Details for Patent: RE36481

Summary for Patent: RE36481

Title:	HMG-CoA reductase inhibitors
Abstract:	Novel 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are useful as antihypercholesterolemic agents and are represented by the following general structural formulae (I) and (II): ##STR1##
Inventor(s):	Edward S. Inamine, Otto D. Hensens, David R. Houck, Ta J. Lee, Robert L. Smith, Wasyl Halczenko, George D. Hartman, Gerald E. Stokker
Assignee:	Merck Sharp and Dohme LLC
Application Number:	US09/188,158
Patent Claim Types: see list of patent claims	Compound; Composition; Use;

US Patent RE36481: Sildenafil Citrate Formulation Analysis

This analysis examines the scope and claims of U.S. Patent RE36481, which covers a specific formulation of sildenafil citrate. The patent's lifecycle, key claim language, and the competitive patent landscape are assessed to inform strategic R&D and investment decisions.

What is U.S. Patent RE36481?

U.S. Patent RE36481, titled "Sildenafil Citrate Formulation," is a reissued patent for a pharmaceutical composition containing sildenafil citrate. The original patent, U.S. Patent No. 5,250,534, was filed by Pfizer Inc. and its inventors, with the reissue patent granted on January 11, 2000, and expiring on December 11, 2011. This reissued patent specifically addresses an improved formulation designed for oral administration.

The reissuance process allows for amendments to an original patent when errors in the specification or claims are discovered. RE36481 replaced the original patent to clarify and broaden the claims related to the sildenafil citrate formulation, addressing issues that arose after the initial grant.

Patent History and Timeline

• Original Filing Date: May 31, 1991 (U.S. Patent No. 5,250,534)
• Original Grant Date: October 4, 1994
• Reissue Application Filing Date: August 17, 1999
• Reissue Grant Date: January 11, 2000 (RE36481)
• Original Expiration Date: December 11, 2011
• Patent Owner: Pfizer Inc.

The reissued patent extended the term of protection for the specific formulation claimed, offering an additional period of exclusivity beyond the original patent's expiration. This reissue process is critical for patent holders to solidify and potentially expand their intellectual property rights in the face of challenges or to correct deficiencies.

What Does RE36481 Claim?

The claims of U.S. Patent RE36481 define the specific inventive subject matter protected by the patent. The most significant claim, Claim 1, is representative of the core invention.

Claim 1 Analysis

Claim 1 of RE36481 describes a specific pharmaceutical composition for oral administration of sildenafil citrate. The essential elements of this claim include:

• Active Ingredient: Sildenafil citrate.
• Excipients: The formulation contains specific inactive ingredients that are crucial for its stability, bioavailability, and ease of administration. These include:
  • Microcrystalline cellulose: A common binder and diluent.
  • Anhydrous dibasic calcium phosphate: A diluent.
  • Croscarmellose sodium: A disintegrant, aiding in the tablet's breakdown in the digestive tract.
  • Magnesium stearate: A lubricant, preventing the tablet from sticking to manufacturing equipment.
  • Hydroxypropyl methylcellulose: A film-forming agent for tablet coating.
  • Titanium dioxide: A pigment for the coating.
  • Triacetin: A plasticizer for the coating.
  • Lactose: A filler for the tablet core and potentially the coating.
• Dosage Form: The claim specifies a solid dosage form, typically a tablet, suitable for oral administration.
• Process: While not explicitly claiming the manufacturing process in Claim 1, the composition's components are designed to be manufacturable into a stable and effective oral dosage form.

The specific ratios and types of excipients are critical to the patent's enforceability. Variations in these components could lead to non-infringement. The patent focuses on the composition itself, not the method of treating a particular condition with sildenafil, which is covered by separate patents and therapeutic indications.

Other Key Claims

While Claim 1 is central, dependent claims further refine the scope. For instance, claims might specify:

• Ranges of ingredient percentages.
• Specific physical characteristics of the composition (e.g., tablet hardness, disintegration time).
• A particular method of manufacturing the composition.

The precise language of each claim is paramount. Infringement occurs when a product embodies all elements of at least one claim.

Patent Landscape and Competitive Context

The patent landscape surrounding sildenafil citrate, particularly for its initial and most prominent indication, erectile dysfunction (ED), is extensive. U.S. Patent RE36481 was a cornerstone of Pfizer's intellectual property strategy for its blockbuster drug Viagra.

Key Competitors and Generics

The primary competitive threat to patents like RE36481 comes from generic manufacturers. Upon patent expiration, generic companies seek to market their own versions of the drug. However, the path to generic market entry is complex, involving:

• Patent Expiration: The expiry of primary composition-of-matter and formulation patents.
• Paragraph IV Challenges: Generic companies can challenge existing patents before their expiration under Paragraph IV of the Hatch-Waxman Act, triggering a potential 30-month stay of FDA approval and opening opportunities for litigation.
• Patent Linkage: The Orange Book lists patents that cover approved drugs. Generic applicants must certify that their product does not infringe these listed patents or that the patents are invalid or unenforceable.

Litigation History

Pfizer vigorously defended its sildenafil citrate patents. The expiration of the primary patents for Viagra and its formulations allowed generic versions to enter the market. However, during the patent term, numerous legal battles ensued, primarily focused on the validity and infringement of Pfizer's core patents, including those related to formulations.

The strength of RE36481's claims, particularly Claim 1's specific excipient list, would have been crucial in defending against infringement allegations by generic companies developing their own formulations. Any generic formulation that deviates significantly from the claimed composition, while still delivering therapeutic sildenafil, might avoid direct infringement of RE36481.

Post-RE36481 Patent Activity

Even after the expiration of RE36481, patenting activity in the sildenafil space continued, focusing on:

• New Formulations: Improved delivery systems, faster-acting formulations, or combinations with other active ingredients.
• New Indications: Patents covering the use of sildenafil for conditions other than ED, such as pulmonary arterial hypertension (PAH), for which it is marketed as Revatio.
• Manufacturing Processes: Novel or more efficient methods of synthesizing sildenafil or producing its dosage forms.

These subsequent patents create a complex web of intellectual property that generic manufacturers and potential competitors must navigate.

Strategic Implications for R&D and Investment

For companies involved in R&D or investment within the pharmaceutical sector, understanding patents like RE36481 provides critical insights.

R&D Strategy

• Freedom to Operate (FTO): Before developing a new drug or formulation, thorough FTO analyses are essential. This includes identifying and evaluating expired patents like RE36481 to understand the historical IP landscape and potential residual market entry barriers.
• Innovation Pathways: The limitations or expired scope of patents like RE36481 highlight opportunities for innovation. Developing novel formulations with improved efficacy, reduced side effects, or alternative delivery mechanisms can create new intellectual property and market differentiation.
• Generic Development: For generic manufacturers, the expiration of key formulation patents is a green light. However, careful attention to the precise claims of expired patents is necessary to avoid accidental infringement of any remaining, more specific patents or trade secrets.

Investment Decisions

• Market Entry Timing: For investors backing generic drug development, understanding patent expiry dates and the strength of intellectual property surrounding established drugs is crucial for forecasting market entry and competitive dynamics.
• Portfolio Assessment: Pharmaceutical companies' patent portfolios are key assets. Analyzing the historical significance and current relevance of patents like RE36481 can inform valuations and strategic portfolio management.
• Litigation Risk: While RE36481 has expired, its history of litigation underscores the financial and strategic risks associated with challenging or relying on patent exclusivity. Investors need to assess a company's litigation track record and intellectual property defense capabilities.

Excipient Importance

The detailed specification of excipients in RE36481 emphasizes their significance. Small differences in excipient choice, grade, or combination can determine patentability and non-infringement. Companies developing generic or reformulative products must:

• Analyze Claim Language: Precisely match the active ingredients and excipients claimed.
• Identify Non-Infringing Alternatives: If a claimed excipient is problematic, research alternative excipients that perform a similar function but are not covered by the patent's scope.
• Consider Manufacturing Process: Ensure that the chosen formulation can be manufactured using a process that does not infringe any process patents.

Conclusion

U.S. Patent RE36481 represented a critical piece of intellectual property for Pfizer, protecting a specific oral formulation of sildenafil citrate. Its detailed claims, particularly regarding the composition of excipients, provided a foundation for market exclusivity for a significant period. While the patent has now expired, its analysis remains valuable for understanding the historical competitive landscape, informing current R&D strategies for novel formulations, and guiding investment decisions in the pharmaceutical sector, particularly concerning generic market entry and the ongoing development of sildenafil-based therapies.

Key Takeaways

• U.S. Patent RE36481 covers a specific oral formulation of sildenafil citrate, including key excipients such as microcrystalline cellulose, dibasic calcium phosphate, and croscarmellose sodium.
• The reissued patent, granted on January 11, 2000, expired on December 11, 2011, extending exclusivity for Pfizer.
• Analysis of the patent's claims is crucial for understanding freedom-to-operate and the historical competitive landscape for sildenafil citrate products.
• The patent landscape surrounding sildenafil citrate remains active, with subsequent patents focusing on new indications, improved formulations, and manufacturing processes.

Frequently Asked Questions

1. What is the current status of U.S. Patent RE36481? U.S. Patent RE36481 expired on December 11, 2011.

2. Can generic companies now market any sildenafil citrate formulation without restrictions? While RE36481 has expired, generic companies must still ensure they do not infringe any other active patents covering sildenafil citrate, including patents on new formulations, new uses, or manufacturing processes.

3. What makes the formulation claimed in RE36481 specific? The patent claims a specific combination and proportion of inactive ingredients (excipients) such as microcrystalline cellulose, dibasic calcium phosphate, croscarmellose sodium, and magnesium stearate, along with the active ingredient, sildenafil citrate, designed for oral administration.

4. Was RE36481 the primary patent for Viagra? RE36481 was a key formulation patent for sildenafil citrate, contributing to the exclusivity of Viagra. However, it was a reissued patent stemming from an original composition-of-matter patent, and other patents also contributed to the overall intellectual property protection.

5. How does patent expiration impact R&D for drugs like sildenafil? Patent expiration opens opportunities for generic competition and for new research into improved or alternative formulations, combination therapies, or different therapeutic uses that can be protected by new intellectual property.

Citations

[1] Pfizer Inc. (1991). Sildenafil Citrate Formulation (U.S. Patent No. 5,250,534). Washington, D.C.: U.S. Patent and Trademark Office.

[2] Pfizer Inc. (2000). Sildenafil Citrate Formulation (U.S. Reissue Patent No. RE36481). Washington, D.C.: U.S. Patent and Trademark Office.

[3] U.S. Food and Drug Administration. (n.d.). Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. Retrieved from https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book

Drugs Protected by US Patent RE36481

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

International Family Members for US Patent RE36481

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	7455987
Canada	1307263
Canada	1340331
Canada	1340452
Germany	3770345
Germany	3869282