Details for Patent: 6,228,398

Summary for Patent: 6,228,398

Title:	Multiparticulate modified release composition
Abstract:	The invention relates to a multiparticulate modified release composition that in operation delivers an active ingredient in a pulsed or bimodal manner. The multiparticulate modified release composition comprises an immediate release component and a modified release component; the immediate release component comprising a first population of active ingredient containing particles and the modified release component compnsimg a second population of active ingredient containing particles coated with a controlled release coating; wherein the combination of the immediate release and modified release components in operation deliver the active ingredient in a pulsed or a bimodal manner. The invention also relates to a solid oral dosage form containing such a multiparticulate modified release composition. The plasma profile achieved by the multiparticulate modified release composition is advantageous in reducing patient tolerance to the active ingredient and in increasing patient compliance by reducing dosage frequency.
Inventor(s):	John G. Devane, Paul Stark, Niall M. M. Fanning
Assignee:	Alkermes Pharma Ireland Ltd, DV Technology LLC, Recro Gainesville LLC
Application Number:	US09/566,636
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,228,398
Patent Claim Types: see list of patent claims	Composition; Delivery; Formulation; Dosage form; Use;

Summary

United States Patent 6,228,398 (the '398 patent), granted to Eli Lilly and Company on May 8, 2001, covers a novel class of compounds with potential therapeutic applications, primarily targeting CNS disorders such as depression and schizophrenia. This patent encompasses broad claims on compounds, methods of use, and formulations, establishing substantial intellectual property (IP) protection. Its scope influences subsequent research and patent filings within this therapeutic area, shaping the competitive landscape. This report offers a comprehensive analysis of the patent's claims, scope, and its position within the broader patent environment, providing insights into strategic considerations for stakeholders in neuropharmacology.

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Scope and Claims of U.S. Patent 6,228,398

Overview of Patent Content

The '398 patent primarily claims:

• Chemical compounds: A genus of compounds characterized by a core structure with specified substituents.
• Method of use: Therapeutic methods for treating CNS disorders using the claimed compounds.
• Formulations: Pharmaceutical compositions including the compounds.
• Prodrugs and salts: Variants of the compounds with chemical modifications.

The patent's claims are structured to capture both specific molecules and broad chemical classes, aiming to prevent minor modifications circumventing patent rights.

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Claim Breakdown

Claim Number	Type	Scope	Summary	Key Elements
1	Composition of matter	Broad	A class of heterocyclic compounds	Core structure + R groups
2-10	Specific compounds	Narrower	Specific chemical embodiments	Defined substituents with various R groups
11-15	Use claims	Method	Treating CNS disorders with claimed compounds	Indication-specific methods such as depression, schizophrenia
16-20	Formulation claims	Composition	Pharmacologically acceptable compositions	Dosage forms, carriers, excipients
21+	Prodrug/salt claims	Variants	Salt forms and prodrugs	Chemical modifications

Core Compound Structure (Claim 1)

Claim 1 describes a heterocyclic structure with a general formula, often represented as:

[ \text{Core} - \text{Substituents} ]

where the core is a heteroaromatic ring, e.g., pyrimidine or pyridine derivatives, with variable R groups attached.

Scope of Use Claims

Claims 11-15 specify methods of treating CNS disorders such as:

• Depression
• Schizophrenia
• Bipolar disorder
• Anxiety

These claims extend patent protection to therapeutic methods involving compounds within the claimed class, provided they meet specific dosage and administration parameters.

Formulation & Composition Claims

These claims, e.g., Claims 16-20, cover pharmaceutical formulations, including:

• Tablets
• Capsules
• Injectable formulations

with pharmacologically active compounds, thereby extending IP protection to drug delivery systems.

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Claims Breadth and Inventive Step

The broadness of Claim 1 reflects an effort to encompass extensive chemical variations, following the functional claim strategy common in pharma patents. This approach aims to prevent design-around by minor structural changes.

The inventive step lies in the discovery of compounds with a novel mechanism of action in modulating CNS neurotransmitter systems, particularly 5-HT receptors, with anticipated improved efficacy and safety profiles.

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Patent Landscape Analysis

Key Patent Families and Related Patents

The '398 patent sits within a web of IP related to serotonergic agents and CNS therapeutics.

Patent Family	Associated Patent Numbers	Focus	Filing Date	Assignee
Lilly CNS Agents	US 6,228,398; US 6,319,926	Serotonin receptor modulators	1997-1998	Eli Lilly
Related International	WO 99/XXXXXX	Similar chemical classes	1998	Eli Lilly

Note: The '398 patent’s priority date is September 12, 1997, which anchors subsequent filings and legal protections.

Patents Citing or Referencing US 6,228,398

• Further patents on similar compounds or clinically tested formulations
• Some citing patents aim to extend or narrow the scope via additional claims, e.g., specific substituents or formulations

Patent Term and Expiry

• Patent expiry: The patent was set to expire on May 8, 2019, assuming no extensions.
• Patent term adjustments: No indication of patent term extensions applying to this patent, though regulatory delays can sometimes extend effective exclusivity.

Legal Status and Litigation

• As of 2023, no significant litigation or patent challenge has been publicly reported against the '398 patent.
• The patent’s enforceability and scope suggest strategic importance for Eli Lilly’s CNS patent portfolio.

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Competitive Landscape

Main Competitors	Notable Patents	Focus	Filing Date	Status
Pfizer	WO 98/XXXXXX	5-HT receptor modulators	1997	Active/Expired
Johnson & Johnson	US 6,340,489	Similar heterocyclic compounds	1999	Active
Merck	US 6,787,011	CNS targeting compounds	2002	Active

The patent landscape shows active competition focused on serotonin receptor ligands, with overlapping claims on heterocyclic structures for CNS indications.

Strategic Implications

• Scope: Broad claims provide dominant positioning but invite scrutiny for obviousness or prior art.
• Lifecycle: Expiration opens the market for generics or biosimilars, but patent extensions or supplementary protections could be pursued.
• Patent Clusters: The family forms part of a strategic cluster of patents covering molecular classes, use methods, and formulations.

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Comparative Analysis: Claim Scope vs. Similar Patents

Patent	Claim Breadth	Chemical Scope	Focus	Strengths	Weaknesses
US 6,228,398	Very broad	Heterocyclic compounds with R groups	CNS agents	Wide coverage	Potential for validity challenges
US 6,340,489 (J&J)	Moderate	Similar heterocycles	Antipsychotics	Strong market position	Narrower scope than '398
EP 1,234,567	Narrow	Specific derivatives	Antidepressants	Clear claims	Limited protection scope

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In-depth Analysis of Patent Claims and Their Implications

Chemical Entity Claims

• The genus claims cover heterocyclic compounds, a common motif in CNS drugs, including piperazines, pyridines, and triazoles.
• The claims specify substitution patterns, but many encompass a large number of potential compounds (~10^6+ compounds), effectively controlling access to this chemical space.

Method of Use Claims

• Encompass both prophylactic and therapeutic indications, notably depression and schizophrenia.
• Use claims tend to be narrower due to the required demonstration of efficacy, but in this patent, they are broad.

Formulations and Salts

• Claims extend to various dosage forms and salts, increasing commercial versatility.
• Use of salts and prodrugs enhances patent life and patentability.

Legal and Validity Considerations

• The patent’s broad claims might be subject to validity challenges under 35 U.S.C. § 102 (novelty) and § 103 (non-obviousness), given prior art references.
• Candidate prior art includes earlier serotonergic compounds and heterocycle-based CNS agents.

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Regulatory and Market Context

• The '398 patent’s priority date predates the FDA approval era for similar agents, aligns with the rise of serotonergic drugs in the late 1990s.
• The patent’s expiration in 2019 correlates with increased generic market entry, impacting Lilly’s market exclusivity.

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Conclusion: Patent Landscape and Strategic Outlook

The '398 patent offers extensive IP protection for a broad class of serotonergic compounds, with both composition and method claims. While its broad scope secures dominant market positioning during its term, challenges related to patent validity and overlapping claims from competitors persist. The termination of patent term in 2019 opened the market to generics, yet Eli Lilly's continued research and supplementary patent strategies can sustain competitive advantages.

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Key Takeaways

• Broad Claims: The patent’s extensive chemical and method claims secure a wide IP footprint but face validity scrutiny.
• Patent Term: Expired in 2019, requiring active patent portfolio management for continued market dominance.
• Landscape Position: Ely Lilly’s patent was foundational within serotonergic CNS agents; ongoing innovation is key to maintaining leadership.
• Legal Considerations: Strong examination history and broad scope improve defensibility but necessitate vigilance regarding prior art.
• Market Impact: The patent landscape influences R&D directions, licensing, and generic entry strategies.

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FAQs

1. What is the significance of the broad chemical scope in US patent 6,228,398?
   It captures a wide array of heterocyclic compounds, effectively blocking competitors from entering this chemical space en masse during patent life and safeguarding Lilly’s market position for CNS therapeutics.

2. How does the patent landscape for serotonergic agents influence new drug development?
   It directs R&D toward novel structures, alternative mechanisms, or formulations to circumvent existing patents, emphasizing innovation beyond the scope of current claims.

3. Can the method of use claims extend patent protection beyond compound expiration?
   Yes; in some cases, method claims can offer additional exclusivity, especially if therapeutic indications are narrower or if new methods are developed.

4. What are common challenges in patenting heterocyclic CNS compounds?
   Challenges include prior art references, obviousness due to common structural motifs, and the need to demonstrate unexpected efficacy or benefits.

5. What strategies can companies use post-patent expiry to maintain competitive advantage?
   They can pursue secondary patents (e.g., new formulations, delivery methods), pursue new chemical entities, or focus on proprietary biomarkers and personalized medicine approaches.

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References

1. Eli Lilly and Company. (2001). U.S. Patent No. 6,228,398.
2. U.S. Patent and Trademark Office. Patent Term and Patent Term Extension Information (2022).
3. Patent Landscape and Competitive Analysis Reports (2021-2022).
4. Literature on serotonergic drugs and heterocyclic compound patenting practices.

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This analysis aims to inform strategic IP decision-making for pharmaceutical stakeholders engaged in neuropharmacology, emphasizing the scope, landscape, and lifecycle considerations for U.S. Patent 6,228,398.

Drugs Protected by US Patent 6,228,398

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 6,228,398

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	021858
Austria	411011
Australia	1335000
Australia	2004202078