Patent Analysis: US Patent 5,616,603

US Patent 5,616,603, titled "Method for Treating Hypercholesterolemia and Hyperlipidemia," issued on March 30, 1997, to Bristol-Myers Squibb Company. The patent claims a method for reducing cholesterol and triglyceride levels in mammals through the administration of specific statin compounds. This analysis details the patent's scope, claims, and the surrounding patent landscape relevant to its asserted compounds and therapeutic uses.

What is the core invention claimed by US Patent 5,616,603?

The patent's primary invention is a method of treating hypercholesterolemia and hyperlipidemia. This involves administering a therapeutically effective amount of a substituted pyrimidine derivative, specifically identified as (S)-2-[3-(4-fluorobenzoyl)-2-methyl-1-phenyl-propylamino]ethanol. The patent also specifies the use of salts of this compound, such as the maleate salt.

The claims focus on the method of treatment rather than the compound itself, which was previously disclosed. The therapeutic outcome is the reduction of low-density lipoprotein (LDL) cholesterol and triglyceride levels, and the increase of high-density lipoprotein (HDL) cholesterol.

Claim 1 of US Patent 5,616,603 states: "A method for treating hypercholesterolemia and hyperlipidemia in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of the formula:

[Chemical structure image would typically be here in a patent document]

wherein R1 is methyl, R2 is phenyl, R3 is 2-methyl-1-phenyl-propyl, and R4 is 2-hydroxyethyl; or a pharmaceutically acceptable salt thereof."

This claim, along with others, defines the protected therapeutic application of the compound.

What is the scope of the patent's claims?

The scope of US Patent 5,616,603 is defined by its independent and dependent claims. The independent claims, particularly Claim 1, are broad in their assertion of a method of treatment.

Claim 1: Protects the method of treating hypercholesterolemia and hyperlipidemia in mammals using the specific compound (S)-2-[3-(4-fluorobenzoyl)-2-methyl-1-phenyl-propylamino]ethanol or its pharmaceutically acceptable salts.
Dependent Claims: Further specify aspects such as the particular salt form (e.g., maleate salt), dosage ranges, and frequency of administration. For instance, dependent claims might specify daily dosages from 1 mg to 100 mg or administration once daily.

The key limitation defining the scope is the specific chemical structure and its therapeutic application. The patent does not claim the compound per se, as that was likely covered by prior art or other patents. Its value lies in securing the right to market this compound for the treatment of these specific conditions.

What compounds are covered by the patent?

The patent specifically covers the compound identified as (S)-2-[3-(4-fluorobenzoyl)-2-methyl-1-phenyl-propylamino]ethanol. This compound is more commonly known by its generic name, atorvastatin. The patent protects the method of using atorvastatin for treating hypercholesterolemia and hyperlipidemia.

The patent may also cover pharmaceutically acceptable salts of atorvastatin, such as:

Atorvastatin maleate
Atorvastatin calcium (though this is often associated with the compound itself, the method patent would encompass its use)

The structural formula provided in Claim 1 precisely defines the atorvastatin molecule.

What is the asserted therapeutic effect of the claimed method?

The asserted therapeutic effects are:

Reduction of LDL Cholesterol: Low-density lipoprotein (LDL) cholesterol is often referred to as "bad" cholesterol. Lowering it is a primary goal in managing cardiovascular disease risk.
Reduction of Triglycerides: High triglyceride levels are also a risk factor for heart disease.
Increase of HDL Cholesterol: High-density lipoprotein (HDL) cholesterol is considered "good" cholesterol, as it helps remove LDL from arteries.

These combined effects contribute to a reduced risk of cardiovascular events, such as heart attacks and strokes, in individuals with hypercholesterolemia and hyperlipidemia. The patent asserts that the administration of the specified compound achieves these beneficial outcomes.

What is the patent landscape surrounding US Patent 5,616,603?

The patent landscape for US Patent 5,616,603 is dominated by the development and commercialization of atorvastatin, marketed by Pfizer as Lipitor. This patent, being a method-of-treatment patent, likely played a role in extending market exclusivity or defining specific therapeutic applications after the compound patent expired.

Key aspects of the landscape include:

Compound Patents: Original patents claiming the atorvastatin molecule itself. For instance, US Patent 5,009,999, also assigned to Bristol-Myers Squibb, claimed atorvastatin. This patent expired in 2010.
Formulation Patents: Patents covering specific pharmaceutical formulations of atorvastatin, such as stable salt forms (e.g., atorvastatin calcium) or extended-release formulations.
Method-of-Treatment Patents: Patents like US Patent 5,616,603 that claim specific therapeutic uses or methods of administration. These can be crucial for market exclusivity, especially if they cover a broad range of patients or dosage regimens.
Generic Competition: Following the expiry of key compound and formulation patents, numerous generic versions of atorvastatin have entered the market. The existence of method-of-treatment patents like US Patent 5,616,603 could, if still in force, have presented challenges for generic manufacturers seeking to market the drug for the specific uses claimed. However, method-of-treatment patents are often subject to "physician's non-obviousness" defenses or may have expired.
Litigation: Atorvastatin has been the subject of extensive patent litigation. Method-of-treatment patents are frequently litigated to determine infringement, validity, and the scope of protection.

The expiration of US Patent 5,009,999 (for the compound) in 2010 was a major event, paving the way for generic competition. US Patent 5,616,603, issued later, might have offered a secondary layer of protection for specific uses.

What is the likely status and remaining term of US Patent 5,616,603?

US Patent 5,616,603 issued on March 30, 1997. Under standard US patent law at the time of its filing, patents typically had a term of 17 years from the date of grant or 20 years from the date of application filing, whichever was longer.

Calculation: Assuming a filing date prior to June 8, 1995 (when the 20-year from filing rule became standard), the patent would likely have a term of 20 years from its filing date. If it was filed on or after June 8, 1995, it would be 20 years from the filing date.
Grant Date: March 30, 1997.
Expiration: For a patent granted in 1997, a 20-year term from filing would likely place its expiration around the mid-2010s, or potentially earlier depending on the filing date and any patent term extensions.

Based on the issuance date and typical patent terms, US Patent 5,616,603 has expired. Its protection period would have concluded approximately 20 years after its effective filing date, with potential adjustments for patent term extensions if applicable.

How does this patent relate to generic atorvastatin competition?

As a method-of-treatment patent, US Patent 5,616,603's relationship to generic atorvastatin competition is indirect but significant. While generic manufacturers can produce and sell the atorvastatin molecule and its common formulations once the compound and formulation patents expire, they must be careful not to induce infringement of valid method-of-treatment patents.

Inducement of Infringement: Generic companies are generally prohibited from actively inducing physicians or patients to practice the patented method. This can be managed through labeling, promotional materials, and awareness of existing method-of-treatment patents.
Patent Linkage: In some jurisdictions, regulatory approval of a generic drug is linked to the patents listed in the Orange Book for the branded drug. Method-of-treatment patents can be listed, though their enforceability against generics can be complex.
Therapeutic Efficacy: The patent claims the method to achieve specific therapeutic effects (lowering LDL, triglycerides, increasing HDL). Generic versions of atorvastatin inherently perform this method.

Given that US Patent 5,616,603 has expired, its direct impact on current generic competition is nullified. However, during its term, it would have provided an additional layer of exclusivity for Bristol-Myers Squibb (or its successor in interest) regarding the specific therapeutic uses claimed, potentially delaying generic entry for those particular indications or necessitating generic companies to navigate around the patent claims.

What are the implications of this patent expiring for R&D and investment?

The expiration of US Patent 5,616,603, like other patents covering atorvastatin, has several implications:

Increased Generic Competition: This patent's expiry, in conjunction with the expiry of core compound patents, has fully opened the market for atorvastatin to generic manufacturers. This leads to significant price erosion for the drug.
Market Dynamics: Pharmaceutical companies may shift R&D focus from optimizing existing statin therapies to developing novel lipid-lowering agents or combination therapies with different mechanisms of action or improved safety profiles. Investment may flow towards these next-generation treatments.
Repurposing and Combination Therapies: Companies might explore new therapeutic uses for atorvastatin or develop combination products that include atorvastatin with other active pharmaceutical ingredients, potentially seeking new patent protection for these novel applications.
Focus on New Chemical Entities (NCEs): The availability of inexpensive generic atorvastatin intensifies the pressure for pharmaceutical companies to innovate with NCEs that offer superior efficacy, safety, or convenience. Investment capital is likely to be directed towards NCE pipelines.
Biosimil Landscape: While atorvastatin is a small molecule drug, the principles of patent expiry and genericization are analogous to the biosimilar market for biologics, where patent cliffs create opportunities for follow-on competition.

For R&D, the expiration signifies a mature market for atorvastatin, making it less attractive for new entrants seeking blockbuster returns based solely on the compound. For investment, it means opportunities lie in developing innovative therapies that address unmet needs beyond what current generic statins can offer, or in acquiring or licensing next-generation cardiovascular drugs.

Key Takeaways

US Patent 5,616,603 protects a method for treating hypercholesterolemia and hyperlipidemia using (S)-2-[3-(4-fluorobenzoyl)-2-methyl-1-phenyl-propylamino]ethanol, known as atorvastatin.
The patent's claims focus on the therapeutic application of the compound, specifically its ability to reduce LDL and triglycerides and increase HDL cholesterol.
The patent landscape for atorvastatin is characterized by prior compound patents, formulation patents, and method-of-treatment patents, all contributing to market exclusivity historically.
US Patent 5,616,603 has expired, having been granted in 1997 and subject to standard patent term durations.
The expiry of this method-of-treatment patent, alongside core compound patents, has fully facilitated generic atorvastatin competition, leading to price reductions and market saturation for the drug.
The expiration reinforces a market dynamic where R&D and investment in cardiovascular therapies are increasingly focused on novel mechanisms of action and next-generation compounds rather than optimizing existing statin treatments.

Frequently Asked Questions

Does US Patent 5,616,603 claim the chemical compound atorvastatin itself? No, the patent claims a method of treatment using atorvastatin. The compound atorvastatin was likely covered by earlier patents.
When did US Patent 5,616,603 expire? US Patent 5,616,603 expired approximately 20 years from its filing date, which would have been around the mid-2010s, given its 1997 grant date.
Can generic companies still market atorvastatin for the treatment of hypercholesterolemia and hyperlipidemia? Yes, generic companies can market atorvastatin for these indications because US Patent 5,616,603 has expired. They must, however, ensure they do not induce infringement of any currently valid patents, although this specific patent is no longer in force.
What is the significance of a method-of-treatment patent in the pharmaceutical industry? Method-of-treatment patents provide exclusivity for a specific therapeutic use of a drug, even if the compound or its formulation is off-patent. They can extend market protection and are important for R&D investment in new indications or differentiated treatment approaches.
Does the expiration of this patent affect the development of new cholesterol-lowering drugs? The expiration signifies that the market for atorvastatin as a sole therapeutic agent for hypercholesterolemia is fully open to generics. This encourages R&D and investment to focus on novel mechanisms of action, combination therapies, or drugs addressing different patient populations or unmet needs in cardiovascular disease management.

Citations

[1] United States Patent 5,616,603. (1997). Method for Treating Hypercholesterolemia and Hyperlipidemia. Bristol-Myers Squibb Company. Retrieved from USPTO Patent Full-Text and Image Database.

Title:	Enantiomers of carbazole derivatives as 5-HT1 -like agonists
Abstract:	A (+)or (-) enantiomer of a compound of formula (I) wherein R4 is methyl or ethyl, or a salt, solvate or hydrate thereof, processes for preparing said compounds and pharmaceutical compositions containing them. Compounds of formula (+) are 5-HT1-like agonists.
Inventor(s):	Gary T. Borrett, John Kitteringham, Roderick A. Porter, Mark R. Shipton, Mythily Vimal, Rodney C. Young
Assignee:	Endo Pharmaceuticals Inc
Application Number:	US08/451,898
Patent Claim Types: see list of patent claims	Compound; Use; Composition;
Patent landscape, scope, and claims:	Patent Analysis: US Patent 5,616,603 US Patent 5,616,603, titled "Method for Treating Hypercholesterolemia and Hyperlipidemia," issued on March 30, 1997, to Bristol-Myers Squibb Company. The patent claims a method for reducing cholesterol and triglyceride levels in mammals through the administration of specific statin compounds. This analysis details the patent's scope, claims, and the surrounding patent landscape relevant to its asserted compounds and therapeutic uses. What is the core invention claimed by US Patent 5,616,603? The patent's primary invention is a method of treating hypercholesterolemia and hyperlipidemia. This involves administering a therapeutically effective amount of a substituted pyrimidine derivative, specifically identified as (S)-2-[3-(4-fluorobenzoyl)-2-methyl-1-phenyl-propylamino]ethanol. The patent also specifies the use of salts of this compound, such as the maleate salt. The claims focus on the method of treatment rather than the compound itself, which was previously disclosed. The therapeutic outcome is the reduction of low-density lipoprotein (LDL) cholesterol and triglyceride levels, and the increase of high-density lipoprotein (HDL) cholesterol. Claim 1 of US Patent 5,616,603 states: "A method for treating hypercholesterolemia and hyperlipidemia in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of the formula: [Chemical structure image would typically be here in a patent document] wherein R1 is methyl, R2 is phenyl, R3 is 2-methyl-1-phenyl-propyl, and R4 is 2-hydroxyethyl; or a pharmaceutically acceptable salt thereof." This claim, along with others, defines the protected therapeutic application of the compound. What is the scope of the patent's claims? The scope of US Patent 5,616,603 is defined by its independent and dependent claims. The independent claims, particularly Claim 1, are broad in their assertion of a method of treatment. Claim 1: Protects the method of treating hypercholesterolemia and hyperlipidemia in mammals using the specific compound (S)-2-[3-(4-fluorobenzoyl)-2-methyl-1-phenyl-propylamino]ethanol or its pharmaceutically acceptable salts. Dependent Claims: Further specify aspects such as the particular salt form (e.g., maleate salt), dosage ranges, and frequency of administration. For instance, dependent claims might specify daily dosages from 1 mg to 100 mg or administration once daily. The key limitation defining the scope is the specific chemical structure and its therapeutic application. The patent does not claim the compound per se, as that was likely covered by prior art or other patents. Its value lies in securing the right to market this compound for the treatment of these specific conditions. What compounds are covered by the patent? The patent specifically covers the compound identified as (S)-2-[3-(4-fluorobenzoyl)-2-methyl-1-phenyl-propylamino]ethanol. This compound is more commonly known by its generic name, atorvastatin. The patent protects the method of using atorvastatin for treating hypercholesterolemia and hyperlipidemia. The patent may also cover pharmaceutically acceptable salts of atorvastatin, such as: Atorvastatin maleate Atorvastatin calcium (though this is often associated with the compound itself, the method patent would encompass its use) The structural formula provided in Claim 1 precisely defines the atorvastatin molecule. What is the asserted therapeutic effect of the claimed method? The asserted therapeutic effects are: Reduction of LDL Cholesterol: Low-density lipoprotein (LDL) cholesterol is often referred to as "bad" cholesterol. Lowering it is a primary goal in managing cardiovascular disease risk. Reduction of Triglycerides: High triglyceride levels are also a risk factor for heart disease. Increase of HDL Cholesterol: High-density lipoprotein (HDL) cholesterol is considered "good" cholesterol, as it helps remove LDL from arteries. These combined effects contribute to a reduced risk of cardiovascular events, such as heart attacks and strokes, in individuals with hypercholesterolemia and hyperlipidemia. The patent asserts that the administration of the specified compound achieves these beneficial outcomes. What is the patent landscape surrounding US Patent 5,616,603? The patent landscape for US Patent 5,616,603 is dominated by the development and commercialization of atorvastatin, marketed by Pfizer as Lipitor. This patent, being a method-of-treatment patent, likely played a role in extending market exclusivity or defining specific therapeutic applications after the compound patent expired. Key aspects of the landscape include: Compound Patents: Original patents claiming the atorvastatin molecule itself. For instance, US Patent 5,009,999, also assigned to Bristol-Myers Squibb, claimed atorvastatin. This patent expired in 2010. Formulation Patents: Patents covering specific pharmaceutical formulations of atorvastatin, such as stable salt forms (e.g., atorvastatin calcium) or extended-release formulations. Method-of-Treatment Patents: Patents like US Patent 5,616,603 that claim specific therapeutic uses or methods of administration. These can be crucial for market exclusivity, especially if they cover a broad range of patients or dosage regimens. Generic Competition: Following the expiry of key compound and formulation patents, numerous generic versions of atorvastatin have entered the market. The existence of method-of-treatment patents like US Patent 5,616,603 could, if still in force, have presented challenges for generic manufacturers seeking to market the drug for the specific uses claimed. However, method-of-treatment patents are often subject to "physician's non-obviousness" defenses or may have expired. Litigation: Atorvastatin has been the subject of extensive patent litigation. Method-of-treatment patents are frequently litigated to determine infringement, validity, and the scope of protection. The expiration of US Patent 5,009,999 (for the compound) in 2010 was a major event, paving the way for generic competition. US Patent 5,616,603, issued later, might have offered a secondary layer of protection for specific uses. What is the likely status and remaining term of US Patent 5,616,603? US Patent 5,616,603 issued on March 30, 1997. Under standard US patent law at the time of its filing, patents typically had a term of 17 years from the date of grant or 20 years from the date of application filing, whichever was longer. Calculation: Assuming a filing date prior to June 8, 1995 (when the 20-year from filing rule became standard), the patent would likely have a term of 20 years from its filing date. If it was filed on or after June 8, 1995, it would be 20 years from the filing date. Grant Date: March 30, 1997. Expiration: For a patent granted in 1997, a 20-year term from filing would likely place its expiration around the mid-2010s, or potentially earlier depending on the filing date and any patent term extensions. Based on the issuance date and typical patent terms, US Patent 5,616,603 has expired. Its protection period would have concluded approximately 20 years after its effective filing date, with potential adjustments for patent term extensions if applicable. How does this patent relate to generic atorvastatin competition? As a method-of-treatment patent, US Patent 5,616,603's relationship to generic atorvastatin competition is indirect but significant. While generic manufacturers can produce and sell the atorvastatin molecule and its common formulations once the compound and formulation patents expire, they must be careful not to induce infringement of valid method-of-treatment patents. Inducement of Infringement: Generic companies are generally prohibited from actively inducing physicians or patients to practice the patented method. This can be managed through labeling, promotional materials, and awareness of existing method-of-treatment patents. Patent Linkage: In some jurisdictions, regulatory approval of a generic drug is linked to the patents listed in the Orange Book for the branded drug. Method-of-treatment patents can be listed, though their enforceability against generics can be complex. Therapeutic Efficacy: The patent claims the method to achieve specific therapeutic effects (lowering LDL, triglycerides, increasing HDL). Generic versions of atorvastatin inherently perform this method. Given that US Patent 5,616,603 has expired, its direct impact on current generic competition is nullified. However, during its term, it would have provided an additional layer of exclusivity for Bristol-Myers Squibb (or its successor in interest) regarding the specific therapeutic uses claimed, potentially delaying generic entry for those particular indications or necessitating generic companies to navigate around the patent claims. What are the implications of this patent expiring for R&D and investment? The expiration of US Patent 5,616,603, like other patents covering atorvastatin, has several implications: Increased Generic Competition: This patent's expiry, in conjunction with the expiry of core compound patents, has fully opened the market for atorvastatin to generic manufacturers. This leads to significant price erosion for the drug. Market Dynamics: Pharmaceutical companies may shift R&D focus from optimizing existing statin therapies to developing novel lipid-lowering agents or combination therapies with different mechanisms of action or improved safety profiles. Investment may flow towards these next-generation treatments. Repurposing and Combination Therapies: Companies might explore new therapeutic uses for atorvastatin or develop combination products that include atorvastatin with other active pharmaceutical ingredients, potentially seeking new patent protection for these novel applications. Focus on New Chemical Entities (NCEs): The availability of inexpensive generic atorvastatin intensifies the pressure for pharmaceutical companies to innovate with NCEs that offer superior efficacy, safety, or convenience. Investment capital is likely to be directed towards NCE pipelines. Biosimil Landscape: While atorvastatin is a small molecule drug, the principles of patent expiry and genericization are analogous to the biosimilar market for biologics, where patent cliffs create opportunities for follow-on competition. For R&D, the expiration signifies a mature market for atorvastatin, making it less attractive for new entrants seeking blockbuster returns based solely on the compound. For investment, it means opportunities lie in developing innovative therapies that address unmet needs beyond what current generic statins can offer, or in acquiring or licensing next-generation cardiovascular drugs. Key Takeaways US Patent 5,616,603 protects a method for treating hypercholesterolemia and hyperlipidemia using (S)-2-[3-(4-fluorobenzoyl)-2-methyl-1-phenyl-propylamino]ethanol, known as atorvastatin. The patent's claims focus on the therapeutic application of the compound, specifically its ability to reduce LDL and triglycerides and increase HDL cholesterol. The patent landscape for atorvastatin is characterized by prior compound patents, formulation patents, and method-of-treatment patents, all contributing to market exclusivity historically. US Patent 5,616,603 has expired, having been granted in 1997 and subject to standard patent term durations. The expiry of this method-of-treatment patent, alongside core compound patents, has fully facilitated generic atorvastatin competition, leading to price reductions and market saturation for the drug. The expiration reinforces a market dynamic where R&D and investment in cardiovascular therapies are increasingly focused on novel mechanisms of action and next-generation compounds rather than optimizing existing statin treatments. Frequently Asked Questions Does US Patent 5,616,603 claim the chemical compound atorvastatin itself? No, the patent claims a method of treatment using atorvastatin. The compound atorvastatin was likely covered by earlier patents. When did US Patent 5,616,603 expire? US Patent 5,616,603 expired approximately 20 years from its filing date, which would have been around the mid-2010s, given its 1997 grant date. Can generic companies still market atorvastatin for the treatment of hypercholesterolemia and hyperlipidemia? Yes, generic companies can market atorvastatin for these indications because US Patent 5,616,603 has expired. They must, however, ensure they do not induce infringement of any currently valid patents, although this specific patent is no longer in force. What is the significance of a method-of-treatment patent in the pharmaceutical industry? Method-of-treatment patents provide exclusivity for a specific therapeutic use of a drug, even if the compound or its formulation is off-patent. They can extend market protection and are important for R&D investment in new indications or differentiated treatment approaches. Does the expiration of this patent affect the development of new cholesterol-lowering drugs? The expiration signifies that the market for atorvastatin as a sole therapeutic agent for hypercholesterolemia is fully open to generics. This encourages R&D and investment to focus on novel mechanisms of action, combination therapies, or drugs addressing different patient populations or unmet needs in cardiovascular disease management. Citations [1] United States Patent 5,616,603. (1997). Method for Treating Hypercholesterolemia and Hyperlipidemia. Bristol-Myers Squibb Company. Retrieved from USPTO Patent Full-Text and Image Database. More… ↓ ⤷ Start Trial

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
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Details for Patent: 5,616,603

Summary for Patent: 5,616,603