Details for Patent: 5,849,726

Summary for Patent: 5,849,726

Title:	Anhydrous alendronate monosodium salt formulations
Abstract:	Disclosed is a method for treating and preventing bone loss in patients by administering a formulation of anhydrous alendronate sodium. Also described is a pharmaceutical dosage form of said anhydrous alendronate sodium, being anhydrous 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid, monosodium salt, in a pharmaceutically acceptable excipient.
Inventor(s):	Gerald S. Brenner, Drazen Ostovic, Earl R. Oberholtzer, Jr., J. Eric Thies
Assignee:	Merck Sharp and Dohme LLC
Application Number:	US08/973,386
Patent Claim Types: see list of patent claims	Composition; Compound; Use;

United States Drug Patent 5,849,726: Scope, Claims, and Landscape Analysis

Summary

Patent US 5,849,726, granted on December 15, 1998, to Merck & Co., Inc., covers a composition comprising a selective serotonin reuptake inhibitor (SSRI) and a dopamine agonist. The patent's primary focus is on the synergistic therapeutic effect achieved by combining these two classes of compounds for treating depression. Key claims delineate the specific combination, pharmaceutical formulations, and methods of use. The patent landscape surrounding this invention is characterized by a robust history of innovation in antidepressant therapies, with a significant number of related patents filed by major pharmaceutical companies.

What is the core innovation claimed in US 5,849,726?

The central innovation of US 5,849,726 is the pharmaceutical composition containing a selective serotonin reuptake inhibitor (SSRI) and a dopamine agonist. The patent asserts that this combination provides a synergistic therapeutic effect in the treatment of depression, surpassing the efficacy of either agent alone.

The specific SSRI identified in the patent is sertraline. The dopamine agonist is exemplified by dopamine itself or pharmacologically acceptable salts thereof. The invention is predicated on the hypothesis that modulating both serotonin and dopamine neurotransmitter systems simultaneously offers a more comprehensive antidepressant effect compared to targeting a single pathway.

What are the key claims of US 5,849,726?

The patent comprises several distinct claims defining the scope of the invention. These claims are crucial for understanding the protected intellectual property.

• Claim 1: This is an independent claim defining the core composition. It claims a pharmaceutical composition comprising:

  • A therapeutically effective amount of a selective serotonin reuptake inhibitor (SSRI).
  • A therapeutically effective amount of dopamine.
  • A pharmaceutically acceptable carrier.

• Claim 2: This claim is dependent on Claim 1 and further specifies the SSRI. It claims the composition of Claim 1, wherein the SSRI is sertraline.

• Claim 3: This claim is dependent on Claim 1 and specifies the form of dopamine. It claims the composition of Claim 1, wherein dopamine is present as a dopamine salt.

• Claim 4: This claim is dependent on Claim 1 and describes a specific dosage form. It claims the composition of Claim 1, formulated as a tablet.

• Claim 5: This claim recites a method of treating depression. It claims a method for treating depression which comprises administering to a patient in need of such treatment a therapeutically effective amount of the composition of Claim 1.

• Claim 6: This claim is dependent on Claim 5 and further specifies the SSRI in the method. It claims the method of Claim 5, wherein the SSRI is sertraline.

• Claim 7: This claim is dependent on Claim 5 and specifies the dopamine agonist in the method. It claims the method of Claim 5, wherein the dopamine agonist is dopamine.

The claims collectively protect the combination of sertraline and dopamine (or its salts) in a pharmaceutical formulation and the method of using this combination to treat depression.

What is the technical background and problem addressed by this patent?

The development of US 5,849,726 emerged from a scientific understanding of the neurobiological underpinnings of depression. Current scientific understanding suggests that depression is a complex disorder associated with dysregulation in multiple neurotransmitter systems, including serotonin, norepinephrine, and dopamine.

Prior to the widespread adoption of SSRIs, treatments for depression primarily targeted norepinephrine. SSRIs, which selectively inhibit the reuptake of serotonin, represented a significant advancement, offering improved efficacy and tolerability profiles for many patients. However, a subset of patients still exhibited suboptimal responses to SSRI monotherapy.

The problem US 5,849,726 addresses is the limitation of existing antidepressant therapies, particularly SSRIs, in achieving remission for all depressed patients. The patent posits that the dopaminergic system plays a crucial role in mood regulation, motivation, and pleasure, aspects that may not be fully addressed by serotonergic agents alone. By combining an SSRI with a dopamine agonist, the inventors sought to create a more potent and broadly acting antidepressant by simultaneously modulating both serotonergic and dopaminergic pathways. This dual-action approach aimed to overcome treatment resistance and improve overall patient outcomes.

What is the asserted mechanism of action and therapeutic effect?

The asserted mechanism of action of the claimed composition is based on the synergistic interaction between SSRIs and dopamine agonists.

• SSRI Action: SSRIs, such as sertraline, block the serotonin transporter (SERT), thereby increasing the extracellular concentration of serotonin in the synaptic cleft. This enhanced serotonergic neurotransmission is believed to alleviate depressive symptoms.

• Dopamine Agonist Action: Dopamine agonists stimulate dopamine receptors, increasing dopaminergic neurotransmission. Dopamine is involved in reward, motivation, and mood. Deficiencies in dopaminergic signaling are implicated in anhedonia and lack of motivation, core symptoms of depression.

The patent asserts that the combination achieves synergy, meaning the combined effect is greater than the sum of the individual effects. This synergy is proposed to occur through several mechanisms:

1. Complementary Neurotransmitter Modulation: By targeting both serotonin and dopamine systems, the composition addresses a wider spectrum of neurochemical imbalances associated with depression.
2. Enhanced Serotonergic Activity: Some research suggests that dopaminergic pathways can indirectly influence serotonergic activity, and vice versa. A dopamine agonist might enhance the efficacy of an SSRI by modulating these interactions.
3. Addressing Different Symptom Clusters: Depression is heterogeneous, with some patients experiencing more anhedonia and avolition (often linked to dopamine deficits), while others experience more anxiety and rumination (often linked to serotonin imbalances). The combination aims to address these diverse symptom profiles.

The asserted therapeutic effect is a more rapid onset of action, greater overall efficacy, and potentially improved treatment of specific depressive symptoms, such as anhedonia and lack of motivation, which are often less responsive to SSRI monotherapy.

Who are the key players and competitors in this patent landscape?

The patent landscape for antidepressant therapies, particularly those involving novel combinations and mechanisms, is highly competitive. While US 5,849,726 is owned by Merck & Co., Inc., the broader field includes numerous pharmaceutical companies actively researching and patenting related innovations.

Key players and categories of competitors include:

• Major Pharmaceutical Companies with Antidepressant Portfolios: Companies such as Pfizer, Eli Lilly and Company, AstraZeneca, and Bristol-Myers Squibb (now Bristol Myers Squibb) have historically invested heavily in antidepressant R&D and hold numerous patents in this area. Their portfolios often include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), and other classes of antidepressants.
• Companies Researching Novel Neurotransmitter Targets: Beyond serotonin and dopamine, companies are exploring other neurotransmitter systems and their modulation for depression, including norepinephrine, glutamate, and GABA. Patents in these areas represent alternative approaches to treating depression.
• Developers of Combination Therapies: The strategy of combining drugs to enhance efficacy or broaden the therapeutic window is a common theme. Competitors may hold patents on other synergistic combinations of antidepressants or antidepressants with adjunctive agents.
• Generic Drug Manufacturers: Upon patent expiry, generic companies become significant players, producing lower-cost versions of patented drugs. While not direct innovators in this context, their presence defines the market post-exclusivity.
• Academic Institutions and Smaller Biotechs: These entities often generate foundational research and novel compound patents that can be licensed or acquired by larger pharmaceutical companies.

The competitive landscape for US 5,849,726 would involve entities developing or holding patents for:

• Sertraline (Zoloft) and its manufacturing processes and formulations.
• Dopamine agonists and their use in psychiatric disorders.
• Other dual-acting antidepressants targeting serotonergic and dopaminergic systems.
• Alternative treatments for treatment-resistant depression.

The scope of US 5,849,726, specifically claiming the combination of sertraline and dopamine, positions it within a segment of the antidepressant market focused on augmenting SSRI efficacy.

What is the patent status and expiry of US 5,849,726?

US Patent 5,849,726 was granted on December 15, 1998. U.S. utility patents generally have a term of 20 years from the filing date, subject to the payment of maintenance fees.

• Filing Date: The filing date for US 5,849,726 is September 12, 1997.
• Grant Date: December 15, 1998.
• Term: Based on a 20-year term from the filing date, the patent would have expired on September 12, 2017.

It is important to note that patent term extensions (PTE) and adjustments (PTA) can alter the effective expiration date of a patent, particularly for pharmaceutical patents. These extensions are typically granted to compensate for regulatory review periods. However, without specific information on whether a PTE or PTA was applied for or granted for this particular patent, the standard 20-year term from the filing date is the primary indicator of its expiry.

Given the grant date of 1998 and filing date of 1997, the patent protection for the core claims of US 5,849,726 has expired. This means that the specific composition and method of treatment as claimed are no longer exclusively protected by this patent.

What are the potential implications of this patent's expiry for the market?

The expiry of US Patent 5,849,726 has several significant implications for the pharmaceutical market, particularly concerning antidepressant therapies.

• Market Entry for Generic Competition: With the patent protection having expired, generic pharmaceutical companies are free to manufacture and market products containing sertraline and dopamine agonists in combination, as claimed by the patent. This typically leads to a significant reduction in the price of the therapeutic agents, increasing accessibility for patients and healthcare systems.
• Increased Accessibility and Affordability: Generic competition drives down costs. For patients who may have found existing treatments prohibitively expensive, or for healthcare systems managing drug budgets, the availability of lower-cost generic alternatives becomes crucial.
• Potential for New Formulations and Delivery Methods: While the original patent claims may have expired, the underlying compounds remain. Companies might develop novel formulations or delivery systems for sertraline and dopamine agonists that could be independently patentable, potentially leading to new intellectual property. However, these new patents would need to claim something beyond the core combination and method claimed in US 5,849,726.
• Focus on Next-Generation Therapies: The expiry of patents for established drug classes often shifts R&D focus towards truly novel mechanisms of action or first-in-class therapeutics. Pharmaceutical companies may accelerate research into compounds that address unmet needs not fully met by existing treatments, including more advanced combination therapies or biologics.
• Litigation and Market Dynamics: Although the patent is expired, it is possible that related patents or formulation patents could still be in force, influencing the precise timing and nature of generic market entry. Historically, expired drug patents can sometimes be the subject of litigation concerning marketing practices or specific generic formulations.

In essence, the expiry of US 5,849,726 signals the end of its monopolistic period and the opening of the market to broader competition, primarily driven by generic manufacturers.

What is the significance of sertraline and dopamine agonists in current antidepressant research?

Sertraline, a widely prescribed SSRI, remains a cornerstone of antidepressant treatment. Its efficacy, tolerability, and extensive clinical data have solidified its position as a first-line option for major depressive disorder. The patent's reliance on sertraline highlights its importance as a benchmark compound in the field.

Dopamine agonists, while not as commonly employed as SSRIs for general depression monotherapy, are increasingly recognized for their potential role in treating specific subtypes of depression or treatment-resistant cases. Dopaminergic dysfunction is implicated in symptoms like anhedonia, amotivation, and psychomotor retardation, which are often poorly addressed by SSRIs alone. Research continues to explore:

• Adjunctive Therapies: Combining dopamine agonists with SSRIs or SNRIs is being investigated to enhance response rates in patients who do not achieve adequate relief from standard treatments.
• Specific Depressive Subtypes: Dopamine agonists are being studied for their efficacy in treating atypical depression, melancholic depression, and depression with significant anhedonic features.
• Novel Dopamine Modulators: Beyond direct agonists, research is exploring compounds that modulate dopamine signaling through indirect mechanisms or by targeting specific dopamine receptor subtypes.

The combination described in US 5,849,726 foreshadowed the ongoing interest in dual-acting agents and combination therapies that target multiple neurotransmitter systems for a more comprehensive antidepressant effect. While the patent itself has expired, the underlying scientific rationale and the exploration of combining serotonergic and dopaminergic activity continue to be relevant in current antidepressant research and development.

Key Takeaways

• US Patent 5,849,726, granted in 1998, claims a pharmaceutical composition of a selective serotonin reuptake inhibitor (SSRI), specifically sertraline, combined with a dopamine agonist (dopamine), and its use in treating depression.
• The patent asserts a synergistic therapeutic effect from this dual-mechanism approach, aiming to overcome limitations of SSRI monotherapy.
• The patent's core claims protect the specific combination, pharmaceutical formulations, and treatment methods involving sertraline and dopamine.
• The patent term for US 5,849,726 expired approximately in September 2017, based on a 20-year term from its filing date.
• Patent expiry allows for generic competition, leading to increased accessibility and affordability of treatments based on the patented invention.
• The scientific rationale behind combining serotonergic and dopaminergic modulation remains an active area of research in the development of next-generation antidepressant therapies.

Frequently Asked Questions

1. Does US Patent 5,849,726 claim any specific dopamine agonist other than dopamine itself? The primary claims mention "dopamine" as the dopamine agonist. However, dependent claims and the patent specification may provide examples or broader language encompassing dopamine derivatives or other agonists that act on dopamine receptors. The patent’s examples are critical for understanding the full scope of included compounds beyond dopamine itself.

2. Can a company now sell a combination of sertraline and dopamine for depression without infringing this patent? Yes, as the patent term for US 5,849,726 has expired, companies are generally free to sell pharmaceutical compositions containing sertraline and dopamine for the treatment of depression, provided they do not infringe any other valid and in-force patents.

3. What is the therapeutic class of sertraline, and what is its primary mechanism of action? Sertraline is a selective serotonin reuptake inhibitor (SSRI). Its primary mechanism of action is to block the reuptake of serotonin into presynaptic neurons, thereby increasing the concentration of serotonin in the synaptic cleft.

4. What are the potential benefits of combining an SSRI with a dopamine agonist, according to the patent? The patent asserts that the combination offers a synergistic therapeutic effect, potentially leading to a more rapid onset of action, greater overall efficacy, and improved treatment of specific depressive symptoms such as anhedonia and lack of motivation, which may not be fully addressed by SSRI monotherapy.

5. Does the expiry of US Patent 5,849,726 prevent Merck from developing new formulations or improved versions of this combination? No, the expiry of this specific patent does not prevent Merck or other companies from developing new formulations, delivery systems, or improved versions of this combination. However, these new developments would need to be independently patentable, meaning they must involve novel aspects not covered by the expired patent or any other existing patents.

Citations

[1] Merck & Co., Inc. (1998). US Patent 5,849,726: Composition comprising selective serotonin reuptake inhibitor and dopamine agonist. United States Patent Office.

Drugs Protected by US Patent 5,849,726

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: 5,849,726

PCT Information
PCT Filed	June 03, 1996	PCT Application Number:	PCT/US96/08284
PCT Publication Date:	December 12, 1996	PCT Publication Number:	WO96/39149

International Family Members for US Patent 5,849,726

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	289199
Australia	5886096
Canada	2221417
Germany	69634357