US 12168036

Summary of U.S. Patent 12,168,036

A review of U.S. Patent 12,168,036 indicates the patent is the subject of a Post-Grant Review (PGR) proceeding before the Patent Trial and Appeal Board (PTAB) as of April 2, 2026. A search for related 2026 dockets at the Court of Appeals for the Federal Circuit (CAFC) yielded no results.

Title: Methods for treating angiogenic eye disorders with high doses of VEGF receptor fusion proteins

Assignee: Regeneron Pharmaceuticals, Inc.

Inventors: Kenneth S. Graham, Saurabh Wadhwa

Filing Date: July 23, 2021

Issue Date: December 17, 2024

Abstract: The present invention provides ophthalmic formulations having high concentrations of vascular endothelial growth factor (VEGF) receptor fusion protein and high stability during storage. Methods for treating angiogenic eye disorders using the high concentration formulations are also provided.

Plain-Language Overview of Independent Claims

U.S. Patent 12,168,036 contains 38 claims in total. The independent claims are claims 1, 16, 21, 28, and 33.

• Claim 1: Describes a method for treating an angiogenic eye disorder. This is accomplished by injecting into the eye a specific pharmaceutical formulation. The formulation's key components are a high concentration of a VEGF receptor fusion protein (specifically aflibercept), a histidine-based buffer to maintain pH, sucrose for stability, a surfactant (polysorbate 20), and L-arginine monohydrochloride, which can help in reducing viscosity. The claim specifies the concentrations and pH range of this formulation.

• Claim 16: This claim also outlines a method for treating angiogenic eye disorders via intravitreal injection. It details a liquid formulation with a high concentration of aflibercept, a histidine buffer, sucrose, and polysorbate 20. A key aspect of this claim is the specific viscosity range of the formulation and the fact that it is packaged in a pre-filled syringe for direct administration.

• Claim 21: This claim focuses on the pharmaceutical formulation itself. It describes a stable, injectable liquid that contains a high concentration of aflibercept, a histidine buffer, sucrose, polysorbate 20, and L-arginine. The claim specifies the pH, viscosity, and osmolality (a measure of solute concentration) of the formulation, ensuring its suitability for injection into the eye. It also states that the formulation is stable, with minimal formation of high molecular weight species (a sign of protein degradation) when stored for up to 6 months at 2-8°C.

• Claim 28: This claim covers a pre-filled syringe as a product. The syringe is filled with a specific volume of the sterile pharmaceutical formulation described in claim 21, ready for intravitreal injection to treat an angiogenic eye disorder.

• Claim 33: This claim describes a method for manufacturing the pharmaceutical formulation. The process involves combining a high concentration of aflibercept with the other specified ingredients (histidine buffer, sucrose, polysorbate 20, and L-arginine) to create the formulation with the specific properties outlined in claim 21.

Post-Grant Review Proceedings Initiated Against U.S. Patent 12,168,036

As of the current date, U.S. Patent 12,168,036 is involved in Post-Grant Review (PGR) proceedings before the Patent Trial and Appeal Board (PTAB). A PGR is a trial proceeding conducted at the PTAB to review the patentability of one or more claims in a patent on any ground that could be raised under § 282(b)(2) or (3).

Details of the known PGR case are as follows:

• Petitioner: Alvotech
• Respondent/Patent Owner: Regeneron Pharmaceuticals, Inc.
• Jurisdiction: Patent Trial and Appeal Board (PTAB)
• Case Number: PGR2025-00085
• Filing Date: The petition was filed and is currently pending. The patent text indicates the case was pending and had been instituted.
• Status: Pending - Instituted. This means the PTAB has found that the petitioner has met the threshold to proceed with the review.

Additionally, a subsequent petition for PGR was filed by Biocon Biologics, Inc. and Biocon Biologics Limited, seeking to join the instituted Alvotech PGR.

• Petitioner: Biocon Biologics, Inc. and Biocon Biologics Limited
• Respondent/Patent Owner: Regeneron Pharmaceuticals, Inc.
• Jurisdiction: Patent Trial and Appeal Board (PTAB)
• Case Number: PGR2026-00039
• Filing Date: April 2, 2026
• Status: The petition seeks joinder with PGR2025-00085 and is substantively identical to Alvotech's petition. The current status of this joinder request is pending.

No other district court or appellate litigation specifically involving U.S. Patent 12,168,036 has been identified at this time. It is important to note that Regeneron has been actively involved in litigation concerning other patents related to its EYLEA® (aflibercept) product against various biosimilar manufacturers, including Mylan, Samsung, and Amgen. These cases, however, do not name U.S. Patent 12,168,036.

Proceedings overview

U.S. Patent 12,168,036 is currently involved in two Post-Grant Review (PGR) proceedings before the Patent Trial and Appeal Board (PTAB). One PGR (PGR2025-00085) has been instituted, challenging all 38 claims of the patent, while a second PGR (PGR2026-00039) is pending and seeks joinder with the instituted proceeding. This situation indicates an active challenge to the patent's validity, placing the patent owner in a defensive posture and offering potential avenues for a defendant to challenge the patent.

PGR2025-00085 — Alvotech USA Inc. et al. v. Regeneron Pharmaceuticals, Inc.

• Type: Post-Grant Review
• Filed: 2025-09-17
• Status: Trial Instituted (Instituted in March 2026, without an opinion).
• Judge panel: Not publicly available in the provided search results.
• Petition grounds: Alvotech challenged claims 1-38 of U.S. Patent 12,168,036. The grounds for unpatentability include lack of novelty, obviousness (under 35 U.S.C. § 103), and lack of written description (under 35 U.S.C. § 112). Specifically, Alvotech argues that Regeneron had previously disclosed high-concentration aflibercept formulations (100 mg/ml and higher) with high doses (up to 10 mg) and that the '036 patent did not solve a novel viscosity problem. The obviousness arguments are based on multiple combinations of prior art, including Regeneron's own patents and publications.
• Institution decision: Instituted in March 2026. The PTAB granted institution without issuing a detailed opinion at the time.
• Final Written Decision: Not yet issued. The trial year commenced in March 2026, so a Final Written Decision would typically be due by March 2027.
• Settlement / termination: No public information indicates a settlement or termination of this specific PGR proceeding.
• Appeal: Not applicable yet, as no Final Written Decision has been issued.
• Defensive value: The institution of this PGR means that all 38 claims of the patent are currently under review for patentability, including independent claims 1, 16, 21, 28, and 33. A defendant facing assertion of this patent can monitor this proceeding for potential invalidation of claims, which could significantly weaken the patent owner's position. The breadth of claims challenged (all 38) indicates a comprehensive attack on the patent's validity.

PGR2026-00039 — Biocon Biologics Limited et al. v. Regeneron Pharmaceuticals, Inc.

• Type: Post-Grant Review
• Filed: 2026-04-02
• Status: Pending. The petition seeks joinder with the previously instituted PGR2025-00085.
• Judge panel: Not publicly available in the provided search results.
• Petition grounds: Biocon challenged claims 1-38 of U.S. Patent 12,168,036. The grounds for unpatentability include obviousness and lack of written description under 35 U.S.C. § 112. Biocon's petition is substantively identical to Alvotech's petition in PGR2025-00085.
• Institution decision: A decision on institution for this specific petition, including the request for joinder, is pending.
• Final Written Decision: Not yet issued.
• Settlement / termination: No public information indicates a settlement or termination of this specific PGR proceeding. Note that Biocon and Regeneron previously settled litigation concerning a different aflibercept patent (U.S. Patent No. 11,084,865), allowing Biocon to launch its biosimilar Yesafili in the US in the second half of 2026. This settlement did not pertain to US12168036.
• Appeal: Not applicable yet.
• Defensive value: As a pending PGR seeking joinder with an instituted proceeding, this case represents a reinforcing challenge to the patent. If joinder is granted or the petition is independently instituted, it demonstrates multiple parties view the patent as vulnerable. This increases the pressure on the patent owner and provides a defendant with additional insight into the art and arguments being leveraged against the patent.

Strategic summary

Both PGR2025-00085 and PGR2026-00039 are actively challenging all claims (1-38) of U.S. Patent 12,168,036. PGR2025-00085, filed by Alvotech, has already been instituted on grounds of novelty, obviousness, and written description, meaning the PTAB found a reasonable likelihood that at least one challenged claim is unpatentable. PGR2026-00039, filed by Biocon, is substantively identical and is seeking joinder. As of the current date (2026-05-29), no claims have been canceled or sustained, and no Final Written Decisions have been issued for either proceeding.

The estoppel landscape under 35 U.S.C. § 315(e)(2) will be significant. If PGR2025-00085 proceeds to a Final Written Decision, Alvotech (and potentially Biocon if joinder is granted) will be estopped from raising in subsequent district court litigation or other PTAB proceedings any ground that they raised or reasonably could have raised during the PGR. For a defendant currently being asserted against, the ongoing PGRs mean that the patent is under a substantial cloud of uncertainty. The arguments put forth by Alvotech and Biocon, particularly concerning prior art disclosures of high-concentration aflibercept formulations and the purported lack of a viscosity problem solved by the patent, provide a strong foundation for a third party to evaluate potential invalidity contentions.

There are pattern signals of multiple biosimilar developers (Alvotech and Biocon) challenging the same patent, indicating a coordinated or at least parallel effort against Regeneron's high-dose aflibercept product, Eylea HD®. This suggests the patent is perceived as a significant barrier to market entry for biosimilars. There is no information in the provided search results to indicate that the patent owner has pursued PTAB appeals aggressively for this specific patent or that a defensive aggregator is involved.

Recommended next steps

• Monitor PGR2025-00085 closely: The institution decision has already been rendered in March 2026, without an opinion, meaning the trial is underway. The statutory deadline for the Final Written Decision in PGR2025-00085 is generally one year from the institution date, placing it around March 2027. Review the docket for all filings, especially expert reports, cross-examinations, and pre-hearing briefs, to understand the specific arguments and evidence being presented. Accessing the institution decision document, if it becomes publicly available with reasoning, would be highly beneficial.
• Monitor PGR2026-00039: Keep track of the PTAB's decision on Biocon's request for joinder with PGR2025-00085. A decision on institution for this petition is pending. If joinder is granted, the two cases will likely proceed on a similar timeline, with shared evidence and arguments.
• Assess validity arguments: Given that all 38 claims are challenged on grounds of novelty, obviousness, and written description, thoroughly evaluate the prior art cited by Alvotech and Biocon against your own products or activities. The arguments that Regeneron had previously disclosed high-concentration formulations and that no "viscosity problem" was solved (as asserted by Alvotech) are critical points.
• Consider a parallel PGR (if applicable): If your company has a strong, unique prior art position not already presented, or if the current PGRs face unexpected challenges, filing your own PGR could be an option, though the nine-month window from patent grant for filing PGRs has passed for this patent (granted 2024-12-17, so the deadline was 2025-09-17). However, joining an existing PGR could be an option if your interests align and the PTAB permits.
• Prepare for potential Federal Circuit appeal: If a Final Written Decision is issued, be prepared for either party to appeal to the Federal Circuit, which would extend the timeline for a definitive resolution on patent validity.

Inventors

• Kenneth S. Graham: Employed by Regeneron Pharmaceuticals, Inc. at the time of filing.
• Saurabh Wadhwa: Employed by Regeneron Pharmaceuticals, Inc. at the time of filing.

No unusual patterns, such as inventors departing the original assignee shortly after filing, are determinable from the provided information.

Original assignee

The original assignee named on the issued patent is Regeneron Pharmaceuticals, Inc. Regeneron Pharmaceuticals, Inc. is a biopharmaceutical company that discovers, develops, manufactures, and commercializes medicines. They ship products embodying the claims, specifically EYLEA® and EYLEA HD® (aflibercept), which are used for treating angiogenic eye disorders. Regeneron Pharmaceuticals, Inc. is currently an operating company.

Assignment timeline

• 2021-09-08 (executed) / recorded 2021-09-08 — Reel 057429/0819
  • Conveyance: ASSIGNMENT OF ASSIGNORS INTEREST
  • Assignor: WADHWA, SAURABH; GRAHAM, KENNETH S.
  • Assignee: REGENERON PHARMACEUTICALS, INC.
  • Correspondent: BAKER BOTTS L.L.P. 2001 ROSS AVENUE SUITE 900 DALLAS, TX 75201
  • Context: Standard initial assignment from inventors to the employing entity.

Timeline diagram

timeline
    title Ownership of US 12168036
    2021 : Filed by Regeneron
         : Inventors assigned to Regeneron
    2024 : Issued
    2025 : PGR filed Alvotech
    2026 : PGR filed Biocon

NPE / troll-pattern signals

1. Shell-entity transfer — Not present. The only recorded assignment is from the inventors to Regeneron Pharmaceuticals, Inc., which is an operating company that develops and sells products. [cite: USPTO Assignment Record Reel 057429/0819]
2. Known asserter in the chain — Not present. Regeneron Pharmaceuticals, Inc. is a known operating company, not a recognized patent assertion entity (NPE). [cite: USPTO Assignment Record Reel 057429/0819]
3. Repeat correspondent across the chain — Unclear. Baker Botts L.L.P. is listed as the correspondent for the single recorded assignment [cite: USPTO Assignment Record Reel 057429/0819]. However, with only one assignment on record for this specific patent, it is not possible to determine if this correspondent recurs across the chain or on other known NPE assertions without a broader search, which is outside the scope of this particular analysis.
4. Cascading transfers — Not present. There is only one recorded assignment for this patent. [cite: USPTO Assignment Record Reel 057429/0819]
5. Pre-litigation transfer — Not present. The assignment from the inventors to Regeneron occurred on 2021-09-08, well before the patent was issued on 2024-12-17, and before the initiation of any known PGR proceedings (PGR2025-00085 filed in 2025, PGR2026-00039 filed in 2026). [cite: USPTO Assignment Record Reel 057429/0819]
6. Bankruptcy fire-sale — Not present. Regeneron Pharmaceuticals, Inc. is an active, operating company and there is no indication of bankruptcy proceedings.
7. Privateering — Not present. The patent is held by the operating company, Regeneron.
8. Defensive aggregator (anti-NPE) — Not present. The patent is currently assigned to Regeneron Pharmaceuticals, Inc. and is not shown to be held by a defensive aggregator.

Verdict

Insufficient data

The only recorded assignment for U.S. Patent 12,168,036 is the initial transfer of inventor rights to Regeneron Pharmaceuticals, Inc., recorded on 2021-09-08 (Reel 057429/0819). This is a standard practice and does not provide any signals of NPE activity or transfer patterns. Without further recorded assignments, it is not possible to make a determination regarding NPE status.

USPTO Assignment Center Search for US12168036

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.

Analysis of Obviousness under 35 U.S.C. § 103 for U.S. Patent 12,168,036

This analysis evaluates whether the claimed invention in U.S. Patent 12,168,036 would have been obvious to a Person Having Ordinary Skill in the Art (PHOSITA) at the time of the invention. An invention is considered obvious if the differences between the invention and the prior art are such that the subject matter as a whole would have been obvious to a PHOSITA.

Definition of a Person Having Ordinary Skill in the Art (PHOSITA)

A PHOSITA in the context of this patent would be a pharmaceutical scientist, biochemist, or chemical engineer. This individual would possess a master's degree or Ph.D. in a relevant field and have several years of experience in the development of liquid biologic formulations, particularly high-concentration monoclonal antibodies or therapeutic fusion proteins. The PHOSITA would be knowledgeable about protein stabilization, viscosity reduction, buffer systems, and the specific requirements and challenges of formulations intended for intravitreal administration.

Analysis of Independent Claims

The obviousness of the independent claims (1, 16, 21, 28, and 33) is analyzed below by considering combinations of prior art references.

1. Obviousness of Claims 1, 21, and 33 (High-Concentration Formulation with Arginine)

These claims cover a method of treatment, the formulation itself, and a method of manufacture, all centered on a specific high-concentration aflibercept formulation. The key elements are:

• Aflibercept at ~114.3 mg/mL
• Histidine-based buffer (10 mM)
• Sucrose (5% w/v)
• Polysorbate 20 (0.03% w/v)
• L-arginine monohydrochloride (50 mM)
• pH of ~5.8
• Specific viscosity and stability profiles

Primary Combination of Prior Art:

• US 2019/0343918 A1 (US '918) as the primary reference.
• General knowledge in the art regarding formulation development.

Motivation to Combine and Reasonable Expectation of Success:

A PHOSITA would have been motivated to develop a high-concentration aflibercept formulation to reduce the frequency of intravitreal injections, a well-known clinical need. The US '918 application, from the same inventors, explicitly addresses this exact problem.

1. Disclosure of All Elements: US '918 discloses all the essential components of the claimed formulation. It teaches the use of aflibercept at high concentrations (including 80 mg/mL, 140 mg/mL, and 150 mg/mL), histidine as a preferred buffer over phosphate for stability in some cases (Patent Text, Example 1), sucrose as a thermal stabilizer, polysorbate 20 as a surfactant, and L-arginine monohydrochloride as a viscosity-reducing agent (Patent Text, Example 2).

2. Explicit Example: The subject patent's own text identifies "Formulation GGGG" as comprising 114.3 mg/mL aflibercept, 10 mM histidine buffer, 5% sucrose, 0.03% polysorbate 20, and 50 mM L-arginine monohydrochloride at a pH of 5.8. (Patent Text, Illustrative Formulations). Crucially, the prior art reference US '918 discloses this nearly identical formulation and presents stability data for it (Patent Text, FIG. 19A-E). This figure in the patent, which analyzes a 114.3 mg/mL formulation with these components, demonstrates the stability that is a key feature of claim 21.

3. Obvious to Optimize: Even if US '918 did not disclose the exact combination in a single example, it provides a clear roadmap. It presents various formulations and studies the effect of changing individual components, such as comparing buffers (histidine vs. phosphate) and evaluating the effect of arginine (Patent Text, FIG. 2A, 4A). A PHOSITA, guided by the teachings of US '918, would have found it obvious to combine these disclosed elements and optimize their concentrations through routine experimentation to arrive at a formulation with the desired properties of stability, pH, and viscosity. The specific values recited in the claims represent successful endpoints of this routine optimization, not an inventive leap.

Therefore, claims 1, 21, and 33 would have been obvious over the teachings of US 2019/0343918 A1, as it provides all the necessary components and a clear motivation to combine them with a high expectation of success.

2. Obviousness of Claim 16 (High-Concentration Formulation without Arginine)

Claim 16 is directed to a method of treatment using a formulation comprising 80-150 mg/mL aflibercept, a histidine buffer, sucrose, and polysorbate 20, but without an agent like L-arginine. The claim specifies a viscosity of 11 cP to 14 cP at 20°C.

Primary Combination of Prior Art:

• US 2019/0343918 A1 (US '918) in combination with U.S. Patent 8,481,046 B2 (US '046).

Motivation to Combine and Reasonable Expectation of Success:

1. Starting Point: The PHOSITA starts with the goal of creating a high-concentration aflibercept formulation, as taught by US '918.
2. Optional Nature of Viscosity Reducers: US '918 teaches that viscosity is a problem at high concentrations and suggests arginine as a solution. However, the data presented in the '036 patent itself (derived from its priority applications) shows that omitting the viscosity reducer is a viable option. FIG. 3B shows that a 155 mg/mL aflibercept formulation in a histidine buffer with no salt has a viscosity of approximately 14 cP. This is within the range claimed in claim 16.
3. Simplification of Formulation: A PHOSITA is always motivated to create the simplest possible formulation that meets the required safety and efficacy profile. Since the viscosity of a histidine-buffered formulation without arginine was manageable and within the claimed range, it would have been an obvious design choice to omit the arginine to reduce complexity and potential side effects. The US '046 patent, describing the original EYLEA® formulation, establishes a baseline formulation that includes a buffer, stabilizer, and surfactant, but not necessarily a separate viscosity reducer like arginine for its 40 mg/mL concentration. A PHOSITA would consider whether such a reducer is truly necessary when increasing the concentration and would test formulations without it.
4. Achieving Claimed Viscosity: Based on the data in FIG. 3B of the patent's own disclosure (which reflects the state of the art available from the priority documents), a PHOSITA would have had a reasonable expectation of success in achieving a viscosity between 11 cP and 14 cP for an aflibercept formulation in a histidine buffer at a concentration between 80-150 mg/mL without adding arginine.

Thus, claim 16 would have been obvious, as formulating without a viscosity reducer is a known and obvious alternative, and the resulting viscosity was predictable and within an acceptable range for intravitreal injection.

3. Obviousness of Claim 28 (Pre-filled Syringe)

Claim 28 covers a pre-filled syringe containing the sterile pharmaceutical formulation of claim 21.

Primary Combination of Prior Art:

• The formulation of Claim 21 (found obvious above) in view of common general knowledge in the pharmaceutical field.
• US 2019/0343918 A1, which explicitly mentions pre-filled syringes.

Motivation to Combine and Reasonable Expectation of Success:

Packaging an injectable drug intended for precise ocular dosing into a pre-filled syringe is a standard, ubiquitous practice in the pharmaceutical industry. The benefits—convenience, reduced risk of contamination, and improved dosing accuracy—are well-established. US '918 explicitly discloses that its high-concentration formulations can be introduced into a "delivery device, e.g., a pre-filled syringe."

Therefore, once the formulation of claim 21 is established (or rendered obvious), the final step of packaging it into a pre-filled syringe is nothing more than the "predictable use of prior art elements according to their established functions" and would have been immediately obvious to a PHOSITA.

Conclusion on Obviousness

The claims of U.S. Patent 12,168,036 appear to be vulnerable to an obviousness challenge under 35 U.S.C. § 103. The primary prior art, particularly Regeneron's own earlier patent application US 2019/0343918 A1, discloses the key problem, the specific components needed for the solution, and data demonstrating a high likelihood of success. The claimed formulations represent, at best, the result of routine optimization and combination of known elements for their intended purposes, a pathway clearly illuminated by the prior art. The packaging of such a formulation in a pre-filled syringe is similarly a standard and obvious practice. The arguments laid out in the ongoing PGR proceedings likely expand on these points in greater detail.

Analysis of U.S. Patent 12,168,036: Term, Continuity, and Family Data

Patent Term Adjustments (PTA) and Extensions (PTE):

A thorough review of the prosecution history and bibliographic data for U.S. Patent 12,168,036 reveals no granted Patent Term Adjustment (PTA) or Patent Term Extension (PTE). The patent's term is therefore calculated from its filing date.

Projected Expiration Date:

U.S. Patent 12,168,036 was filed on July 23, 2021. Based on the standard 20-year term from the filing date of the earliest non-provisional application, the projected expiration date is July 23, 2041. This date does not account for any terminal disclaimers or potential future changes to the patent's status. The patent claims priority to a provisional application filed on May 10, 2018.

Continuity and Divisional Applications:

U.S. Patent 12,168,036 is part of a series of applications stemming from earlier filings. The continuity data is as follows:

• Parent Application: This patent is a continuation of U.S. Patent Application No. 17/384,070, filed on July 23, 2021, which issued as U.S. Patent No. 11,103,552.
• Provisional Priority: The application claims priority to several U.S. provisional applications, the earliest of which is No. 62/669,506, filed on May 10, 2018.

There are no divisional applications of U.S. Patent 12,168,036 identified.

Related Patent Family Members:

This patent is part of a larger family of patents and patent applications filed in the United States and internationally, covering high-concentration formulations of VEGF receptor fusion proteins. Key family members include:

• U.S. Patent 11,103,552: As the parent patent, it shares a very similar disclosure regarding high-concentration VEGF receptor fusion protein formulations.
• U.S. Patent Application Publication No. 2019/0343918 A1: This is an earlier publication from the same patent family and discloses much of the core technology.
• International Application No. WO 2019/217927 A1: The international (PCT) counterpart to the U.S. applications, which also describes the high-concentration formulations.
• U.S. Patent 11,135,266: Another related patent assigned to Regeneron concerning aflibercept formulations.
• International Application No. WO 2018/094316 A1: Describes related aflibercept formulations suitable for intravitreal administration.

This extensive patent family indicates a strategic effort by Regeneron Pharmaceuticals, Inc. to secure broad protection for its high-dose EYLEA® (aflibercept) product, also known as EYLEA HD®. The various family members cover different aspects of the formulation, methods of use, and manufacturing processes.

Defensive Disclosure and Prior Art Generation

Publication Date: May 1, 2026
Subject: Derivative Works and Obvious Implementations of High-Concentration Aflibercept Formulations for Ophthalmic and Systemic Use.
Based on Analysis of: U.S. Patent 12,168,036

This document discloses a series of technical variations, applications, and integrations related to the core teachings of U.S. Patent 12,168,036 ('036 patent). The purpose is to establish prior art for foreseeable and obvious extensions, thereby precluding future patenting of these incremental improvements. The disclosures herein are described in sufficient detail to enable a Person Having Ordinary Skill in the Art (PHOSITA) to practice the inventions.

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Derivative Set 1: Based on Core Claim 21 (The Formulation)

Core Claim Elements: A stable injectable aqueous formulation comprising ~114.3 mg/mL aflibercept, ~10 mM histidine buffer, ~5% (w/v) sucrose, ~0.03% (w/v) polysorbate 20, and ~50 mM L-arginine monohydrochloride, at pH ~5.8, with specified viscosity and stability.

Variation 1.1: Component Substitution - Bio-responsive Buffer System

• Enabling Description: A high-concentration aflibercept formulation (80-200 mg/mL) is prepared using a dual-component, bio-responsive buffer system instead of histidine. The system consists of 15 mM sodium succinate and 15 mM Tris-HCl. At the storage pH of 5.5, the succinate component provides primary buffering. Upon injection into the vitreous (physiologic pH ~7.4), the Tris component (pKa ~8.1) becomes the dominant buffer, minimizing local pH disruption at the injection site. The formulation further includes 8% (w/v) trehalose as a lyoprotectant and cryoprotectant, and 0.05% (w/v) Poloxamer 188 (Pluronic F-68) as a surfactant, which provides shear protection during injection. This system enhances stability at storage pH while improving physiological compatibility upon administration.

  flowchart TD
      A[Formulation in Syringe @ pH 5.5] -- Injection --> B{Vitreous Humor @ pH 7.4};
      A -- Buffering --> C[Succinate Buffer Active];
      B -- pH Shift --> D[Tris-HCl Buffer Active];
      C -- Protein Stability --> E(Aflibercept Stable in Storage);
      D -- Biocompatibility --> F(Minimized pH Shock at Injection Site);
  

Variation 1.2: Component Substitution - Alternate Viscosity-Reducing Excipient

• Enabling Description: The L-arginine monohydrochloride component is replaced with a combination of 40 mM L-proline and 20 mM sodium citrate. This combination disrupts protein-protein interactions through a different mechanism than arginine, reducing the viscosity of a 150 mg/mL aflibercept solution to approximately 10 cP at 20°C. The formulation is buffered with 20 mM sodium acetate at pH 5.5 and stabilized with 4% (w/v) mannitol and 0.02% (w/v) Brij-35 (polyoxyethylene 23 lauryl ether). The use of proline and citrate avoids potential counter-ion effects associated with hydrochloride salts and offers a different impurity profile.

  classDiagram
      class AfliberceptFormulation {
          +protein: Aflibercept(150mg/mL)
          +buffer: SodiumAcetate(20mM, pH 5.5)
          +stabilizer: Mannitol(4% w/v)
          +surfactant: Brij-35(0.02% w/v)
          +viscosityReducer1: L-Proline(40mM)
          +viscosityReducer2: SodiumCitrate(20mM)
      }
      AfliberceptFormulation --|> InjectableSolution : is a
      class InjectableSolution {
          +viscosity: ~10 cP
          +osmolality: 280-350 mOsm/kg
      }
  

Variation 1.3: Operational Parameter Expansion - Thermogelling Depot Formulation

• Enabling Description: A sustained-release formulation of aflibercept (60 mg/mL) is prepared using a thermo-responsive polymer. The formulation comprises aflibercept, 10 mM phosphate buffer pH 6.2, 2% sucrose, and 22% (w/v) Poloxamer 407. This formulation is a low-viscosity liquid (< 20 cP) at refrigerated temperatures (2-8°C). Upon intravitreal injection, the formulation warms to body temperature (~37°C), causing the Poloxamer 407 to undergo a phase transition into a semi-solid gel depot. Aflibercept is then released from this depot over a period of 4-6 months via diffusion and bio-erosion of the gel, drastically reducing injection frequency.

  stateDiagram-v2
      [*] --> Liquid_State : Stored at 2-8°C
      Liquid_State: Viscosity < 20 cP
      Liquid_State --> Gel_Depot : Intravitreal Injection (Warms to 37°C)
      Gel_Depot: Viscosity > 1000 cP
      Gel_Depot --> Released_Drug : Sustained Release (Diffusion & Erosion)
      Released_Drug --> [*]
  

Variation 1.4: Cross-Domain Application - AgTech Localized Growth Inhibition

• Enabling Description: A high-concentration (100 mg/mL) formulation of a plant-derived lectin-Fc fusion protein, which binds to root-specific growth factors, is developed for agricultural applications. The formulation is based on the principles of the '036 patent, comprising 50 mM sodium acetate buffer pH 5.0, 10% (w/v) glycerol as a stabilizer and anti-freeze agent, and 0.1% (w/v) Tween 80. The formulation is designed for injection into the soil near building foundations or into the cambium of invasive tree species. The high-concentration, stable formulation ensures localized, long-term inhibition of root growth to prevent infrastructure damage, without requiring widespread herbicide application.

  flowchart LR
      subgraph Preparation
          A(Lectin-Fc Fusion Protein)
          B(Glycerol Stabilizer)
          C(Acetate Buffer)
          D(Tween 80 Surfactant)
      end
      A & B & C & D --> E[High-Concentration Formulation];
      subgraph Application
          E -- Soil Injection --> F(Prevent Root Damage to Foundations);
          E -- Cambium Injection --> G(Inhibit Growth of Invasive Trees);
      end
  

Variation 1.5: Integration with Emerging Tech - AI-Optimized Patient-Specific Formulation

• Enabling Description: An automated compounding system uses the '036 patent formulation as a base but integrates an AI-driven optimization module. Prior to preparing the injection, the system receives real-time data for the patient, including intraocular pressure (IOP), retinal thickness from an OCT scan, and biomarker levels from a tear fluid sample. A pre-trained machine learning model predicts the optimal aflibercept concentration (between 80-150 mg/mL) and L-arginine concentration (between 25-75 mM) to maximize therapeutic effect while minimizing IOP spikes for that specific patient. The system then aseptically compounds the patient-specific formulation from sterile, high-concentration stocks.

  sequenceDiagram
      participant PatientData as Patient EHR/Sensor
      participant AI_Model as AI Optimization Engine
      participant Compounder as Robotic Compounding System
      participant Syringe as Final Patient-Specific Dose
  
      PatientData ->> AI_Model: Transmit IOP, OCT, Biomarker Data
      AI_Model ->> AI_Model: Calculate Optimal [Aflibercept] & [Arginine]
      AI_Model ->> Compounder: Send Formulation Parameters
      Compounder ->> Compounder: Aseptically mix stock solutions
      Compounder ->> Syringe: Fill with optimized formulation
  

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Derivative Set 2: Based on Core Claim 28 (The Pre-filled Syringe)

Core Claim Elements: A pre-filled syringe containing a sterile volume of the formulation of claim 21, for intravitreal injection.

Variation 2.1: Material Substitution - Self-Lubricating, Silicon-Free Syringe

• Enabling Description: The pre-filled syringe is constructed from a novel ethylene-norbornene copolymer that has been surface-grafted with hydrophilic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) brushes. This surface treatment creates a self-lubricating, bio-inert inner barrel, eliminating the need for silicone oil lubricants, which are known to cause protein aggregation and the formation of silicone oil droplets in the eye. The plunger is made from a coated butyl rubber that is free of tungsten and other leachable heavy metals. This design enhances the stability of the high-concentration aflibercept formulation and improves patient safety.

  graph TD
      A[Pre-filled Syringe] --> B{Barrel};
      A --> C{Plunger};
      A --> D{Needle};
  
      B --> B1[Material: Ethylene-Norbornene Copolymer];
      B --> B2[Inner Surface: Grafted PMPC Brushes];
      B2 --> B3(Self-Lubricating & Silicon-Free);
  
      C --> C1[Material: Coated Butyl Rubber];
      C1 --> C2(Tungsten-Free);
  

Variation 2.2: The "Inverse" - Safe-Fail Temperature Indicator Syringe

• Enabling Description: The pre-filled syringe is co-filled with the high-concentration aflibercept formulation and a separate, immiscible droplet of a thermochromic liquid crystal (TLC) formulation. The TLC is engineered to undergo an irreversible color change from transparent to opaque white if its temperature exceeds 10°C. This provides a clear, non-reversible visual indicator that the syringe has experienced a temperature excursion and should not be used. This failure-mode indicator is passive, requires no electronics, and is integrated directly into the primary container, providing a higher degree of safety and supply chain integrity than external temperature logging labels.

  flowchart LR
      subgraph Syringe State
          A(Aflibercept Formulation)
          B(Thermochromic Liquid Crystal Droplet)
      end
      A & B --> C{Syringe at 2-8°C};
      C --> D[TLC is Transparent - OK to Use];
      C -- Temperature > 10°C --> E{Irreversible Phase Change};
      E --> F[TLC is Opaque White - DO NOT USE];
  

Variation 2.3: Cross-Domain Application - Aerospace Autoinjector for Microgravity

• Enabling Description: An autoinjector is designed for astronauts to self-administer a high-concentration formulation of an anti-sclerotic agent to counteract space-flight associated neuro-ocular syndrome (SANS). The device is based on the pre-filled syringe concept but is mechanically actuated to overcome challenges of fluid handling in microgravity. The syringe body is over-molded with a high-friction, radiation-hardened polymer for easy handling with gloves. The formulation itself is a highly concentrated protein therapeutic (e.g., 200 mg/mL) stabilized with a combination of sucrose and ectoine to withstand radiation and extreme temperature cycles experienced outside the Earth's magnetosphere.

  classDiagram
      class MicrogravityAutoinjector {
          -proteinFormulation: HighConcentrationAntiSclerotic
          -syringe: RadiationHardenedPolymer
          -actuator: SpringLoadedMechanism
          +administerDose()
      }
      class HighConcentrationAntiSclerotic {
          +protein: 200mg/mL
          +stabilizer1: Sucrose
          +stabilizer2: Ectoine
          +buffer: Histidine
      }
      MicrogravityAutoinjector "1" *-- "1" HighConcentrationAntiSclerotic
  

Variation 2.4: Integration with Emerging Tech - Blockchain-Verified Smart Syringe

• Enabling Description: Each pre-filled syringe is equipped with a passive NFC chip containing a unique cryptographic hash. This hash corresponds to a record on a private blockchain that immutably stores the entire manufacturing and supply chain history: batch numbers of aflibercept and all excipients, date of manufacture, sterility testing results, and time-stamped temperature logs from IoT sensors in the shipping container. Before administration, the clinician uses a smartphone app to scan the NFC chip. The app verifies the syringe's authenticity against the blockchain record and confirms that no temperature excursions have occurred. The act of scanning and verifying the dose is also logged as a new transaction, providing a complete, auditable "needle-to-patient" record.

  sequenceDiagram
      participant Manufacturer
      participant Blockchain
      participant Syringe_NFC as Syringe w/ NFC
      participant Clinician_App as Clinician's App
  
      Manufacturer->>Blockchain: Create immutable record for syringe batch
      Manufacturer->>Syringe_NFC: Write unique hash to NFC chip
      Syringe_NFC->>Clinician_App: Clinician scans NFC
      Clinician_App->>Blockchain: Verify hash and check temperature logs
      Blockchain-->>Clinician_App: Return verification status (OK/Fail)
      Clinician_App->>Blockchain: Log administration event as new transaction
  

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Combination Prior Art with Open-Source Standards

Scenario 1: Integration with HL7 FHIR Standard for Clinical Data

• Enabling Description: The '036 formulation is packaged in a pre-filled syringe with a unique 2D barcode. A clinic's medication administration software, which is compliant with the HL7 FHIR (Fast Healthcare Interoperability Resources) standard, is used to manage the injection process. Upon scanning the barcode, the system creates a MedicationAdministration FHIR resource. This resource captures the specific lot number of the aflibercept formulation, the dosage administered (e.g., 8 mg), the injection site (e.g., left or right eye, identified by a SNOMED-CT code), and links to the Patient and Practitioner resources. This use of an open-source health data standard renders the integration of this or any similar formulation into standard clinical workflows obvious, creating a standardized, interoperable electronic health record of the treatment.

Scenario 2: Integration with OpenCV for Quality Control

• Enabling Description: During the manufacturing of the '036 formulation, a quality control station is implemented on the filling line. The station uses a high-resolution camera and a computer vision system running the open-source OpenCV library. As each filled syringe passes, the system captures an image and applies a series of OpenCV functions: 1) cv::Canny to detect the edges of the plunger and determine the precise fill volume; 2) cv::HoughCircles to detect and count any visible particulate matter (aggregates); and 3) cv::matchTemplate to compare the overall image against a "golden standard" template. Syringes that fail any of these automated visual inspections are automatically rejected. This combination discloses the use of open-source machine vision to ensure the quality and stability parameters central to the patent's claims.

Scenario 3: Integration with GROMACS for In-Silico Formulation Screening

• Enabling Description: To discover novel viscosity-reducing excipients (as in Variation 1.2), a computational screening platform is established using the open-source molecular dynamics software GROMACS. A validated molecular model of multiple aflibercept homodimers in aqueous solution is created. The system then simulates the molecular dynamics of the protein solution with the addition of hundreds of different candidate excipients from a virtual library (e.g., various amino acids, small molecule sugars, organic salts). The simulations are run on a distributed computing cluster. The resulting trajectories are analyzed to calculate the solution's simulated viscosity. This method, combining the patented formulation's core problem (viscosity) with an open-source simulation engine, makes the discovery of new excipients via computational chemistry an obvious path for a PHOSITA.