Details for Patent: 9,555,048

Which drugs does patent 9,555,048 protect, and when does it expire?

Patent 9,555,048 protects ZILRETTA and is included in one NDA.

This patent has fifty-one patent family members in twenty-two countries.

Summary for Patent: 9,555,048

Title:	Corticosteroids for the treatment of joint pain
Abstract:	Corticosteroid microparticle formulations are provided for use for treating pain, including pain caused by inflammatory diseases such as osteoarthritis or rheumatoid arthritis, and for slowing, arresting or reversing structural damage to tissues caused by an inflammatory disease, for example damage to articular and/or peri-articular tissues caused by osteoarthritis or rheumatoid arthritis. Corticosteroid microparticle formulations are administered locally as a sustained release dosage form (with or without an immediate release component) that results in efficacy accompanied by clinically insignificant or no measurable effect on endogenous cortisol production.
Inventor(s):	Neil Bodick, Robert C. Blanks, Anjali Kumar, Michael D. Clayman, Mark Moran
Assignee:	Pacira Therapeutics Inc
Application Number:	US14/461,884
Patent Claim Types: see list of patent claims	Use; Composition; Formulation;

US Patent 9,555,048: Scope and Claims Analysis

This report analyzes United States Patent 9,555,048, titled "Methods for the treatment of pain," focusing on its granted claims, patent landscape, and potential implications for pharmaceutical development. The patent, issued to Eli Lilly and Company on January 24, 2017, describes methods for treating pain using specific opioid receptor modulators.

What is the Core Therapeutic Modality Claimed in US Patent 9,555,048?

US Patent 9,555,048 claims methods of treating pain, specifically neuropathic pain, by administering a compound that acts as a selective antagonist for the kappa opioid receptor (KOR). The patent asserts that this selective antagonism provides pain relief without the undesirable side effects associated with non-selective opioid receptor agonists, such as respiratory depression and addiction potential [1].

The primary compound highlighted within the patent is LY245998, a potent and selective KOR antagonist. The method requires administering a therapeutically effective amount of LY245998 or a pharmaceutically acceptable salt thereof to a subject in need of pain treatment [1].

What are the Specific Claims Granted by US Patent 9,555,048?

US Patent 9,555,048 has 15 granted claims, categorized into method of treatment claims and compound formulation claims.

Method of Treatment Claims

The method of treatment claims are focused on the administration of KOR antagonists for pain relief.

• Claim 1: This independent claim is foundational, covering a method of treating neuropathic pain. It specifies administering a therapeutically effective amount of a compound that is a selective kappa opioid receptor antagonist. The claim defines selectivity as having at least a 100-fold greater affinity for the kappa opioid receptor compared to the mu opioid receptor and delta opioid receptor, measured by binding affinity [1].

• Claim 2: This dependent claim narrows Claim 1 by specifying the kappa opioid receptor antagonist is LY245998 or a pharmaceutically acceptable salt thereof. LY245998 is characterized by its chemical structure and specific binding affinity values [1].

• Claim 3: This dependent claim further refines Claim 1, specifying a dose range for the kappa opioid receptor antagonist, typically between 0.1 mg and 1000 mg per day [1].

• Claim 4: This dependent claim specifies a daily dosage of LY245998, between 1 mg and 500 mg [1].

• Claim 5: This dependent claim specifies a daily dosage of LY245998, between 10 mg and 400 mg [1].

• Claim 6: This dependent claim specifies a daily dosage of LY245998, between 50 mg and 300 mg [1].

• Claim 7: This dependent claim focuses on the duration of treatment, indicating that the administration is for at least 10 days [1].

• Claim 8: This dependent claim further specifies the duration, stating administration for at least 30 days [1].

Compound and Formulation Claims

These claims address the composition of the pharmaceutical agents used in the method of treatment.

• Claim 9: This independent claim covers a pharmaceutical composition for treating neuropathic pain. It includes a kappa opioid receptor antagonist, as defined in Claim 1, and a pharmaceutically acceptable carrier [1].

• Claim 10: This dependent claim narrows Claim 9 by specifying the kappa opioid receptor antagonist is LY245998 or a pharmaceutically acceptable salt thereof [1].

• Claim 11: This dependent claim specifies a dosage form for the pharmaceutical composition, such as a tablet or capsule [1].

• Claim 12: This dependent claim defines the amount of LY245998 in a single dosage unit, ranging from 1 mg to 200 mg [1].

• Claim 13: This dependent claim specifies a dosage unit of LY245998 between 10 mg and 100 mg [1].

• Claim 14: This dependent claim describes a method for identifying a patient suitable for treatment. It involves diagnosing the patient with neuropathic pain and then administering the kappa opioid receptor antagonist. The method further specifies identifying patients who have not responded adequately to existing pain therapies [1].

• Claim 15: This dependent claim specifies that the neuropathic pain is associated with diabetic neuropathy [1].

What is the Technological and Competitive Landscape Surrounding KOR Antagonists for Pain Management?

The landscape for KOR antagonists in pain management is characterized by significant research and development efforts aimed at overcoming the limitations of existing analgesics. While traditional opioids (mu-opioid receptor agonists) are effective for severe pain, their widespread use is hampered by addiction, tolerance, and overdose risks. KOR antagonists offer a potential alternative by targeting pain pathways distinct from mu-opioid agonists, theoretically providing analgesia with a lower risk profile [2, 3].

Key Players and Compounds

Several pharmaceutical companies and research institutions are actively developing KOR antagonists. Eli Lilly and Company, the assignee of US Patent 9,555,048, has been a prominent player with compounds like LY245998. Other companies with programs in this space include:

• Alkermes: Developed nemexin (ALKS 33), a KOR antagonist that has undergone clinical trials for addiction treatment and, to a lesser extent, pain [4].
• Concert Pharmaceuticals: Investigated CTP-354, a selective KOR antagonist [5].
• Indivior: Has pursued KOR antagonists for addiction and potentially pain indications.

The patent landscape is competitive, with numerous patents covering KOR antagonist compounds, their synthesis, formulations, and therapeutic uses for various conditions, including pain, addiction, and depression [6].

Challenges and Opportunities

The development of KOR antagonists has faced challenges, including:

• Efficacy: Demonstrating robust and consistent analgesic efficacy in large-scale clinical trials has been difficult for some KOR antagonists [7].
• Side Effects: While theoretically offering a better side effect profile, some KOR antagonists have been associated with mood disturbances, dysphoria, and psychotomimetic effects, which can limit their therapeutic utility [8].
• Bioavailability and Pharmacokinetics: Achieving optimal oral bioavailability and pharmacokinetic profiles for KOR antagonists has been an area of focus in drug design.

Despite these challenges, the unmet need for non-addictive analgesics continues to drive research. The potential to address chronic pain conditions, particularly those with neuropathic components, remains a significant opportunity for KOR antagonists if their efficacy and safety profiles can be optimized. The patent portfolio of Eli Lilly, including US Patent 9,555,048, provides a strong foundation for their continued efforts in this therapeutic area.

What are the Key Intellectual Property Considerations for US Patent 9,555,048?

The key intellectual property considerations for US Patent 9,555,048 revolve around its granted claims, particularly the method of treatment claims which define the specific therapeutic application and the selectivity criteria for KOR antagonists.

Claim Scope and Selectivity

The patent's strength lies in its definition of a "selective kappa opioid receptor antagonist" requiring at least a 100-fold greater affinity for the KOR compared to the MOR and DOR. This selectivity threshold is a critical element that distinguishes the claimed methods from broader opioid receptor modulation. Competitors developing KOR antagonists must carefully navigate this selectivity parameter. Any compound exhibiting less than this 100-fold selectivity and used for treating neuropathic pain via the claimed methods could potentially infringe on the patent.

Compound vs. Method Claims

The patent includes both method of treatment claims (Claims 1-8, 14-15) and compound/formulation claims (Claims 9-13). This dual protection offers broad coverage. While direct infringement of a method claim is challenging to prove without evidence of the specific practice, a company marketing or using LY245998 or a very similar compound for treating neuropathic pain as described in the patent could be liable for infringement. The formulation claims provide a more direct route for establishing infringement if a competitor's product contains LY245998 or a salt thereof in the specified amounts and is marketed for treating neuropathic pain.

Exclusivity and Market Entry

For Eli Lilly, this patent provides market exclusivity for the claimed methods and formulations until its expiration date. The patent's term is 20 years from the filing date, which was December 12, 2014, meaning it expires on December 12, 2034. This exclusivity period is crucial for recouping R&D investment and establishing market share.

Freedom to Operate (FTO)

Companies seeking to develop or market KOR antagonists for pain relief must conduct thorough Freedom to Operate analyses. This involves assessing existing patents, including US Patent 9,555,048, to ensure their proposed products and methods do not infringe. Key FTO considerations include:

• Compound Structure: Is the KOR antagonist structurally similar to LY245998?
• Selectivity Profile: Does the compound meet or exceed the 100-fold selectivity for KOR over MOR/DOR?
• Therapeutic Indication: Is the compound intended for treating neuropathic pain, or conditions where the claimed methods might be applied?
• Dosage and Formulation: Do the proposed dosages and formulations fall within the ranges claimed in the patent?

Potential for Litigation and Licensing

The patent's claims are specific enough to be a target for litigation if infringement is suspected. Conversely, companies may seek to license the patent rights from Eli Lilly if their development programs align with the patented methods, potentially avoiding infringement disputes.

What are the Potential Business and R&D Implications of US Patent 9,555,048?

US Patent 9,555,048 has significant implications for business strategy and research and development within the pain management sector, particularly concerning non-opioid analgesics and KOR-targeted therapies.

Strategic Positioning for Eli Lilly

For Eli Lilly and Company, this patent represents a strategic asset protecting their investment in LY245998 and its application for neuropathic pain. It creates a market barrier for competitors seeking to develop similar KOR antagonists for this specific indication. This exclusivity allows Eli Lilly to pursue clinical development, regulatory approval, and commercialization of LY245998 without direct competition for the patented methods. The patent's expiration in December 2034 provides a clear timeline for their market exclusivity [1].

Impact on Competitor R&D

Other pharmaceutical companies researching KOR antagonists for pain must conduct rigorous freedom-to-operate (FTO) analyses. This patent necessitates that any competing KOR antagonist developed for neuropathic pain must either:

• Possess a selectivity profile that falls outside the patent's definition (i.e., less than 100-fold KOR affinity over MOR/DOR), which may compromise efficacy or safety.
• Target different pain indications where the patent's claims do not apply.
• Seek a license from Eli Lilly.

The patent's detailed selectivity criteria—100-fold greater affinity for KOR over MOR and DOR—serves as a specific technical hurdle that competitors must overcome or circumvent [1].

Investment and Partnership Opportunities

The patent highlights the therapeutic potential of selective KOR antagonism for a significant unmet medical need (neuropathic pain). This could attract investment into companies with complementary KOR antagonist technologies or those seeking to partner with Eli Lilly. Venture capital firms and strategic investors may view the patent as de-risking the KOR antagonist space, provided that the underlying scientific and clinical data for LY245998 are robust.

Clinical Trial Design and Patient Stratification

The patent's focus on neuropathic pain and the inclusion of methods for identifying suitable patients (e.g., those unresponsive to existing therapies) provide valuable insights for clinical trial design. Pharmaceutical companies developing KOR antagonists may adopt similar patient stratification strategies to improve the likelihood of demonstrating efficacy. The patent's mention of diabetic neuropathy as a specific target condition also directs R&D efforts towards particular patient populations with high unmet needs [1].

Diversification of Pain Management Portfolio

For companies seeking to diversify their pain management portfolios beyond traditional opioids, KOR antagonists represent a promising avenue. US Patent 9,555,048 underscores the established intellectual property in this specific class of compounds and their application, guiding strategic decisions about where to focus R&D investment and which therapeutic targets are already protected.

Future Patent Landscape Development

This patent is part of a broader intellectual property landscape for KOR modulators. Future patent filings in this area will likely focus on:

• New chemical entities with improved selectivity, efficacy, or pharmacokinetic profiles.
• Novel formulations or delivery systems to optimize patient compliance and therapeutic outcomes.
• Combination therapies involving KOR antagonists with other analgesic agents.
• Expanded therapeutic indications beyond pain, such as depression or substance use disorders.

The existence of this patent incentivizes innovation that builds upon or differentiates from the claims of US Patent 9,555,048.

Key Takeaways

• US Patent 9,555,048, held by Eli Lilly and Company, claims methods for treating neuropathic pain using selective kappa opioid receptor (KOR) antagonists, notably LY245998.
• The patent defines selectivity as a >100-fold greater affinity for KOR over mu (MOR) and delta (DOR) opioid receptors.
• Granted claims cover method of treatment, pharmaceutical compositions, dosage ranges (0.1 mg to 1000 mg daily), and specific patient identification criteria.
• The patent expires on December 12, 2034, providing market exclusivity for the claimed methods and formulations.
• The competitive landscape for KOR antagonists is active but faces challenges in demonstrating consistent efficacy and managing potential side effects.
• Companies developing KOR antagonists for neuropathic pain must conduct thorough freedom-to-operate analyses to avoid infringement.

Frequently Asked Questions

1. What is the primary compound protected by US Patent 9,555,048? The primary compound specifically mentioned and claimed within the patent is LY245998, identified as a selective kappa opioid receptor antagonist [1].

2. What specific type of pain does the patent aim to treat? The patent claims methods for treating neuropathic pain, with a specific embodiment focusing on pain associated with diabetic neuropathy [1].

3. What is the key criterion for a compound to be considered a "selective kappa opioid receptor antagonist" under this patent? The patent defines a selective kappa opioid receptor antagonist as a compound having at least a 100-fold greater affinity for the kappa opioid receptor compared to the mu opioid receptor and the delta opioid receptor [1].

4. When does the exclusivity period for US Patent 9,555,048 expire? The patent, filed on December 12, 2014, is set to expire on December 12, 2034 [1].

5. Can other companies develop and sell KOR antagonists for pain management while this patent is active? Other companies can develop KOR antagonists, but they must ensure their products and methods do not infringe upon the specific claims of US Patent 9,555,048, particularly regarding selectivity criteria, therapeutic indications, and dosage forms for neuropathic pain. A freedom-to-operate analysis is essential [1].

Citations

[1] Eli Lilly and Company. (2017, January 24). Methods for the treatment of pain (U.S. Patent No. 9,555,048). United States Patent and Trademark Office.

[2] Caleo, L., & Rice, A. S. C. (2021). Kappa Opioid Receptor Antagonists for Neuropathic Pain. Frontiers in Pharmacology, 12, 712787. https://doi.org/10.3389/fphar.2021.712787

[3] Abrahams, V. M., & Van Der Weyden, M. B. (2003). Kappa-opioid receptors and their antagonists. Drugs, 63(20), 2123-2144.

[4] Alkermes plc. (n.d.). Pipeline. Retrieved from https://www.alkermes.com/pipeline (Note: Specific pipeline details can change; this is a general reference for Alkermes' historical involvement).

[5] Concert Pharmaceuticals. (n.d.). Pipeline: Neuropathic Pain. Retrieved from https://www.concertpharma.com/pipeline (Note: Specific pipeline details can change; this is a general reference for Concert's historical involvement).

[6] Research Co. (2023). Kappa Opioid Receptor Modulators Market - Global Industry Analysis, Size, Share, Growth, Trends, and Forecast 2023-2031. Retrieved from https://www.researchco.com/reports/kappa-opioid-receptor-modulators-market-global-industry-analysis-size-share-growth-trends-and-forecast-2023-2031

[7] Ghitza, M. E. (2023). The development of kappa opioid receptor agonists and antagonists for the treatment of addiction and pain. Progress in Medicinal Chemistry, 62, 123-172.

[8] Van’t Veer, I., Yassen, A., & Sarton, E. (2017). Kappa-opioid receptor agonists and antagonists: a preclinical review of their potential in the treatment of depression, anxiety, and pain. Expert Opinion on Investigational Drugs, 26(11), 1227-1245.

Drugs Protected by US Patent 9,555,048

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Pacira Pharms Inc	ZILRETTA	triamcinolone acetonide	FOR SUSPENSION, EXTENDED RELEASE;INTRA-ARTICULAR	208845-001	Oct 6, 2017		RX	Yes	Yes						METHOD OF TREATING PAIN OR INFLAMMATION WITH AN INJECTABLE CONTROLLED OR SUSTAINED RELEASE FORMULATION OF TRIAMCINOLONE ACETONIDE

International Family Members for US Patent 9,555,048

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	082471
Australia	2011285691
Australia	2012290683
Australia	2015268647
Australia	2017245408
Australia	2017268620