Obviousness

Obviousness Analysis under 35 U.S.C. § 103

This analysis identifies combinations of prior art references that would render the claims of US Patent 11084865 obvious to a person having ordinary skill in the art (PHOSITA), along with the motivation to combine these references. The primary focus for this analysis will be on Claim 1, as a representative independent claim, and the principles can be extended to other claims directed to similar formulations or packaging.

Relevant Claims

Claim 1 recites: "A vial comprising an ophthalmic formulation suitable for intravitreal administration that comprises: a vascular endothelial growth factor (VEGF) antagonist an organic co-solvent, a buffer, and a stabilizing agent, wherein said VEGF antagonist fusion protein is glycosylated and comprises amino acids 27-457 of SEQ ID NO:4; and wherein at least 98% of the VEGF antagonist is present in native conformation following storage at 5° C. for two months as measured by size exclusion chromatography."

Other claims specify concentrations, pH ranges, specific excipients (e.g., polysorbate, sodium phosphate, sucrose, NaCl), and packaging in pre-filled syringes or vials, and higher stability thresholds.

Identified Prior Art

The following references, published before the priority date of US11084865 (2006-06-16), are cited in the patent and are relevant for an obviousness analysis:

1. WO2005000895A2 (Regeneron Pharmaceuticals, Inc.): "VEGF traps and therapeutic uses thereof" (Published 2005-01-06).
2. US6676941 (Genentech, Inc.): "Ophthalmic formulation of a VEGF antibody" (Published 2001-01-09).
3. US20030138417A1 (Kaisheva Elizabet A.): "Stable liquid pharmaceutical formulation of IgG antibodies" (Published 2003-07-24).
4. WO2006047325A1 (Genentech, Inc.): "Method for treating intraocular neovascular diseases" (Published 2006-05-04).

Obviousness Combination and Rationale

A PHOSITA would have been motivated to combine the teachings of WO2005000895A2 and US6676941, supplemented by general knowledge of protein formulation (e.g., US20030138417A1) and intravitreal administration (e.g., WO2006047325A1), to arrive at the claimed invention.

1. Teaching of the VEGF Antagonist (WO2005000895A2):
WO2005000895A2, assigned to the same entity (Regeneron) as US11084865, teaches the vascular endothelial growth factor (VEGF) antagonist fusion protein, specifically "VEGF traps," and their therapeutic uses. The specification of US11084865 explicitly refers to "VEGF trap" described in Kim et al. (2002) and Holash et al. (2002), and states that "the fusion protein has the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4. Preferably, the VEGF antagonist is a dimer comprising two fusion proteins of SEQ ID NO:4." WO2005000895A2 would have disclosed the VEGF trap of SEQ ID NO:4, its structural details including comprising amino acids 27-457, and its production in mammalian cells (e.g., CHO cells), thereby imparting glycosylation. Thus, the active pharmaceutical ingredient, its glycosylated nature, and its specific amino acid sequence would be known from this prior art.

2. Teaching of Stable Ophthalmic Formulations for VEGF Antagonists (US6676941):
US6676941 describes stable aqueous pharmaceutical formulations of anti-VEGF antibodies suitable for ophthalmic use and intravitreal administration. This patent specifically teaches a formulation comprising:

• A VEGF antagonist (an antibody in this case, but still a large therapeutic protein targeting VEGF).
• A buffer (e.g., histidine buffer, phosphate buffer).
• A salt (e.g., NaCl) as a tonicity agent.
• A polysorbate (e.g., polysorbate 20 or polysorbate 80) as an organic co-solvent.
• A sugar (e.g., trehalose, sucrose) as a stabilizing agent.
• Suitable pH ranges (e.g., between 5.5 and 7.0, which overlaps with the claimed pH of 5.8-7.0 in US11084865).

The patent further emphasizes the importance of stability for these protein formulations.

3. Motivation to Combine:
A PHOSITA, aware of the therapeutic potential of the VEGF trap (SEQ ID NO:4) from WO2005000895A2 for treating ocular conditions involving neovascularization (a known use for VEGF antagonists reinforced by WO2006047325A1), would have been strongly motivated to develop a stable pharmaceutical formulation for its intravitreal administration.

US6676941 provides direct guidance and a proven template for formulating a stable VEGF antagonist for ophthalmic and intravitreal use. Given that both the VEGF antibody (in US6676941) and the VEGF trap (in WO2005000895A2) are large therapeutic proteins designed to inhibit VEGF, a PHOSITA would reasonably expect similar formulation challenges and solutions to ensure stability and efficacy. It would be a routine optimization for a PHOSITA to adapt the formulation components (organic co-solvent, buffer, stabilizing agent, tonicity agent) and their concentrations, as taught in US6676941, to the specific VEGF trap of SEQ ID NO:4 from WO2005000895A2.

The selection of a vial or pre-filled syringe for packaging an injectable ophthalmic formulation is a conventional choice for such products and would be within the general knowledge of a PHOSITA. The achievement of specific stability criteria, such as "at least 98% of the VEGF antagonist is present in native conformation following storage at 5° C. for two months," is a standard and expected goal in protein therapeutic formulation development, and would be achieved through routine experimentation and optimization based on the teachings of US6676941 and other protein formulation art (e.g., US20030138417A1).

Therefore, a PHOSITA would have found it obvious to combine the known VEGF antagonist (SEQ ID NO:4) from WO2005000895A2 with the established ophthalmic formulation principles for VEGF antagonists taught by US6676941, and to package it in a conventional manner, with the expectation of achieving a stable formulation through routine optimization.