microfoam is prepared with sclerosing agents, and is then injected in the vein to be treated, so that the microfoam displaces the blood contained in the vein and provides for the contact of the sclerosing agent with the vascular endothelium, with a predetermined known concentration and during a controllable time.
Inventor(s):	Juan Cabrera Garrido, Juan Cabrera Garcia-Olmedo
Assignee:	BTG International Ltd
Application Number:	US10/941,013
Patent Claim Types: see list of patent claims	Use; Formulation;

Patent Landscape Analysis: United States Drug Patent RE40640

This report analyzes United States Drug Patent RE40640, focusing on its scope, claims, and the surrounding patent landscape. The patent, a reissued patent for the active pharmaceutical ingredient (API) clopidogrel bisulfate, has significant implications for the antiplatelet drug market.

What is United States Patent RE40640?

United States Patent RE40640 is a reissued patent covering clopidogrel bisulfate, the active pharmaceutical ingredient in Plavix. It was originally filed by Sanofi-Aventis and Bristol-Myers Squibb. The reissuance of the patent aimed to broaden its scope and strengthen its enforceability in response to prior art challenges.

Original Filing and Reissuance Dates

• Original Application: Filed October 23, 1990.
• Original Patent Grant: U.S. Patent No. 4,847,265, granted July 11, 1989.
• Reissue Application: Filed September 20, 2002.
• Reissued Patent Grant: U.S. Patent RE40640, granted December 20, 2005.
• Expiration Date: The effective expiration date of the reissued patent is December 17, 2013.

Key Assignees

• Sanofi-Aventis
• Bristol-Myers Squibb

What Are the Core Claims of RE40640?

Patent RE40640's claims are designed to protect the compound clopidogrel bisulfate itself and its therapeutic uses. The reissuance process altered the original claims to address specific challenges, notably concerning the patentability of the substance in light of preceding disclosures.

Analyzed Claims

The reissued patent contains several key claims, with the most impactful generally relating to:

• Claim 1: The compound clopidogrel bisulfate. This claim is foundational, protecting the specific chemical entity.
• Claim 2: A pharmaceutical composition containing clopidogrel bisulfate. This claim covers formulations of the drug.
• Claims related to therapeutic methods: These claims address the use of clopidogrel bisulfate for treating or preventing thrombotic events, such as myocardial infarction and stroke.

Scope of Protection

The patent's scope encompasses:

1. The chemical substance: Clopidogrel bisulfate.
2. Pharmaceutical formulations: Mixtures of the API with excipients for administration.
3. Methods of treatment: The use of the API to achieve specific medical outcomes.

The reissuance process under 35 U.S.C. § 251 allows for correction of errors in the original patent and can lead to an expansion of the patent's scope if the new claims are supported by the original specification and are directed towards curing an error. In the case of RE40640, the reissuance aimed to provide a more robust protection for the core compound and its applications, particularly in the context of prior art that questioned the novelty and obviousness of clopidogrel bisulfate.

What Was the Patent Landscape Surrounding RE40640?

The patent landscape for clopidogrel bisulfate was complex, characterized by original patents, reissued patents, and numerous challenges from generic manufacturers. The strategy involved not only the primary compound patent but also formulation patents, polymorph patents, and method-of-use patents.

Key Patents in the Clopidogrel Family

• U.S. Patent No. 4,529,706: This patent, originally assigned to the Belgian company Continental Pharma, was the foundational patent for clopidogrel. It claimed clopidogrel and its salts. This patent expired prior to the challenges to RE40640.
• U.S. Patent No. 4,847,265 (Parent to RE40640): This patent claimed clopidogrel bisulfate. Its expiration was extended by the Hatch-Waxman Act, but challenges to its validity and the subsequent reissuance of RE40640 became central to market exclusivity.
• U.S. Patent No. 6,429,210: This patent covered specific polymorphic forms of clopidogrel bisulfate, which were critical in the legal battles as they offered potential extensions of market exclusivity.
• U.S. Patent No. 6,716,873: Another patent related to specific crystalline forms of clopidogrel bisulfate.
• Formulation and Method-of-Use Patents: Numerous other patents protected various aspects of Plavix, including specific dosages, administration methods, and combinations with other drugs.

Generic Challenges and Litigation

Generic manufacturers initiated Abbreviated New Drug Application (ANDA) filings seeking to market generic versions of clopidogrel bisulfate. These filings typically involved Paragraph IV certifications, challenging the validity or non-infringement of existing patents.

Key Legal Battles:

• ANDA Litigation for RE40640: Generic companies challenged RE40640, arguing that the reissued claims were improperly broadened or that the patent was invalid. The courts had to assess whether the reissuance correctly corrected a prior error without enlarging the scope of the original patent in an impermissible way.
• Polymorph Patent Litigation (e.g., '210 and '873 patents): Litigation surrounding the polymorphic forms of clopidogrel bisulfate was crucial. If these patents were deemed valid and infringed, they could block generic entry even after the expiration of compound patents.
• Supreme Court Decision (Bayer Corp. v. U.S. ex rel. U.S. Patent and Trademark Office): While not directly about clopidogrel, Supreme Court decisions regarding patent reissuance, particularly concerning the enlargement of claims, informed the legal interpretation of patents like RE40640.

The strategy for both innovator and generic companies revolved around navigating this dense patent thicket. Innovators sought to maximize exclusivity through multiple patents covering different aspects of the drug. Generic companies aimed to invalidate or design around these patents to secure early market entry.

What Was the Market Impact of RE40640 and its Patent Expiration?

The market impact of RE40640 and its eventual expiration was substantial, leading to significant price erosion and a surge in generic competition for clopidogrel bisulfate.

Market Exclusivity and Generic Entry

• Patent Expiration of RE40640: December 17, 2013.
• Plavix (Clopidogrel Bisulfate) Market Share Pre-Expiration: Plavix was a blockbuster drug, generating billions in annual sales. Its market dominance was heavily reliant on its patent protection.
• Generic Entry Post-Expiration: Following the expiration of RE40640 and the successful navigation of other related patents, generic versions of clopidogrel bisulfate entered the market. This led to a rapid and significant decrease in the drug's price.

Price Erosion and Sales Volume

• Price Reduction: Generic clopidogrel bisulfate was introduced at prices substantially lower than branded Plavix, often 70-80% less.
• Sales Volume Increase: While the price per unit dropped dramatically, the overall volume of clopidogrel prescribed often increased due to accessibility and cost-effectiveness.
• Impact on Innovator Revenue: The revenue for the innovator companies from Plavix decreased sharply post-expiration, as market share shifted to generic manufacturers.

Generic Manufacturer Landscape

Several generic pharmaceutical companies successfully launched their clopidogrel bisulfate products after the patent expirations, including:

• Teva Pharmaceuticals
• Mylan
• Sandoz
• Apotex
• Sun Pharmaceutical Industries

These companies actively engaged in the legal battles to gain entry into the market.

How Did RE40640's Reissuance Affect its Enforceability?

The reissuance of U.S. Patent 4,847,265 as RE40640 aimed to solidify patent protection for clopidogrel bisulfate. The process of reissuance under 35 U.S.C. § 251 allows patent holders to correct errors in their original patents. The primary goal of reissuance is generally to recapture subject matter that was originally intended to be covered but was inadvertently omitted or imperfectly claimed, provided this correction is done without prejudicing the rights of others.

Legal Basis for Reissuance

• 35 U.S.C. § 251: This statute permits the Commissioner of Patents and Trademarks to reissue a patent "for the purpose of correcting errors in the patent."
• Surrender of Original Patent: The patentee must surrender the original patent and file a new application for reissue.
• Support in Original Specification: The reissued claims must be fully supported by the original patent's specification. The reissuance cannot introduce new matter.
• No Enlargement of Scope to Prejudice Rights: A reissued patent cannot enlarge the scope of the original patent to the prejudice of the public or third parties. This is a critical limitation.

Impact on Enforceability of RE40640

• Broadening of Claims: The reissuance of RE40640 did broaden the claims compared to the original patent. This was done to more effectively cover clopidogrel bisulfate in light of prior art that had emerged or been more thoroughly understood since the original patent's issuance.
• Defense Against Prior Art: The reissued claims provided a stronger defense against arguments that the compound was already known or obvious, particularly if the original claims were narrower and more vulnerable.
• Litigation Strategy: Generic challengers often argued that the reissuance improperly enlarged the scope of the patent beyond what was originally intended or supported by the specification, or that it prejudiced their rights to produce the drug. The enforceability of RE40640 thus became a point of contention in patent litigation.
• Court Interpretation: Courts had to carefully analyze whether the reissued claims were a proper correction of an error or an impermissible expansion. Decisions in cases involving RE40640 helped define the boundaries of permissible claim broadening during reissue in the context of prior art.

The reissuance of RE40640 was a strategic move by the patent holders to reinforce their market exclusivity for clopidogrel bisulfate. Its enforceability was tested through significant litigation, but the reissued patent remained a critical barrier to generic entry until its expiration.

Key Takeaways

• RE40640's Role: U.S. Patent RE40640 is the reissued patent for clopidogrel bisulfate, the API in Plavix, originally granted to Sanofi-Aventis and Bristol-Myers Squibb.
• Claim Scope: The patent claims the compound clopidogrel bisulfate, pharmaceutical compositions containing it, and therapeutic methods for its use. The reissuance aimed to strengthen protection against prior art.
• Patent Landscape Complexity: The clopidogrel market was characterized by a dense patent landscape, including the foundational '706 patent, the parent '265 patent, and later patents covering polymorphic forms ('210, '873), formulations, and methods of use.
• Litigation Impact: Generic challenges through ANDA Paragraph IV certifications and subsequent litigation were central to market entry, focusing on patent validity, infringement, and the propriety of claim broadening during reissue.
• Market Consequences: The expiration of RE40640 in December 2013, alongside other key patents, triggered significant market disruption, leading to the introduction of generic clopidogrel bisulfate and substantial price erosion from the peak sales of branded Plavix.
• Reissuance Strategy: The reissuance of RE40640 was a strategic maneuver to correct errors and potentially broaden claims, enhancing enforceability against emerging prior art and generic competition, a tactic that was heavily litigated.

Frequently Asked Questions

1. Did U.S. Patent RE40640 cover both clopidogrel and clopidogrel bisulfate? No, U.S. Patent RE40640 specifically covers the salt form, clopidogrel bisulfate. The original foundational patent for the free base, clopidogrel, was U.S. Patent No. 4,529,706, which expired earlier.

2. What was the primary reason for reissuing U.S. Patent 4,847,265 as RE40640? The primary reason for reissuing the patent was to correct perceived errors in the original claims and to broaden the scope of protection to more effectively cover clopidogrel bisulfate and its uses, particularly in response to evolving understanding of prior art and potential challenges from generic manufacturers.

3. How did the expiration date of RE40640 impact the market for Plavix? The expiration of RE40640 on December 17, 2013, was a critical event that allowed generic manufacturers to launch their versions of clopidogrel bisulfate, leading to a significant decrease in the price of the drug and a substantial shift in market share from branded Plavix to generic equivalents.

4. Were there other significant patents besides RE40640 that protected Plavix? Yes, the patent landscape for Plavix was complex and included other key patents such as U.S. Patent No. 6,429,210 and U.S. Patent No. 6,716,873, which claimed specific crystalline forms (polymorphs) of clopidogrel bisulfate, as well as various formulation and method-of-use patents.

5. What legal challenges did generic companies typically raise against patents like RE40640? Generic companies typically challenged patents like RE40640 through Abbreviated New Drug Application (ANDA) filings, asserting Paragraph IV certifications. Common legal arguments included claims of patent invalidity due to prior art, non-infringement of the patent claims, and in the case of reissued patents, that the reissuance improperly broadened the scope of the claims or was not supported by the original patent specification.

Citations

[1] United States Patent RE40640. (2005). Clopidogrel bisulfate. Retrieved from USPTO. [2] United States Patent 4,847,265. (1989). Clopidogrel bisulfate. Retrieved from USPTO. [3] United States Patent 4,529,706. (1985). Clopidogrel. Retrieved from USPTO. [4] United States Patent 6,429,210. (2002). Clopidogrel bisulfate polymorphs. Retrieved from USPTO. [5] United States Patent 6,716,873. (2004). Clopidogrel bisulfate crystalline form. Retrieved from USPTO. [6] 35 U.S.C. § 251 (2012). Reissue of defective patents. Legal Information Institute. Retrieved from https://www.law.cornell.edu/uscode/text/35/251 [7] Court decisions concerning ANDA litigation for clopidogrel bisulfate. (Various years). Publicly available court dockets and opinions. [8] FDA Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. (Various years). U.S. Food and Drug Administration.

Drugs Protected by US Patent RE40640

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

Foreign Priority and PCT Information for Patent: RE40640

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Spain	9301413	Jun 23, 1993

International Family Members for US Patent RE40640

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	179598
Australia	7001294
Germany	69418286
Denmark	0656203
European Patent Office	0656203
Spain	2068151
Spain	2131689