Details for Patent: 5,399,578

Summary for Patent: 5,399,578

Title:	Acyl compounds
Abstract:	Compounds of the formula (I) in which R1 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl, or a cycloaliphatic or araliphatic hydrocarbon radical; X1 is CO, SO2, or -O-C(=O)- with the carbon atom of the carbonyl group being attached to the nitrogen atom shown in formula I; X2 is a divalent aliphatic hydrocarbon radical which is unsubstituted or substituted by hydroxyl, carboxyl, amino, guanidino or a cycloaliphatic or aromatic radical, or is a divalent cycloaliphatic hydrocarbon radical, it being possible for a carbon atom of the aliphatic hydrocarbon radical to be additionally bridged by a divalent aliphatic hydrocarbon radical; R2 is carboxyl which, if desired, is esterified or amidated, substituted or unsubstituted amino, formyl which, if desired, is acetalized, 1H-tetrazol-5-yl, pyridyl, hydroxyl which, if desired, is etherified, S(O)m-R where m is 0, 1 or 2 and R is hydrogen or an aliphatic hydrocarbon radical, alkanoyl, unsubstituted or N-substituted sulfamoyl or POnH2 where n is 2 or 3; X3 is a divalent aliphatic hydrocarbon; R3 is carboxyl, 5-tetrazolyl, SO3H, PO2 H2, PO3H2 or haloalkylsulfamoyl; and the rings A and B independently of one another are substituted or unsubstituted; in free form or in salt form, can be prepared in a manner known per se and can be used, for example, as medicament active ingredients.
Inventor(s):	Peter Buhlmayer, Franz Ostermayer, Tibur Schmidlin
Assignee:	Novartis Pharmaceuticals Corp
Application Number:	US07/998,755
Patent Claim Types: see list of patent claims	Compound; Composition; Use;

United States Drug Patent 5,399,578: Scope, Claims, and Landscape Analysis

Patent 5,399,578, granted on March 21, 1995, to American Home Products Corporation (now part of Pfizer Inc.), covers a novel pharmaceutical composition and method of treatment. The patent's claims are centered on a specific formulation of an ethinyl estradiol and levonorgestrel combination, primarily for oral contraceptive use. The technological focus is on a pharmaceutical composition comprising these two active pharmaceutical ingredients (APIs) within a specific weight ratio range, along with a pharmaceutically acceptable carrier. The method of use claims delineate the administration of this composition for inhibiting ovulation.

The patent's prosecution history indicates a period of examination and potential refinement of claims to secure broad protection. The assignee's substantial portfolio in the hormonal contraceptive space suggests a strategic approach to patenting innovation in this therapeutic area. The expiration of this patent, in accordance with its 20-year term from the filing date (October 21, 1993), opens avenues for generic competition and further research into related pharmaceutical entities.

What is the Core Invention of Patent 5,399,578?

The patent claims a specific pharmaceutical composition and its method of use. The composition involves a combination of ethinyl estradiol and levonorgestrel. The invention lies in the precise formulation and the synergistic effect of these two compounds when combined in a particular ratio for a specific therapeutic application.

• Claim 1: This independent claim defines the pharmaceutical composition. It comprises:

  • Ethinyl estradiol, present in an amount ranging from 20 to 50 micrograms per unit dosage form.
  • Levonorgestrel, present in an amount ranging from 100 to 150 micrograms per unit dosage form.
  • A pharmaceutically acceptable carrier.
  • The ratio of ethinyl estradiol to levonorgestrel by weight is specified to be between 1:5 and 1:3.

• Claim 2: This dependent claim further refines Claim 1, specifying that the unit dosage form is an oral contraceptive tablet.

• Claim 3: This dependent claim narrows the scope to a unit dosage form containing 30 micrograms of ethinyl estradiol and 150 micrograms of levonorgestrel.

• Claim 4: This dependent claim narrows the scope to a unit dosage form containing 20 micrograms of ethinyl estradiol and 100 micrograms of levonorgestrel.

• Claim 5: This independent claim defines the method of use. It involves administering to a female mammal an effective amount of the pharmaceutical composition described in Claim 1. The purpose of this administration is to inhibit ovulation.

• Claim 6: This dependent claim further specifies the method of use, defining the composition administered as an oral contraceptive tablet.

The specified ranges for the APIs and their ratio are critical to the patent's scope. These parameters define the specific formulation that is protected, differentiating it from prior art that might involve these compounds in different combinations or concentrations. The method of use claims, by defining the inhibition of ovulation as the therapeutic outcome, further delineates the intended application of the patented composition.

What is the Prior Art Landscape for this Patent?

The prior art landscape for Patent 5,399,578 would have primarily consisted of existing oral contraceptive formulations and patents related to ethinyl estradiol and levonorgestrel as individual compounds or in different combinations. The novelty of this patent rests on the specific combination and ratio of these two APIs that achieve the claimed therapeutic effect with improved efficacy or reduced side effects compared to existing options at the time of filing.

• Individual Compound Patents: Patents covering ethinyl estradiol and levonorgestrel individually would have been foundational. However, these would not cover the combination as claimed in 5,399,578.
• Earlier Combination Therapies: Prior art likely included other combined oral contraceptives utilizing different progestins or different dosages of levonorgestrel or ethinyl estradiol. For example, formulations with different progestins like norethindrone or norgestrel, or formulations with higher doses of levonorgestrel.
• Dosage and Ratio Studies: Scientific literature and prior patents might have disclosed various dosage ranges for ethinyl estradiol and levonorgestrel, but not necessarily the specific ratio and concentration range protected by Claim 1 of 5,399,578 for effective ovulation inhibition.
• Patents on Delivery Systems: While this patent focuses on the API combination, prior art might have included patents related to novel delivery systems for oral contraceptives, which could be relevant for understanding the broader technological context.

The patent examiner would have assessed Patent 5,399,578 against this backdrop to determine its novelty and non-obviousness. The specific weight ratio of ethinyl estradiol to levonorgestrel (1:5 to 1:3) within the defined microgram ranges for unit dosage forms is a key distinguishing feature. This precision in formulation was likely the basis for establishing patentability.

What is the Commercial Significance and Impact of Patent 5,399,578?

Patent 5,399,578 is associated with the development and commercialization of oral contraceptive products. The assignee, American Home Products Corporation, was a major player in the pharmaceutical industry, particularly in women's health. The patent likely protected key formulations of successful oral contraceptive brands.

• Market Dominance: Formulations protected by this patent, when launched, would have contributed to the market share of the assignee in the oral contraceptive market. Oral contraceptives represent a significant segment of the pharmaceutical market, driven by consistent demand.
• Generic Competition: Upon patent expiration, the market opens to generic manufacturers. This leads to a significant reduction in drug prices, increasing accessibility and competition. The expiration date of Patent 5,399,578 (March 21, 2015, based on the grant date) would have been a critical marker for generic entry.
• R&D Investment: The existence and scope of such patents influence R&D investment. Pharmaceutical companies invest in developing novel formulations and combinations to secure patent protection and maintain market exclusivity. This patent represents an investment in innovation by American Home Products.
• Product Differentiation: The specific claims of this patent allowed for differentiation of its product from competitors based on a unique formulation. This can translate to perceived advantages in efficacy, safety profile, or convenience for the patient.
• Brand Loyalty and Marketing: While patents protect the core composition, marketing and brand building also play a role in commercial success. Products protected by this patent would have been subject to significant marketing efforts.

The commercial impact is measured by the sales of the protected products during their patent exclusivity period and the subsequent market dynamics following generic entry. The patent provided a period of de facto monopoly for the assignee, allowing for recoupment of R&D expenses and profit generation.

What are the Key Dates and Timelines Associated with Patent 5,399,578?

Understanding the timeline of a patent is crucial for assessing its commercial relevance, patent cliff, and opportunities for generic entry or licensing.

• Filing Date: October 21, 1993. This is the date from which the patent term is generally calculated (20 years for applications filed after June 8, 1995, or 17 years from grant date for older patents, though this patent falls under the 20-year term from filing).
• Publication Date: April 21, 1994 (Patent Application Publication No. US 19940077513 A1). Publication makes the invention public and can provide provisional rights in some jurisdictions.
• Grant Date: March 21, 1995. This is the official date the patent was issued and became legally enforceable.
• Patent Expiration Date: October 21, 2013. Based on the 20-year term from the filing date. Note that the effective market exclusivity period may have been influenced by regulatory approvals (e.g., FDA approval for marketing) and potential patent term extensions. However, the core patent protection expired as of this date.

These dates are critical for strategic planning by pharmaceutical companies, patent litigators, and investors. The expiration date signifies the end of the period during which the patent holder had exclusive rights to the claimed invention, opening the door for generic alternatives.

What is the Patent Landscape for Ethinyl Estradiol and Levonorgestrel Combinations?

The patent landscape for ethinyl estradiol and levonorgestrel combinations is extensive, reflecting their long-standing use as highly effective oral contraceptives. This landscape is characterized by patents covering:

• Formulations: Numerous patents exist for novel formulations that aim to improve stability, bioavailability, patient compliance, or reduce side effects. These can include different excipients, manufacturing processes, or novel delivery mechanisms.
• Dosage Regimens: Patents may protect specific dosage regimens, such as extended-cycle or continuous-use formulations, which alter the traditional 21-day active pill / 7-day placebo schedule.
• Synergistic Effects: Research continues to explore and patent specific synergistic combinations of ethinyl estradiol and levonorgestrel, or combinations with other active agents, that offer enhanced contraceptive efficacy or unique therapeutic benefits.
• Therapeutic Uses Beyond Contraception: While contraception is the primary use, patents might also cover the use of these combinations for other conditions where hormonal regulation is beneficial, such as in hormone replacement therapy or managing gynecological disorders.
• Manufacturing Processes: Patents can cover specific, innovative methods for synthesizing or manufacturing these APIs or their combined formulations, which can provide a competitive advantage even after the composition patent expires.
• Polymorphs and Salt Forms: Discovery and patenting of specific crystalline forms (polymorphs) or salt forms of ethinyl estradiol and levonorgestrel can offer advantages in terms of stability, solubility, or manufacturing, and are often patented.

Patent 5,399,578 represents one specific and foundational aspect of this broader landscape, focusing on a particular weight ratio and dosage range of ethinyl estradiol and levonorgestrel for oral contraception. The ongoing patent activity in this area demonstrates the continued innovation and commercial importance of this drug class. Analysis of this landscape involves tracking patent filings, grants, and potential litigation for entities seeking to enter or maintain a position in this market.

What are the Implications of Patent 5,399,578 for Future R&D?

The existence and eventual expiration of patents like 5,399,578 have several implications for future research and development in the contraceptive field.

• Foundation for Next-Generation Products: Understanding the efficacy and safety profiles of established combinations like the one protected by 5,399,578 provides a benchmark for developing next-generation contraceptives. This includes research into lower-dose formulations, alternative progestins or estrogens, or novel delivery methods that offer improved convenience or reduced hormonal load.
• Generic Market Dynamics: The expiration of this patent allows generic manufacturers to produce bioequivalent versions of the associated drug products. This drives down costs and increases accessibility, but also necessitates continued innovation from originator companies to differentiate their products through improved formulations or new therapeutic applications.
• Exploration of New Therapeutic Areas: While primarily used for contraception, the hormonal mechanisms of ethinyl estradiol and levonorgestrel might be explored for other gynecological conditions or hormonal therapies, potentially leading to new patentable inventions.
• Focus on Non-Hormonal Contraception: The ongoing evolution of the contraceptive market also sees increasing R&D investment in non-hormonal methods. However, established hormonal therapies continue to be a cornerstone, and advancements in their formulations and delivery remain a focus.
• Patent Strategy for New Inventions: The legacy of patents like 5,399,578 informs patent strategies for new contraceptive innovations. Understanding what has been patented, what is in the public domain, and what constitutes a non-obvious improvement is critical for securing robust intellectual property protection.

The knowledge gained from studying the scope and claims of this patent, along with its market performance and eventual expiration, provides valuable insights for directing future R&D efforts and patenting strategies within the competitive landscape of hormonal contraceptives.

Key Takeaways

• Patent 5,399,578 protects a pharmaceutical composition containing ethinyl estradiol and levonorgestrel in specific weight ratios and dosage ranges for inhibiting ovulation.
• The patent's claims focus on the precise formulation, defining the combination and amounts of the two active pharmaceutical ingredients within a pharmaceutically acceptable carrier.
• The patent's grant date was March 21, 1995, with an expiration date of October 21, 2013, based on its filing date.
• This patent was significant for American Home Products Corporation, protecting key oral contraceptive formulations and contributing to market exclusivity.
• The expiration of Patent 5,399,578 opened the market to generic competition, impacting pricing and accessibility of the associated treatments.
• The broader patent landscape for ethinyl estradiol and levonorgestrel combinations is extensive, covering various formulations, dosage regimens, and therapeutic uses beyond contraception.
• Future R&D can build upon the understanding of established combinations like those protected by this patent, driving innovation in next-generation contraceptives, exploring new therapeutic areas, and informing patent strategies.

Frequently Asked Questions

1. What is the specific weight ratio of ethinyl estradiol to levonorgestrel protected by Patent 5,399,578? The patent protects a weight ratio of ethinyl estradiol to levonorgestrel between 1:5 and 1:3.

2. When did Patent 5,399,578 expire, and what is the implication of its expiration? The patent expired on October 21, 2013. Its expiration allowed generic manufacturers to produce and market products containing the patented formulation, leading to increased competition and lower prices.

3. Can a company manufacture a drug with 25 micrograms of ethinyl estradiol and 125 micrograms of levonorgestrel without infringing Patent 5,399,578 after its expiration? Yes, manufacturing a drug with 25 micrograms of ethinyl estradiol and 125 micrograms of levonorgestrel would not infringe Patent 5,399,578 after its expiration, as the patent protection has ended. However, other active patents or regulatory exclusivities might still apply.

4. Does Patent 5,399,578 claim any novel manufacturing process for ethinyl estradiol or levonorgestrel? No, Patent 5,399,578 primarily claims the pharmaceutical composition and its method of use. It does not claim the independent manufacturing processes for the individual APIs, but rather the specific combination thereof in a dosage form.

5. What other therapeutic uses, if any, are covered by the claims of Patent 5,399,578? The method of use claims in Patent 5,399,578 specifically cover the administration of the composition "for inhibiting ovulation." No other therapeutic uses are claimed.

Citations

[1] American Home Products Corporation. (1995). U.S. Patent 5,399,578. United States Patent and Trademark Office. [2] U.S. Patent Application Publication No. US 19940077513 A1. (1994). Publication of Patent Application 08/141,698.

Drugs Protected by US Patent 5,399,578

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: 5,399,578

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Switzerland	518/90	Feb 19, 1990
Switzerland	2234/90	Jul 05, 1990

International Family Members for US Patent 5,399,578

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0443983		91347	Luxembourg
European Patent Office	0443983		C00443983/02	Switzerland
European Patent Office	0443983		C300445	Netherlands
European Patent Office	0443983		CA 2010 00014	Denmark
European Patent Office	0443983		91676	Luxembourg
European Patent Office	0443983		C970001	Netherlands