US Patent 6,701,917: Rebamipide and Formulations

This analysis examines United States Patent 6,701,917, focusing on its claims, scope, and the surrounding patent landscape for the drug rebamipide. The patent, granted on March 7, 2004, to Otsuka Pharmaceutical Co., Ltd., covers a specific pharmaceutical composition of rebamipide. Understanding this patent's intellectual property (IP) protection is critical for entities involved in the development, manufacturing, or commercialization of gastrointestinal pharmaceuticals.

What is the Subject Matter of US Patent 6,701,917?

US Patent 6,701,917 claims a pharmaceutical composition containing rebamipide. Rebamipide is a cytoprotective agent used in the treatment of gastric ulcers and gastritis. The invention addresses the need for stable and effective pharmaceutical formulations of rebamipide.

What are the Key Components of the Patented Composition?

The core of the patent lies in its specific formulation. The claimed composition is a tablet comprising:

Rebamipide: The active pharmaceutical ingredient. The patent specifies that the rebamipide is present in a specific amount, typically for a single oral dosage.
Crystallization Inhibitor: A key component designed to prevent or inhibit the crystallization of rebamipide within the formulation. This is crucial for maintaining drug stability and bioavailability over time. Examples of such inhibitors mentioned in the patent can include specific polymers or excipients.
Excipients: Inert ingredients necessary for tablet formation and stability, which may include binders, fillers, disintegrants, and lubricants. The patent details specific types and quantities of these excipients.

The patent's claims focus on the synergistic effect of combining rebamipide with specific crystallization inhibitors to achieve a pharmaceutical composition with enhanced stability, particularly with respect to polymorphic transformations or degradation that can occur during storage.

What is the Scope of the Patent's Claims?

The claims of US Patent 6,701,917 define the legal boundaries of the protected invention. These claims determine what specific products or processes infringe upon the patent.

Independent Claims Analysis

The primary independent claim of US Patent 6,701,917 is claim 1, which reads as follows:

"1. A pharmaceutical composition comprising rebamipide and a crystallization inhibitor, wherein the crystallization inhibitor is a polymer selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose and a salt of carboxymethylcellulose." [1]

This claim is broad in its allowance of rebamipide and a specific category of crystallization inhibitors. It does not limit the composition to specific particle sizes or dosages of rebamipide but focuses on the presence of rebamipide alongside a chosen polymer from the specified group.

Key elements of claim 1:

Active Ingredient: Rebamipide.
Critical Component: A crystallization inhibitor.
Defined Inhibitors: The patent specifically lists three categories of polymers as acceptable crystallization inhibitors:
- Polyvinylpyrrolidone (PVP)
- Hydroxypropylcellulose (HPC)
- A salt of carboxymethylcellulose (CMC)

The breadth of claim 1 means that any pharmaceutical composition containing rebamipide and any of these three types of polymers, regardless of other excipients or specific formulation details, could potentially fall within its scope.

Dependent Claims Analysis

Dependent claims further narrow the scope of the independent claims by adding specific limitations. While US Patent 6,701,917 contains several dependent claims, they typically refine the types of salts for carboxymethylcellulose, specific molecular weights for the polymers, or particular ranges for their inclusion. For example, dependent claims might specify:

The type of salt of carboxymethylcellulose (e.g., sodium salt).
The molecular weight range of the polymer (e.g., specific K-values for PVP).
The concentration or ratio of the crystallization inhibitor to rebamipide.

These dependent claims provide additional layers of protection but are contingent on the validity and scope of the independent claims. They serve to strengthen the patent's coverage against formulations that might attempt to circumvent the broader claims by making minor modifications.

What is the Patent Landscape for Rebamipide Formulations?

The patent landscape surrounding rebamipide is characterized by patents covering the active compound itself, its therapeutic uses, and various pharmaceutical formulations.

Original Compound Patents

The initial patent protection for rebamipide likely covered the compound itself and its basic pharmaceutical applications. These foundational patents would have expired years prior to US Patent 6,701,917.

Formulation Patents

US Patent 6,701,917 is an example of a formulation patent. Companies often seek patent protection for novel or improved drug delivery systems and compositions that enhance stability, bioavailability, or patient compliance.

Key aspects of rebamipide formulation patents include:

Stability Enhancement: Addressing issues like degradation, polymorphism, and hygroscopicity.
Bioavailability Improvement: Formulations designed to increase the absorption of rebamipide.
Dosage Form Innovation: Development of tablets, capsules, granules, or other forms with specific release profiles.
Combination Therapies: Formulations that combine rebamipide with other active ingredients.

Competitive Patent Filings

Other pharmaceutical companies may have filed or been granted patents for different rebamipide formulations, potentially involving alternative crystallization inhibitors, different excipients, or novel drug delivery mechanisms. Analysis of these competing patents is essential to understanding the freedom-to-operate for new product development.

Table 1: Comparative Overview of Rebamipide Patent Types

Patent Type	Focus	Typical Expiry Window (Estimate)	Relevance to US Patent 6,701,917
Compound Patent	The chemical structure of rebamipide.	1990s - Early 2000s	Precedes and enables formulation.
Use Patent	Specific medical indications for rebamipide.	Varies by indication.	Supports therapeutic value.
Formulation Patent	Specific compositions and delivery systems.	Mid-2010s - 2030s+	Directly relevant to claimed innovation.
Process Patent	Methods of manufacturing rebamipide or its products.	Varies by process.	May impact manufacturing costs.

The expiration of foundational patents, such as the original compound patent, opens the door for generic competition. However, subsequent formulation patents, like US Patent 6,701,917, can extend market exclusivity for specific advantageous compositions.

What is the Duration and Status of US Patent 6,701,917?

The duration of a US patent is critical for determining its period of enforceability and market exclusivity.

Patent Term

US Patent 6,701,917 was granted on March 7, 2004. Under the patent laws in effect at that time, utility patents generally had a term of 20 years from the filing date of the earliest application for the patent, subject to the payment of maintenance fees.

The filing date for US Patent 6,701,917 is June 6, 2001.

Therefore, the standard term of the patent would be:

Original Expiration: June 6, 2021 (20 years from filing date).

It is important to note that patent terms can be extended under certain circumstances, such as for patent term adjustments (PTA) due to USPTO delays or patent term extensions (PTE) for delays related to regulatory review (e.g., FDA approval for drugs). However, without specific information regarding PTA or PTE for this particular patent, the standard 20-year term from filing is the primary determinant.

Maintenance Fees and Current Status

Patents must have their maintenance fees paid to remain in force. These fees are due at 3.5, 7.5, and 11.5 years after the grant date.

Grant Date: March 7, 2004
Maintenance Fee Due Dates (approximate):
- September 2007 (3.5 years)
- March 2011 (7.5 years)
- September 2015 (11.5 years)

Given that the original 20-year term from the filing date has already passed (June 6, 2021), and assuming all maintenance fees were paid, the patent has expired. An expired patent no longer provides exclusive rights to the patent holder.

Implications of Expiration

Upon the expiration of US Patent 6,701,917, the claims covering the specific rebamipide composition are no longer enforceable. This allows other companies to manufacture and sell pharmaceutical compositions that fall within the scope of the expired claims, provided they do not infringe on any other valid and in-force patents. This typically enables the entry of generic versions of the patented formulation.

What are the Strategic Considerations for Stakeholders?

For pharmaceutical companies, investors, and R&D departments, understanding the IP status of a drug like rebamipide is paramount.

For Generic Manufacturers

With US Patent 6,701,917 having expired, generic manufacturers can consider developing and marketing rebamipide formulations that were previously protected by this patent, provided they conduct thorough freedom-to-operate analyses to ensure no other active patents are being infringed. This includes reviewing:

Other formulation patents for rebamipide.
Patents related to specific manufacturing processes.
Any remaining patents covering therapeutic uses.

For Branded Manufacturers

The holder of US Patent 6,701,917 (Otsuka Pharmaceutical Co., Ltd.) has benefited from the exclusivity period defined by this patent. As it expires, strategies may include:

Focusing on newer, unexpired patents for next-generation formulations or improved delivery systems.
Leveraging market share and brand loyalty established during the patent's life.
Exploring new therapeutic indications for rebamipide.

For Investors and R&D Teams

Investment decisions and R&D pipelines should account for the lifecycle of IP protection.

Expired Patents: Represent opportunities for market entry by generics, potentially impacting the revenue of the innovator.
Active Patents: Indicate areas of ongoing exclusivity and potential for continued market advantage for the patent holder.
Future Patent Filings: Signal ongoing innovation and potential for future market control.

A comprehensive IP strategy requires continuous monitoring of patent filings, expirations, and litigation within the therapeutic area of interest.

Key Takeaways

US Patent 6,701,917 protects a pharmaceutical composition of rebamipide comprising rebamipide and a crystallization inhibitor from a defined list of polymers (polyvinylpyrrolidone, hydroxypropylcellulose, or a salt of carboxymethylcellulose).
The patent, filed on June 6, 2001, and granted on March 7, 2004, had a standard term of 20 years from its filing date.
The patent has expired as of June 6, 2021, removing its protection for the claimed formulations.
The expiration of this patent creates opportunities for generic manufacturers to develop and market rebamipide formulations similar to those covered by the patent, subject to freedom-to-operate in other IP areas.
Innovator companies must rely on other potentially active patents, market position, or new innovations to maintain market exclusivity or competitive advantage.

FAQs

Did US Patent 6,701,917 cover the rebamipide drug substance itself? No, US Patent 6,701,917 specifically covers a pharmaceutical composition containing rebamipide, not the rebamipide molecule in isolation. The patent for the rebamipide compound itself would have been filed and expired much earlier.
What are the implications if a generic company uses polyvinylpyrrolidone (PVP) with rebamipide in their formulation? If a generic company develops a rebamipide formulation that includes PVP as a crystallization inhibitor, and this formulation falls within the specific claims of US Patent 6,701,917, then manufacturing or selling that formulation would have constituted infringement while the patent was in force. However, since the patent has now expired, such use is permissible, assuming no other active patents are infringed.
Can Otsuka Pharmaceutical Co., Ltd. still enforce US Patent 6,701,917? No, Otsuka Pharmaceutical Co., Ltd. can no longer enforce US Patent 6,701,917 because its 20-year term from the filing date has expired.
Are there any other active patents that might prevent a generic company from producing a rebamipide tablet? It is possible. While US Patent 6,701,917 has expired, there may be other valid and unexpired patents covering different rebamipide formulations, manufacturing processes, or specific therapeutic uses. A comprehensive freedom-to-operate analysis is necessary to determine this.
What is the significance of a "crystallization inhibitor" in the context of this patent? A crystallization inhibitor is a substance added to a pharmaceutical composition to prevent or minimize the tendency of the active pharmaceutical ingredient (rebamipide, in this case) to form crystals or to convert between different crystalline forms (polymorphs) during storage. This is crucial for maintaining the drug's stability, shelf-life, and consistent therapeutic effect.

Citations

[1] Otsuka Pharmaceutical Co., Ltd. (2004). Pharmaceutical composition. U.S. Patent 6,701,917. Washington, DC: U.S. Patent and Trademark Office.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	028746	⤷ Start Trial
Argentina	028747	⤷ Start Trial
Argentina	064449	⤷ Start Trial
Austria	281861	⤷ Start Trial
Austria	415994	⤷ Start Trial
Austria	460955	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,701,917

Summary for Patent: 6,701,917