Prior art

Analysis of Prior Art Cited in U.S. Patent 12,168,036

This analysis details the prior art references cited during the prosecution of U.S. Patent 12,168,036. For each reference, a brief description is provided along with an assessment of which claims it could potentially anticipate under 35 U.S.C. § 102. Anticipation under § 102 requires that a single prior art reference discloses each and every element of a claimed invention.

A review of the patent file wrapper indicates the following documents were cited by the examiner as relevant prior art.

U.S. Patent Publications

1. US 2019/0343918 A1

• Full Citation: United States Patent Application Publication No. 2019/0343918 A1.
• Publication Date: November 14, 2019.
• Filing Date: May 9, 2019.
• Brief Description: This patent application, from the same inventors and assignee (Regeneron), discloses high-concentration formulations of VEGF receptor fusion proteins, including aflibercept. It describes formulations with varying concentrations of aflibercept (e.g., 80 mg/mL, 140 mg/mL, 150 mg/mL), buffers (including histidine and phosphate), stabilizers (like sucrose), surfactants (like polysorbate 20), and viscosity-reducing agents (such as L-arginine monohydrochloride). It also discusses methods of treating angiogenic eye disorders using these formulations.
• Potential Anticipation: This document is highly relevant and appears to disclose many elements of the claimed invention.
  • Claims 1, 21, and 33: The application explicitly describes formulations containing high concentrations of aflibercept, a histidine-based buffer, sucrose, polysorbate 20, and L-arginine monohydrochloride at similar concentrations and pH ranges to those claimed. For instance, it mentions a formulation with about 115 mg/mL aflibercept, 10 mM histidine buffer, 5% sucrose, 0.03% polysorbate 20, and 50 mM L-arginine monohydrochloride at a pH of about 5.8. This closely mirrors the elements of claims 1, 21, and 33.
  • Claims 16 and 28: The application discloses the use of pre-filled syringes for administering these high-concentration formulations. While it describes the components and their suitability for injection, the explicit combination of the specific formulation of claim 16 within a pre-filled syringe as claimed in claim 28 may require closer examination for direct anticipation. However, the motivation to place such a formulation in a pre-filled syringe for intravitreal injection is strongly suggested.

International Patent Publications

2. WO 2019/217927 A1

• Full Citation: World Intellectual Property Organization Publication No. WO 2019/217927 A1.
• Publication Date: November 14, 2019.
• Filing Date: May 9, 2019.
• Brief Description: This is the published PCT application corresponding to US 2019/0343918 A1. As such, its disclosure is substantially identical. It details the development of stable, high-concentration formulations of VEGF receptor fusion proteins (aflibercept) for ophthalmic use, addressing challenges like viscosity and protein aggregation.
• Potential Anticipation: Similar to its U.S. counterpart, this document provides a strong basis for anticipation.
  • Claims 1, 21, and 33: Discloses formulations with high-concentration aflibercept, histidine buffer, sucrose, polysorbate 20, and arginine hydrochloride. The specific ranges and combinations described closely align with the limitations of these claims.
  • Claims 16 and 28: The disclosure includes packaging these formulations in administration-ready formats like pre-filled syringes, making it relevant to the subject matter of these claims.

3. WO 2018/094316 A1

• Full Citation: World Intellectual Property Organization Publication No. WO 2018/094316 A1.
• Publication Date: May 24, 2018.
• Filing Date: November 20, 2017.
• Brief Description: This application describes ophthalmic formulations of aflibercept suitable for intravitreal administration. It focuses on achieving stable formulations with a desired osmolality (around 300 mOsm/kg) and a pH between 5.0 and 6.5. The formulations comprise a buffer, a polyol, and an amino acid, with a low concentration of chloride anions.
• Potential Anticipation: This reference is relevant but may not anticipate all claims directly.
  • It teaches stable, injectable aflibercept formulations for ophthalmic use, which is the broad subject matter of the patent. However, the specific combination of excipients at the concentrations recited in the independent claims of US 12,168,036, particularly the combination of a histidine buffer with specific concentrations of sucrose, polysorbate 20, and L-arginine monohydrochloride to achieve the claimed viscosity and stability profile, may not be explicitly disclosed in a single embodiment.

Other Relevant Patents by the Same Assignee

The patent also cites several other U.S. patents assigned to Regeneron that relate to aflibercept, its uses, and general formulation technology. These patents establish the background of the technology but are less likely to anticipate the specific high-concentration formulation claims.

• U.S. Patent 8,481,046 B2: Discloses ophthalmic formulations of a VEGF-specific fusion protein antagonist suitable for intravitreal administration, including stable liquid and lyophilizable formulations. While relevant, it primarily concerns the formulation of what became the commercial 40 mg/mL EYLEA® product and does not teach the specific high-concentration formulations claimed in US 12,168,036.
• U.S. Patent 11,103,552 B2: This patent is part of the same family as US 12,168,036 and shares a priority claim. It also covers high-concentration VEGF receptor fusion protein formulations. Its disclosure is very similar to US 2019/0343918 A1 and is highly relevant, potentially anticipating the claims for the same reasons.

Conclusion

The most relevant prior art references that could potentially anticipate the claims of U.S. Patent 12,168,036 are US 2019/0343918 A1, its international counterpart WO 2019/217927 A1, and the related family member U.S. Patent 11,103,552 B2. These documents, originating from the same inventors and assignee, disclose the core elements of the claimed high-concentration aflibercept formulation, including the specific combination of excipients, concentrations, and pH. The key question for an anticipation challenge would be whether a single embodiment within these references discloses all the limitations of an independent claim, including the specific viscosity and stability profiles recited. Given the detailed examples in these applications, it is plausible that they provide an anticipating disclosure for one or more of the independent claims, a matter that is likely being argued in the ongoing PGR proceedings.