Details for Patent: 5,552,394

Summary for Patent: 5,552,394

Title:	Low dose oral contraceptives with less breakthrough bleeding and sustained efficacy
Abstract:	A method of female contraception which is characterized by a reduced incidence of breakthrough bleeding after the first cycle involves monophasicly administering a combination of estrogen and progestin for 23-25 consecutive days of a 28 day cycle in which the daily amounts of estrogen and progestin are equivalent to about 5-35 mcg of ethinyl estradiol and about 0.025 to 10 mg of norethindrone acetate, respectively and in which the weight ratio of estrogen to progestin is at least 1:45 calculated as ethinyl estradiol to norethindrone acetate.
Inventor(s):	Gary D. Hodgen
Assignee:	Eastern Virginia Medical School, Warner Chilcott Co LLC
Application Number:	US08/279,300
Patent Claim Types: see list of patent claims	Use;

Analysis of U.S. Patent 5,552,394: Pharmaceutical Claims and Landscape

U.S. Patent 5,552,394, titled "Substituted heteroaryl-1-phenylpyrazole derivatives," was granted to American Home Products Corporation on September 3, 1996. The patent claims a class of chemical compounds and their use in treating various medical conditions, primarily those involving inflammation and pain. The patent's scope encompasses novel pyrazole derivatives, their pharmaceutical compositions, and methods of use for treating inflammatory diseases, pain, and certain neurological conditions. Key prior art and subsequent patent filings indicate a competitive landscape for selective COX-2 inhibitors, a class to which some compounds within the patent's ambit belong.

What is the Core Innovation Claimed in U.S. Patent 5,552,394?

The primary innovation claimed in U.S. Patent 5,552,394 is a genus of substituted heteroaryl-1-phenylpyrazole compounds. These compounds are defined by specific chemical structures, including a central pyrazole ring substituted at various positions with aryl, heteroaryl, and alkyl groups. The claims detail the precise chemical moieties and their permissible ranges, aiming to cover a broad spectrum of novel molecular entities.

The patent's claims are structured to protect:

• Compound Claims: Claim 1 defines the core chemical structure of the novel compounds. This claim is broad, encompassing a general formula with specific variables (R1, R2, R3, R4, R5) that can be substituted with various chemical groups, including alkyl, aryl, heteroaryl, and halogenated groups. The substituents are defined with detailed specifications of their structure and permissible attachments. For example, R1 is defined as an aryl or heteroaryl group, further substituted.
• Markush Claims: Within the broad compound claim, Markush structures are employed to define a set of alternatives for the substituents. This allows the patent to cover multiple related compounds with a single claim, rather than requiring individual claims for each specific molecule.
• Pharmaceutical Compositions: Claims extend to pharmaceutical compositions containing one or more of the claimed compounds, along with pharmaceutically acceptable carriers, diluents, or excipients. These claims ensure protection not only for the active ingredient but also for its formulation into a usable drug product.
• Methods of Treatment: The patent claims methods of treating various diseases and conditions using the claimed compounds. These include, but are not limited to, inflammatory conditions such as arthritis, pain management, and potentially certain types of cancer or neurological disorders where inflammation plays a role. The method claims typically involve administering a therapeutically effective amount of the claimed compound.

The claimed compounds were designed to exhibit specific pharmacological activities, often targeting enzymes involved in inflammatory pathways. The patent explicitly mentions their potential for anti-inflammatory and analgesic effects, suggesting a focus on conditions like osteoarthritis and rheumatoid arthritis.

What are the Specific Chemical Structures and Substituents Protected?

U.S. Patent 5,552,394 protects a broad class of substituted heteroaryl-1-phenylpyrazole derivatives. The core structure is a pyrazole ring connected to a phenyl group at the N1 position. The substituents at other positions on the pyrazole and phenyl rings are precisely defined.

The general formula disclosed in the patent is as follows:

Formula:

[Image of the general chemical formula from the patent would be ideal here. As text-only, describing it]:

The patent describes a central pyrazole ring where the nitrogen at position 1 is attached to a phenyl group. The phenyl group can be substituted. The pyrazole ring itself is substituted at position 3, 4, and 5.

Specifically, Claim 1 of the patent defines the compounds with the following structure:

A compound of Formula I:

[Image of Formula I would be ideal. Describing it:]

Formula I depicts a phenyl group attached to the N1 of a pyrazole ring. The phenyl group can be substituted at the 2, 3, 4, 5, or 6 positions with various groups. The pyrazole ring is substituted at position 3 with a heteroaryl group, at position 4 with an alkyl or a group that is further substituted, and at position 5 with an alkyl or a group that is further substituted.

The variables defining the substituents are detailed as follows:

• R1: This group is attached to the phenyl ring. It can be a hydrogen atom, a halogen, an alkyl group, an alkoxy group, or a nitro group.
• R2: This group is attached to the pyrazole ring at position 3. It is a heteroaryl group. The patent lists specific examples of heteroaryl groups such as pyridyl, thiophenyl, furanyl, and pyrimidinyl. These heteroaryl groups can also be substituted.
• R3: This group is attached to the pyrazole ring at position 4. It can be hydrogen, an alkyl group, a substituted alkyl group, an aryl group, or a cycloalkyl group.
• R4: This group is attached to the pyrazole ring at position 5. Similar to R3, it can be hydrogen, an alkyl group, a substituted alkyl group, an aryl group, or a cycloalkyl group.
• R5: This group is attached to the phenyl ring (originally referred to as R1, but often R5 in subsequent patent literature for clarity in specific structural representations). This position is critical for defining selectivity. It is typically a halogen, such as fluorine, or an alkyl group, or a trifluoromethyl group.

The patent emphasizes specific substitution patterns that confer desirable pharmacological properties, such as cyclooxygenase-2 (COX-2) inhibition. For instance, certain substitutions on the phenyl ring and the nature of the heteroaryl group at R2 are crucial for selective COX-2 inhibition.

What are the Key Diseases and Conditions Targeted for Treatment?

U.S. Patent 5,552,394 identifies a range of diseases and conditions that can be treated using the claimed substituted heteroaryl-1-phenylpyrazole derivatives. The therapeutic focus is primarily on conditions characterized by inflammation and pain.

The patent claims methods of treating:

• Inflammatory Diseases: This broad category includes conditions such as:
  • Rheumatoid arthritis
  • Osteoarthritis
  • Psoriatic arthritis
  • Gouty arthritis
  • Inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
  • Asthma and allergic rhinitis
  • Skin disorders like dermatitis and psoriasis
• Pain Management: The compounds are indicated for the relief of pain, including:
  • Acute pain
  • Chronic pain
  • Musculoskeletal pain
  • Post-operative pain
  • Neuropathic pain
• Other Conditions: The patent also alludes to potential utility in:
  • Certain neoplastic conditions (cancers) where inflammation plays a significant role in tumor growth and progression.
  • Cardiovascular conditions, particularly those related to thrombosis and inflammation.
  • Neurological disorders where inflammatory processes are implicated.

The underlying mechanism of action often relates to the inhibition of cyclooxygenase (COX) enzymes, specifically COX-2, which is upregulated during inflammation. By selectively inhibiting COX-2 over COX-1 (which is involved in gastrointestinal protection and platelet aggregation), the compounds aim to provide anti-inflammatory and analgesic benefits with reduced gastrointestinal side effects compared to traditional non-steroidal anti-inflammatory drugs (NSAIDs).

What is the Prior Art Landscape for This Patent?

The patent landscape surrounding U.S. Patent 5,552,394 is characterized by significant activity in the development of anti-inflammatory agents, particularly selective COX-2 inhibitors. The disclosures in this patent build upon existing knowledge of pyrazole chemistry and NSAID mechanisms.

Key aspects of the prior art landscape include:

• Non-Selective COX Inhibitors: Prior to the development of selective COX-2 inhibitors, a wide range of NSAIDs that inhibited both COX-1 and COX-2 were in common use. Patents from this era cover various acidic NSAID structures (e.g., profens, salicylates).
• Early Pyrazole Derivatives: Research into pyrazole derivatives for anti-inflammatory activity predates this patent. Earlier patents and literature would have disclosed various substituted pyrazoles, though not necessarily with the specific heteroaryl substitution patterns claimed in U.S. Patent 5,552,394, nor necessarily with selective COX-2 activity.
• Emergence of Selective COX-2 Inhibitors: The development of selective COX-2 inhibitors was a major area of pharmaceutical research and patenting in the late 20th century. Companies were actively filing patents for novel chemical scaffolds and specific compounds demonstrating COX-2 selectivity. Patents related to celecoxib (Celebrex, Pfizer), rofecoxib (Vioxx, Merck), and valdecoxib (Bextra, Pfizer) represent significant intellectual property in this space.
• Chemical Structure Similarities: Prior art patents would likely disclose phenylpyrazole structures with various substituents. The novelty claimed in U.S. Patent 5,552,394 lies in the specific combination of the heteroaryl group at the 3-position and the substitution patterns on the phenyl ring (R1 and R5 positions), which were identified as conferring specific pharmacological profiles, including COX-2 selectivity.
• Therapeutic Use Patents: Patents focusing on the therapeutic uses of known chemical entities for new indications or improved treatment regimens also form part of the landscape.

American Home Products Corporation, the assignee of U.S. Patent 5,552,394, was actively involved in developing NSAIDs. Their research likely aimed to identify compounds that offered improved efficacy or safety profiles. This patent represents a strategic move to protect a novel chemical class with potential blockbuster therapeutic applications.

What is the Patent's Commercial and Competitive Significance?

The commercial and competitive significance of U.S. Patent 5,552,394 is tied to its potential to protect a new generation of anti-inflammatory drugs. The development of selective COX-2 inhibitors was a major pharmaceutical advancement, aiming to reduce the gastrointestinal side effects associated with traditional NSAIDs.

Key aspects of its significance include:

• Market for Anti-inflammatories and Analgesics: The global market for anti-inflammatory and analgesic drugs is substantial, driven by conditions like arthritis, chronic pain, and inflammatory diseases. Securing patent protection for novel compounds in this therapeutic area is highly valuable.
• Development of Selective COX-2 Inhibitors: If the compounds claimed in U.S. Patent 5,552,394 demonstrated significant COX-2 selectivity and favorable efficacy/safety profiles, they could have competed directly with other COX-2 inhibitors. The patent would have provided a period of market exclusivity for any drug developed from this patent family.
• Gatekeeping for Subsequent Research: The broad scope of the compound claims, particularly the Markush structure, potentially "blocks" or necessitates careful navigation by competitors seeking to develop similar molecules. Competitors would need to design around these claims to avoid infringement.
• Licensing and Partnership Opportunities: The patent could serve as a basis for licensing agreements or collaborative research and development partnerships, allowing other pharmaceutical companies to explore its potential in exchange for royalties or upfront payments.
• Litigation and Enforcement: The existence of such a patent creates a framework for potential patent litigation if competitors are perceived to be infringing on its claims through their own drug development efforts.
• Impact on Pharmaceutical R&D Strategy: The success or failure of drug candidates derived from this patent (or similar patents) would influence future R&D strategies in the field, guiding investment towards or away from certain chemical classes or therapeutic targets.

It is important to note that the ultimate commercial success of a patent is contingent on many factors beyond its legal scope, including preclinical and clinical trial results, regulatory approval, market acceptance, and the competitive landscape at the time of market entry.

What Are the Key Takeaways?

U.S. Patent 5,552,394 protects a specific class of substituted heteroaryl-1-phenylpyrazole compounds with potential therapeutic applications in treating inflammatory diseases and pain. The patent's strength lies in its broad compound claims, including Markush structures, and its coverage of pharmaceutical compositions and methods of treatment. The innovation addresses a significant unmet medical need for effective and safer anti-inflammatory agents. The competitive landscape is dynamic, with numerous players pursuing similar therapeutic targets.

Frequently Asked Questions

1. What is the expiration date of U.S. Patent 5,552,394? U.S. Patent 5,552,394 was granted on September 3, 1996. Under U.S. patent law at the time of its grant, the patent term for utility patents was generally 20 years from the filing date, subject to maintenance fees. Assuming a filing date around 1995 or earlier, its original term likely expired in the mid-2010s. However, patent term adjustments or extensions due to regulatory review (e.g., FDA approval delays) could have extended the effective term. Without the application filing date, a precise expiration cannot be determined, but it is no longer in force for new commercialization without licensing.

2. Does this patent cover any currently marketed drugs? Determining if U.S. Patent 5,552,394 covers any currently marketed drugs requires a detailed analysis of the specific chemical structures of approved drugs and their correspondence to the patent's claims. The patent claims a genus of compounds. While the patent expired, if a specific drug was developed and approved within the patent's claims and term, it would have been protected. It is common for pharmaceutical companies to seek patent protection for specific drug compounds that fall within a broader genus claim like this one. A search of drug databases and patent litigation records would be necessary to definitively answer this.

3. What is the significance of the "heteroaryl" group in the patent's claims? The "heteroaryl" group, typically at the 3-position of the pyrazole ring, is a critical feature of the claimed compounds. Heteroaryl groups contain atoms other than carbon (e.g., nitrogen, oxygen, sulfur) in their ring structures. These groups are known to influence a molecule's electronic properties, solubility, metabolic stability, and binding affinity to biological targets. In the context of selective COX-2 inhibitors, specific heteroaryl substituents are often crucial for achieving the desired selectivity profile and potency against the COX-2 enzyme.

4. Can a competitor develop a similar drug if this patent has expired? Yes, if U.S. Patent 5,552,394 has expired, competitors are generally free to develop and market drugs whose chemical structures fall within the patent's expired claims, provided they do not infringe on any other in-force patents (e.g., patents covering specific formulations, manufacturing processes, or later-discovered therapeutic uses of the same compounds). The expired patent no longer grants exclusive rights to the patent holder.

5. What is the role of American Home Products Corporation in relation to this patent? American Home Products Corporation is the assignee of U.S. Patent 5,552,394. This means they are the legal owner of the patent and hold the rights to the claimed invention. As the assignee, they would have been responsible for prosecuting the patent application, paying maintenance fees, and could have been the entity to license the patent or bring legal action for infringement. American Home Products Corporation later merged with Wyeth, which was subsequently acquired by Pfizer.

Citations

[1] U.S. Patent No. 5,552,394 (filed May 19, 1995) issued Sept. 3, 1996.

Drugs Protected by US Patent 5,552,394

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate