IP Verse

Vegf Antagonist Formulations Suitable For Intravitreal Administration

Patent No. US12331099 (titled "Vegf Antagonist Formulations Suitable For Intravitreal Administration") was filed by Regeneron Pharmaceuticals Inc on Oct 23, 2024.

What is this patent about?

’099 is related to the field of pharmaceutical formulations, specifically those suitable for intravitreal administration to the eye. The formulations are designed to deliver agents that inhibit vascular endothelial growth factor (VEGF), a key mediator of tumor neoangiogenesis and a factor in various ophthalmic diseases. The background acknowledges the use of lyophilization for long-term protein storage and the need for stable liquid formulations.

The underlying idea behind ’099 is to create stable ophthalmic formulations of a VEGF-specific fusion protein antagonist (a 'VEGF trap') that can be administered directly into the eye. This involves carefully balancing the components of the formulation to prevent degradation, aggregation, and oxidation of the protein, ensuring its efficacy and safety for intravitreal injection. The invention addresses the challenge of maintaining protein stability in liquid form and after reconstitution from a lyophilized state.

The claims of ’099 focus on a liquid ophthalmic formulation containing 40 mg/ml of a glycosylated VEGF antagonist fusion protein (amino acids 27-457 of SEQ ID NO: 4) in water. The formulation also includes an organic co-solvent (polysorbate) and a stabilizing agent. The pH is maintained between 5.8 and 7.0, and the formulation is suitable for intravitreal administration. A key aspect is the protein's stability, with minimal aggregation and high purity.

The formulation achieves stability through a combination of factors. The use of polysorbate as a co-solvent helps to prevent protein aggregation, while the stabilizing agent, such as sucrose and trehalose, further protects the protein's structure. Maintaining the pH within a specific range is also crucial for preventing degradation. The glycosylation of the VEGF antagonist is also important for its activity and stability.

The invention differentiates itself from prior approaches by providing specific formulations that demonstrate long-term stability, as shown in the provided examples. The formulations maintain the VEGF antagonist's native configuration and prevent aggregation, ensuring its effectiveness in inhibiting VEGF and treating ophthalmic conditions. The use of a pre-filled syringe is also highlighted as a convenient method for intravitreal administration, further distinguishing it from other formulations.

How does this patent fit in bigger picture?

Technical landscape at the time

In the mid-2000s when ’099 was filed, at a time when protein formulations were typically stabilized using lyophilization or liquid formulations with excipients, chemical and physical stability were primary concerns. Systems commonly relied on buffering agents, tonicity adjusters, and stabilizers to prevent degradation, aggregation, and oxidation. Hardware or software constraints made precise control of pH and impurity levels non-trivial.

Novelty and Inventive Step

Claims 12-41 were pending. Claims 12-41 were rejected for non-statutory double patenting over multiple US patents. The rejection stated that the claims were not patentably distinct because the scope of the ophthalmic formulation of the VEGF antagonist recited in the instant claims was overlapping in scope with the ophthalmic formulation of VEGF antagonist recited in the claims of the prior patents. A substitute specification was required to correct the size of the ASCII text file. No claims were allowed.

Claims

This patent contains 30 claims, with independent claims numbered 1, 11, 22, and 26. The independent claims are directed to liquid ophthalmic formulations containing a VEGF antagonist fusion protein. The dependent claims generally specify particular components, concentrations, pH ranges, or stability characteristics of the formulations described in the independent claims.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)Support for SpecificationInterpretation
Glycosylated vascular endothelial growth factor (Vegf) antagonist fusion protein comprising amino acids 27-457 of Seq Id No: 4
(Claim 1, Claim 11, Claim 22, Claim 26)		“In a specific embodiment, the fusion protein comprises amino acids 27-457 of SEQ ID NO:4 and is glycosylated at Asn residues 62, 94, 149, 222 and 308. Preferably, the VEGF antagonist is a dimer composed of two fusion proteins of SEQ ID NO:4.”A protein that inhibits VEGF, is glycosylated, and has a specific amino acid sequence derived from SEQ ID NO:4.
Organic co-solvent comprising polysorbate
(Claim 1, Claim 11)		“In one or more specific embodiments, the organic co-solvent may be polysorbate, for example, polysorbate 20 or polysorbate 80, polyethylene glycol (PEG), for example, PEG 3350, or propylene glycol, or a combination thereof; the tonicity agent may be, for example, sodium chloride or potassium chloride; the stabilizing agent may be sucrose, sorbitol, glycerol, trehalose, or mannitol; and the buffering agent may be, for example, phosphate buffer.”A solvent that aids in dissolving or stabilizing the formulation, specifically containing polysorbate.
Organic co-solvent comprising polysorbate 80
(Claim 22, Claim 26)		“In one or more specific embodiments, the organic co-solvent may be polysorbate, for example, polysorbate 20 or polysorbate 80, polyethylene glycol (PEG), for example, PEG 3350, or propylene glycol, or a combination thereof; the tonicity agent may be, for example, sodium chloride or potassium chloride; the stabilizing agent may be sucrose, sorbitol, glycerol, trehalose, or mannitol; and the buffering agent may be, for example, phosphate buffer.”A solvent that aids in dissolving or stabilizing the formulation, specifically containing polysorbate 80.
Stabilizing agent
(Claim 1, Claim 11, Claim 22, Claim 26)		“The formulation can also comprise one or more pharmaceutically acceptable carriers, buffers, tonicity agents, stabilizers, and/or excipients. An example of a pharmaceutically acceptable liquid formulation comprises a VEGF antagonist in a pharmaceutically effective amount, a buffer, an organic co-solvent such as polysorbate, a tonicity agent such as NaCl, and optionally, a stabilizer such as sucrose or trehalose.”A substance that prevents degradation or aggregation of the VEGF antagonist.
Stabilizing agent comprising sucrose and trehalose
(Claim 22, Claim 26)		“The formulation can also comprise one or more pharmaceutically acceptable carriers, buffers, tonicity agents, stabilizers, and/or excipients. An example of a pharmaceutically acceptable liquid formulation comprises a VEGF antagonist in a pharmaceutically effective amount, a buffer, an organic co-solvent such as polysorbate, a tonicity agent such as NaCl, and optionally, a stabilizer such as sucrose or trehalose.”A substance that prevents degradation or aggregation of the VEGF antagonist, specifically containing sucrose and trehalose.

Litigation Cases New

US Latest litigation cases involving this patent.

Case NumberFiling DateTitle
1:25-cv-00074Jan 17, 2025Eagle Pharmaceuticals, Inc. V. Apotex Inc.

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US12331099

REGENERON PHARMACEUTICALS INC
Application Number
US18924707
Filing Date
Oct 23, 2024
Status
Granted
Expiry Date
Jun 14, 2027
External Links
Slate, USPTO, Google Patents