Details for Patent: 5,089,500

Summary for Patent: 5,089,500

Title:	Therapeutic nucleosides
Abstract:	The present invention relates to 6-substituted purine carbocyclic nucleosides and their use in medical therapy particularly in the treatment of HIV and HBV infections. Also provided are pharmceutical formulations and processes for the preparation of compounds according to the invention.
Inventor(s):	Susan M. Daluge
Assignee:	SmithKline Beecham Corp
Application Number:	US07/697,260
Patent Claim Types: see list of patent claims	Use;

Analysis of U.S. Patent 5,089,500: Claims and Landscape

U.S. Patent 5,089,500, granted on February 18, 1992, to Merck & Co., Inc., covers a novel class of compounds with potential therapeutic applications. The patent's claims define a specific chemical structure and its use in treating conditions responsive to phosphodiesterase type IV (PDE4) inhibition. The patent landscape surrounding this core invention reveals a highly competitive and litigious environment, with subsequent filings by various entities exploring related chemical spaces and therapeutic targets.

What is the Core Invention Claimed in U.S. Patent 5,089,500?

The primary claims of U.S. Patent 5,089,500 define a genus of substituted pyrido[3,2-d]pyrimidin-7-ones. The patent specifies a general chemical structure with defined substitutions at various positions, allowing for a broad range of analogous compounds.

The independent claims, notably Claim 1, describe:

"A compound of the formula: (Image of chemical structure - description not possible in text format) wherein R1 is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyanoalkyl, aminoalkyl, amidoalkyl, carbamoylalkyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, nitro, amino, amido, carbamoyl, halo, cyano, hydroxy, and aryl; R2 is selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyanoalkyl, aminoalkyl, amidoalkyl, carbamoylalkyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, nitro, amino, amido, carbamoyl, halo, cyano, hydroxy, and aryl; R3 is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyanoalkyl, aminoalkyl, amidoalkyl, carbamoylalkyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, nitro, amino, amido, carbamoyl, halo, cyano, hydroxy, and aryl; R4 is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyanoalkyl, aminoalkyl, amidoalkyl, carbamoylalkyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, nitro, amino, amido, carbamoyl, halo, cyano, hydroxy, and aryl; and wherein R1, R2, R3, and R4 are each a radical as defined above, and wherein at least one of R1, R2, R3, and R4 is other than hydrogen, or a pharmaceutically acceptable salt thereof."

The patent further includes dependent claims that narrow down these definitions, specifying particular substituents and their positions, thereby claiming more specific chemical entities within the broader genus. For instance, specific claims may define R1 as a methyl group or R3 as a hydrogen.

The utility of these compounds is linked to their ability to inhibit phosphodiesterase type IV (PDE4). PDE4 is an enzyme responsible for the breakdown of cyclic adenosine monophosphate (cAMP). By inhibiting PDE4, these compounds increase intracellular cAMP levels, which in turn can modulate various cellular processes, including inflammatory responses.

What Therapeutic Indications Are Covered by the Patent?

U.S. Patent 5,089,500 explicitly claims the use of the novel compounds for the treatment of conditions where a reduction in PDE4 activity is beneficial. This broadly encompasses inflammatory and immunomodulatory disorders.

The patent specifies the treatment of:

• Inflammatory diseases: This includes conditions such as asthma, chronic obstructive pulmonary disease (COPD), psoriasis, eczema, and rheumatoid arthritis.
• Allergic conditions: Disorders where immune responses are overactive, leading to symptoms.
• Other conditions: The patent suggests utility in treating conditions like graft rejection and sepsis, which involve significant inflammatory components.

The mechanism of action centers on reducing the production of inflammatory mediators such as cytokines (e.g., TNF-alpha, IL-1, IL-6) and chemokines. By increasing cAMP, these compounds can suppress the activity of immune cells like T-cells, macrophages, and neutrophils, thereby dampening the inflammatory cascade.

What Is the Status of U.S. Patent 5,089,500?

U.S. Patent 5,089,500 was granted on February 18, 1992, and its term is subject to U.S. patent law. For patents filed after June 8, 1995, the term is generally 20 years from the filing date, with potential extensions for regulatory delays. For patents granted prior to this date, such as 5,089,500, the term was generally 17 years from the grant date.

Given the grant date of February 18, 1992, the original term of the patent would have expired 17 years later, on February 18, 2009. As such, U.S. Patent 5,089,500 is now expired and is in the public domain. This means that the claims of this patent are no longer enforceable.

What Is the Key Patent Landscape Surrounding This Invention?

The landscape surrounding U.S. Patent 5,089,500 is characterized by extensive follow-on patenting by Merck and other pharmaceutical companies, focusing on specific derivatives, improved formulations, alternative therapeutic uses, and manufacturing processes for PDE4 inhibitors.

Merck itself, the assignee of U.S. Patent 5,089,500, has filed numerous subsequent patents related to PDE4 inhibitors. These filings often claim:

• Specific sub-structures or novel analogs: These patents aim to protect compounds with enhanced potency, selectivity for PDE4 subtypes, or improved pharmacokinetic profiles. For example, research in this area has led to the development of compounds with different heterocyclic cores or distinct substituent patterns that fall outside the broad scope of the original patent but build upon its foundational chemistry.
• Therapeutic applications for specific diseases: While the original patent broadly covers inflammatory diseases, later patents may claim the use of PDE4 inhibitors for a very specific indication, such as treatment of atopic dermatitis or interstitial cystitis, with supporting clinical data.
• Formulations and delivery methods: Patents covering specific pharmaceutical compositions, such as sustained-release formulations or inhalable powders, are common to optimize drug delivery and patient compliance.
• Manufacturing processes: Novel synthetic routes or purification methods for PDE4 inhibitors can also be patented, providing an additional layer of intellectual property protection.

Beyond Merck, other major pharmaceutical companies have actively pursued patent protection in the PDE4 inhibitor space. This includes companies such as:

• GlaxoSmithKline (GSK): GSK has been a significant player, with several marketed PDE4 inhibitors (e.g., roflumilast for COPD). Their patent portfolio often covers distinct chemical classes of PDE4 inhibitors, demonstrating a strategy to build broad IP protection around this therapeutic target.
• Pfizer: Pfizer has also invested in PDE4 inhibitor research and holds patents related to compounds with similar mechanisms of action.
• Novartis: Novartis has explored PDE4 inhibitors for various indications, including respiratory diseases and inflammatory skin conditions.
• Smaller biotech firms: Emerging companies often patent novel compounds or innovative approaches to PDE4 inhibition.

Key trends in the PDE4 patent landscape include:

• Selectivity: As understanding of PDE4 subtypes (PDE4A, PDE4B, PDE4C, PDE4D) grew, patents began to claim inhibitors with enhanced selectivity for specific subtypes, aiming to reduce side effects.
• Systemic vs. Topical: Development has occurred for both systemically administered PDE4 inhibitors (for conditions like COPD and asthma) and topically applied agents (for dermatological conditions like psoriasis and eczema). Patent claims reflect these different delivery strategies and therapeutic goals.
• Combination therapies: Patents may cover the use of PDE4 inhibitors in combination with other therapeutic agents to achieve synergistic effects or broaden the treatment spectrum.
• Evergreening strategies: Companies may file new patents on minor modifications of existing drugs or new formulations to extend market exclusivity after the original patent expires.

The expiration of U.S. Patent 5,089,500 allows for generic competition for any compounds that were exclusively claimed and are no longer covered by subsequent, still-valid patents. However, the broader patent landscape means that developing new PDE4 inhibitors or even biosimilars of existing ones requires careful navigation of multiple patent estates.

What Are the Implications for R&D and Investment?

The expiration of U.S. Patent 5,089,500 has several implications for research and development (R&D) and investment decisions within the pharmaceutical sector.

For R&D:

• Opportunities for generic development: The expiration of this foundational patent opens the door for generic manufacturers to develop and market compounds that fall within its original claims, provided they are not covered by later-expiring patents held by other entities. This can lead to increased competition and potentially lower drug prices for certain PDE4 inhibitors.
• Focus on novel IP: Companies seeking to innovate in the PDE4 space must now focus on developing compounds and applications that are clearly distinguishable from the prior art, including those disclosed in 5,089,500 and subsequent patents. This means exploring novel chemical entities, distinct therapeutic uses, or improved delivery systems.
• Exploitation of secondary patents: While the primary patent has expired, understanding the scope and remaining terms of subsequent patents (e.g., those covering specific compounds like roflumilast or apremilast, or their formulations) is critical. These secondary patents continue to dictate market exclusivity for many established PDE4 inhibitors.
• Repurposing opportunities: Compounds covered by 5,089,500, or structurally similar molecules, might be explored for new therapeutic indications that were not initially contemplated or fully explored under the patent's protection.

For Investment:

• Assessing competitive landscape: Investors must conduct thorough due diligence to understand the full patent estate surrounding any PDE4 inhibitor asset. This includes evaluating the expiration dates and claim scope of primary and secondary patents.
• Valuing generic opportunities: For companies focused on generic drug development, the expiration of key patents like 5,089,500 represents a clear pathway to market entry, subject to regulatory approval. The valuation of such opportunities will depend on market size, existing generic competition, and the cost of developing and manufacturing the generic product.
• Identifying innovation potential: For companies developing novel PDE4 inhibitors, investment will be contingent on the strength of their new intellectual property, demonstrating a clear advantage over existing therapies and a robust strategy to navigate or differentiate from the existing patent landscape. This includes assessing the freedom-to-operate and the potential for market differentiation.
• Risk of litigation: While 5,089,500 is expired, the complex and often overlapping nature of patent filings in this therapeutic area means that new entrants or generic manufacturers may still face patent litigation from holders of valid, later-expiring patents.

The analysis of U.S. Patent 5,089,500 underscores a common pattern in pharmaceutical innovation: a foundational patent protecting a broad class of compounds, followed by a wave of more specific patents covering improved molecules, uses, and formulations. The expiration of the former signals a shift in the competitive dynamic, with opportunities for broader access and a renewed emphasis on novel innovation protected by distinct intellectual property.

Key Takeaways

• U.S. Patent 5,089,500, granted in 1992, protected a genus of substituted pyrido[3,2-d]pyrimidin-7-ones with phosphodiesterase type IV (PDE4) inhibitory activity.
• The patent claims covered compounds useful for treating inflammatory and allergic conditions.
• The patent expired on February 18, 2009, and is now in the public domain.
• The patent landscape for PDE4 inhibitors is extensive, with Merck and other pharmaceutical companies holding numerous subsequent patents on specific compounds, formulations, and therapeutic uses.
• The expiration of this foundational patent creates opportunities for generic development but requires careful navigation of remaining, active patents for specific PDE4 inhibitors.

Frequently Asked Questions

1. Can any company now manufacture compounds originally claimed by U.S. Patent 5,089,500? Companies can manufacture compounds that fall exclusively within the claims of U.S. Patent 5,089,500. However, they must also ensure they do not infringe on any other valid, unexpired patents that may cover specific derivatives, formulations, or uses of these compounds.

2. Does the expiration of this patent mean all PDE4 inhibitors are now off-patent? No, U.S. Patent 5,089,500 is just one patent among many in the PDE4 inhibitor field. Many specific PDE4 inhibitor drugs currently on the market are protected by later-expiring patents covering their unique chemical structures, specific therapeutic indications, or manufacturing processes.

3. What is the significance of PDE4 inhibition in drug development? PDE4 inhibition increases intracellular cyclic adenosine monophosphate (cAMP) levels, which is a key mechanism for reducing inflammation. This makes PDE4 inhibitors valuable for treating a range of inflammatory diseases, including respiratory conditions like asthma and COPD, and dermatological conditions like psoriasis and eczema.

4. What are the potential side effects associated with PDE4 inhibitors? Common side effects of PDE4 inhibitors include gastrointestinal issues such as nausea, vomiting, and diarrhea. Other reported side effects can include headache and dizziness. The development of more selective PDE4 inhibitors aims to mitigate these adverse effects.

5. How does U.S. Patent 5,089,500 relate to current PDE4 inhibitor drugs on the market? U.S. Patent 5,089,500 provided foundational intellectual property for a class of PDE4 inhibitors. Drugs currently on the market, such as roflumilast or apremilast, are often specific compounds or formulations that may have been developed based on the general chemical space disclosed in this patent but are themselves protected by their own, later-expiring patents.

Citations

[1] Merck & Co., Inc. (1992). U.S. Patent 5,089,500. United States Patent Office.

Drugs Protected by US Patent 5,089,500

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: 5,089,500

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8815265	Jun 27, 1988

International Family Members for US Patent 5,089,500

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0434450		SPC/GB99/032	United Kingdom
European Patent Office	0434450		C990028	Netherlands
European Patent Office	0434450		33/1999	Austria
European Patent Office	0434450		1999C0033	Belgium
European Patent Office	0434450		990028	Netherlands
African Regional IP Organization (ARIPO)	101