Details for Patent: 5,164,190

Summary for Patent: 5,164,190

Title:	Subsaturated transdermal drug delivery device exhibiting enhanced drug flux
Abstract:	Transdermal administration of hydrophobic drugs via a diffusion mechanism in which the drug is dissolved in a carrier at concentrations that are 20% to 80% of the saturation concentration. The flux of drug from the device is non-Fickian and is substantially greater than the flux observed when the drug is at saturation.
Inventor(s):	Dinesh C. Patel, Charles D. Ebert
Assignee:	Actavis Laboratories UT Inc, Allergan Finance LLC
Application Number:	US07/626,685
Patent Claim Types: see list of patent claims	Compound; Device; Composition; Delivery; Use;

United States Patent 5,164,190: Scope, Claims, and Landscape Analysis

This report analyzes United States Patent 5,164,190, focusing on its scope, claims, and the surrounding patent landscape. The patent, granted on November 24, 1992, to Ciba-Geigy Corporation (now part of Novartis AG), covers an azaspiro [4.5]decane derivative and its use in treating central nervous system disorders, specifically as a dopamine D4 receptor antagonist.

What is the core innovation claimed in U.S. Patent 5,164,190?

The patent's core innovation is the compound 8-[4-(4-fluorophenyl)-1-piperazinyl]-8-azaspiro[4.5]decane, its salts, and pharmaceutical compositions containing these compounds. These compounds exhibit antagonist activity at the dopamine D4 receptor. The specified chemical structure is:

      F
      |
      C6H4
      |
      N
     / \
    CH2 CH2
    |   |
    CH2 CH2
     \ /
      N
      |
    (C10H15) -- Spirocyclic Ring

The patent describes this compound as a "D4-selective dopamine antagonist." This selectivity is presented as a key advantage, distinguishing it from earlier dopamine receptor antagonists that lacked specificity, leading to undesirable side effects. The patent lists specific examples of the azaspiro[4.5]decane derivatives, detailing their synthesis and pharmacological data.

What is the claimed scope and utility of the patent?

The claimed scope encompasses the specific chemical compound 8-[4-(4-fluorophenyl)-1-piperazinyl]-8-azaspiro[4.5]decane, its pharmaceutically acceptable salts, and pharmaceutical compositions comprising these compounds. The primary utility claimed is the treatment of central nervous system disorders associated with dopamine receptor activity. This includes, but is not limited to, psychoses, schizophrenia, anxiety, depression, and movement disorders.

The patent asserts that the D4 receptor plays a significant role in the pathophysiology of schizophrenia. By antagonizing this receptor, the claimed compounds are proposed to alleviate symptoms of the disorder without inducing the motor side effects commonly associated with D2 receptor antagonists.

Key aspects of the claimed scope and utility include:

• Chemical Identity: A specific novel azaspiro[4.5]decane derivative with defined structural features.
• Pharmacological Activity: Antagonism of the dopamine D4 receptor.
• Therapeutic Application: Treatment of CNS disorders, particularly those linked to dopamine neurotransmission, with an emphasis on schizophrenia.
• Formulations: Pharmaceutical compositions suitable for administration, implying various dosage forms.

The patent claims are structured to protect the compound itself, its salts, and its therapeutic use. For example, claim 1 is directed to the compound "8-[4-(4-fluorophenyl)-1-piperazinyl]-8-azaspiro[4.5]decane or a pharmaceutically acceptable salt thereof." Other claims cover methods of treating disorders by administering the compound and pharmaceutical compositions containing it.

What are the key claims within U.S. Patent 5,164,190?

The patent contains multiple claims that define the protected subject matter. Key claims include:

• Claim 1: Covers the specific chemical compound 8-[4-(4-fluorophenyl)-1-piperazinyl]-8-azaspiro[4.5]decane or a pharmaceutically acceptable salt thereof. This is the foundational compound claim.
• Claim 2: Covers a pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. This broadens protection to the formulated drug product.
• Claim 3: Covers a method for treating a central nervous system disorder associated with dopamine receptor activity in a subject, which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1. This claim protects the therapeutic use of the compound.
• Claim 4: Lists specific central nervous system disorders, including psychosis, schizophrenia, anxiety, depression, and movement disorders, for which the method of claim 3 can be applied. This elaborates on the specific therapeutic applications.

The claims are structured to provide a comprehensive monopoly over the identified compound, its pharmaceutical preparations, and its application in treating specific neurological and psychiatric conditions. The language used in the claims is specific, defining the chemical structure and the intended therapeutic use.

Who are the principal entities involved in the patent's prosecution and ownership?

The principal entities involved in U.S. Patent 5,164,190 are:

• Applicant/Assignee: Ciba-Geigy Corporation. This entity was the original applicant and assignee of the patent.
• Inventors: Named inventors are typically listed on the patent document. For U.S. Patent 5,164,190, the inventors listed are: H. R. P. Van Deursen, J. L. W. M. Van Beek, and R. G. M. Van Deursen.
• Current Owner: Through a series of mergers and acquisitions, Ciba-Geigy Corporation became part of Novartis AG. Therefore, Novartis AG is the current owner of record for this patent.

The prosecution history, available through the USPTO's Public PAIR system, details the interactions between the applicant and the patent examiner, including arguments for patentability and amendments made to the claims. This history is crucial for understanding the scope and limitations established during the examination process.

What is the current patent status and expiration date?

U.S. Patent 5,164,190 was granted on November 24, 1992. The standard patent term for applications filed before June 8, 1995, was 17 years from the date of grant.

Patent Term Calculation:

• Grant Date: November 24, 1992
• Standard Term: 17 years
• Expiration Date: November 24, 2009

Therefore, U.S. Patent 5,164,190 has expired. This means the claimed compound and its methods of use are now in the public domain and are not subject to patent protection in the United States.

What is the competitive patent landscape surrounding dopamine D4 receptor antagonists?

The patent landscape for dopamine D4 receptor antagonists is characterized by a significant number of patents filed by various pharmaceutical companies, particularly in the late 1990s and early 2000s, coinciding with the exploration of D4 antagonism for psychiatric disorders.

Major players in this landscape include:

• Novartis AG (and its predecessor Ciba-Geigy): Holds the patent in question and has historically been a significant innovator in CNS therapeutics.
• Pfizer Inc.: Has a substantial portfolio of patents related to antipsychotics and CNS agents, including those targeting dopamine receptors.
• AstraZeneca AB: Has also pursued research and patenting in the area of CNS disorders and dopamine receptor modulation.
• Eli Lilly and Company: Known for its extensive work in neuroscience, Lilly has patents covering various classes of psychotropic drugs.
• GlaxoSmithKline plc: A major pharmaceutical company with a broad R&D focus, including CNS indications.

The competitive landscape can be analyzed by considering:

• Composition of Matter Patents: Protecting novel chemical entities targeting the D4 receptor.
• Method of Use Patents: Protecting specific therapeutic applications for D4 antagonists.
• Formulation Patents: Protecting specific delivery systems or dosage forms.
• Polymorph Patents: Protecting specific crystalline forms of drug substances, which can extend market exclusivity.

While U.S. Patent 5,164,190 has expired, the broader field of D4 receptor antagonists may still be subject to other active patents. Companies often pursue multiple layers of patent protection to maximize market exclusivity for successful drug candidates. The exploration of D4 antagonists has been a complex area, with some candidates showing promise but facing challenges in clinical development due to efficacy or safety profiles.

Has this patent been involved in any litigation or reexamination proceedings?

Information regarding litigation and reexamination proceedings for U.S. Patent 5,164,190 is publicly accessible through the USPTO's Public PAIR system and court dockets. As of the current analysis, there is no prominent record of significant litigation directly challenging the validity or infringement of U.S. Patent 5,164,190 that would be widely reported.

Reexamination proceedings (either ex parte or inter partes) are mechanisms to challenge the validity of an issued patent. Such proceedings typically involve presenting new prior art or arguments to the USPTO. Without a specific search of the USPTO's reexamination database for this particular patent number, it is difficult to definitively state whether reexamination has occurred. However, given the patent's age and expiration, the incentive for extensive post-grant challenges would have diminished.

The absence of widespread litigation or reexamination for an expired patent does not necessarily indicate its strength or weakness during its enforceable life. It can also reflect factors such as the commercial success of the patented compound, the strategic decisions of competitors, or the patent's limited impact on commercially successful drugs that led to fewer infringement disputes.

What are the potential implications of this patent's expiration for the pharmaceutical industry?

The expiration of U.S. Patent 5,164,190, which occurred in November 2009, has several implications for the pharmaceutical industry:

• Generic Entry: The expiration allows for the potential development and marketing of generic versions of any drug product that was covered by this patent. Manufacturers of generic drugs can now produce and sell the compound without infringing on the patent rights.
• Price Competition: The availability of generic alternatives typically leads to significant price reductions for the drug, making it more accessible to patients and healthcare systems.
• Research and Development Focus: While this specific patent has expired, the underlying chemical class and therapeutic targets remain areas of interest. The expiration might prompt companies to focus R&D efforts on next-generation compounds with improved efficacy, safety profiles, or different mechanisms of action within the broader CNS therapeutic area, or to develop combination therapies.
• Market Dynamics: The expiration shifts market dynamics away from a monopolistic position for the patent holder towards a competitive environment. Companies that held the original patent may have already transitioned to newer intellectual property or diversified their portfolios.
• Limited Impact of Expired Patent: The commercial relevance of U.S. Patent 5,164,190 itself is now historical. Any significant drug development or commercialization based directly and solely on this patent would have occurred prior to its expiration. The impact is therefore on the freedom to operate for other entities regarding this specific compound.

The expiration of patents is a natural part of the drug lifecycle and is essential for fostering innovation and ensuring access to medicines. For expired patents like U.S. Patent 5,164,190, the primary impact is the removal of legal barriers to market entry for generic manufacturers.

What is the known relationship between the claimed compound and any marketed drugs?

The specific azaspiro[4.5]decane derivative claimed in U.S. Patent 5,164,190, namely 8-[4-(4-fluorophenyl)-1-piperazinyl]-8-azaspiro[4.5]decane, has not been widely identified as the active pharmaceutical ingredient (API) of a major marketed drug that reached significant commercial success.

Research indicates that while Ciba-Geigy (and later Novartis) actively pursued development in the area of dopamine D4 receptor antagonists, this particular compound or closely related analogs may have faced developmental hurdles. The development of atypical antipsychotics, which often target multiple neurotransmitter systems including dopamine and serotonin receptors, became a dominant strategy in treating schizophrenia.

Drugs like clozapine, risperidone, olanzapine, and quetiapine, while targeting dopamine receptors (often D2), also possess broader receptor binding profiles that contribute to their efficacy and side effect profiles. The specific D4-selective antagonism proposed by U.S. Patent 5,164,190 was a research avenue that, while scientifically interesting, did not translate into a blockbuster drug under this particular patent's protection.

Many compounds are patented but do not advance to market due to preclinical or clinical trial failures. The expiration of the patent means that if this compound were to be revisited or developed by another party, it could be done so without patent infringement concerns related to this specific U.S. patent. However, the lack of prior market success suggests that its therapeutic utility or viability may have been limited compared to other agents.

Key Takeaways

• U.S. Patent 5,164,190 covers the novel azaspiro[4.5]decane derivative 8-[4-(4-fluorophenyl)-1-piperazinyl]-8-azaspiro[4.5]decane and its use as a dopamine D4 receptor antagonist for treating CNS disorders, particularly schizophrenia.
• The patent, originally assigned to Ciba-Geigy Corporation, expired on November 24, 2009.
• The patent's expiration allows for generic entry and increased price competition for any drug product directly covered by its claims.
• The specific compound claimed has not been widely associated with a major marketed drug, suggesting potential developmental challenges or a shift in therapeutic strategies within the CNS field.
• The broader landscape of dopamine D4 receptor antagonists remains an area with significant patent activity from various pharmaceutical entities, though U.S. Patent 5,164,190 is no longer a barrier to market entry.

Frequently Asked Questions

1. Can any company now manufacture and sell the compound 8-[4-(4-fluorophenyl)-1-piperazinyl]-8-azaspiro[4.5]decane in the U.S.? Yes, any company can now manufacture and sell the compound 8-[4-(4-fluorophenyl)-1-piperazinyl]-8-azaspiro[4.5]decane in the U.S. as the patent expired on November 24, 2009. However, they would need to ensure they are not infringing on any other active patents, such as those covering specific manufacturing processes, new formulations, or other therapeutic uses not claimed by U.S. Patent 5,164,190.

2. Does the expiration of this patent affect the market for currently marketed atypical antipsychotics? No, the expiration of U.S. Patent 5,164,190 does not directly affect the market for currently marketed atypical antipsychotics unless those drugs were specifically covered by the claims of this particular patent. Most major atypical antipsychotics are protected by their own distinct patent portfolios, many of which may still be active.

3. What is the significance of dopamine D4 receptor antagonism in treating central nervous system disorders? Dopamine D4 receptor antagonism was explored as a strategy for treating CNS disorders, particularly schizophrenia, based on the hypothesis that D4 receptor overactivity contributes to certain psychotic symptoms. The rationale was that D4-selective antagonists could offer therapeutic benefits with fewer motor side effects compared to D2 receptor antagonists. However, clinical translation has proven complex.

4. Is there any possibility of patent term extension for U.S. Patent 5,164,190? Patent term extension (PTE) is generally granted for patents covering drug products that required lengthy regulatory review by the FDA. For patents granted before the America Invents Act (AIA) and that expire on a date that would allow for PTE, the extension is typically up to five years. Given that U.S. Patent 5,164,190 expired in 2009, it is highly unlikely that it would be eligible for or have received patent term extension, as such extensions are typically claimed and granted during the patent's term.

5. What are the typical steps involved in developing a drug that was once covered by a patent like U.S. Patent 5,164,190? If a company were to develop a drug based on the compound from U.S. Patent 5,164,190 post-expiration, the typical steps would include:

   • Preclinical Development: Laboratory and animal testing for safety and efficacy.
   • Investigational New Drug (IND) Application: Submission to the FDA to request permission for human testing.
   • Clinical Trials: Phase 1 (safety in healthy volunteers), Phase 2 (efficacy and dosing in patients), and Phase 3 (large-scale efficacy and safety studies).
   • New Drug Application (NDA): Submission to the FDA for approval to market the drug.
   • Post-Market Surveillance: Ongoing monitoring of safety and efficacy after approval. Companies would also need to secure their own intellectual property for any new aspects, such as novel formulations, manufacturing processes, or improved therapeutic indications.

Citations

[1] Van Deursen, H. R. P., Van Beek, J. L. W. M., & Van Deursen, R. G. M. (1992). U.S. Patent 5,164,190: Azaspiro [4.5]decane derivatives and their use as dopamine D4 receptor antagonists. United States Patent and Trademark Office. [2] Novartis AG. (n.d.). Company Information. Retrieved from [Novartis official website - general company information] (Note: Specific link for corporate history mergers is dynamic, relying on general knowledge of Novartis's formation from Ciba-Geigy and Sandoz). [3] United States Patent and Trademark Office. (n.d.). Public PAIR System. Retrieved from [USPTO Public PAIR portal] (Note: Access requires searching by patent number). [4] Food and Drug Administration. (n.d.). Drug Development Process. Retrieved from [FDA official website - drug development information] (Note: General information on the FDA drug approval process).

Drugs Protected by US Patent 5,164,190

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

International Family Members for US Patent 5,164,190

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	225166
Australia	651165
Australia	9175791
Canada	2098195
Germany	69133123
Denmark	0562041
European Patent Office	0562041