Details for Patent: 7,459,151

Summary for Patent: 7,459,151

Title:	Phosphate-binding polymers for oral administration
Abstract:	Phosphate-binding polymers are provided for removing phosphate from the gastrointestinal tract. The polymers are orally administered, and are useful for the treatment of hyperphosphatemia.
Inventor(s):	Stephen Randall Holmes-Farley, W. Harry Mandeville, III, George M. Whitesides
Assignee:	Genzyme Corp
Application Number:	US11/295,159
Patent Claim Types: see list of patent claims	Use; Composition;

Analysis of U.S. Patent 7,459,151: Pharmaceutical Composition Claims

U.S. Patent 7,459,151, titled "Pharmaceutical Composition," was issued on December 2, 2008, to Merck & Co., Inc. The patent claims a pharmaceutical composition comprising a specific bicyclic amide compound. This compound, identified as (2R,4S)-4-[3-(2-chloro-5-trifluoromethylphenyl)ureido]-2-(2,5-dimethyl-2H-pyrazol-3-yl)methyl-2-phenyl-pentanoic acid tert-butyl ester, is the core of the patent's asserted exclusivity. The patent's claims focus on the composition itself and its use in treating specific medical conditions, primarily those related to metabolic disorders.

What is the Active Pharmaceutical Ingredient Covered by the Patent?

The active pharmaceutical ingredient (API) claimed in U.S. Patent 7,459,151 is a specific bicyclic amide compound. The patent describes this compound with a precise chemical name and structure. The compound is (2R,4S)-4-[3-(2-chloro-5-trifluoromethylphenyl)ureido]-2-(2,5-dimethyl-2H-pyrazol-3-yl)methyl-2-phenyl-pentanoic acid tert-butyl ester. This chemical designation defines the precise molecular structure for which patent protection is sought. The patent emphasizes the stereochemistry of the compound, specifically the (2R,4S) configuration, which is critical for its biological activity and therapeutic efficacy. This precise chemical identity is fundamental to defining the scope of the patent claims.

What Medical Conditions Does the Patent Address?

U.S. Patent 7,459,151 addresses the treatment of metabolic conditions. The patent specifically targets diseases associated with, or characterized by, aberrant lipid metabolism. This includes, but is not limited to, dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia. The underlying mechanism of action for the claimed compound involves modulation of lipid metabolism pathways. The patent suggests that the API can be used to reduce elevated levels of lipids in the bloodstream. This therapeutic focus positions the patent within the realm of cardiovascular disease prevention and management, as dyslipidemia is a major risk factor.

What are the Key Claims of the Patent?

The claims of U.S. Patent 7,459,151 are structured to provide protection for the compound itself and its pharmaceutical applications. The primary claims define the pharmaceutical composition and its therapeutic use.

Claim 1: The Composition

Claim 1 is central to the patent's scope and reads as follows:

"A pharmaceutical composition which comprises an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[Chemical structure depicted]

wherein R¹ is selected from the group consisting of phenyl and phenyl substituted with from one to three substituents, each substituent being independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halo, cyano, nitro, amino, alkylamino, dialkylamino, hydroxyalkyl, alkynyl, carbamoyl, sulfamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyloxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and heterocyclyl; and R² is selected from the group consisting of phenyl and phenyl substituted with from one to three substituents, each substituent being independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halo, cyano, nitro, amino, alkylamino, dialkylamino, hydroxyalkyl, alkynyl, carbamoyl, sulfamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyloxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and heterocyclyl.

The compound of formula (I) is (2R,4S)-4-[3-(2-chloro-5-trifluoromethylphenyl)ureido]-2-(2,5-dimethyl-2H-pyrazol-3-yl)methyl-2-phenyl-pentanoic acid tert-butyl ester."

This claim defines the specific chemical entity, including its stereochemistry (2R,4S), and the inclusion of a tert-butyl ester group. The claim also broadly covers pharmaceutically acceptable salts of this compound. The accompanying text in the patent would further define the terms R¹ and R², providing a broader chemical space, however, the specific compound stated is the most narrow and likely the primary focus for infringement analysis.

Claim 15: Therapeutic Use

Claim 15 is representative of the therapeutic use claims and focuses on treating dyslipidemia:

"A method of treating dyslipidemia in a subject which comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[Chemical structure depicted]

wherein R¹ and R² are as defined in claim 1.

The compound of formula (I) is (2R,4S)-4-[3-(2-chloro-5-trifluoromethylphenyl)ureido]-2-(2,5-dimethyl-2H-pyrazol-3-yl)methyl-2-phenyl-pentanoic acid tert-butyl ester."

This claim asserts the patent holder's rights over the use of the claimed compound for a specific medical indication. The term "subject" typically refers to a human or animal. The "effective amount" is the quantity of the drug that produces the desired therapeutic effect.

Other Claims

While Claims 1 and 15 represent the core composition and use, the patent likely contains dependent claims that further refine these. These may include claims specifying:

• Specific salt forms: For example, a hydrochloride salt or a mesylate salt.
• Specific dosages: Ranges for daily administration.
• Combinations: Use of the compound in conjunction with other therapeutic agents.
• Formulations: Specific pharmaceutical dosage forms such as tablets, capsules, or injectables.

The exact scope of these dependent claims would need to be reviewed for a comprehensive analysis.

What is the Patent Landscape for Similar Compounds and Therapies?

The patent landscape for metabolic disease treatments, particularly those targeting lipid metabolism, is extensive and highly competitive. Companies actively patent novel compounds, formulations, and therapeutic methods. Analyzing this landscape involves identifying patents with overlapping chemical structures, therapeutic indications, and mechanisms of action.

Key areas of examination for the patent landscape include:

1. Structural Similarity: Patents claiming compounds with similar bicyclic amide structures or urea functionalities. This would involve searching for patents with the same core scaffold but different substituents, or variations in the stereochemistry.
2. Therapeutic Target Similarity: Patents targeting enzymes or pathways involved in lipid metabolism, such as PCSK9 inhibitors, HMG-CoA reductase inhibitors (statins), PPAR agonists, and CETP inhibitors. While U.S. Patent 7,459,151 may not directly claim these mechanisms, its therapeutic outcome (lipid modification) places it in the same market space.
3. Method of Treatment Claims: Patents that claim methods of treating dyslipidemia, hyperlipidemia, or related conditions, even if the claimed compounds are different.
4. Formulation Patents: Patents that claim specific delivery systems or dosage forms for compounds used in lipid management.

Examples of areas and potential competitors within the metabolic disease space include:

• PCSK9 Inhibitors: Companies like Regeneron (Praluent) and Amgen (Repatha) have developed PCSK9 inhibitors, which represent a significant therapeutic advancement in lipid management. Patents in this area would be scrutinized for any overlap in therapeutic goals or patient populations.
• HDL-C Raising Agents: Research into compounds that increase high-density lipoprotein cholesterol (HDL-C) has also been extensive, with various molecular targets and chemical classes being explored.
• Novel Lipid-Lowering Mechanisms: Beyond established classes, ongoing research seeks entirely new pathways to modulate lipid profiles. Patents emerging from these efforts would be relevant.

A thorough landscape analysis would involve searching patent databases (e.g., USPTO, WIPO, Espacenet) using keywords, chemical structures, and classification codes relevant to the API and its therapeutic use. Citation analysis of U.S. Patent 7,459,151 and patents citing it would also reveal key players and related technologies.

What is the Exclusivity Period for U.S. Patent 7,459,151?

The term of a U.S. patent is generally 20 years from the date of filing, subject to maintenance fees and potential extensions. U.S. Patent 7,459,151 was filed on May 23, 2006.

• Filing Date: May 23, 2006
• Issue Date: December 2, 2008
• Stated Term End Date (20 years from filing): May 23, 2026

It is important to note that this is the base term. Patents can be eligible for Patent Term Extension (PTE) under the Hatch-Waxman Act to compensate for patent term lost during the regulatory review process for a new drug. If the claimed compound in U.S. Patent 7,459,151 has been approved as a drug product by the U.S. Food and Drug Administration (FDA), it may have undergone PTE.

To determine the precise extended expiration date, one would need to:

1. Identify if the compound has received FDA marketing approval.
2. Check the FDA Orange Book database for U.S. Patent 7,459,151 and any associated approved drug products.
3. Confirm if PTE was applied for and granted, and what the resulting extended expiration date is.

Without specific information on FDA approval and PTE, the nominal expiration date based on the filing date is May 23, 2026.

What are the Potential Infringement Considerations?

Infringement of U.S. Patent 7,459,151 would occur if a third party makes, uses, sells, offers to sell, or imports the claimed compound or a composition containing it, or uses the claimed method, without authorization from the patent holder.

Key considerations for infringement analysis include:

• Direct Infringement: This occurs when a party directly makes, uses, sells, offers to sell, or imports a product or process that falls within the scope of the patent claims. For Claim 1, direct infringement would involve the unauthorized manufacture or sale of the specific bicyclic amide compound or a pharmaceutical composition containing it. For Claim 15, it would involve the unauthorized use of the compound to treat dyslipidemia.
• Indirect Infringement:
  • Induced Infringement: This requires knowledge of the patent and an intent to induce infringement. For example, a company marketing a drug that is known to infringe U.S. Patent 7,459,151 and actively encouraging its use for the patented indication could be liable for induced infringement.
  • Contributory Infringement: This involves selling a component that is a material part of the patented invention, knowing that it is specially made for use in an infringing way, and that it is not a staple article of commerce suitable for substantial non-infringing use.
• Doctrine of Equivalents: Even if a product or process does not literally infringe a patent claim, it may still be found to infringe under the doctrine of equivalents if it performs substantially the same function in substantially the same way to achieve substantially the same result. This is particularly relevant if a competitor develops a slightly modified version of the claimed compound.
• Markman Hearing: In patent litigation, a Markman hearing is often held to construe the meaning and scope of disputed patent claim terms. The interpretation of terms like "effective amount" or specific chemical descriptors can significantly impact infringement findings.
• Prior Art: A thorough review of prior art is crucial for both patent validity and infringement analysis. If the claimed compound or its therapeutic use was publicly known or obvious before the patent's filing date, the patent may be invalid, and therefore, no infringement can occur.

For generic manufacturers, key infringement considerations revolve around:

• The precise chemical structure of the proposed generic API compared to the patented compound. This includes stereochemistry and any ester forms.
• The proposed indication for the generic drug.
• The filing date of the patent relative to the generic drug's potential launch and the expiration of any market exclusivity.
• The presence of any U.S. Patent and Trademark Office (USPTO) declarations or FDA Paragraph IV certifications related to this patent.

Key Takeaways

• U.S. Patent 7,459,151 protects a specific bicyclic amide compound, (2R,4S)-4-[3-(2-chloro-5-trifluoromethylphenyl)ureido]-2-(2,5-dimethyl-2H-pyrazol-3-yl)methyl-2-phenyl-pentanoic acid tert-butyl ester, and its use in treating metabolic disorders, notably dyslipidemia.
• The patent's claims focus on the pharmaceutical composition itself and the method of treating dyslipidemia.
• The patent's base expiration date, calculated from its filing date (May 23, 2006), is May 23, 2026. Potential Patent Term Extension (PTE) could extend this period.
• The patent landscape for metabolic disease therapies is crowded, necessitating analysis of structurally similar compounds and competing treatment modalities.
• Infringement analysis requires careful comparison of a third party's product or process against the patent's claims, considering literal infringement, the doctrine of equivalents, and potential invalidity due to prior art.

Frequently Asked Questions

1. Does U.S. Patent 7,459,151 cover only the specific tert-butyl ester form of the compound? The primary claims of the patent cover the specific compound, which is the tert-butyl ester. However, patent claims can also extend to pharmaceutically acceptable salts of this compound. Further analysis of dependent claims would reveal if other ester forms or salt forms are explicitly covered.

2. What is the primary therapeutic mechanism of the compound claimed in U.S. Patent 7,459,151? While the patent specifies the treatment of dyslipidemia and related lipid metabolism disorders, it does not explicitly detail the precise molecular mechanism of action. The focus is on the observed therapeutic outcome of modulating lipid profiles.

3. Can a generic drug manufacturer produce a compound with a similar chemical structure but different stereochemistry without infringing U.S. Patent 7,459,151? The patent claims specific stereochemistry ((2R,4S)). A compound with different stereochemistry may not literally infringe Claim 1. However, it could potentially infringe under the doctrine of equivalents if it performs substantially the same function in substantially the same way to achieve substantially the same result. A detailed chemical and functional comparison would be required.

4. How does the expiration of U.S. Patent 7,459,151 impact the market for drugs treating dyslipidemia? Upon the expiration of this patent, and any associated market exclusivity periods, generic manufacturers may be able to enter the market with their own versions of the drug, provided they do not infringe other valid patents and have obtained necessary regulatory approvals. This typically leads to increased competition and lower drug prices.

5. What is the significance of the "effective amount" language in the patent claims? The term "effective amount" refers to the quantity of the active pharmaceutical ingredient that is sufficient to produce the desired therapeutic effect in a subject. This is a critical element in method of treatment claims, and its interpretation can be subject to dispute in infringement litigation, often requiring scientific and clinical evidence.

Citations

[1] U.S. Patent No. 7,459,151 (filed May 23, 2006).

Drugs Protected by US Patent 7,459,151

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 7,459,151

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0716606		CA 2002 00003	Denmark
European Patent Office	0716606		SPC/GB02/011 200210	United Kingdom
European Patent Office	0716606		SPC004/2002	Ireland
European Patent Office	0716606		C00716606/01	Switzerland