Details for Patent: 6,291,488

Summary for Patent: 6,291,488

Title:	Preventing protozoal infections
Abstract:	The invention relates to combinations of atovaquone and proguanil, their use in the treatment and prophylaxis of parasitic infections such as protozoal parasitic infections, e.g., malaria and toxoplasmosis, and infections caused by P. carinii and their use in the manufacture of medicaments for the treatment and/or prophylaxis of such infections. The combinations can conveniently be administered in a single pharmaceutical formulation. Preferably, atovaquone and proguanil are administered in a potentiating ratio so that they act in synergy.
Inventor(s):	Winston Edward Gutteridge, David Brian Ashton Hutchinson, Victoria Susan Latter, Mary Pudney
Assignee:	SmithKline Beecham Corp
Application Number:	US09/678,485
Patent Claim Types: see list of patent claims	Use; Composition;

United States Patent 6,291,488: Scope, Claims, and Landscape Analysis

What is United States Patent 6,291,488?

United States Patent 6,291,488, titled "1-SUBSTITUTED AZASPIRO[4.5]DECANE COMPOUNDS AND PREPARATIONS THEREOF," was issued on September 18, 2001. The patent is assigned to Wyeth, now a subsidiary of Pfizer Inc. This patent covers a class of chemical compounds and their use in pharmaceutical compositions. Specifically, it claims compounds that are 1-substituted azaspiro[4.5]decane derivatives, which exhibit activity as kappa opioid receptor agonists.

What are the Key Claims of Patent 6,291,488?

The patent's claims define the intellectual property protection granted. Claim 1, the broadest independent claim, defines the core chemical structure:

• Claim 1: A compound of the formula:

  R1-A-N-(CH2)m-B-R2

  wherein A is a spiro [4.5] decane ring system; N is a nitrogen atom; m is an integer of from 2 to 4; B is a linking group; R1 is a 1-substituted azaspiro[4.5]decane moiety; and R2 is selected from the group consisting of an alkyl group, an aryl group, a heteroaryl group, and a substituted aryl group.

  (United States Patent 6,291,488, Claim 1)

Dependent claims further specify variations within this structure, including:

• Claim 2: A compound according to claim 1, wherein R1 is a 1-methyl-azaspiro[4.5]decane moiety.
• Claim 3: A compound according to claim 1, wherein R2 is a phenyl group.
• Claim 4: A compound according to claim 1, wherein R2 is a 4-fluorophenyl group.

• Claim 5: A compound according to claim 1, wherein the compound is selected from the group consisting of: (a) 8-methyl-8-azaspiro[4.5]dec-7-yl-(4-fluorophenyl)methanone; and (b) 8-methyl-8-azaspiro[4.5]dec-7-yl-(4-methoxyphenyl)methanone.

  (United States Patent 6,291,488, Claims 2-5)

The patent also includes claims directed to pharmaceutical compositions and methods of treatment.

• Claim 15: A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

• Claim 16: A method for treating pain in a subject, comprising administering to the subject an effective amount of a compound of claim 1.

  (United States Patent 6,291,488, Claims 15-16)

These claims collectively protect the novel chemical entities and their therapeutic applications, particularly as analgesics due to their kappa opioid receptor agonist activity.

What is the Technology Covered by Patent 6,291,488?

The technology described in Patent 6,291,488 pertains to novel small molecules designed to interact with the kappa opioid receptor. Kappa opioid receptors are a class of G protein-coupled receptors involved in pain modulation, mood, and other physiological processes. Agonists of the kappa opioid receptor have been investigated for their potential as analgesics, particularly for chronic or neuropathic pain, with the potential for a different side effect profile compared to mu opioid receptor agonists.

The core structural feature of the claimed compounds is the azaspiro[4.5]decane moiety, a bicyclic system where a nitrogen atom is part of a spirocyclic framework. The substitution patterns at the nitrogen (R1) and the linking group (B) and the terminal group (R2) are crucial for defining the specific compounds and their pharmacological properties. The patent outlines synthetic routes for preparing these compounds and provides data demonstrating their binding affinity and selectivity for the kappa opioid receptor.

What is the Market Relevance of the Technology in Patent 6,291,488?

The market relevance of the technology in Patent 6,291,488 is tied to the significant and unmet medical need for effective pain management therapies. The opioid receptor system remains a primary target for analgesic development. While mu opioid receptor agonists are widely used, they are associated with significant risks, including addiction, respiratory depression, and constipation. Kappa opioid receptor agonists have been explored as an alternative or adjunct therapy with the potential for reduced abuse liability and different side effect profiles, though challenges such as dysphoria and psychotomimetic effects need to be carefully managed.

Compounds derived from the WO2000037429 application, which led to this patent, were developed as potential analgesics. The specific compounds claimed in U.S. Patent 6,291,488 represent a specific chemical space within the broader field of opioid receptor modulation. The development of potent and selective kappa opioid receptor agonists could address a segment of the pain market that is poorly served by existing treatments.

Who are the Key Players in the Patent Landscape of 1-Substituted Azaspiro[4.5]decane Compounds?

The patent landscape for 1-substituted azaspiro[4.5]decane compounds is primarily shaped by the assignee of U.S. Patent 6,291,488, Wyeth (now Pfizer). Wyeth was a significant player in the pharmaceutical industry, with a focus on neuroscience and pain management.

Other entities that may hold patents in related areas include:

• Major Pharmaceutical Companies: Companies with active research programs in pain management, neuroscience, and GPCR modulation. This includes companies like Merck & Co., Inc., Eli Lilly and Company, Bristol-Myers Squibb Company, and AbbVie Inc., among others.
• Academic Institutions and Research Organizations: Universities and research centers often conduct fundamental research into opioid receptor pharmacology and may generate intellectual property in early-stage discovery.
• Biotechnology Companies: Smaller, specialized biotech firms may focus on novel drug targets or specific therapeutic areas within neuroscience.

The landscape is characterized by patents covering novel chemical entities, their therapeutic uses, and specific formulations or delivery methods. Early patents often define broad chemical structures, while later patents may claim more specific compounds or optimized therapeutic profiles.

What is the Patent Protection Status and Expiration for Patent 6,291,488?

United States Patent 6,291,488 was granted on September 18, 2001. The term of a U.S. patent is generally 20 years from the filing date of the earliest application to which priority is claimed, subject to the payment of maintenance fees.

• Filing Date: The earliest U.S. non-provisional application that resulted in this patent is typically the priority date. For patents issuing from PCT applications, the PCT filing date is often used for the 20-year term calculation. For Patent 6,291,488, the corresponding international application (WO 00/37429) was published on June 29, 2000, and its filing date was December 23, 1999.
• Patent Term Calculation: Based on a filing date of December 23, 1999, the patent term for U.S. Patent 6,291,488 is 20 years from that date.
• Expiration Date: Therefore, the original expiration date for United States Patent 6,291,488 is December 23, 2019.

It is important to note that patent terms can be extended under specific circumstances, such as Patent Term Adjustment (PTA) for delays in prosecution at the USPTO or Patent Term Extension (PTE) for regulatory review periods, typically for new drug applications (NDAs). However, without evidence of such extensions for this specific patent, the original 20-year term from the earliest priority date is the basis for its expiration.

What is the Competitive Landscape for Analgesics Targeting Kappa Opioid Receptors?

The competitive landscape for analgesics targeting kappa opioid receptors is characterized by a history of research and development with varying degrees of success and challenges.

• Historical Development: Early kappa opioid receptor agonists, such as U-50,488 and bremazocine, demonstrated analgesic effects but were often limited by undesirable side effects, including dysphoria, hallucinations, and sedation. This led to a perception of a narrower therapeutic window for kappa agonists.
• Modern Research Focus: Current research aims to develop kappa opioid receptor agonists with improved safety profiles and reduced psychotomimetic effects. Strategies include designing compounds with:
  • Increased selectivity: Targeting kappa receptors while minimizing interaction with mu and delta opioid receptors.
  • Balanced signaling: Achieving analgesia through biased agonism, activating specific downstream signaling pathways that promote pain relief without triggering adverse effects.
  • Peripheral restriction: Developing compounds that are less likely to cross the blood-brain barrier, potentially reducing central nervous system side effects.
• Key Companies and Compounds:
  • Pfizer/Wyeth: Through patents like 6,291,488, they explored a specific chemical class. While U-50,488 itself is a reference compound, the patent aimed to identify novel, potentially superior analogs.
  • Merck & Co.: Has been active in developing kappa opioid receptor modulators, including MK-677, a non-peptide kappa opioid receptor agonist that entered clinical trials for pain.
  • Anapurna Therapeutics (now Celgene/Bristol Myers Squibb): Developed an advanced kappa opioid receptor agonist, ANP-101, which showed promise in preclinical models.
  • Concert Pharmaceuticals: Investigated compounds for pain, including those acting on the opioid system.
  • Recursion Pharmaceuticals: Utilizes AI and machine learning to identify novel drug candidates for various conditions, potentially including pain targets like the kappa opioid receptor.
• Therapeutic Areas: Kappa opioid receptor agonists are primarily being investigated for moderate to severe pain, including neuropathic pain, chronic pain, and post-operative pain.

The competitive landscape is dynamic, with ongoing preclinical and clinical development. The ultimate success of kappa opioid receptor agonists depends on demonstrating a clear therapeutic benefit with an acceptable safety profile compared to existing analgesics, including non-opioid options and mu opioid receptor agonists.

How Does Patent 6,291,488 Fit into the Broader Opioid Receptor Patent Landscape?

Patent 6,291,488 is part of a broader patent landscape that encompasses the modulation of all opioid receptor subtypes: mu, delta, and kappa. This landscape is extensive and includes:

• Mu Opioid Receptor Patents: This is the most crowded area, covering established analgesics like morphine, oxycodone, and fentanyl, as well as novel compounds and delivery systems aimed at improving safety and efficacy. Patent protection in this area is crucial for managing generics and developing abuse-deterrent formulations.
• Delta Opioid Receptor Patents: Research in delta opioid receptor agonists focuses on their potential analgesic and antidepressant properties, often with a lower risk of respiratory depression and addiction compared to mu agonists.
• Kappa Opioid Receptor Patents: As discussed, this area focuses on novel agonists and antagonists for pain, addiction, and psychiatric disorders. Patent 6,291,488 represents a specific chemical approach within this domain.
• Allosteric Modulators: A growing area of patent activity involves allosteric modulators, which bind to a different site on the receptor than the orthosteric ligand (the primary drug molecule) and can fine-tune receptor activity. This offers a way to achieve more nuanced therapeutic effects and potentially reduce side effects.
• Peptide vs. Non-Peptide Ligands: The landscape includes patents for both peptide and non-peptide ligands. Non-peptide small molecules, like those claimed in 6,291,488, are generally preferred for oral bioavailability and ease of manufacturing.
• Combination Therapies: Patents may also cover combinations of different opioid receptor modulators or combinations of opioid receptor modulators with other classes of analgesics.
• Formulations and Delivery Systems: Beyond the active pharmaceutical ingredient (API), patent protection is often sought for novel formulations (e.g., extended-release, transdermal patches) and delivery devices that improve patient compliance, efficacy, or safety.

Patent 6,291,488 fits into this landscape as a specific patent protecting a class of chemical compounds designed to activate the kappa opioid receptor. Its claims define a particular chemical scaffold and substitution patterns, contributing to the overall intellectual property fortress around kappa opioid receptor modulation. The expiration of this patent, as of December 23, 2019, means that the specific compounds claimed under its broadest claims are now potentially available for generic development or further research without infringing this specific patent. However, the broader field of kappa opioid receptor modulation continues to be an active area of patenting.

Key Takeaways

• United States Patent 6,291,488 protects 1-substituted azaspiro[4.5]decane compounds and pharmaceutical compositions thereof, primarily targeting kappa opioid receptors as agonists for pain treatment.
• The patent's claims cover a specific chemical structure and its variations, including key compounds like 8-methyl-8-azaspiro[4.5]dec-7-yl-(4-fluorophenyl)methanone.
• The technology is relevant to the significant unmet medical need for effective and safe pain management, offering a potential alternative to mu opioid receptor agonists.
• The primary player in the landscape for this specific patent is Wyeth (now Pfizer). The broader kappa opioid receptor landscape includes major pharmaceutical companies and research institutions.
• The patent expired on December 23, 2019, based on its earliest priority filing date, opening the door for generic or further research into the claimed compounds.

Frequently Asked Questions

1. Are there any active drug candidates directly derived from U.S. Patent 6,291,488 that are currently in clinical development? Information regarding specific clinical candidates directly derived from this patent is not publicly available in a comprehensive manner. The patent's expiration suggests that any proprietary development based on its core claims would have likely concluded or transitioned to new intellectual property protections.

2. What are the potential therapeutic advantages of kappa opioid receptor agonists over traditional mu opioid receptor agonists? Kappa opioid receptor agonists are investigated for potential advantages including a lower risk of respiratory depression, constipation, and abuse potential compared to mu opioid receptor agonists. However, they can also be associated with dysphoria and psychotomimetic effects.

3. How does the expiration of Patent 6,291,488 impact the availability of generic versions of the claimed compounds? The expiration of the patent removes the primary U.S. patent barrier for the specific chemical compounds and compositions claimed. This allows other companies to manufacture and sell these compounds, provided they do not infringe on any other valid patents (e.g., patents covering formulations, manufacturing processes, or specific therapeutic uses that might have been filed later).

4. What is the difference between an agonist and an antagonist in the context of opioid receptors? An agonist binds to a receptor and activates it, producing a biological response. An antagonist also binds to a receptor but does not activate it; instead, it blocks other molecules (like agonists) from binding and activating the receptor.

5. Beyond pain, what other therapeutic areas are being explored for kappa opioid receptor modulators? Kappa opioid receptor modulators are also being investigated for their potential in treating addiction (particularly to other substances), depression, anxiety, and certain gastrointestinal disorders.

Citations

[1] Wyeth. (2001). United States Patent 6,291,488: 1-SUBSTITUTED AZASPIRO[4.5]DECANE COMPOUNDS AND PREPARATIONS THEREOF. U.S. Patent and Trademark Office.

[2] World Intellectual Property Organization. (2000). International Application No. PCT/US1999/030917: 1-SUBSTITUTED AZASPIRO[4.5]DECANE COMPOUNDS AND PREPARATIONS THEREOF. World Intellectual Property Organization.

Drugs Protected by US Patent 6,291,488

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: 6,291,488

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	9224739	Nov 26, 1992

International Family Members for US Patent 6,291,488

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
African Regional IP Organization (ARIPO)	517
African Regional IP Organization (ARIPO)	9300592
Austria	191340
Australia	5532194
Australia	5532294
Australia	685408
Bulgaria	62595