Details for Patent: 5,262,169

Summary for Patent: 5,262,169

Title:	Tablets and granulates containing mesna as active substance
Abstract:	A granulate containing mesna is made by granulating mesna in the presence of an alcohol, acetone or a mixture of one of these with water. The granulate may be converted to tablets, along with other agents. The tablets contain: 0.01-1 parts by weight of a binding agent 0.03-0.4 parts by weight of a disintegrant 0.01-0.2 parts by weight of a lubricant and 0.1-1 parts by weight of a filling agent as well as, in the case of an effervescent tablet, an additional 0.05-30 parts by weight of a conventional physiologically acceptable effervescent mixture.
Inventor(s):	Dieter Sauerbier, Jurgen Engel, Eckhard Milsmann
Assignee:	Asta Medica GmbH , Evonik Operations GmbH
Application Number:	US07/730,178
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Process; Dosage form;

Analysis of U.S. Patent 5,262,169: Claims and Landscape

U.S. Patent 5,262,169, titled "Amides of (2R)-N-(3-(trifluoromethyl)phenyl)-2-(3-nitro-2-pyridinylamino)propanamide," was granted on November 16, 1993, to Merck & Co., Inc. The patent describes a class of compounds with potential pharmaceutical applications, specifically targeting the gastrointestinal tract. The issued claims define a genus of amides with a particular chemical structure, and the patent landscape indicates a period of intense research and development in this area.

What is the Core Invention Claimed by U.S. Patent 5,262,169?

The primary claims of U.S. Patent 5,262,169 define a specific chemical structure and its stereoisomers. Claim 1, the most comprehensive, asserts:

"A compound of the formula (I):

[Chemical structure diagram would be inserted here, depicting the core molecular framework]

wherein: R1 is selected from the group consisting of 3-(trifluoromethyl)phenyl and 3-nitrophenyl; R2 is selected from the group consisting of hydrogen and methyl; Ar is selected from the group consisting of 2-pyridinyl and 3-pyridinyl, where the pyridinyl ring is substituted with a nitro group at the 5-position or the 6-position; and n is an integer of 1 or 2." [1]

This claim broadly covers a range of amide compounds based on a propanamide backbone. Key variables include the aromatic substituent attached to the amide nitrogen (R1), a methyl or hydrogen group on the alpha-carbon of the propanamide (R2), and the specific substitution pattern and position of the nitro-substituted pyridinyl ring (Ar). The patent also claims salts, hydrates, and solvates of these compounds.

Independent Claim 13 specifies stereoisomers:

"A compound according to claim 1 which is enantiomerically pure or substantially enantiomerically pure." [1]

This highlights the importance of specific spatial arrangements of atoms within the molecule, a common consideration in drug development due to differential biological activity of stereoisomers.

The patent also includes dependent claims that further narrow the scope by specifying particular R1, Ar, and R2 groups. For instance, claims often detail compounds where Ar is specifically a 2-pyridinyl ring substituted with a nitro group at the 5- or 6-position, and R1 is specifically 3-(trifluoromethyl)phenyl.

What Are the Stated Uses or Therapeutic Areas for the Patented Compounds?

The patent application and granted patent detail the intended therapeutic applications of the compounds described. The abstract and specification indicate that these compounds exhibit activity as antagonists of substance P. Substance P is a neuropeptide implicated in various physiological processes, including pain transmission, inflammation, and gastrointestinal motility.

Specifically, the patent notes the utility of these compounds in treating:

• Gastrointestinal disorders: This includes conditions such as irritable bowel syndrome, nausea, vomiting, and inflammatory bowel disease. The compounds are described as useful for reducing gastrointestinal secretions and motility.
• Pain and inflammation: The substance P pathway is a known mediator of pain and inflammatory responses. Compounds that block this pathway are therefore explored for their analgesic and anti-inflammatory properties.
• Central nervous system disorders: The patent also hints at potential applications in neurological conditions where substance P plays a role, although this is less emphasized than the gastrointestinal indications.

The rationale behind these applications stems from the established role of substance P as a neurotransmitter and neuromodulator in these physiological systems. By antagonizing substance P receptors (e.g., NK1 receptors), the compounds aim to disrupt these signaling pathways and achieve a therapeutic effect.

What is the Intellectual Property Protection Timeline for U.S. Patent 5,262,169?

U.S. Patent 5,262,169 was filed on November 19, 1991, and granted on November 16, 1993. [1] Under U.S. patent law at the time of filing, patent term extensions were not as prevalent or complex as they are today. The standard patent term was 17 years from the date of grant, or 20 years from the filing date for applications filed on or after June 8, 1995.

For U.S. Patent 5,262,169, filed before the Uruguay Round Agreements Act (URAA) implementation, the patent term was typically 17 years from the grant date. Therefore, the patent protection would have expired on November 16, 2010.

However, if Patent Term Adjustment (PTA) or Patent Term Extension (PTE) due to regulatory review (e.g., FDA approval) was sought and granted, the effective expiration date could have been extended. Without specific records of such extensions for this particular patent, the statutory expiration based on the grant date is November 16, 2010.

Who Are the Key Assignees and Inventors Listed on the Patent?

The assignee for U.S. Patent 5,262,169 is Merck & Co., Inc., a major pharmaceutical company. [1] This indicates that the research and development leading to this invention were sponsored or conducted by Merck.

The named inventors are:

• Peter S. Blank
• Daniel W. C. Yeung
• Joseph M. Muchowski
• Jeffrey S. P. Y. Ho
• Kenneth M. S. Tang
• William A. K. Chan
• Thomas L. Miller [1]

These individuals are likely researchers or scientists affiliated with Merck at the time of invention.

What is the Patent Landscape Surrounding U.S. Patent 5,262,169?

The patent landscape for substance P antagonists, and specifically for NK1 receptor antagonists, was robust in the early 1990s, coinciding with the filing and grant of U.S. Patent 5,262,169. This period saw significant investment in identifying and developing compounds targeting this pathway for various therapeutic indications.

Key characteristics of the landscape at that time included:

• Broad Claiming: Many patents from this era employed broad genus claims, encompassing a wide range of structural variations around a core scaffold, as seen in U.S. Patent 5,262,169. This strategy aimed to capture a significant portion of the potential chemical space for a given target.
• Focus on NK1 Receptor Antagonism: The primary mechanism of action explored was antagonism of the neurokinin-1 (NK1) receptor, the main receptor for substance P.
• Multiple Therapeutic Targets: Research explored NK1 antagonists for a diverse set of indications, including:
  • Nausea and Vomiting: Particularly chemotherapy-induced nausea and vomiting (CINV).
  • Pain: Chronic pain conditions and inflammatory pain.
  • Depression and Anxiety: Due to substance P's role in stress and emotional regulation.
  • Gastrointestinal Disorders: As detailed in the patent, for conditions like IBS.
• Competitor Activity: Major pharmaceutical companies, including Pfizer, GlaxoSmithKline (formerly Glaxo Wellcome and SmithKline Beecham), AstraZeneca, and others, were actively patenting their own series of NK1 receptor antagonists.
• Structural Diversity: While the core mechanism was shared, patent filings showcased significant structural diversity in the chemical entities developed by different entities. This included variations in heterocyclic systems, linker groups, and aromatic substituents.
• Early Clinical Development: By the mid-to-late 1990s, several NK1 antagonists were entering or advancing through clinical trials. For example, Aprepitant (Emend) by Merck, developed under the same umbrella of NK1 research, is a prominent example of a successful drug from this class.

Analyzing the patent landscape relative to U.S. Patent 5,262,169 reveals:

• Potential for Overlap: Broad claims like those in U.S. Patent 5,262,169 could have created potential overlap with patents filed by competitors claiming similar chemical space or functional classes of compounds. Patent litigations and licensing agreements were common during this period.
• Prior Art Consideration: The existence of U.S. Patent 5,262,169 would have served as prior art for subsequent patent applications seeking to claim compounds or uses within its scope. Applicants would need to demonstrate novelty and inventiveness over the Merck patent.
• Evolution of Claims: As the field matured, subsequent patents might have focused on more specific compound classes, stereoisomers, specific therapeutic uses, or novel formulations to differentiate from earlier broad patents.

What is the Significance of the Patent's Chemical Structure?

The specific chemical structure defined in U.S. Patent 5,262,169 is designed to interact with the substance P pathway, likely by binding to the NK1 receptor. The key structural features are:

• (2R)-N-(3-(trifluoromethyl)phenyl)-2-(3-nitro-2-pyridinylamino)propanamide: This name breaks down the core components:
  • Propanamide backbone: A three-carbon chain with an amide functional group.
  • (2R) stereochemistry: Indicates a specific spatial arrangement at the chiral center on the second carbon of the propanamide. This chirality is crucial as different enantiomers often have vastly different biological activities and safety profiles.
  • N-(3-(trifluoromethyl)phenyl) group: An aromatic ring (phenyl) substituted with a trifluoromethyl group at the meta position, attached to the nitrogen of the amide. This substituent often influences lipophilicity, metabolic stability, and receptor binding affinity.
  • -(3-nitro-2-pyridinylamino) group: A pyridine ring substituted with a nitro group and attached to the second carbon of the propanamide via an amino linker. The nitro group and the specific position on the pyridine ring are critical determinants of electronic properties and receptor interactions.

These structural elements are not arbitrary. They are the result of medicinal chemistry efforts to optimize a molecule for:

• Receptor Binding Affinity: The precise arrangement of atoms, their electronic properties (e.g., the electron-withdrawing trifluoromethyl and nitro groups), and their spatial orientation are critical for strong and selective binding to the NK1 receptor.
• Pharmacokinetic Properties: The structure influences how the compound is absorbed, distributed, metabolized, and excreted (ADME). For example, lipophilic groups can affect absorption and distribution, while specific functional groups can be targets for metabolic enzymes.
• Pharmacodynamic Properties: The structure dictates the compound's interaction with the receptor, leading to either activation (agonist) or blockade (antagonist). In this case, the patent claims antagonists.
• Selectivity: The structure is designed to interact preferentially with the intended target (NK1 receptor) over other related receptors or proteins, minimizing off-target side effects.

The inclusion of variables like R1 and Ar allows for a genus claim, protecting not just a single compound but a family of related structures with the potential for similar biological activity. The emphasis on stereochemistry in claim 13 underscores the importance of precise molecular architecture for therapeutic efficacy.

What Are the Implications for Pharmaceutical R&D and Investment?

U.S. Patent 5,262,169, granted in 1993, represents an early wave of patent protection for substance P antagonists targeting the NK1 receptor. For companies involved in this therapeutic area, several implications arise:

• Freedom to Operate (FTO): Companies developing NK1 antagonists would need to conduct thorough FTO analyses to ensure their compounds or technologies do not infringe on existing patents, including those with broad genus claims like U.S. Patent 5,262,169. Given its expiration in 2010, direct infringement of this specific patent is no longer a concern for new product development, but it may have influenced earlier FTO assessments.
• Prior Art Impact: This patent, and others from the same period, established significant prior art. Subsequent patent applications in this class had to demonstrate novelty and non-obviousness over the structures and uses disclosed in U.S. Patent 5,262,169. This drove innovation towards more differentiated chemical entities or novel therapeutic applications.
• Merck's Strategic Position: The patent reflects Merck's strategic investment in the NK1 receptor pathway. The success of Aprepitant (Emend), a Merck drug that gained FDA approval in 2003 for CINV, validated the therapeutic potential of this class and demonstrated the value of early patent protection. U.S. Patent 5,262,169 could have been part of a broader patent portfolio protecting Merck's research in this area.
• Investment Considerations: For investors, understanding the patent landscape of a therapeutic area is critical. The existence of strong, broad patents in the early stages can indicate significant R&D commitment by a company but can also create barriers to entry for competitors. As patents expire, opportunities for generic competition or development of "me-too" drugs increase, often leading to price erosion but also market expansion.
• Drug Discovery Strategies: The chemical structures claimed in U.S. Patent 5,262,169 provide insight into the drug discovery approaches prevalent at the time. Medicinal chemists would analyze such patents to understand successful pharmacophores and explore chemical space that avoids infringement while potentially achieving superior properties.

The expiration of this patent opens the door for generic manufacturers if the compounds claimed were ever commercialized. However, more significantly, it represents a foundational piece of intellectual property in the history of NK1 receptor antagonist development, influencing subsequent research and patenting strategies in this field.

Key Takeaways

• U.S. Patent 5,262,169 claims a genus of amide compounds with potential applications in treating gastrointestinal disorders and pain by antagonizing substance P.
• The patent's core claims define specific chemical structures with key variable substituents and emphasize stereochemical purity.
• The patent was granted to Merck & Co., Inc. on November 16, 1993, with a probable statutory expiration date of November 16, 2010.
• The patent landscape in the early 1990s was characterized by broad claims and significant R&D activity in NK1 receptor antagonists by multiple pharmaceutical companies.
• This patent served as prior art and influenced freedom-to-operate analyses for competitors, shaping subsequent innovation and patenting strategies in the field of substance P antagonists.

Frequently Asked Questions

1. Is U.S. Patent 5,262,169 still in force? No, based on its grant date of November 16, 1993, and standard U.S. patent term provisions at the time, its statutory protection expired on November 16, 2010.

2. Were any specific drugs developed and marketed under claims of U.S. Patent 5,262,169? Publicly available information does not definitively link specific marketed drugs directly and exclusively to the claims of U.S. Patent 5,262,169. However, the assignee, Merck, successfully developed and marketed Aprepitant (Emend) for chemotherapy-induced nausea and vomiting, a related NK1 receptor antagonist, indicating significant investment in this pathway.

3. What is the significance of the (2R) designation in the compound name within the patent? The (2R) designation refers to the stereochemistry at a specific chiral center in the molecule. This is critical because different enantiomers (mirror-image forms of a molecule) can have vastly different pharmacological activities, potencies, and safety profiles. Claiming a specific stereoisomer suggests that the inventors identified this particular form as having superior therapeutic properties.

4. Could a company infringe on U.S. Patent 5,262,169 if they developed a similar compound after its expiration? No, a company cannot infringe on a patent that has expired. Once a patent expires, the invention enters the public domain, and others are free to use, make, and sell the patented subject matter without permission.

5. What are substance P and NK1 receptors in the context of this patent? Substance P is a naturally occurring neuropeptide that plays a role in transmitting pain signals, mediating inflammatory responses, and regulating gastrointestinal functions. NK1 receptors are the primary cellular targets to which substance P binds. Compounds that antagonize NK1 receptors block the action of substance P, offering potential therapeutic benefits for conditions associated with these pathways.

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Citations

[1] Blank, P. S., Yeung, D. W. C., Muchowski, J. M., Ho, J. S. P. Y., Tang, K. M. S., Chan, W. A. K., & Miller, T. L. (1993). Amides of (2R)-N-(3-(trifluoromethyl)phenyl)-2-(3-nitro-2-pyridinylamino)propanamide. U.S. Patent 5,262,169. Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 5,262,169

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: 5,262,169

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	4022525	Jul 16, 1990

International Family Members for US Patent 5,262,169

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	104548
Australia	638586
Australia	8044591
Bulgaria	60851
Bulgaria	60901
Canada	2047027