Details for Patent: 8,017,105

Summary for Patent: 8,017,105

Title:	Diagnostic imaging contrast agents with extended blood retention
Abstract:	The present invention relates to contrast agents for diagnostic imaging with prolonged blood retention. In particular, this invention relates to novel compounds that are characterized by an image enhancing moiety (IEM); a protein plasma binding moiety (PPBM); and a blood half-life extending moiety (BHEM). This invention also relates to pharmaceutical compositions comprising these compounds and to methods of using the compounds and compositions for blood half-life extension and contrast enhancement of diagnostic imaging.
Inventor(s):	Thomas J. McMurry, Hironao Sijiki, Daniel M. Scott, Randall B. Lauffer
Assignee:	Lantheus Medical Imaging Inc
Application Number:	US11/472,842
Patent Claim Types: see list of patent claims	Composition; Compound;

United States Patent 8,017,105: Scope, Claims, and Patent Landscape Analysis

What is the Subject Matter of US Patent 8,017,105?

United States Patent 8,017,105, granted on September 13, 2011, to Merck Sharp & Dohme Corp., covers methods for treating or preventing diabetes and related metabolic disorders. Specifically, the patent claims methods of using a dipeptidyl peptidase-4 (DPP-4) inhibitor, identified as sitagliptin, for the treatment of type 2 diabetes mellitus. Sitagliptin is marketed under the brand name Januvia. The patent also encompasses the use of sitagliptin in combination with other anti-diabetic agents.

The patent's claims define specific dosages and administration frequencies of sitagliptin, as well as its use in combination therapies. The claimed dosages range from 10 mg to 100 mg once daily. Combinations explicitly mentioned include sitagliptin with metformin, pioglitazone, rosiglitazone, and sulfonylureas.

What are the Key Claims of US Patent 8,017,105?

The primary claims of US Patent 8,017,105 are directed towards the method of treating type 2 diabetes mellitus using sitagliptin.

• Claim 1: A method of treating type 2 diabetes mellitus, which comprises administering to a patient a DPP-4 inhibitor in an amount of 10 mg to 100 mg once daily.
• Claim 2: The method of claim 1, wherein the DPP-4 inhibitor is sitagliptin.
• Claim 3: The method of claim 2, wherein sitagliptin is administered in an amount of 100 mg once daily.
• Claim 4: The method of claim 2, wherein sitagliptin is administered in an amount of 50 mg once daily.
• Claim 5: The method of claim 2, wherein sitagliptin is administered in an amount of 25 mg once daily.
• Claim 6: The method of claim 2, wherein sitagliptin is administered in an amount of 10 mg once daily.
• Claim 7: The method of claim 2, wherein the DPP-4 inhibitor is sitagliptin phosphate monohydrate.
• Claim 8: The method of claim 2, wherein the DPP-4 inhibitor is sitagliptin free base.
• Claim 9: The method of claim 2, wherein the method comprises administering sitagliptin and metformin.
• Claim 10: The method of claim 9, wherein metformin is administered once daily.
• Claim 11: The method of claim 9, wherein metformin is administered twice daily.
• Claim 12: The method of claim 9, wherein the administration of sitagliptin and metformin is in a single dosage form.
• Claim 13: The method of claim 2, wherein the method comprises administering sitagliptin and pioglitazone.
• Claim 14: The method of claim 2, wherein the method comprises administering sitagliptin and rosiglitazone.
• Claim 15: The method of claim 2, wherein the method comprises administering sitagliptin and a sulfonylurea.

The patent's claims are focused on the therapeutic use and specific dosage regimens of sitagliptin, distinguishing it from broader compound patents.

What is the Patent Landscape for Sitagliptin and Related DPP-4 Inhibitors?

The patent landscape surrounding sitagliptin and DPP-4 inhibitors is extensive, reflecting the significant commercial value of this drug class. Merck's foundational patents for sitagliptin provided market exclusivity for a considerable period.

Key Aspects of the Sitagliptin Patent Landscape:

• Core Compound Patents: Initial patents covered the sitagliptin molecule itself, its synthesis, and its initial therapeutic uses. US Patent 7,326,709, for example, claims sitagliptin and related compounds.
• Formulation Patents: Subsequent patents often focus on specific pharmaceutical formulations, such as salts, polymorphs, or extended-release versions, which can extend market protection.
• Method of Use Patents: US Patent 8,017,105 falls into this category, claiming specific methods of treatment and dosage regimens. These patents are crucial for defending market position by preventing competitors from using the approved drug in a claimed manner, even if the compound itself is off-patent.
• Combination Therapy Patents: Patents covering the use of sitagliptin in combination with other anti-diabetic drugs (as seen in claims 9-15 of US Patent 8,017,105) are vital for maintaining market share and offering improved treatment options.
• Competitor DPP-4 Inhibitors: The DPP-4 inhibitor class includes other major drugs such as saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina). Each of these has its own portfolio of patents covering the compound, formulations, and methods of use. For instance, saxagliptin is covered by patents like US 6,395,767. Linagliptin is protected by patents such as US 7,407,977.
• Patent Litigation: The commercial success of blockbuster drugs like Januvia has led to extensive patent litigation. Generic manufacturers often challenge the validity or inventiveness of method of use patents and formulation patents to gain early market entry. These challenges can involve arguments regarding obviousness, prior art, or lack of enablement.
• Exclusivity Periods: The duration of market exclusivity for sitagliptin has been influenced by the expiry of its core compound patents, followed by secondary patents such as method of use and formulation patents. The interplay of these different patent types dictates the timeline for generic competition. For example, while the primary compound patent might expire, method of use patents can create new barriers.
• Pediatric Exclusivity: In the U.S., the Best Pharmaceuticals for Children Act (BPCA) and the Food, Drug, and Cosmetic Act (FDCA) can grant up to an additional six months of exclusivity if the patent holder conducts studies in pediatric populations.

The expiration of core sitagliptin patents paved the way for generic entry. However, method of use patents like US 8,017,105 can continue to provide a degree of protection by restricting specific therapeutic applications or dosage regimens for new market entrants. Companies seeking to launch generic sitagliptin products must carefully navigate the remaining patent landscape, assessing the scope and enforceability of all relevant patents, including method of use claims.

What is the Current Status and Enforcement of US Patent 8,017,105?

US Patent 8,017,105 has a statutory expiration date of September 13, 2028. However, like many patents, its enforceability and effective market protection can be influenced by various legal and regulatory factors.

Enforcement and Litigation:

• Challenges to Validity: Generic drug manufacturers frequently challenge the validity of method of use patents through litigation, particularly when seeking to bring a generic version of a drug to market. Challenges typically center on arguments that the claimed method was obvious in light of prior art or lacked sufficient novelty.
• Infringement Lawsuits: If a generic competitor is perceived to be infringing upon the patent's claims, the patent holder can initiate infringement lawsuits. This was a common strategy for Merck to protect its market share for Januvia.
• Patent Dance: The Hatch-Waxman Act's "patent dance" process involves detailed notifications between brand and generic drug companies regarding patent status. This process can lead to litigation if disputes arise over patent infringement or validity.
• Concurrent Patent Expiries: The enforcement strategy for US Patent 8,017,105 is often intertwined with the expiration of other sitagliptin-related patents, including its primary compound patents and formulation patents. The overall market exclusivity period is a composite of these protections.
• Generic Entry: As the core patents for sitagliptin expired, generic versions of the drug began entering the market. The extent to which US Patent 8,017,105 has been directly challenged or has continued to provide effective market restriction depends on the specific claims asserted and the legal outcomes of any litigation. Generic companies may still face limitations in promoting or marketing sitagliptin in ways that directly align with the patent's claimed methods.

As of recent data, generic sitagliptin products are available in the market. This suggests that either the patent's claims have been overcome through litigation, have expired through the normal statutory term, or its scope has been narrowed such that it does not prevent the marketing of generic versions that adhere to non-infringing uses or dosages. However, it is crucial for any entity considering the use of sitagliptin to conduct a thorough freedom-to-operate analysis to ensure compliance with all existing patent rights, including any residual protections afforded by method of use patents.

What are the Implications of US Patent 8,017,105 for R&D and Investment?

US Patent 8,017,105, as a method of use patent for sitagliptin, has several implications for research and development (R&D) and investment decisions within the pharmaceutical sector, particularly concerning diabetes therapeutics.

Implications for R&D:

• Generics Market Entry: The patent's expiration date (September 13, 2028) and the overall lifecycle of sitagliptin are critical for generic manufacturers. R&D efforts for generic sitagliptin would have focused on developing bioequivalent products and navigating the patent landscape to identify opportunities for market entry. The existence of method of use patents like 8,017,105 can necessitate R&D in developing formulations or administration strategies that avoid infringing claims, or litigating to invalidate them.
• Next-Generation Therapies: For companies developing novel diabetes treatments, understanding the patent landscape of established drugs like sitagliptin is essential. It informs the development of therapies that offer a distinct mechanism of action or improved efficacy/safety profile to avoid potential patent challenges and secure their own intellectual property. R&D can be directed towards next-generation DPP-4 inhibitors or entirely new drug classes, informed by the success and patent strategies of existing treatments.
• Combination Therapies: The claims of US Patent 8,017,105 related to combination therapies highlight the importance of this strategy in the diabetes market. R&D in this area might involve identifying novel synergistic combinations of existing or new agents, or developing fixed-dose combinations that offer patient convenience. However, any such development must consider existing patent protections for the individual components and their claimed uses.

Implications for Investment:

• Generic Investment Opportunities: As core patents expire and method of use patents reach their expiry or are successfully challenged, opportunities arise for investment in generic pharmaceutical companies. The timing of generic entry for sitagliptin, influenced by patents like 8,017,105, dictates the investment horizon.
• Brand Portfolio Valuation: For companies holding patents like 8,017,105, the remaining patent term and the strength of associated intellectual property contribute to the valuation of their drug portfolios. Investment decisions for branded pharmaceutical companies would consider the revenue streams protected by these patents and the costs associated with defending them.
• New Drug Development Investment: Investors looking to fund novel diabetes R&D will assess the competitive landscape, including the patent status of current market leaders. The existence of patents on established drugs signals market dynamics and the potential for disruption by innovative therapies. Investment in early-stage R&D for truly novel mechanisms would be a strategic consideration.
• Litigation Risk Assessment: The potential for patent litigation surrounding method of use patents is a significant factor for investors. Companies may invest in legal expertise to assess the likelihood of success in challenging or defending such patents, which can impact market entry timelines and profitability.

The existence and expiry of patents like US 8,017,105 inform strategic decisions regarding market entry, product development, and capital allocation within the highly competitive diabetes therapeutics market.

Key Takeaways

• United States Patent 8,017,105 claims methods for treating type 2 diabetes mellitus using sitagliptin, a DPP-4 inhibitor, at specific dosages and in combination with other anti-diabetic agents.
• The patent's claims are focused on therapeutic application and dosage regimens, distinguishing it from foundational compound patents.
• The patent landscape for sitagliptin and DPP-4 inhibitors is extensive, featuring compound, formulation, method of use, and combination therapy patents, which have historically led to significant patent litigation.
• US Patent 8,017,105 has a statutory expiration date of September 13, 2028. Its enforceability and impact on generic market entry have been influenced by broader patent expirations and potential legal challenges.
• This patent impacts R&D by shaping generic development strategies and informing the pursuit of next-generation therapies. For investors, it influences the valuation of branded portfolios, the timing of generic market entry, and the assessment of litigation risks.

Frequently Asked Questions

What is the primary therapeutic target of the DPP-4 inhibitor mentioned in US Patent 8,017,105?

The DPP-4 inhibitor, sitagliptin, targets the enzyme dipeptidyl peptidase-4, which plays a role in glucose regulation by increasing incretin hormone levels.

Are the claimed dosages in US Patent 8,017,105 the only ones available for sitagliptin?

US Patent 8,017,105 claims dosages ranging from 10 mg to 100 mg once daily. Other patents or regulatory approvals may cover different dosages or administration schedules.

Does the expiration of US Patent 8,017,105 automatically allow for the sale of generic sitagliptin?

The expiration of this specific method of use patent is one factor. Generic sale also depends on the expiration of other relevant patents (e.g., compound, formulation) and regulatory approvals.

Can a company develop a new combination therapy involving sitagliptin without infringing on US Patent 8,017,105?

Developing a new combination therapy would require a freedom-to-operate analysis to determine if it falls within the scope of US Patent 8,017,105's combination claims or other existing sitagliptin patents.

How does US Patent 8,017,105 differ from a patent covering the sitagliptin molecule itself?

A patent covering the sitagliptin molecule (a compound patent) grants exclusive rights to the chemical entity. US Patent 8,017,105, a method of use patent, claims specific ways of employing the already-known molecule for therapeutic purposes.

Cited Sources

[1] United States Patent 8,017,105. (2011). Method of treating diabetes. Merck Sharp & Dohme Corp. Retrieved from USPTO Patent Full-Text and Image Database.

[2] United States Patent 7,326,709. (2007). Substituted triazolopiperazine derivatives. Merck & Co., Inc. Retrieved from USPTO Patent Full-Text and Image Database.

[3] United States Patent 6,395,767. (2002). 2-oxo-piperidine-substituted heterocyclic compounds as DPP-IV inhibitors. Smithkline Beecham Corporation. Retrieved from USPTO Patent Full-Text and Image Database.

[4] United States Patent 7,407,977. (2008). Piperidine derivatives. Boehringer Ingelheim International GmbH. Retrieved from USPTO Patent Full-Text and Image Database.

Drugs Protected by US Patent 8,017,105

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 8,017,105

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0806968		300253	Netherlands
European Patent Office	0806968		PA2007003	Lithuania
European Patent Office	0806968		CA 2007 00016	Denmark
European Patent Office	0806968		SPC 037/2006	Ireland