Obviousness

To analyze the obviousness of US patent 10828345 under 35 U.S.C. § 103, we will consider the claims, particularly independent claim 1, and identify combinations of prior art references that would render it obvious.

Independent Claim 1:
A method for treating an angiogenic eye disorder in a patient, said method comprising sequentially administering to the patient a single initial dose of a VEGF antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF antagonist;
wherein each secondary dose is administered 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered 12 weeks after the immediately preceding dose;
wherein the VEGF antagonist is a receptor-based chimeric molecule comprising an immunoglobin-like (Ig) domain 2 of a first VEGF receptor which is Flt1 and Ig domain 3 of a second VEGF receptor which is Flk1, and a multimerizing component.

Elements of Claim 1 and Corresponding Prior Art:

1. Angiogenic eye disorder and treatment with VEGF antagonist: The patent's background section clearly establishes that "Several eye disorders are associated with pathological angiogenesis" and that "Release of vascular endothelial growth factor (VEGF) contributes to increased vascular permeability in the eye and inappropriate new vessel growth." It further notes that "inhibiting the angiogenic-promoting properties of VEGF appears to be an effective strategy for treating angiogenic eye disorders." Thus, treating angiogenic eye disorders with a VEGF antagonist was well-known prior art.
2. VEGF antagonist as a receptor-based chimeric molecule (Ig domain 2 of Flt1, Ig domain 3 of Flk1, and a multimerizing component): This describes aflibercept, also referred to in the patent as "VEGFT" or "VEGFR1R2-FcΔC1(a)." The patent explicitly states that "Additional VEGF receptor-based chimeric molecules which can be used in the context of the present invention are disclosed in U.S. Pat. Nos. 7,396,664, 7,303,746 and WO 00/75319." These patents, with priority dates well before the January 13, 2011 priority date of US10828345, serve as prior art for the VEGF antagonist molecule itself.
3. Sequential administration with initial, secondary, and tertiary doses: The concept of sequential dosing regimens for therapeutic agents is a basic pharmacological principle. The patent's definition of "sequentially administering" confirms this general understanding.
4. Specific Dosing Frequencies:
   • Secondary doses administered 4 weeks after the immediately preceding dose: The background section of the patent notes that "FDA-approved treatments of angiogenic eye disorders such as AMD and CRVO include the administration of an anti-VEGF antibody called ranibizumab (Lucentis®, Genentech, Inc.) on a monthly basis by intravitreal injection." "Monthly" dosing is explicitly defined in the patent as "equivalent to dosing once every four weeks." This demonstrates that a 4-week dosing interval for initial or ongoing treatment of angiogenic eye disorders with VEGF antagonists was established prior art.
   • Tertiary doses administered 12 weeks after the immediately preceding dose: This is the most distinguishing feature of Claim 1. The patent's description, however, primarily highlights an 8-week interval for tertiary doses as an "exemplary embodiment" and in its Figure 1. The FDA approval information for aflibercept in November 2011 (after the priority date) also mentions a 2 mg dose every 8 weeks after initial monthly doses.

Prior Art References for Obviousness Analysis:

• Reference A (VEGF-Trap Molecule): U.S. Pat. Nos. 7,396,664, 7,303,746, and WO 00/75319 (e.g., WO 00/75319, published December 14, 2000). These references disclose the VEGF-Trap (aflibercept) molecule, its structure as a receptor-based chimeric molecule comprising Ig domain 2 of Flt1, Ig domain 3 of Flk1, and a multimerizing component, and its use as a VEGF antagonist.
• Reference B (Ranibizumab Dosing): Prescribing information for ranibizumab (Lucentis®), which established monthly (4-week) intravitreal injections as a standard of care for angiogenic eye disorders like AMD.
• Reference C (Aflibercept Clinical Trial Designs): The patent itself details Phase III clinical trials for VEGFT in neovascular AMD (Example 4), describing a 2Q8 arm where 2 mg VEGFT was administered every 4 weeks to week 8 (initial doses) and then every 8 weeks for maintenance. More significantly, for the second year of these trials, the protocol specified that subjects would receive IVT injections "at intervals determined by specific dosing criteria, but at least every 12 weeks." While these trials are described within the patent, the design and conduct of these clinical trials would have preceded the January 13, 2011 priority date and would be discoverable as prior art (e.g., through clinical trial registrations, preliminary scientific presentations, or publications).

Obviousness Argument under 35 U.S.C. § 103:

A person having ordinary skill in the art (PHOSITA) on January 13, 2011, would have been motivated to combine these prior art references to arrive at the claimed invention.

1. Known Drug and Condition: The PHOSITA would know aflibercept (VEGF-Trap) as a potent VEGF antagonist (Reference A) and that VEGF antagonists are effective for treating angiogenic eye disorders (General Knowledge and Reference B).
2. Motivation for Extended Dosing: The standard monthly (4-week) dosing of ranibizumab (Reference B) would have created a strong motivation for a PHOSITA to develop less frequent dosing regimens for new anti-VEGF agents like aflibercept. Reducing the frequency of intravitreal injections would significantly improve patient convenience, compliance, and quality of life. The patent itself highlights this advantage.
3. Pathway to 12-Week Dosing: The ongoing clinical development of aflibercept (Reference C) would have already demonstrated the feasibility and efficacy of extending maintenance dosing intervals to 8 weeks after an initial loading phase (the 2Q8 arm in Example 4). This success with 8-week dosing would naturally lead a PHOSITA to explore even longer intervals to further optimize the treatment burden. Crucially, the same clinical trial protocol explicitly included a provision for flexible dosing in the second year, where injections would be given "at intervals determined by specific dosing criteria, but at least every 12 weeks." This directly shows that a 12-week interval was contemplated and deemed a clinically relevant and achievable dosing frequency within the aflibercept development program.
4. Predictable Optimization: Given the established efficacy of anti-VEGF therapy, the known properties of aflibercept, the success with an 8-week maintenance regimen, and the explicit consideration of 12-week intervals in the clinical trial design (even if initially in a flexible "as needed" context), selecting a fixed 12-week interval for tertiary doses after an initial 4-week loading phase would be a predictable and obvious optimization. A PHOSITA would routinely test various extended dosing frequencies to find the optimal balance between efficacy and reduced treatment burden. The "surprise" mentioned in the patent of efficacy at "8 or more weeks" for tertiary doses would only reinforce the motivation to explore the upper end of this range, making 12 weeks a logical step.

Therefore, the claimed method in Claim 1, which combines the known VEGF antagonist aflibercept with an initial 4-week dosing phase followed by a 12-week maintenance phase, would have been obvious to a PHOSITA in light of the prior art, specifically References A, B, and C, driven by the motivation to reduce injection burden while maintaining therapeutic efficacy.