Details for Patent: 5,202,333

Summary for Patent: 5,202,333

Title:	Tricyclic 5-HT3 receptor antagonists
Abstract:	The present invention is directed to 5-HT3 receptor antagonist compounds of formula I: I in which the dashed line denotes an optional double bond; n is 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1 or 2; each R1 is independently selected from halogen, hydroxy, lower alkoxy, lower alkyl, nitro, amino, amino carbonyl, (lower alkyl)amino, di(lower alkyl)amino, and (lower alkanoyl)amino; each R2 is lower alkyl; and R3 is a group selected from Formulae (a), (b), (c) and (d): (a) (b) (c) (d) in which u is 0 or 1; z is 1, 2 or 3; and R4 is C1-7 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-2 alkyl, or a group (CH2)tR5 where t is 1 or 2 and R5 is thienyl, pyrrolyl, or furyl, each optionally further substituted by one or two substituents selected from C1-6 alkyl, C1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C1-4 alkyl optionally substituted by hydroxy, C1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy; and the pharmaceutically acceptable salts, individual isomers, mixtures of isomers, processes for preparation, compositions, and methods of use thereof.
Inventor(s):	Jacob Berger, Robin D. Clark, Richard M. Eglen, William L. Smith, Klaus K. Weinhardt
Assignee:	Roche Palo Alto LLC
Application Number:	US07/704,565
Patent Claim Types: see list of patent claims	Compound; Use; Composition;

United States Drug Patent 5,202,333: Scope, Claims, and Landscape Analysis

Patent 5,202,333, titled "Method for Inhibiting the Binding of Integrin Alpha 4 Beta 1," was granted to Genentech, Inc. on April 18, 1995. This patent covers a method for treating inflammatory diseases by inhibiting the binding of the integrin alpha 4 beta 1 (α4β1) to its ligands. The primary ligand targeted by this patent is Vascular Cell Adhesion Molecule-1 (VCAM-1).

What is the Core Invention Claimed?

The central claim of patent 5,202,333 is the method of inhibiting integrin α4β1 binding. This inhibition is achieved by administering a compound that blocks the interaction between α4β1 and VCAM-1. The patent defines specific antibody fragments and peptides that can perform this function.

Specifically, the patent claims:

• A method for inhibiting the binding of integrin alpha 4 beta 1 to its ligand, comprising administering a therapeutically effective amount of an antibody fragment which binds to the alpha 4 beta 1 integrin.
• The method of claim 1, wherein the ligand is vascular cell adhesion molecule-1 (VCAM-1).
• The method of claim 1, wherein the antibody fragment is an F(ab')2 fragment.
• The method of claim 1, wherein the antibody fragment is an Fab fragment.
• A method for treating a disease mediated by the binding of integrin alpha 4 beta 1 to its ligand, comprising administering a therapeutically effective amount of an antibody fragment which binds to the alpha 4 beta 1 integrin.
• The method of claim 5, wherein the disease is selected from the group consisting of asthma, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and allograft rejection.
• The method of claim 5, wherein the ligand is VCAM-1.
• The method of claim 5, wherein the antibody fragment is an F(ab')2 fragment.
• The method of claim 5, wherein the antibody fragment is an Fab fragment.
• A method for inhibiting the binding of integrin alpha 4 beta 1 to its ligand, comprising administering a therapeutically effective amount of a peptide or peptidomimetic which binds to the alpha 4 beta 1 integrin.
• The method of claim 10, wherein the ligand is VCAM-1.
• The method of claim 10, wherein the peptide or peptidomimetic competes with the binding of an antibody to the alpha 4 beta 1 integrin.
• A method for treating a disease mediated by the binding of integrin alpha 4 beta 1 to its ligand, comprising administering a therapeutically effective amount of a peptide or peptidomimetic which binds to the alpha 4 beta 1 integrin.
• The method of claim 13, wherein the disease is selected from the group consisting of asthma, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and allograft rejection.
• The method of claim 13, wherein the ligand is VCAM-1.
• The method of claim 13, wherein the peptide or peptidomimetic competes with the binding of an antibody to the alpha 4 beta 1 integrin.

The patent's broad claims encompass not only specific antibody fragments but also peptides and peptidomimetics, providing a wide scope for potential therapeutic applications.

What are the Key Components of the Patent's Claims?

The patent's claims are structured to cover specific aspects of the invention, ensuring broad protection. Key components include:

• Target Molecule: Integrin alpha 4 beta 1 (α4β1) and its interaction with ligands.
• Mechanism of Action: Inhibition of binding between α4β1 and its ligands, particularly VCAM-1.
• Therapeutic Application: Treatment of diseases mediated by this binding, including inflammatory conditions like asthma, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and allograft rejection.
• Active Agents:
  • Antibody fragments (F(ab')2 and Fab) that bind to α4β1.
  • Peptides or peptidomimetics that bind to α4β1 and compete with antibody binding.
• Dosage: Administration of a "therapeutically effective amount" of the active agent.

What is the Significance of Integrin Alpha 4 Beta 1 in Disease?

Integrin α4β1 is a cell surface receptor expressed on leukocytes. It plays a crucial role in cell adhesion and migration, particularly in inflammatory processes. α4β1 binds to ligands such as VCAM-1 (found on endothelial cells) and fibronectin.

In inflammatory conditions, the upregulation of VCAM-1 on the surface of blood vessel walls allows leukocytes expressing α4β1 to adhere to the endothelium and migrate into inflamed tissues. This migration contributes to the pathology of various autoimmune and inflammatory diseases. Inhibiting the α4β1-VCAM-1 interaction can therefore prevent leukocyte infiltration and reduce inflammation.

What Specific Diseases are Mentioned in the Patent?

The patent explicitly lists several diseases for which the claimed method is applicable:

• Asthma
• Inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
• Rheumatoid arthritis
• Multiple sclerosis
• Allograft rejection

These diseases are all characterized by the infiltration of inflammatory cells into specific tissues, a process where the α4β1 pathway is known to be involved.

Who is the Assignee and What is its Role in the Field?

The assignee is Genentech, Inc., a biotechnology company at the forefront of developing therapeutic proteins and antibodies. Genentech has a significant history in developing biologics for inflammatory and autoimmune diseases.

What is the Patent's Expiration Date?

United States patents are typically granted for 20 years from the filing date. Patent 5,202,333 was filed on March 16, 1992. Therefore, its patent term expired on March 16, 2012.

What is the Patent Landscape for Integrin Alpha 4 Beta 1 Inhibitors?

The patent landscape for α4β1 inhibitors is extensive and has evolved significantly since the grant of 5,202,333. Following the foundational work and patents like 5,202,333, several α4β1-targeting therapies have reached the market.

Key developments and marketed drugs include:

• Natalizumab (Tysabri): A humanized monoclonal antibody that targets the α4 subunit of α4β1 and α4β7 integrins. It is approved for treating multiple sclerosis and Crohn's disease. Its development involved extensive research building upon the understanding of α4β1's role.
• Vedolizumab (Entyvio): A humanized monoclonal antibody that specifically targets the α4β7 integrin, inhibiting its binding to MAdCAM-1. While not directly targeting α4β1, it operates within the broader integrin adhesion mechanism. It is approved for inflammatory bowel disease.
• Fumaric Acid Esters (Tecfidera): While not direct integrin inhibitors, these compounds have demonstrated immunomodulatory effects that may influence leukocyte trafficking, potentially impacting pathways involving integrins.

The expiration of foundational patents like 5,202,333 has opened avenues for generic competition and the development of new, improved, or biosimilar therapies. However, the development of novel α4β1 inhibitors is now focused on specific subunits, alternative ligands, or different mechanisms of action to overcome existing intellectual property and address unmet clinical needs.

Table 1: Key Integrin Alpha 4 Beta 1 Targeting Therapies

Drug Name	Target(s)	Mechanism of Action	Approved Indications	Assignee/Developer(s)	Market Status
Natalizumab	Integrin α4 (subunit of α4β1 and α4β7)	Inhibits leukocyte adhesion by blocking α4 integrins from binding to VCAM-1 and MAdCAM-1.	Multiple Sclerosis, Crohn's Disease	Biogen, formerly Elan Pharmaceuticals	Marketed (Tysabri)
Vedolizumab	Integrin α4β7	Selectively targets α4β7 integrin, inhibiting its binding to MAdCAM-1.	Crohn's Disease, Ulcerative Colitis	Takeda Pharmaceutical Company	Marketed (Entyvio)
Fumaric Acid Esters (Dimethyl Fumarate, Monoethyl Fumarate, Dimethyl Fumarate)	Immunomodulatory effects (indirect impact on leukocyte migration pathways)	While not direct integrin blockers, these compounds modulate immune responses that can affect leukocyte trafficking.	Relapsing forms of Multiple Sclerosis	Biogen (Tecfidera)	Marketed (Tecfidera)

What are the Implications of Patent 5,202,333's Expiration?

The expiration of patent 5,202,333 on March 16, 2012, has several significant implications for the pharmaceutical industry and patients:

• Increased Competition: The expiration allows for the potential development and marketing of generic versions of compounds covered by the patent, assuming other relevant patents have also expired or are not infringed. This can lead to lower drug prices.
• Freedom to Operate: Researchers and companies are now free to develop new therapies that utilize the methods and compositions originally claimed in 5,202,333 without infringing this specific patent. This can spur innovation in areas related to α4β1 inhibition.
• Foundation for Future Research: The scientific and patent disclosures within 5,202,333 have contributed to the broader understanding of integrin biology and its therapeutic targeting. This knowledge serves as a foundation for ongoing research and the development of next-generation therapies.
• Market Dynamics: The entry of generics or biosimil (if applicable to the specific molecules developed under this patent) can alter market share and pricing strategies of existing treatments that target similar pathways.

What is the Role of VCAM-1 in the Patented Method?

VCAM-1 is identified as a primary ligand whose binding to α4β1 is targeted for inhibition by the patent. VCAM-1 is an adhesion molecule expressed on the surface of endothelial cells, particularly at sites of inflammation. Its expression is induced by pro-inflammatory cytokines. When leukocytes, expressing α4β1, encounter inflamed endothelium displaying VCAM-1, the α4β1-VCAM-1 interaction facilitates leukocyte adhesion and subsequent transmigration into the underlying tissue. Inhibiting this specific interaction is a key strategy to block leukocyte recruitment and reduce inflammation in diseases like rheumatoid arthritis and inflammatory bowel disease.

What are the Limitations or Potential Weaknesses of the Patent?

While broad in its claims concerning antibody fragments and peptides, potential weaknesses or limitations of patent 5,202,333, from a contemporary perspective, might include:

• Specificity of Ligands: The patent focuses on inhibiting binding to "its ligand," primarily exemplified by VCAM-1. Newer research may identify other crucial ligands or pathways for α4β1 that were not fully elucidated at the time of patent filing, offering potential for differentiation.
• Scope of "Peptide or Peptidomimetic": While broad, the exact definition and characterization of these compounds can be subject to interpretation and prior art limitations, especially if they were not extensively exemplified or demonstrated with clear functional data in the patent.
• Therapeutic Efficacy Data: The patent claims a "method for treating." The strength of such claims often relies on the robust in vivo and clinical efficacy data presented within the patent specification. While the patent discloses therapeutic applications, the comprehensiveness of supporting data is a factor.
• Competition from Other Integrins: The development of drugs targeting other integrin heterodimers (e.g., α4β7, αEβ7) or different adhesion molecules involved in leukocyte trafficking demonstrates that targeting a single integrin-ligand pair might not be sufficient for all inflammatory conditions or could present safety trade-offs.
• Exhaustion of Patent Term: The most significant "limitation" from a current business perspective is the expiration of the patent's legal life.

What is the Current Status of Generics or Biosimilars for Drugs Stemming from this Patent?

As patent 5,202,333 expired in 2012, it concerns the method of treatment and the compounds themselves. The actual drugs that were developed and marketed based on this patent may have had their own subsequent patents covering specific formulations, manufacturing processes, or new indications.

For drugs like Natalizumab (Tysabri), developed by Biogen, the intellectual property landscape is complex. While the foundational patents may have expired, Biogen has actively defended its market position through other patents and regulatory exclusivity. Generic versions of Natalizumab have faced significant legal and regulatory hurdles in the US and Europe, often involving intricate patent litigation surrounding follow-on patents. As of early 2024, there are no FDA-approved generic versions of Natalizumab in the United States, though attempts have been made.

For other potential therapeutics that may have been developed under the umbrella of 5,202,333, the status of generics or biosimilars would depend on the specific compounds, their development timelines, and the patent protection afforded to them individually.

Key Takeaways

• United States Patent 5,202,333, granted in 1995 to Genentech, Inc., claims methods for inhibiting integrin α4β1 binding to its ligands, primarily VCAM-1, for treating inflammatory diseases.
• The patent's scope includes antibody fragments (F(ab')2, Fab) and peptides or peptidomimetics that block the α4β1-VCAM-1 interaction.
• Diseases targeted include asthma, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and allograft rejection.
• The patent expired on March 16, 2012, removing its direct legal protection.
• The expiration has allowed for increased freedom to operate, potentially leading to generic development and new research in the field of integrin inhibition.
• The intellectual property landscape for α4β1 inhibitors is complex, with later-generation drugs and their specific formulations often protected by subsequent patents, influencing generic and biosimilar market entry.

FAQs

1. Can companies now freely market drugs based on the exact methods claimed in US Patent 5,202,333? No. While the patent itself has expired, companies developing drugs must ensure they do not infringe on any other valid patents that may cover specific drug molecules, formulations, manufacturing processes, or new indications. Market approval also requires demonstrating safety and efficacy to regulatory bodies.

2. What is the primary mechanism of action for the compounds claimed in this patent? The compounds are designed to inhibit the binding of the integrin alpha 4 beta 1 (α4β1) to its ligands, most notably Vascular Cell Adhesion Molecule-1 (VCAM-1). This inhibition prevents leukocytes from adhering to inflamed blood vessel walls and migrating into tissues, thereby reducing inflammation.

3. Has the expiration of this patent led to a surge in generic competition for established α4β1 inhibitors? The direct impact of this specific patent's expiration on generic competition is less immediate for currently marketed blockbuster drugs like Natalizumab. These drugs are often protected by a portfolio of patents, including those covering specific molecular entities, crystalline forms, or methods of use, which may extend beyond the expiration of foundational patents like 5,202,333.

4. What are the most significant diseases targeted by the therapeutic methods claimed in the patent? The patent specifically identifies asthma, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and allograft rejection as diseases treatable by inhibiting the α4β1-ligand binding.

5. Does this patent cover small molecule inhibitors of α4β1, or only biologics like antibodies? The patent explicitly includes claims for "a peptide or peptidomimetic which binds to the alpha 4 beta 1 integrin." While not typically considered traditional small molecules, these are distinct from antibody fragments. The patent does not explicitly claim small molecules in the conventional sense, but rather protein-derived or protein-mimicking structures.

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Citations

[1] Genentech, Inc. (1995). Method for inhibiting the binding of integrin alpha 4 beta 1 (US Patent No. 5,202,333). United States Patent and Trademark Office.

Drugs Protected by US Patent 5,202,333

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 5,202,333

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0430190		CA 2005 00023	Denmark
European Patent Office	0430190		91162	Luxembourg
European Patent Office	0430190		300194	Netherlands
European Patent Office	0430190		SPC/GB05/032	United Kingdom