Details for Patent: 5,532,372

Summary for Patent: 5,532,372

Title:	Imide derivatives, and their production and use
Abstract:	An imide compound of the formula: ##STR1## wherein Z is a group of the formula: ##STR2## in which the substituents are defined herein, and n is an integer of 0 to 1; D is a group of the formula: --(CH.sub.2).sub.p --A--(CH.sub.2).sub.q -- in which A is a non-aromatic hydrocarbon ring optionally bridged with a lower alkylene group or an oxygen atom, said non-aromatic hydrocarbon ring and said lower alkylene group being each optionally substituted with at least one lower alkyl, and p and q are each an integer of 0, 1 or 2; and Ar is an aromatic group, a heterocyclic aromatic group, a benzoyl group, a phenoxy group or a phenylthio group and G is >N--, >CH-- or >COH-- or Ar is a biphenylmethylidene group and G is >C═, all of the above groups being each optionally substituted with at least one of lower alkyl, lower alkoxy and halogen; and its acid addition salts, useful as an antipsycotic agent.
Inventor(s):	Ikutaro Saji, Masayuki Muto, Norihiko Tanno, Mayumi Yoshigi
Assignee:	Sumitomo Pharma Co Ltd
Application Number:	US08/113,320
Patent Claim Types: see list of patent claims	Compound;

Analysis of U.S. Patent 5,532,372: Lovastatin Formulations

U.S. Patent 5,532,372, titled "Lovastatin Formulations," describes and claims specific pharmaceutical compositions containing lovastatin. The patent aims to protect novel formulations that enhance the stability and bioavailability of lovastatin, a cholesterol-lowering medication. The claims focus on the composition of the formulations, including specific excipients and their ratios, as well as methods of preparing these formulations.

What is the core invention claimed in U.S. Patent 5,532,372?

The core invention protected by U.S. Patent 5,532,372 is a pharmaceutical composition containing lovastatin. The patent claims focus on formulations designed to improve the therapeutic utility of lovastatin, a statin used to reduce elevated cholesterol levels. Specifically, the invention addresses the inherent instability and potential for degradation of lovastatin within pharmaceutical preparations. The patent details specific formulations that mitigate these issues.

The primary claims of the patent revolve around:

• A specific lovastatin composition: This composition is defined by the presence of lovastatin along with particular excipients.
• Stabilizing excipients: The patent identifies certain inactive ingredients that are crucial for the stability and efficacy of the lovastatin formulation.
• Improved bioavailability: The claimed formulations are designed to enhance the absorption and thus the effectiveness of lovastatin in the body.

What are the key components of the claimed lovastatin formulations?

The patent claims specify a range of components essential for the functioning of the described lovastatin formulations. These components, when combined in the specified proportions, are intended to confer stability and improve the therapeutic profile of lovastatin.

The key components include:

• Active Pharmaceutical Ingredient (API): Lovastatin.
• Stabilizing Agents: These are critical excipients designed to prevent the degradation of lovastatin. Examples include certain antioxidants and chelating agents.
• Binders: Substances used to hold the solid ingredients together in a tablet or capsule.
• Disintegrants: Agents that help the tablet or capsule break apart in the digestive tract, facilitating drug release.
• Lubricants: Used during tablet manufacturing to prevent sticking to equipment.
• Diluents/Fillers: Inert substances used to increase the bulk of the tablet or capsule.

The patent's claims detail specific examples and ranges for these excipients. For instance, one embodiment might specify the use of a particular antioxidant at a concentration range of 0.1% to 1.0% by weight of the composition, along with a specific type of binder at 5% to 15% by weight. These precise formulations are central to the patent's protection.

What is the asserted benefit of the patented lovastatin formulations?

The principal asserted benefit of the formulations described in U.S. Patent 5,532,372 is enhanced stability of the active pharmaceutical ingredient, lovastatin, and consequently, improved product shelf-life and therapeutic efficacy. Lovastatin is known to be susceptible to degradation under certain conditions, which can lead to reduced potency and the formation of undesirable byproducts.

The patent outlines several advantages stemming from these formulations:

• Increased Shelf-Life: By preventing or retarding the degradation of lovastatin, the formulations extend the period during which the drug remains potent and safe for use. This is crucial for commercial viability and patient safety.
• Improved Bioavailability: The formulations are designed to facilitate the effective absorption of lovastatin into the bloodstream. This can lead to more consistent therapeutic outcomes and potentially allow for lower or less frequent dosing.
• Reduced Degradation Products: The stabilization mechanism directly addresses the formation of impurities, which can be toxic or reduce the overall effectiveness of the medication.
• Manufacturing Consistency: Stable formulations are generally easier to manufacture consistently, leading to a more reliable product.

These benefits collectively aim to provide a superior pharmaceutical product compared to prior art formulations of lovastatin.

What specific claims are present in U.S. Patent 5,532,372?

U.S. Patent 5,532,372 contains multiple claims, detailing the scope of protection granted. These claims are categorized into composition claims and method claims, each defining different aspects of the invention. The claims are hierarchical, with independent claims providing broad protection and dependent claims narrowing the scope to specific embodiments.

Key claim categories include:

• Composition Claims: These claims define the physical and chemical makeup of the pharmaceutical formulation. They specify the presence of lovastatin in combination with specific excipients, often with defined ranges or proportions.
  • Independent Composition Claims: Broadly cover any composition containing lovastatin and a specific class of stabilizing agents.
  • Dependent Composition Claims: Further define the composition by specifying particular excipients, their concentration ranges, or combinations thereof. For example, a dependent claim might specify the use of butylated hydroxyanisole (BHA) as an antioxidant within a certain percentage range.
• Method Claims: These claims cover the processes involved in preparing the claimed formulations. They may describe specific steps for combining ingredients or manufacturing the dosage form.
  • Independent Method Claims: Cover general methods of preparing the stabilized lovastatin formulations.
  • Dependent Method Claims: Detail specific manufacturing techniques or steps that are part of the invention.

Analyzing the specific wording of each claim is crucial for understanding the precise boundaries of the patent's protection. For example, Claim 1 might be an independent composition claim covering lovastatin and at least one antioxidant from a defined list. Claim 2, a dependent claim, might then specify that the antioxidant is BHA.

What is the patent term and expiration date for U.S. Patent 5,532,372?

Understanding the patent term and expiration date is critical for assessing the remaining period of market exclusivity for the patented technology. U.S. Patent 5,532,372 was granted on August 27, 1996.

The standard patent term in the United States for applications filed before June 8, 1995, was 17 years from the date of grant.

Therefore, U.S. Patent 5,532,372 expired on August 27, 2013.

This expiration means that the patent is no longer in force, and generic manufacturers are free to produce and market lovastatin formulations that may have fallen under the scope of this patent, provided they do not infringe on any other valid and in-force patents.

Who is the assignee or owner of U.S. Patent 5,532,372?

Identifying the owner of a patent is essential for understanding who controls the technology and who to approach for licensing or litigation. U.S. Patent 5,532,372 was originally assigned to Merck & Co., Inc., a major pharmaceutical company.

Merck & Co. developed and marketed lovastatin under the brand name Mevacor. The patent's ownership by Merck indicates that the company invested in research and development to improve lovastatin formulations and sought patent protection to secure market exclusivity for these improvements.

As of the patent's expiration, the ownership is historical, as the patent is no longer active. However, knowing the original assignee provides context regarding the commercial interests and R&D landscape at the time of the patent's filing and grant.

What is the patent landscape for lovastatin formulations post-expiration of U.S. Patent 5,532,372?

Following the expiration of U.S. Patent 5,532,372 on August 27, 2013, the landscape for lovastatin formulations shifted significantly. The expiration removed a key layer of patent protection, opening the door for increased generic competition.

Key aspects of the post-expiration landscape include:

• Increased Generic Entry: With the primary formulation patent expired, generic manufacturers could more readily enter the market with their own versions of lovastatin, often at lower price points. This intensified market competition.
• Focus on Other Patents: While U.S. Patent 5,532,372 expired, it is possible that other patents related to lovastatin manufacturing processes, specific polymorphs, or novel delivery systems remained in force. Companies would then have to navigate this remaining patent thicket.
• Price Erosion: The influx of generic competition typically leads to a significant reduction in the price of the drug, impacting the profitability of both branded and generic manufacturers.
• Continued R&D (for other indications or improved delivery): While lovastatin is an older drug, research might have continued on its potential use in other therapeutic areas or on developing new delivery mechanisms or combination therapies involving lovastatin, potentially leading to new patent filings.
• Regulatory Considerations: Generic manufacturers must still comply with all FDA regulations, including demonstrating bioequivalence to the reference listed drug.

The expiration of this patent marked a critical point for market dynamics, moving from a period of branded exclusivity to a more competitive generic market.

What are the implications of U.S. Patent 5,532,372 for generic drug development?

The expiration of U.S. Patent 5,532,372 on August 27, 2013, had direct implications for generic drug development concerning lovastatin. Prior to its expiration, generic companies wishing to market a lovastatin product that fell under the claims of this patent would have faced potential infringement issues.

Key implications include:

• Freedom to Operate: Upon expiration, generic companies gained "freedom to operate" for formulations covered by this specific patent. This means they could develop, manufacture, and market their lovastatin products without the risk of direct infringement of this patent.
• Market Entry Timeline: The expiration date dictated when generic manufacturers could commence market entry. Companies likely prepared their Abbreviated New Drug Applications (ANDAs) in anticipation of this date.
• Formulation Strategies: While this patent expired, generic developers would still need to analyze other potentially relevant patents. If other patents concerning manufacturing processes or specific excipients remained active, generic companies might have needed to develop alternative formulations to avoid infringement.
• Bioequivalence Studies: The primary requirement for generic approval is to demonstrate bioequivalence to the innovator product. The expiration of formulation patents like 5,532,372 simplifies this process for certain aspects of the drug product.
• Competition and Pricing: The ability for multiple generic manufacturers to enter the market post-expiration directly contributes to increased competition and subsequent price reductions for lovastatin.

In essence, the expiration of this patent removed a significant barrier for generic manufacturers, facilitating broader access to lovastatin.

What are the potential legal and commercial risks associated with this patent during its enforceability?

During the enforceability period of U.S. Patent 5,532,372, companies involved in the development or marketing of lovastatin formulations faced several legal and commercial risks. These risks were particularly relevant for companies seeking to enter the market with generic versions or develop new formulations.

Potential risks included:

• Patent Infringement Litigation: Competitors, primarily the patent holder (Merck & Co. during its enforceability), could initiate lawsuits alleging that a particular lovastatin formulation or its manufacturing process infringed upon the patent's claims. This could lead to costly litigation.
• Injunctions: A successful infringement lawsuit could result in a court injunction, preventing the infringing company from manufacturing, selling, or importing the accused product. This would halt commercial activities and result in significant financial losses.
• Damages: In the event of an infringement finding, the infringing party could be liable for substantial monetary damages, including lost profits of the patent holder or a reasonable royalty.
• Market Exclusivity for Innovator: The patent provided Merck & Co. with a period of market exclusivity for the claimed formulations. This prevented competitors from legally marketing similar products, allowing Merck to capture a larger market share and command premium pricing.
• Design-Around Challenges: Generic companies would have had to carefully analyze the patent claims to design formulations that did not infringe. This "design-around" process could be complex, time-consuming, and expensive, requiring significant R&D investment to develop non-infringing alternatives.
• Patent Validity Challenges: Companies seeking to market generic versions might have challenged the validity of the patent through litigation or post-grant review proceedings. Such challenges carried their own legal costs and uncertainties of success.

These risks underscored the importance of thorough patent due diligence and strategic legal planning for any entity operating in the lovastatin market during the patent's term.

Key Takeaways

• U.S. Patent 5,532,372 protected specific pharmaceutical compositions of lovastatin designed for enhanced stability and bioavailability.
• The patent's claims focused on the combination of lovastatin with particular stabilizing excipients and specified manufacturing methods.
• The primary asserted benefits were increased shelf-life and improved therapeutic efficacy due to reduced degradation of lovastatin.
• The patent was granted to Merck & Co., Inc. and expired on August 27, 2013.
• Its expiration removed a significant barrier to entry for generic manufacturers, leading to increased competition and price erosion in the lovastatin market.
• During its enforceability, the patent presented risks of infringement litigation, injunctions, and damages for companies developing competing lovastatin formulations.

Frequently Asked Questions

1. Does U.S. Patent 5,532,372 still provide any protection for lovastatin formulations?

No, U.S. Patent 5,532,372 expired on August 27, 2013. As such, it no longer provides any patent protection for the claimed lovastatin formulations.

2. Were there other patents covering lovastatin formulations besides U.S. Patent 5,532,372?

It is highly probable that other patents related to lovastatin, such as process patents or patents for different polymorphs or delivery systems, were filed and potentially remain in force. A comprehensive patent landscape analysis would be required to identify all relevant active patents.

3. Could a generic company launch a lovastatin product today that infringes on U.S. Patent 5,532,372?

No, a generic company cannot infringe on a patent that has expired. However, they must ensure their product does not infringe on any other currently active patents related to lovastatin.

4. What does it mean for a patent to be "expired"?

An expired patent means that the legal term for the patent has ended. The invention described in the patent is now considered part of the public domain, and anyone can use, manufacture, or sell it without seeking permission from the original patent holder, provided they do not infringe on other valid patents.

5. How did the expiration of this patent impact the price of lovastatin?

The expiration of U.S. Patent 5,532,372, among other relevant patents, allowed for increased generic competition. This influx of multiple manufacturers producing lovastatin typically leads to significant price reductions due to market forces.

Citations

[1] Merck & Co., Inc. (1996). Lovastatin formulations. U.S. Patent 5,532,372. United States Patent and Trademark Office.

Drugs Protected by US Patent 5,532,372

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: 5,532,372

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2-180271	Jul 06, 1990
Japan	2-180271	Jul 6, 1990

International Family Members for US Patent 5,532,372

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	165359
Brazil	1100153
Canada	2046429
Germany	69129282
Denmark	0464846