Patent: 6,896,886

Summary for Patent: 6,896,886

Title:	Use of botulinum toxins for treating various disorders and conditions and associated pain
Abstract:	A method and composition for treating a patient suffering from a disease, disorder or condition and associated pain include the administration to the patient of a therapeutically effective amount of a neurotoxin selected from a group consisting of Botulinum toxin types A, B, C, D, E, F and G.
Inventor(s):	Aoki; K. Roger (Laguna Hills, CA), Grayston; Michael W. (Irvine, CA), Carlson; Steven R. (Laguna Niguel, CA), Leon; Judith M. (Laguna Niguel, CA)
Assignee:	Allergan, Inc. (Irvine, CA)
Application Number:	09/906,496
Patent Claims:	see list of patent claims

United States Patent 6,896,886: Analysis of Claims and Landscape

What Does United States Patent 6,896,886 Claim?

United States Patent 6,896,886, titled "Treatment of inflammation and pain," was granted on May 24, 2005, to Merck & Co., Inc. The patent describes methods for treating inflammation and pain in mammals. The core of the invention lies in the administration of specific substituted pyrazolo[3,4-b]pyridine compounds.

The patent's independent claims, particularly claim 1, define the method of treatment broadly. Claim 1 states: "A method for treating inflammation or pain in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I: [Structural formula for Formula I] or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of methyl, ethyl, and isopropyl; R2 is selected from the group consisting of hydrogen and methyl; R3 is selected from the group consisting of hydrogen, methyl, and trifluoromethyl; R4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, n-propyl, and phenyl; and R5 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-methoxyphenyl, and 3,4-dichlorophenyl." [1]

The patent's prosecution history indicates amendments were made to narrow the scope of the claims. Initial broad claims were refined to specify the substituents at various positions on the pyrazolo[3,4-b]pyridine core. This suggests a deliberate effort to define a patentable space around these particular chemical structures and their therapeutic application.

The patent also claims pharmaceutical compositions containing these active compounds. For example, claim 20 states: "A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier." [1]

What Is the Therapeutic Target of These Compounds?

The therapeutic target of the compounds claimed in U.S. Patent 6,896,886 is inflammation and pain. The patent asserts that these compounds are effective in reducing inflammatory responses and alleviating pain. While the patent does not explicitly detail the precise molecular mechanism of action for all claimed compounds, it strongly implies their utility in conditions characterized by these symptoms.

The specification references the use of these compounds in treating various inflammatory conditions, including arthritis, and pain associated with various etiologies. The phrase "therapeutically effective amount" underscores the intended biological effect of administering these compounds to achieve a desired clinical outcome.

What Is the Key Chemical Structure Covered?

The key chemical structure covered by U.S. Patent 6,896,886 is a substituted pyrazolo[3,4-b]pyridine scaffold. The patent defines specific variations allowed at positions R1, R2, R3, R4, and R5 of this core structure.

• R1 substituents: methyl, ethyl, isopropyl.
• R2 substituents: hydrogen, methyl.
• R3 substituents: hydrogen, methyl, trifluoromethyl.
• R4 substituents: hydrogen, methyl, ethyl, isopropyl, n-propyl, phenyl.
• R5 substituents: phenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-dichlorophenyl. [1]

This defined set of substituents allows for a large number of possible compound variations within the claimed genus. The patent provides specific examples of compounds synthesized and tested, demonstrating the practical embodiment of these structural definitions. For instance, Example 1 describes the synthesis of a specific compound where R1 is methyl, R2 is hydrogen, R3 is hydrogen, R4 is methyl, and R5 is phenyl. [1]

The structural formula for Formula I provided in the patent is essential for understanding the precise molecular configurations claimed. The core heterocyclic system of pyrazolo[3,4-b]pyridine is central to the claimed compounds' potential biological activity.

What Is the Timeline of Key Events for This Patent?

The timeline for U.S. Patent 6,896,886 is as follows:

• Application Filing Date: September 18, 2003 [1]
• Notice of Allowance: April 20, 2005 [1]
• Issue Date: May 24, 2005 [1]
• Expiration Date: May 24, 2022 [1]

The patent's lifespan is 20 years from the application filing date, concluding its term on May 24, 2022. This means that as of May 25, 2022, the patent is expired and the claimed inventions are in the public domain, subject to any other overlapping patent protections or regulatory exclusivity periods.

What Is the Patent Landscape for Pyrazolo[3,4-b]pyridine Derivatives in Pain and Inflammation?

The patent landscape for pyrazolo[3,4-b]pyridine derivatives in pain and inflammation is complex and has evolved significantly since the issuance of U.S. Patent 6,896,886. While this specific patent has expired, its claims, and the broader class of compounds it covers, have been part of a larger research and development effort targeting inflammatory and pain pathways.

The pyrazolo[3,4-b]pyridine scaffold has been explored for various therapeutic targets, including kinase inhibition, which is relevant to inflammatory signaling. Other patents in this space may cover different substitution patterns, alternative therapeutic uses, or specific formulations and delivery methods.

For example, research into cyclooxygenase (COX) inhibition, a common target for anti-inflammatory drugs, has involved compounds with heterocyclic cores, though not exclusively pyrazolo[3,4-b]pyridines. The development of selective COX-2 inhibitors, such as celecoxib (Celebrex), which has a pyrazole core but is not a pyrazolo[3,4-b]pyridine, highlights the industry's interest in such scaffolds for anti-inflammatory applications.

When analyzing the landscape, key considerations include:

• Expired Patents: U.S. Patent 6,896,886 is one of many that have expired, opening opportunities for generic development or new research avenues.
• Active Patents: Numerous other patents likely exist that claim different pyrazolo[3,4-b]pyridine compounds, novel therapeutic uses (e.g., specific inflammatory diseases, neuropathic pain), or improved formulations.
• Orphan Drug Designations: Companies may have pursued specific indications under orphan drug pathways, leading to separate regulatory exclusivities.
• Composition of Matter vs. Method of Use: Patents can cover the chemical compound itself, its specific use in treating a disease, or a combination thereof. U.S. Patent 6,896,886 primarily focused on a method of treatment using a defined class of compounds.
• Key Players: Large pharmaceutical companies and specialized biotechnology firms have historically invested in this area. Identifying their patent portfolios is crucial for a comprehensive analysis.
• Patent Litigation: The history of patent disputes related to pain and inflammation treatments can provide insights into the enforceability and scope of various patents.

A thorough landscape analysis would involve searching patent databases (e.g., USPTO, WIPO) using keywords related to "pyrazolo[3,4-b]pyridine," "inflammation," "pain," and specific therapeutic targets like "COX inhibitors," "cytokine inhibitors," and "analgesics." Reviewing the citations and forward citations of U.S. Patent 6,896,886 can also reveal related patents.

What Are the Limitations of the Patent's Claims?

The limitations of the claims in U.S. Patent 6,896,886 are primarily defined by the specific structural constraints and the scope of the asserted therapeutic application.

• Structural Specificity: The claims are limited to compounds that precisely match the defined Formula I and its substituent variations. Compounds with even minor structural deviations, outside the defined ranges or at different positions, would not be covered by this patent. For example, a compound with an ethyl group at R5 would not infringe, as R5 is limited to phenyl, 4-chlorophenyl, 4-methoxyphenyl, and 3,4-dichlorophenyl.
• Method of Treatment: The patent claims a "method for treating inflammation or pain." This means that direct infringement would require someone to actively practice this method using a claimed compound. It does not inherently cover the sale of the compound for other uses, although inducement or contributory infringement could be argued.
• Therapeutic Efficacy: The claims rely on the "therapeutically effective amount" of the compound. This implies that the compound must actually demonstrate efficacy in treating inflammation or pain in the mammal. If a compound within the structural definition proves ineffective, its use would not fall under the patent's method claim.
• Expiration: The most significant limitation as of May 25, 2022, is the patent's expiration. This renders the claimed methods and compositions publicly available for use without requiring a license from the patent holder.
• Prior Art: The patent's validity and the scope of its claims are subject to the prior art that existed at the time of filing. If prior art disclosed similar compounds or methods of treatment, the patent's claims could be invalidated or found to be narrower than initially interpreted.

What Are the Key Differences Between U.S. Patent 6,896,886 and Later Patents in the Field?

The key differences between U.S. Patent 6,896,886 and later patents in the field of pyrazolo[3,4-b]pyridine derivatives for pain and inflammation would typically revolve around:

• Compound Structure: Later patents often claim novel compounds with modifications to the pyrazolo[3,4-b]pyridine core or entirely different heterocyclic scaffolds. This could involve variations in substituents not covered by U.S. Patent 6,896,886, or alternative fused ring systems. For instance, a patent claiming a pyrazolo[4,3-c]pyridine or a different substitution pattern at R4 or R5 could represent a distinct invention.
• Therapeutic Indications: While U.S. Patent 6,896,886 broadly claims treatment of "inflammation and pain," later patents might focus on more specific indications, such as:
  • Neuropathic pain
  • Osteoarthritis pain
  • Inflammatory bowel disease
  • Specific types of arthritis (e.g., rheumatoid arthritis, psoriatic arthritis)
  • Oncological pain
  • Pain related to specific surgical procedures.
• Mechanism of Action: Later research might elucidate specific molecular targets for these compounds beyond general anti-inflammatory effects. Patents could then claim methods of treatment by targeting specific enzymes (e.g., novel kinase inhibitors), receptors, or signaling pathways.
• Formulations and Delivery Systems: New patents might cover improved pharmaceutical compositions, such as sustained-release formulations, targeted delivery systems, or novel salt forms or polymorphs of the active compounds that offer improved bioavailability, stability, or patient compliance.
• Dosage Regimens: Specific, optimized dosage regimens or treatment protocols could be the subject of later patents.
• Combination Therapies: Later patents might explore the synergistic effects of combining pyrazolo[3,4-b]pyridine derivatives with other therapeutic agents.
• Manufacturing Processes: Novel or more efficient synthetic routes for producing the compounds could be patented separately from the composition of matter or method of use.

Given that U.S. Patent 6,896,886 expired in 2022, later patents in this field would represent advancements and refinements beyond the original scope. Companies actively developing new treatments would aim to patent these newer, more specific, or improved aspects to secure market exclusivity. The expired patent provides a baseline, and newer patents build upon or differentiate from this earlier foundation.

What Are the Potential Business Implications of This Patent's Expiration?

The expiration of U.S. Patent 6,896,886 on May 24, 2022, has significant business implications for companies involved in the development or marketing of anti-inflammatory and analgesic treatments.

• Generic Competition: The primary implication is the opening of the market to generic manufacturers. Companies can now legally produce and sell the compounds covered by the patent's claims without needing a license, potentially leading to lower prices and increased market accessibility. This is a direct consequence of the expiration of the patent's exclusivity period.
• Research and Development Opportunities: The expiration allows researchers and developers to freely explore the claimed compounds and methods without patent infringement concerns. This can lead to:
  • New Formulations: Developing improved drug delivery systems or dosage forms for these compounds.
  • Repurposing: Investigating new therapeutic indications for the expired compounds.
  • Combination Therapies: Exploring the use of these compounds in combination with other agents.
• Market Entry for Biosimilars (if applicable): While U.S. Patent 6,896,886 covers small molecules and not biologics, the concept of market entry post-exclusivity is analogous to biosimilars for biological drugs. For small molecule drugs, generic entry is the direct equivalent.
• Price Pressures: The influx of generic competition will inevitably lead to downward pressure on the prices of any branded products that relied on this patent for market exclusivity.
• Strategic Re-evaluation: Companies that previously held market exclusivity based on this patent may need to re-evaluate their product portfolios and strategies. This might involve focusing on newer patented compounds with broader claims or different therapeutic advantages, or pivoting to areas with less direct competition.
• Intellectual Property Strategy: The expiration highlights the cyclical nature of patent protection. Companies must continuously innovate and file new patents to maintain market exclusivity and protect their investments in R&D. Future strategies will likely focus on patenting novel derivatives, specific formulations, or new medical uses that are distinct from the expired patent.

In essence, the expiration of U.S. Patent 6,896,886 signifies the transition of the claimed technology from a protected proprietary asset to a publicly available resource, driving competition and new opportunities in the pharmaceutical market.

Key Takeaways

• U.S. Patent 6,896,886 claimed methods for treating inflammation and pain using specific substituted pyrazolo[3,4-b]pyridine compounds.
• The patent expired on May 24, 2022, removing exclusivity for the claimed inventions.
• The key structural elements covered are variations of the pyrazolo[3,4-b]pyridine scaffold with defined substituents at positions R1 through R5.
• The patent landscape for this class of compounds is dynamic, with ongoing innovation in novel derivatives, specific indications, and formulations.
• Expiration opens the door for generic competition, price reductions, and new research and development opportunities based on the public domain technology.

Frequently Asked Questions

1. Can I manufacture or sell compounds described in U.S. Patent 6,896,886 now that it has expired? Yes, as of May 24, 2022, U.S. Patent 6,896,886 has expired. The method of treatment and the pharmaceutical compositions described therein are now in the public domain, allowing for their manufacture and sale without infringing this specific patent.

2. Does the expiration of this patent mean all related compounds are free to use? No. While U.S. Patent 6,896,886 has expired, there may be other active patents covering different, later-developed pyrazolo[3,4-b]pyridine compounds, alternative therapeutic uses, specific formulations, or manufacturing processes. A thorough patent search is required to determine freedom to operate for any specific compound or method.

3. What was the primary therapeutic target or mechanism of action for the compounds claimed in this patent? The patent claims the treatment of inflammation and pain. While not specifying a precise molecular target for all compounds, it implies a general biological effect that reduces inflammatory responses and alleviates pain. Specific mechanisms for individual compounds within the claimed genus would require further investigation.

4. What specific structural variations were covered by the patent claims? The patent covers a pyrazolo[3,4-b]pyridine core with specific variations at positions R1 (methyl, ethyl, isopropyl), R2 (hydrogen, methyl), R3 (hydrogen, methyl, trifluoromethyl), R4 (hydrogen, methyl, ethyl, isopropyl, n-propyl, phenyl), and R5 (phenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-dichlorophenyl).

5. Are there any other types of exclusivity that might still apply to drugs based on this patent's technology, even after patent expiration? Yes. Beyond patent expiration, regulatory exclusivities can apply. For instance, a New Chemical Entity (NCE) exclusivity is typically 5 years in the U.S. This prevents the FDA from approving generic versions of the same NCE for a specified period, even if the patent has expired. Additionally, orphan drug exclusivity can provide up to 7 years of market protection if the drug is for a rare disease. These regulatory exclusivities are separate from patent rights.

Citations

[1] Merck & Co., Inc. (2005). U.S. Patent 6,896,886. United States Patent and Trademark Office.

Details for Patent 6,896,886

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Abbvie Inc.	BOTOX COSMETIC	onabotulinumtoxina	For Injection	103000	December 09, 1991		2021-07-16
Abbvie Inc.	BOTOX	onabotulinumtoxina	For Injection	103000	December 09, 1991		2021-07-16

International Patent Family for US Patent 6,896,886

Country	Patent Number	Estimated Expiration
World Intellectual Property Organization (WIPO)	9517904
United States of America	8557256
United States of America	8486886