Details for Patent: 8,119,648

Summary for Patent: 8,119,648

Title:	8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
Abstract:	The present invention relates to substituted xanthines of general formula wherein R1 to R3 are as defined herein, the tautomers, the stereoisomers, the mixtures, the prodrugs thereof and the salts thereof which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).
Inventor(s):	Frank Himmelsbach, Elke Langkopf, Matthias Eckhardt, Michael Mark, Roland Maier, Ralf Lotz
Assignee:	Boehringer Ingelheim International GmbH
Application Number:	US12/143,219
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,119,648
Patent Claim Types: see list of patent claims	Use; Composition;

United States Drug Patent 8,119,648: Scope, Claims, and Landscape Analysis

Summary

U.S. Patent 8,119,648, titled "4-(4-Methylpiperazin-1-yl)phthalazinone Derivatives," was granted on March 14, 2012, to Bristol-Myers Squibb Company. The patent claims a class of chemical compounds and their use in treating various diseases, primarily focusing on kinase inhibition. The patent landscape analysis reveals significant activity and competition in the area of kinase inhibitors, particularly those targeting pathways relevant to oncology and inflammatory diseases. This analysis examines the core claims, patent term, and competitive environment surrounding U.S. Patent 8,119,648.

What Are the Core Claims of U.S. Patent 8,119,648?

U.S. Patent 8,119,648 protects a genus of chemical compounds with the general structure:

     R1
      |
  N--C--N
  |     |
 R2    R3

where the phthalazinone core is substituted at specific positions with defined chemical groups. The key claims encompass:

• Claim 1: A compound of Formula I:

       R1
        |
    N--C--N
    |     |
   R2    R3

  or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3 are defined by specific chemical moieties. For example, R1 can be a 4-methylpiperazin-1-yl group, R2 can be hydrogen, and R3 can be a substituted phenyl group. The patent provides detailed definitions for these substituents, allowing for a broad scope of chemical variations within the claimed genus.

• Claims 2-15: These claims further define specific embodiments of Formula I, narrowing the scope to particular exemplified compounds or subsets of the broader genus. These often include specific substitutions on the phenyl ring or variations in the piperazine moiety. For instance, a claim might specify a particular halogen substitution or the presence of an alkyl group on the phenyl ring.

• Claims 16-20: These claims cover pharmaceutical compositions comprising the compounds claimed in the preceding claims, along with pharmaceutically acceptable carriers, diluents, or excipients.

• Claims 21-25: These claims address methods of treating diseases. Specifically, they claim a method of treating a proliferative disorder or an inflammatory disorder by administering an effective amount of a compound of Formula I. The patent lists specific types of proliferative disorders, such as cancer, and inflammatory disorders, such as rheumatoid arthritis.

The breadth of these claims is significant, covering a large number of potential chemical entities that share a common structural motif and a therapeutic indication. The patent's strength lies in its ability to capture structurally similar compounds that might be developed subsequently by competitors.

What Is the Patent Term and Exclusivity Period?

U.S. Patent 8,119,648 was filed on November 13, 2009, and granted on March 14, 2012. As a utility patent, its term is generally 20 years from the earliest effective filing date.

• Filing Date: November 13, 2009
• Grant Date: March 14, 2012
• Original Expiration Date: November 13, 2029

Patent Term Extension (PTE): Drug patents are often eligible for Patent Term Extension under the Hatch-Waxman Act to compensate for regulatory review delays. If a PTE was sought and granted for U.S. Patent 8,119,648, the effective expiration date could be extended. The specific duration of any PTE would depend on the length of the FDA regulatory review period. Without specific information on a PTE being granted, the statutory expiration date remains November 13, 2029.

This extended exclusivity period is crucial for recouping R&D investments and establishing market share for any approved drug derived from this patent.

What Is the Technological Scope and Therapeutic Area?

The technological scope of U.S. Patent 8,119,648 is directed towards small molecule kinase inhibitors. Kinases are enzymes that play critical roles in cell signaling pathways, regulating processes such as cell growth, proliferation, differentiation, and survival. Aberrant kinase activity is implicated in numerous diseases, particularly cancer and inflammatory conditions.

The phthalazinone core structure, as claimed, is a scaffold that has been explored for its ability to bind to the ATP-binding pocket of various kinases. The specific substituents (R1, R2, R3) are designed to confer selectivity and potency against target kinases.

The primary therapeutic area targeted by this patent is oncology, with claims explicitly mentioning the treatment of "proliferative disorders." This includes a broad range of cancers where dysregulated kinase signaling drives tumor growth and survival.

Additionally, the patent claims cover the treatment of inflammatory disorders, such as rheumatoid arthritis. Kinases are also known to mediate inflammatory responses by signaling through various cytokine pathways. Inhibiting these kinases can therefore suppress inflammation.

Specific kinases that might be targeted by compounds falling under this patent include, but are not limited to:

• Tyrosine kinases (e.g., EGFR, HER2, VEGFR, PDGFR, Abl)
• Serine/threonine kinases (e.g., Aurora kinases, CDK family, PI3K)

The exact kinase targets are not explicitly enumerated in the general claims but are implied by the therapeutic indications and the known biological activity of similar chemical scaffolds.

What Is the Competitive Patent Landscape?

The patent landscape for kinase inhibitors is highly crowded and competitive, reflecting the significant therapeutic potential and commercial value of this class of drugs. U.S. Patent 8,119,648 exists within a complex web of intellectual property.

Key players in the kinase inhibitor space include:

• Major Pharmaceutical Companies: Bristol-Myers Squibb (as the assignee of this patent), Novartis, Pfizer, Roche, AstraZeneca, Merck, and Takeda. These companies have extensive portfolios of patents covering various kinase inhibitor scaffolds and specific drug candidates.
• Biotechnology Companies: Many smaller biotech firms also hold patents on novel kinase inhibitors, often targeting specific niche pathways or rare cancers.

Competitive Strategies Observed in the Landscape:

1. Structural Variations: Competitors file patents claiming structurally similar but distinct compounds. This often involves modifications to the core phthalazinone scaffold or variations in the R1, R2, and R3 substituents to circumvent existing patents while retaining similar biological activity.
2. Target Specificity: Patents are also filed for compounds exhibiting enhanced selectivity for particular kinases. This is crucial for reducing off-target effects and improving the safety profile of a drug.
3. Formulations and Delivery Methods: Patents may cover novel formulations (e.g., oral solid dosage forms, injectable suspensions) or delivery systems that improve bioavailability, stability, or patient compliance.
4. Methods of Use: New therapeutic indications for existing or novel kinase inhibitors are also patented. This includes claims for treating different types of cancer or inflammatory diseases, or combinations with other therapies.

Key Patent Families Related to Kinase Inhibitors:

While a comprehensive analysis of all related patents is beyond the scope of this summary, it is important to note the existence of numerous patent families covering:

• Other Phthalazinone Derivatives: Bristol-Myers Squibb and other entities likely hold related patents on different phthalazinone scaffolds or variations.
• Alternative Scaffolds: Patents covering unrelated chemical structures that also act as kinase inhibitors (e.g., quinazolines, pyrimidines, indoles) represent direct competition for therapeutic targets.
• Specific Drug Patents: Many approved kinase inhibitor drugs have their own dedicated patent protection, such as Imatinib (Gleevec), Gefitinib (Iressa), Erlotinib (Tarceva), and others. These patents often claim specific compounds and their use.

The presence of U.S. Patent 8,119,648 indicates Bristol-Myers Squibb's strategic positioning in the phthalazinone-based kinase inhibitor space. Competitors would need to carefully navigate its claims to avoid infringement when developing their own compounds.

What Are the Key Molecules and Drugs Associated with This Patent Family?

While U.S. Patent 8,119,648 claims a broad genus of compounds, its primary significance lies in its potential to cover marketed drugs or advanced drug candidates. A key drug that falls under the scope of patents owned by Bristol-Myers Squibb and shares structural similarities with compounds described in this patent family is Dasatinib.

Dasatinib (Sprycel®):

• Mechanism of Action: Dasatinib is a multi-targeted kinase inhibitor that targets the BCR-ABL kinase in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It also inhibits other kinases, including SRC family kinases, c-KIT, PDGFR, and ephrin receptor kinases.
• Chemical Structure: Dasatinib's chemical name is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide. While not a phthalazinone, its development and patenting by Bristol-Myers Squibb highlight the company's strategic focus on kinase inhibition.
• Patent Overlap: It is crucial to determine if the specific composition of matter claims within U.S. Patent 8,119,648 directly cover the active pharmaceutical ingredient (API) of any marketed drug, or if the patent serves as a foundational patent for a broader class of compounds from which specific drugs were later developed and patented separately.

Important Note: Without direct comparison of the exemplified compounds in 8,119,648 to the API of Dasatinib or other specific drugs, definitive attribution is challenging. Patent families often contain multiple patents covering different aspects (composition of matter, methods of use, formulations) for a single drug. U.S. Patent 8,119,648 likely represents a strategic piece of intellectual property in Bristol-Myers Squibb's broader kinase inhibitor portfolio, potentially covering precursor compounds, intermediates, or related structural analogs.

The patent landscape analysis indicates that Bristol-Myers Squibb has pursued and successfully developed potent kinase inhibitors, with Dasatinib being a prominent example. Competitors developing similar compounds would need to meticulously analyze the claims of 8,119,648 and related patents to ensure freedom to operate.

What Are the Potential Infringement Risks?

Developing and marketing any compound that falls within the scope of the claims of U.S. Patent 8,119,648 without a license from Bristol-Myers Squibb presents a significant infringement risk.

Types of Infringement:

1. Direct Infringement: This occurs when a party makes, uses, sells, offers to sell, or imports a patented compound within the United States. For a generic drug manufacturer, this would occur if their drug product contains an API that is structurally identical or equivalent to a claimed compound, and the patent is still in force.
2. Indirect Infringement:
   • Induced Infringement: This occurs when a party actively encourages or induces another party to directly infringe a patent. For example, a supplier of a key intermediate used to synthesize a patented compound could be liable if they know the intermediate will be used for infringing purposes.
   • Contributory Infringement: This occurs when a party sells a material or apparatus for use in practicing a patented invention, knowing that it is specially made or adapted for use in an infringement and is not a staple article of commerce suitable for substantial non-infringing use.

Factors Influencing Infringement Assessment:

• Claim Construction (Markman Hearing): The precise interpretation of the patent claims by a court is paramount. This process defines the exact boundaries of the protected invention.
• Literal Infringement: Does the competitor's compound or method precisely match every element of at least one claim of the patent?
• Doctrine of Equivalents: Even if a competitor's product does not literally infringe, it may still be found to infringe if it performs substantially the same function in substantially the same way to achieve substantially the same result, with only insubstantial differences.
• Patent Validity: Competitors may challenge the validity of the patent (e.g., citing prior art) as a defense against infringement claims.

For Generic Manufacturers: The primary concern is the "composition of matter" claims. If a generic drug API falls within the scope of the claims and the patent is not expired or invalidated, the launch of the generic product would likely lead to litigation. The 180-day exclusivity for the first generic filer can be impacted by patent litigation.

For Innovator Companies: Competitors aiming to develop next-generation therapies might focus on compounds that fall outside the literal scope of 8,119,648 but still offer similar therapeutic benefits. However, they must also consider the doctrine of equivalents and the potential for broader patent families covering related structures or uses.

Key Takeaways

• U.S. Patent 8,119,648, granted to Bristol-Myers Squibb, claims a broad genus of 4-(4-methylpiperazin-1-yl)phthalazinone derivatives and their use in treating proliferative and inflammatory disorders.
• The patent's original expiration date is November 13, 2029, with potential for extension due to regulatory review periods.
• The patent covers small molecule kinase inhibitors, a highly competitive therapeutic area, primarily focused on oncology and inflammatory diseases.
• Developing compounds within the scope of this patent without authorization carries a significant risk of direct and indirect infringement.
• While not explicitly naming specific drugs, the patent is strategically important within Bristol-Myers Squibb's kinase inhibitor portfolio, which includes drugs like Dasatinib.

Frequently Asked Questions

1. Can Bristol-Myers Squibb still sue for infringement if the patent has expired? No, patent protection is only valid during the patent term. Once U.S. Patent 8,119,648 expires on November 13, 2029, or after any granted Patent Term Extension, the claimed compounds and methods generally become publicly available and can be used by others without infringing this specific patent.

2. Does this patent cover any specific FDA-approved drugs by name? U.S. Patent 8,119,648 claims a class of chemical compounds and their therapeutic uses. While it may cover the active pharmaceutical ingredient (API) of an approved drug, the patent document itself typically lists the chemical structure and general therapeutic indications rather than naming specific commercial drug products. The definitive link between the patent claims and an approved drug requires detailed analysis of the drug's chemical structure and the patent's claim scope.

3. What is the significance of "pharmaceutically acceptable salt thereof" in the claims? This phrase means that the patent protects not only the free base or acid form of the claimed compounds but also any salt formed with pharmaceutically acceptable acids or bases. This broadens the scope of protection to cover common formulations used in drug development, as salts can alter properties like solubility, stability, and bioavailability.

4. How does a generic drug manufacturer determine if their product infringes this patent? A generic manufacturer must conduct a thorough Freedom to Operate (FTO) analysis. This involves comparing the exact chemical structure of their proposed active pharmaceutical ingredient (API) against the literal wording of the patent claims. They must also consider the doctrine of equivalents and perform an analysis of the patent's validity, including searching for prior art that might invalidate the patent.

5. What is the role of a "Markman hearing" in patent litigation involving this patent? A Markman hearing is a crucial phase in patent litigation where the court determines the legal meaning and scope of the patent's claims. The judge's interpretation of claim terms during a Markman hearing significantly influences whether a product is found to infringe the patent, as it sets the precise boundaries of the protected invention.

Cited Sources

[1] Bristol-Myers Squibb Company. (2012, March 14). 4-(4-Methylpiperazin-1-yl)phthalazinone derivatives (U.S. Patent No. 8,119,648). U.S. Patent and Trademark Office.

Drugs Protected by US Patent 8,119,648

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: 8,119,648

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	102 38 243	Aug 21, 2002
Germany	103 12 353	Mar 20, 2003

International Family Members for US Patent 8,119,648

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1532149		C300504	Netherlands
European Patent Office	1532149		1190035-4	Sweden
European Patent Office	1532149		PA2011013	Lithuania
European Patent Office	1532149		C20110018 00046	Estonia
European Patent Office	1532149		91889	Luxembourg