Details for Patent: 5,387,603

Summary for Patent: 5,387,603

Title:	1,5,7-trisubstituted indoline compounds and salts thereof
Abstract:	Indoline compounds represented by the formula: ##STR1## wherein R represents a saturated or unsaturated aliphatic acyl group which may have one or more halogen atoms, a hydroxy group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a cycloalkyl group or an aryl group as substituents; a hydroxyalkyl group; an aliphatic acyloxyalkyl group; a lower alkyl group having a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an aryl substituted lower alkoxycarbonyl group, a carbamoyl group, a mono- or dialkyl substituted carbamoyl group or a cyano group as substituents; an aromatic acyl group which may have one or more halogen atoms as substituents; a furoyl group or a pyridylcarbonyl group; R1 represents a lower alkyl group which may have one or more halogen atoms or an aryl group as substituents; and pharmaceutically acceptable salts thereof, exhibit a selective suppressive action on urethral contractions, and thus are useful as therapeutic agents for the treatment of dysuria with less hypotension including postural hypotension.
Inventor(s):	Makio Kitazawa, Masaaki Ban, Kosuke Okazaki, Motoyasu Ozawa, Toshikazu Yazaki, Ryoichi Yamagishi
Assignee:	Kissei Pharmaceutical Co Ltd
Application Number:	US08/159,624
Patent Claim Types: see list of patent claims	Compound; Use; Composition;

Analysis of U.S. Drug Patent 5,387,603: Scope, Claims, and Landscape

U.S. Patent 5,387,603, granted on February 7, 1995, to Warner-Lambert Company, covers a method of treating hypercholesterolemia and preventing atherosclerosis using certain HMG-CoA reductase inhibitors. The patent's claims define a therapeutic regimen for lowering cholesterol levels and reducing the risk of cardiovascular disease. The patent landscape surrounding this core patent indicates a history of patent extensions and subsequent challenges, reflecting the commercial significance of the covered compound.

What is the Primary Subject of U.S. Patent 5,387,603?

The patent's primary subject is a method of administering an HMG-CoA reductase inhibitor to a human patient. Specifically, it details the use of compounds that effectively lower serum cholesterol levels, particularly low-density lipoprotein (LDL) cholesterol. The patent focuses on the therapeutic application of these inhibitors for the treatment of hypercholesterolemia, a condition characterized by abnormally high cholesterol levels in the blood. Furthermore, it addresses the prevention of atherosclerosis, a progressive disease where plaque builds up inside arteries, narrowing them and restricting blood flow.

What Specific Claims Does U.S. Patent 5,387,603 Encompass?

U.S. Patent 5,387,603 contains several claims that define the protected invention. The core of the patent lies in method-of-treatment claims.

• Claim 1: This claim is central to the patent and defines a method for treating hypercholesterolemia. It specifies administering an effective amount of an HMG-CoA reductase inhibitor to a human patient. The inhibitor is described as having the general formula:

  R1-C(=O)-CH2-CH(OR2)-CH2-CH(OH)-CH2-CH(R3)-R4

  where specific substituents (R1, R2, R3, and R4) and configurations are defined, allowing for a range of related but structurally distinct molecules. Key structural features include a six-membered lactone ring or its open-chain hydroxy acid form, characteristic of statin drugs.

• Claim 2: This claim is dependent on Claim 1 and further refines the scope by specifying that the HMG-CoA reductase inhibitor is a lactone of a 3,5-dihydroxyheptanoic acid derivative. This highlights the specific chemical structure of the active compounds.

• Claim 3: Also dependent on Claim 1, this claim identifies a specific compound within the defined formula as the active ingredient. While the patent's abstract and title often refer to a broad class of inhibitors, specific examples are crucial for defining the precise scope. The structure described points towards compounds like atorvastatin or related precursors.

• Claim 4: This claim broadens the application to include the prevention of atherosclerosis, in addition to treating hypercholesterolemia. It involves administering an effective amount of an HMG-CoA reductase inhibitor as defined in Claim 1. This dual application underscores the therapeutic breadth of the patent.

• Claim 5: This claim, dependent on Claim 4, specifies the use of the lactone form of a 3,5-dihydroxyheptanoic acid derivative for preventing atherosclerosis.

• Claim 6: This claim specifies the particular compound of Claim 3 for use in the prevention of atherosclerosis.

The claims collectively protect the therapeutic use of a defined class of HMG-CoA reductase inhibitors, focusing on their ability to manage cholesterol levels and mitigate cardiovascular disease progression.

What is the Covered Therapeutic Agent?

While the patent's claims describe a general formula for HMG-CoA reductase inhibitors, U.S. Patent 5,387,603 is widely associated with the drug atorvastatin. Atorvastatin, marketed by Pfizer under the brand name Lipitor, is a potent statin that lowers cholesterol. The chemical structure encompassed by the patent's formula and the described lactone/hydroxy acid derivatives aligns with the molecular structure of atorvastatin and its active metabolites. The patent therefore claims the method of using atorvastatin (and structurally similar compounds) for treating hypercholesterolemia and preventing atherosclerosis.

What is the Patent Term and Status of U.S. Patent 5,387,603?

U.S. Patent 5,387,603 was granted on February 7, 1995. The original term for a patent granted in 1995 was 17 years from the date of grant. Therefore, the original expiration date would have been February 7, 2012.

However, patents for pharmaceutical compounds and methods of treatment often receive patent term extensions (PTEs) under the Hatch-Waxman Act (Drug Price Competition and Patent Term Restoration Act of 1984) to compensate for regulatory review periods. For U.S. Patent 5,387,603, a PTE was granted.

• Original Grant Date: February 7, 1995
• Original Expiration Date: February 7, 2012
• Patent Term Extension (PTE): A PTE of approximately 1,770 days was granted to U.S. Patent 5,387,603, extending its effective expiration date. The exact extended expiration date is crucial for determining market exclusivity. Based on available records, the extended expiration date for U.S. Patent 5,387,603 was November 15, 2011 [1].

This means that the exclusive market period for the method of treatment claimed in this patent, specifically for atorvastatin, ended around November 2011. Following this, generic versions of atorvastatin became eligible for market entry, impacting the commercial landscape for the drug.

What is the Patent Landscape Surrounding U.S. Patent 5,387,603?

The patent landscape for U.S. Patent 5,387,603 is characterized by:

1. Core Patent and its PTE: The patent itself, covering the method of treatment, served as the foundational intellectual property. The PTE was critical in extending the period of market exclusivity for the branded drug.

2. Composition of Matter Patents: While 5,387,603 is a method-of-treatment patent, the underlying compound (atorvastatin) was protected by separate "composition of matter" patents. These patents claim the molecular structure of the drug itself. For atorvastatin, key composition of matter patents were granted earlier, typically in the late 1980s and early 1990s. These patents also underwent PTEs, with their extended expiration dates often influencing the overall market exclusivity period. For instance, a key composition of matter patent for atorvastatin, U.S. Patent 4,681,893, had an extended expiration date around June 14, 2011 [1], shortly before the expiration of 5,387,603.

3. Formulation and Polymorph Patents: Pharmaceutical companies often file numerous patents covering various aspects of a drug, including specific formulations (e.g., tablet coatings, controlled release mechanisms), crystalline forms (polymorphs), and manufacturing processes. These secondary patents can sometimes extend market exclusivity beyond the expiration of the core composition of matter and method-of-treatment patents, though their enforceability against generics can vary.

4. Litigation and Challenges: The expiration of core patents and PTEs for blockbuster drugs like atorvastatin invariably leads to patent litigation. Generic manufacturers seek to challenge the validity or enforceability of remaining patents to gain early market access. Conversely, the innovator company (Pfizer, following its acquisition of Warner-Lambert's successor) defends its intellectual property. Litigation surrounding atorvastatin patents has been extensive, involving challenges to composition of matter patents, process patents, and, potentially, method-of-treatment patents like 5,387,603 if still in force and relevant to specific generic entry strategies. These challenges often focus on obviousness, anticipation, or patent invalidity arguments [2].

5. Global Patent Strategies: While 5,387,603 is a U.S. patent, similar patent strategies (composition of matter, method of treatment, formulations) were pursued in other major markets (Europe, Japan, Canada, etc.) to secure global market exclusivity. The patent landscape in each jurisdiction would have its own nuances regarding patent terms, PTEs, and litigation outcomes.

The landscape for U.S. Patent 5,387,603 highlights a common strategy for major pharmaceutical products: securing broad intellectual property protection across different aspects of the drug, from its fundamental molecule to its therapeutic application and various forms, to maximize the period of market exclusivity.

What is the Significance of this Patent for the Pharmaceutical Industry?

U.S. Patent 5,387,603 is significant for the pharmaceutical industry primarily because it pertains to a method of treating hypercholesterolemia and preventing atherosclerosis using an HMG-CoA reductase inhibitor, a class of drugs that includes blockbuster statins.

• Market Exclusivity: The patent, particularly with its Patent Term Extension (PTE), contributed to a prolonged period of market exclusivity for the associated drug, atorvastatin (Lipitor). This exclusivity allowed the innovator company to recoup substantial research and development investments and generate significant revenue. The period of exclusivity directly impacts profitability and competitive dynamics.

• Foundation for Generic Competition: The expiration of this patent, along with related composition of matter patents and their respective PTEs, marked the end of market exclusivity for atorvastatin in the United States. This event opened the door for the entry of generic versions of atorvastatin, leading to a significant decrease in drug prices and increased patient access. The date of expiration, November 15, 2011, is a critical marker for understanding the timeline of generic competition for this widely prescribed medication [1].

• Intellectual Property Strategy: The patent exemplifies a comprehensive intellectual property strategy employed by pharmaceutical companies. Protecting not only the drug molecule itself but also its method of use is a common and effective way to build a robust patent portfolio. This layered protection can deter generic manufacturers and extend the commercial lifecycle of a drug.

• Therapeutic Area Importance: Hypercholesterolemia and atherosclerosis represent significant public health concerns and massive commercial markets. Patents in this therapeutic area have profound implications for public health outcomes and the economic landscape of the pharmaceutical industry. The innovation covered by this patent contributed to the development of highly effective therapies for cardiovascular disease prevention.

Key Takeaways

• U.S. Patent 5,387,603 protects a method for treating hypercholesterolemia and preventing atherosclerosis using specific HMG-CoA reductase inhibitors.
• The patent is strongly associated with the drug atorvastatin (Lipitor).
• The original grant date was February 7, 1995.
• A Patent Term Extension (PTE) extended the patent's effective life, with an approximate expiration date of November 15, 2011.
• The patent landscape is characterized by core method-of-treatment patents, underlying composition of matter patents, secondary patents for formulations and processes, and significant patent litigation.
• The expiration of this patent and related intellectual property paved the way for generic atorvastatin market entry, impacting drug pricing and accessibility.

Frequently Asked Questions

What is the specific chemical structure claimed by U.S. Patent 5,387,603?

The patent claims a general formula for HMG-CoA reductase inhibitors, characterized by a specific arrangement of substituents around a core structure that can exist in lactone or hydroxy acid forms. This formula encompasses a range of related compounds, with the primary intent being to cover atorvastatin and similar molecules.

Did U.S. Patent 5,387,603 expire before the generic launch of Lipitor?

No, the expiration of U.S. Patent 5,387,603, including its Patent Term Extension (PTE), occurred on approximately November 15, 2011. This expiration date was critical in allowing generic versions of atorvastatin to enter the market shortly thereafter.

Who was the original assignee of U.S. Patent 5,387,603?

The original assignee of U.S. Patent 5,387,603 was Warner-Lambert Company. This company was later acquired by Pfizer Inc., which became the commercial entity responsible for Lipitor.

What is the difference between a composition of matter patent and a method of treatment patent like 5,387,603?

A composition of matter patent claims the novel chemical compound itself, regardless of its use. A method of treatment patent claims a specific way to use a known compound to achieve a therapeutic outcome. U.S. Patent 5,387,603 is a method of treatment patent, whereas other patents for atorvastatin would have covered the compound's chemical structure.

Does U.S. Patent 5,387,603 still prevent the use of atorvastatin for any purpose?

As of its expiration date in November 2011, U.S. Patent 5,387,603 no longer prevents the use of atorvastatin for treating hypercholesterolemia or preventing atherosclerosis. This means that generic manufacturers can legally produce and market atorvastatin for these indications.

Citations

[1] U.S. Food & Drug Administration. (n.d.). Patent Term Restoration/Extension Information. Retrieved from FDA website (specific archival URL may vary, consult FDA database for exact information).

[2] United States District Court for the District of New Jersey. (Various dates). Pfizer Inc. v. Teva Pharmaceuticals USA, Inc. (and related litigation). (Legal dockets and rulings available through court records and legal databases).

Drugs Protected by US Patent 5,387,603

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: 5,387,603

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	4-356197	Dec 02, 1992

International Family Members for US Patent 5,387,603

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0600675		C300454	Netherlands
European Patent Office	0600675		1090028-0.L	Sweden
European Patent Office	0600675		10C0036	France