US 11084865

US Patent 11,084,865, titled "VEGF antagonist formulations suitable for intravitreal administration," was issued to Regeneron Pharmaceuticals Inc. on August 10, 2021, from an application filed on January 10, 2020. The inventors are Eric Furfine, Daniel Dix, Kenneth Graham, and Kelly Frye.

Abstract:
The patent describes ophthalmic formulations of a vascular endothelial growth factor (VEGF)-specific fusion protein antagonist that are suitable for intravitreal administration to the eye. These formulations include both stable liquid formulations and lyophilizable formulations. The preferred protein antagonist has an amino acid sequence of SEQ ID NO:4.

Plain-Language Overview of Independent Claims:

• Claim 1 (Vial containing formulation): This claim describes a vial that holds an ophthalmic formulation intended for injection into the vitreous of the eye. The formulation contains a VEGF antagonist fusion protein (specifically one that is glycosylated and includes amino acids 27-457 of SEQ ID NO:4), an organic co-solvent, a buffer, and a stabilizing agent. A key characteristic is the stability of the VEGF antagonist, with at least 98% of it retaining its native form after two months of storage at 5° C., as measured by size exclusion chromatography.

• Claim 26 (Pre-filled syringe containing formulation): Similar to Claim 1, this claim describes a pre-filled syringe containing an ophthalmic formulation for intravitreal administration. The formulation again includes a glycosylated VEGF antagonist fusion protein (amino acids 27-457 of SEQ ID NO:4), an organic co-solvent, a buffer, and a stabilizing agent. Like the vial, the formulation in the syringe must maintain the VEGF antagonist in at least 98% native conformation after two months of storage at 5° C.

• Claim 51 (Specific ophthalmic formulation): This claim defines a particular ophthalmic formulation suitable for intravitreal administration. It specifies the concentration of the glycosylated VEGF antagonist fusion protein (40 mg/ml, comprising amino acids 27-457 of SEQ ID NO:4), the organic co-solvent (0.03% to 0.1% polysorbate), the buffer (5-40 mM sodium phosphate buffer, pH between 5.8-7.0), and includes sucrose as a stabilizing agent. This formulation also requires the VEGF antagonist to be at least 98% in its native conformation after two months of storage at 5° C.

CAFC 2026 Dockets:
While the Google Patents link for US11084865 lists several CAFC cases filed in 2024 and mentions litigation activity continuing into 2025 (e.g., appeals upheld in January and March 2025, and PTAB IPR denials in June 2025), a direct search for "CAFC 2026 dockets US11084865" did not yield specific 2026 docket numbers for the Federal Circuit. However, it is evident that the patent has been extensively litigated. Regeneron has asserted the patent in BPCIA litigations against multiple biosimilar manufacturers, including Mylan, Samsung Bioepis, Celltrion, Formycon, and Amgen. There have been preliminary injunctions granted and upheld on appeal against Samsung Bioepis, Formycon, and Celltrion, preventing their biosimilar launches, with these decisions occurring in early 2025. PTAB panels have also denied institution of several inter partes review (IPR) petitions against the patent, citing advanced parallel district court proceedings. Fresenius Kabi filed IPR petitions against claims of this patent in July 2025. The ongoing nature of this litigation suggests that proceedings related to this patent may extend into 2026, even if specific CAFC 2026 docket numbers are not explicitly returned by the search.

The search results provide substantial details for the litigation involving US Patent 11084865, particularly highlighting the extensive Biologics Price Competition and Innovation Act (BPCIA) litigation related to Regeneron's Eylea® and its biosimilar versions.

Here is a summary of the known litigation involving US Patent 11084865:

Plaintiff: Regeneron Pharmaceuticals, Inc. (common plaintiff across all identified cases related to the '865 patent).

1. Regeneron Pharmaceuticals, Inc. v. Mylan Pharmaceuticals Inc. et al.

• Jurisdiction: U.S. District Court for the Northern District of West Virginia, and subsequently appealed to the U.S. Court of Appeals for the Federal Circuit.
• Case Number:
  • District Court: 1:22-cv-00061 (N.D.W. Va.)
  • MDL: 1:24-md-03103 (N.D.W. Va.)
  • CAFC Appeals: 24-1965, 24-1966, 24-2002, 24-2009, 24-2019, 24-2058, 24-2082, 24-2083, 24-2147, 24-2156, 24-2351 (various appeals involving Mylan and other defendants, all related to the '865 patent)
• Filing Date: August 2022 (District Court case against Mylan)
• Outcome/Current Status: In the district court, Regeneron secured a victory, with the court finding that Mylan infringed certain claims of the '865 patent and had not shown those claims to be invalid. Mylan appealed this judgment. On April 15, 2025, Biocon (associated with Mylan for biosimilar Yesafili™) announced a settlement agreement with Regeneron, leading to the dismissal of CAFC Appeal No. 24-2002 and District Court Case No. 1:22-cv-00061, allowing commercialization of Yesafili™ in the second half of 2026. CAFC Appeals 24-1965, 24-1966, 24-2082, 24-2083 were decided on January 29, 2025, affirming preliminary injunctions against Samsung Bioepis and Formycon, which were linked to the Mylan case. CAFC Appeal 24-2351 was dismissed on March 14, 2025.

2. Regeneron Pharmaceuticals, Inc. v. Samsung Bioepis Co., Ltd.

• Jurisdiction: U.S. District Court for the Northern District of West Virginia, and U.S. Court of Appeals for the Federal Circuit. Also PTAB.
• Case Number:
  • District Court: 1:23-cv-00094 (N.D.W. Va.), 1:23-cv-00106 (N.D.W. Va.)
  • MDL: 1:24-md-03103 (N.D.W. Va.)
  • CAFC Appeal: 24-1965, 24-1966, 24-2082, 24-2083 (related to preliminary injunctions)
  • PTAB IPR: IPR2025-00176
• Filing Date: Late 2023 (District Court), November 20, 2024 (IPR2025-00176)
• Outcome/Current Status: The district court granted a preliminary injunction against Samsung Bioepis on June 14, 2024, finding Regeneron likely to succeed on infringement and validity. The Federal Circuit affirmed this preliminary injunction on January 29, 2025. For IPR2025-00176, the PTAB denied institution on discretionary grounds.

3. Regeneron Pharmaceuticals, Inc. v. Formycon AG

• Jurisdiction: U.S. District Court for the Northern District of West Virginia, and U.S. Court of Appeals for the Federal Circuit. Also PTAB.
• Case Number:
  • District Court: 1:23-cv-00097 (N.D.W. Va.)
  • MDL: 1:24-md-03103 (N.D.W. Va.)
  • CAFC Appeal: 24-2009 (related to preliminary injunction)
  • PTAB IPR: IPR2025-00233
• Filing Date: Late 2023 (District Court), December 2, 2024 (IPR2025-00233)
• Outcome/Current Status: The district court granted a preliminary injunction against Formycon on June 21, 2024. The Federal Circuit affirmed this preliminary injunction on January 29, 2025. For IPR2025-00233, the PTAB denied institution on discretionary grounds.

4. Regeneron Pharmaceuticals, Inc. v. Celltrion, Inc.

• Jurisdiction: U.S. District Court for the Northern District of West Virginia, and U.S. Court of Appeals for the Federal Circuit. Also PTAB.
• Case Number:
  • District Court: 1:23-cv-00089 (N.D.W. Va.), 1:24-cv-00053 (N.D.W. Va.)
  • MDL: 1:24-md-03103 (N.D.W. Va.)
  • CAFC Appeal: 24-2058, 24-2147
  • PTAB IPR: IPR2025-00456
• Filing Date: Late 2023 (District Court), January 15, 2025 (IPR2025-00456)
• Outcome/Current Status: The district court granted a preliminary injunction against Celltrion in June-July 2024. The Federal Circuit affirmed this preliminary injunction on March 5, 2025. For IPR2025-00456, the PTAB denied institution on discretionary grounds.

5. Regeneron Pharmaceuticals, Inc. v. Amgen Inc.

• Jurisdiction: U.S. District Court for the Central District of California (transferred to N.D.W. Va.), and U.S. Court of Appeals for the Federal Circuit.
• Case Number:
  • District Court: 2:24-cv-00264 (C.D. Cal.) (transferred to N.D.W. Va., C.A. 1:24-cv-00039)
  • MDL: 1:24-md-03103 (N.D.W. Va.)
  • CAFC Appeal: 24-2351
• Filing Date: January 10, 2024 (District Court)
• Outcome/Current Status: The district court denied Regeneron's motion for a preliminary injunction against Amgen because it found Regeneron unlikely to succeed on infringement, due to Amgen's biosimilar design-around related to the buffer component. The Federal Circuit upheld this denial of a preliminary injunction on March 14, 2025. Amgen launched its biosimilar, Pavblu™, at-risk in October 2024.

6. Regeneron Pharmaceuticals, Inc. v. Sandoz Inc.

• Jurisdiction: U.S. District Court for the Northern District of West Virginia.
• Case Number: 1:24-cv-00085 (N.D.W. Va.)
  • MDL: 1:24-md-03103 (N.D.W. Va.)
• Filing Date: Not explicitly found in search results, but referenced alongside other 2024 cases.
• Outcome/Current Status: Ongoing. Sandoz's biosimilar Enzeevu™ was approved in August 2024.

7. Fresenius Kabi SwissBioSim GmbH v. Regeneron Pharmaceuticals, Inc.

• Jurisdiction: PTAB
• Case Number: IPR2025-01268
• Filing Date: Not explicitly stated, but the "Effective date" is July 14, 2025. (Unified Patents lists filing date 2024-11-20 in other context, but the Google patent entry gives an effective date of July 14, 2025, for the opponent names)
• Outcome/Current Status: Not Instituted - Procedural. The petition relies on different prior art than other IPRs.

8. PTAB Cases with "Not Instituted - Procedural" Status (Details not fully identified in search results beyond the PTAB status)

• Jurisdiction: PTAB
• Case Number:
  • IPR2025-00176 (Samsung Bioepis) - Covered under Samsung Bioepis above.
  • IPR2025-00233 (Formycon AG) - Covered under Formycon AG above.
  • IPR2025-00456 (Celltrion, Inc.) - Covered under Celltrion, Inc. above.

9. Court of Appeals for the Federal Circuit Cases (Specific details for these individual entries are generally covered by the consolidated appeals mentioned above involving Regeneron vs. Mylan, Samsung Bioepis, Formycon, Amgen, and Celltrion, which often involve multiple appeals under one decision or related issues.)

• Jurisdiction: Court of Appeals for the Federal Circuit
• Case Numbers:
  • 24-1402, 24-1405: Dismissed for lack of jurisdiction on April 12, 2024.
  • 24-1965, 24-1966, 24-2002, 24-2009, 24-2019, 24-2082, 24-2083, 24-2147, 24-2156, 24-2351: These are Federal Circuit appeals primarily involving Regeneron against various biosimilar manufacturers (Mylan, Samsung Bioepis, Formycon, Celltrion, Amgen) concerning preliminary injunctions and district court judgments regarding the '865 patent. Their outcomes are integrated into the specific defendant entries above.

10. New Jersey District Court Case:

• Jurisdiction: New Jersey District Court
• Case Number: 3:24-cv-08760
• Filing Date: Not explicitly found in search results.
• Outcome/Current Status: Status unknown from current search results, but context indicates likely BPCIA litigation against another biosimilar applicant.

Summary of Litigation involving US Patent 11084865:

US Patent 11084865, owned by Regeneron Pharmaceuticals, Inc., is extensively involved in BPCIA (Biologics Price Competition and Innovation Act) litigation concerning biosimilar versions of Regeneron's Eylea® (aflibercept). The majority of these cases are in the U.S. District Court for the Northern District of West Virginia, often consolidated under MDL 1:24-md-03103, with numerous appeals to the U.S. Court of Appeals for the Federal Circuit and challenges at the PTAB.

The patent is directed to ophthalmic formulations of aflibercept suitable for intravitreal administration, claiming specific stability and formulation requirements.

Known Litigation Cases:

1. Plaintiff: Regeneron Pharmaceuticals, Inc.

   • Defendant(s): Mylan Pharmaceuticals Inc. (and Biocon Biologics Inc.)
   • Jurisdiction: U.S. District Court for the Northern District of West Virginia; U.S. Court of Appeals for the Federal Circuit
   • Case Number(s):
     • District Court: 1:22-cv-00061 (N.D.W. Va.)
     • MDL: 1:24-md-03103 (N.D.W. Va.)
     • CAFC Appeals: 24-2002, along with multiple other related appeals (e.g., 24-1965, 24-1966, 24-2019, 24-2058, 24-2082, 24-2083, 24-2147, 24-2156, 24-2351)
   • Filing Date: August 2022 (District Court)
   • Outcome/Current Status: District court found Mylan infringed and claims were not invalid. Appeals to CAFC were filed. On April 15, 2025, Biocon (for Mylan's biosimilar Yesafili™) settled with Regeneron, dismissing CAFC Appeal No. 24-2002 and District Court Case No. 1:22-cv-00061, allowing commercialization of Yesafili™ in the second half of 2026. CAFC Appeal 24-2351 was dismissed on March 14, 2025.

2. Plaintiff: Regeneron Pharmaceuticals, Inc.

   • Defendant(s): Samsung Bioepis Co., Ltd.
   • Jurisdiction: U.S. District Court for the Northern District of West Virginia; U.S. Court of Appeals for the Federal Circuit; PTAB
   • Case Number(s):
     • District Court: 1:23-cv-00094 (N.D.W. Va.), 1:23-cv-00106 (N.D.W. Va.)
     • MDL: 1:24-md-03103 (N.D.W. Va.)
     • CAFC Appeals: 24-1965, 24-1966, 24-2082, 24-2083
     • PTAB IPR: IPR2025-00176
   • Filing Date: Late 2023 (District Court); November 20, 2024 (IPR2025-00176)
   • Outcome/Current Status: District court granted preliminary injunction (June 14, 2024). Federal Circuit affirmed preliminary injunction (January 29, 2025). PTAB IPR2025-00176: Not Instituted - Procedural (discretionary denial).

3. Plaintiff: Regeneron Pharmaceuticals, Inc.

   • Defendant(s): Formycon AG
   • Jurisdiction: U.S. District Court for the Northern District of West Virginia; U.S. Court of Appeals for the Federal Circuit; PTAB
   • Case Number(s):
     • District Court: 1:23-cv-00097 (N.D.W. Va.)
     • MDL: 1:24-md-03103 (N.D.W. Va.)
     • CAFC Appeal: 24-2009
     • PTAB IPR: IPR2025-00233
   • Filing Date: Late 2023 (District Court); December 2, 2024 (IPR2025-00233)
   • Outcome/Current Status: District court granted preliminary injunction (June 21, 2024). Federal Circuit affirmed preliminary injunction (January 29, 2025). PTAB IPR2025-00233: Not Instituted - Procedural (discretionary denial).

4. Plaintiff: Regeneron Pharmaceuticals, Inc.

   • Defendant(s): Celltrion, Inc.
   • Jurisdiction: U.S. District Court for the Northern District of West Virginia; U.S. Court of Appeals for the Federal Circuit; PTAB
   • Case Number(s):
     • District Court: 1:23-cv-00089 (N.D.W. Va.), 1:24-cv-00053 (N.D.W. Va.)
     • MDL: 1:24-md-03103 (N.D.W. Va.)
     • CAFC Appeal: 24-2058, 24-2147
     • PTAB IPR: IPR2025-00456
   • Filing Date: Late 2023 (District Court); January 15, 2025 (IPR2025-00456)
   • Outcome/Current Status: District court granted preliminary injunction (June-July 2024). Federal Circuit affirmed preliminary injunction (March 5, 2025). PTAB IPR2025-00456: Not Instituted - Procedural (discretionary denial).

5. Plaintiff: Regeneron Pharmaceuticals, Inc.

   • Defendant(s): Amgen Inc.
   • Jurisdiction: U.S. District Court for the Central District of California (transferred to N.D.W. Va.); U.S. Court of Appeals for the Federal Circuit
   • Case Number(s):
     • District Court: 2:24-cv-00264 (C.D. Cal.), transferred to 1:24-cv-00039 (N.D.W. Va.)
     • MDL: 1:24-md-03103 (N.D.W. Va.)
     • CAFC Appeal: 24-2351
   • Filing Date: January 10, 2024 (District Court)
   • Outcome/Current Status: District court denied preliminary injunction. Federal Circuit upheld the denial of preliminary injunction (March 14, 2025). Amgen launched biosimilar Pavblu™ at-risk in October 2024.

6. Plaintiff: Regeneron Pharmaceuticals, Inc.

   • Defendant(s): Sandoz Inc.
   • Jurisdiction: U.S. District Court for the Northern District of West Virginia
   • Case Number(s): 1:24-cv-00085 (N.D.W. Va.)
     • MDL: 1:24-md-03103 (N.D.W. Va.)
   • Filing Date: Not explicitly stated, but within the context of other 2024 filings.
   • Outcome/Current Status: Ongoing. Sandoz's biosimilar Enzeevu™ was approved in August 2024.

7. Plaintiff(s): Fresenius Kabi SwissBioSim GmbH (and related entities)

   • Defendant(s): Regeneron Pharmaceuticals, Inc.
   • Jurisdiction: PTAB
   • Case Number(s): IPR2025-01268
   • Filing Date: Not explicitly stated, but "Effective date: 20250714". (Other sources indicate petitions for IPRs in this timeframe for other parties were filed in late 2024/early 2025).
   • Outcome/Current Status: Not Instituted - Procedural.

8. Plaintiff: Not specified (implied by "US case filed in New Jersey District Court")

   • Defendant(s): Not specified
   • Jurisdiction: New Jersey District Court
   • Case Number: 3:24-cv-08760
   • Filing Date: Not explicitly found in search results.
   • Outcome/Current Status: Status unknown from current search results.

Note: Several CAFC cases listed in the initial patent document (e.g., 24-1402, 24-1405) were dismissed for lack of jurisdiction. The numerous other CAFC case numbers (e.g., 24-1965, 24-1966, etc.) are generally appeals related to the district court actions and preliminary injunctions against the biosimilar manufacturers listed above, and their outcomes are incorporated into those respective entries.

Proceedings overview

One AIA trial proceeding has been filed against US Patent 11084865. The proceeding is IPR2025-01268, which has a status of Discretionary Denial. This means the patent has not been challenged on its merits through an IPR and the claims remain untested and intact.

IPR2025-01268 — Fresenius Kabi SwissBioSim GmbH et al. v. Eric FURFINE et al

• Type: Inter Partes Review
• Filed: 2025-07-14
• Status: Discretionary Denial
• Judge panel: Not publicly available yet for this stage of the proceeding.
• Petition grounds: Not publicly available yet as institution was denied.
• Institution decision: Denied (date not available, but indicated by "last modified 2026-03-09" and "status: Discretionary Denial"). The reasoning for discretionary denial is not yet publicly detailed in the provided data.
• Final Written Decision: Not applicable; institution was denied.
• Settlement / termination: Not applicable; institution was denied.
• Appeal: Not applicable; institution was denied, so there is no Final Written Decision to appeal.
• Defensive value: The discretionary denial of this IPR means that the claims of US11084865 remain unchallenged by this specific petitioner. Any future defendant facing assertion of this patent would still have the opportunity to challenge the patent through new IPRs or other validity arguments in district court, as estoppel under § 315(e)(2) does not apply when institution is denied.

Strategic summary

All claims of US Patent 11084865 are currently UNTESTED through AIA trial proceedings. The single IPR filed, IPR2025-01268, was denied institution on discretionary grounds, meaning the merits of the patentability challenge were not decided by the PTAB. Consequently, no claims have been canceled or sustained through an IPR FWD.

The estoppel landscape remains open for future challengers. Since institution of IPR2025-01268 was denied, Fresenius Kabi SwissBioSim GmbH et al. and their privies are not barred by § 315(e)(2) from raising any grounds that could have been raised in this petition in a subsequent district court litigation or a new IPR (though a new IPR would face its own institution challenges). For a defendant currently being asserted against, all prior-art grounds remain available for potential invalidity arguments, either in court or in a newly filed PTAB petition.

There are no apparent pattern signals of multiple IPR filings by the same petitioner or aggressive PTAB appeals by the patent owner based on the information provided. The discretionary denial suggests that the PTAB, for reasons not yet fully detailed in this dataset, opted not to proceed with a trial.

Recommended next steps

Since there is no active PTAB proceeding and the single filed IPR was denied institution, the claims of US11084865 are currently considered valid from a PTAB perspective. If you are a defendant facing assertion of this patent, you would need to evaluate the claims and prior art independently to determine if a new IPR challenge is warranted. The absence of instituted PTAB activity might suggest that the patent has not faced a robust validity challenge, or that previous challenges (like the denied IPR) were found to be procedurally deficient or did not meet the institution threshold for discretionary reasons. Reviewing the PTAB's detailed decision for the discretionary denial of IPR2025-01268 (when publicly available on USPTO PTAB Decisions) would be crucial for understanding the specific reasons for denial and informing any future strategy.

Inventors

• Eric Furfine (Regeneron Pharmaceuticals Inc)
• Daniel Dix (Regeneron Pharmaceuticals Inc)
• Kenneth Graham (Regeneron Pharmaceuticals Inc)
• Kelly Frye (Regeneron Pharmaceuticals Inc)

Original assignee

Regeneron Pharmaceuticals Inc.
Regeneron Pharmaceuticals Inc. is a biotechnology company that invents, develops, manufactures, and commercializes medicines. They ship products embodying the claims, specifically Eylea (aflibercept), which is a VEGF antagonist formulation for intravitreal administration. Regeneron is currently an operating company.

Assignment timeline

• 2020-07-08 (executed) / recorded 2020-07-08 — Reel 051939/0634
  • Conveyance: Assignment
  • Assignor: DIX, DANIEL; GRAHAM, KENNETH S.; FURFINE, ERIC; FRYE, KELLY
  • Assignee: REGENERON PHARMACEUTICALS, INC.
  • Correspondent: REGENERON PHARMACEUTICALS, INC., 777 OLD SAW MILL RIVER ROAD, TARRYTOWN, NEW YORK, UNITED STATES, 10591-6707.
  • Context: Internal reorg (assignment from individual inventors to the corporate entity).

Timeline diagram

timeline
    title Ownership of US 11084865
    2006 : Priority date
    2020 : Application filed
    2020 : Inventors assigned to Regeneron
    2021 : Issued

NPE / troll-pattern signals

1. Shell-entity transfer — not present
2. Known asserter in the chain — not present
3. Repeat correspondent across the chain — not present
4. Cascading transfers — not present
5. Pre-litigation transfer — not present
6. Bankruptcy fire-sale — not present
7. Privateering — not present
8. Defensive aggregator (anti-NPE) — not present

Verdict

Operating-company assertion
The patent was assigned from the individual inventors to Regeneron Pharmaceuticals Inc., a known operating company that commercializes products embodying the claims. There are no other assignments on record, indicating the patent remains with the original operating company.
USPTO Assignment Center search for US11084865

US Patent 11084865, titled "VEGF antagonist formulations suitable for intravitreal administration," was issued on August 10, 2021, from an application filed on January 10, 2020, by Regeneron Pharmaceuticals Inc.. The patent describes ophthalmic formulations of a vascular endothelial growth factor (VEGF)-specific fusion protein antagonist, including stable liquid and lyophilizable formulations, particularly those with the protein antagonist having the amino acid sequence of SEQ ID NO:4.

Anticipation under 35 U.S.C. § 102 means that a claimed invention is not novel because every element of the claim is disclosed, either expressly or inherently, in a single prior art reference.

Here are some of the most relevant prior art documents cited in US11084865:

• US 7,608,261 B2

  • Full Citation: US 7,608,261 B2 to Regeneron Pharmaceuticals, Inc., titled "VEGF antagonist formulations suitable for intravitreal administration".
  • Publication/Filing Date: Issued on October 27, 2009, from an application filed on June 14, 2007. This patent is a direct antecedent to US11084865, claiming benefit from the same provisional application filed June 16, 2006.
  • Brief Description: This patent also describes VEGF antagonist formulations for intravitreal administration, including liquid and lyophilized forms of the VEGF trap protein (SEQ ID NO:4). It covers formulations with similar components (VEGF antagonist, buffer, organic co-solvent, tonicity agent, stabilizing agent) and pH ranges as US11084865.
  • Potential Anticipated Claim(s): Given that US11084865 is a continuation of a lineage tracing back to US 7,608,261, and both share a common priority date and subject matter, US 7,608,261 potentially anticipates many, if not all, of the claims of US11084865, particularly those directed to the general composition of stable liquid or lyophilized VEGF antagonist formulations for intravitreal administration and the specific components and concentrations. For example, claims 1 and 26 of US11084865, which broadly cover a vial or pre-filled syringe comprising an ophthalmic formulation with a VEGF antagonist, organic co-solvent, buffer, and stabilizing agent, where the VEGF antagonist is glycosylated and comprises amino acids 27-457 of SEQ ID NO:4 and exhibits specified stability, are likely anticipated by the earlier patent's disclosures of similar formulations and stability. Further, claims like 51, describing a specific formulation with 40 mg/ml of the VEGF antagonist, polysorbate, sodium phosphate buffer, and sucrose, might also be anticipated if this specific combination falls within the scope of the formulations taught in US 7,608,261.

• US 6,436,897 B1

  • Full Citation: US 6,436,897 B1 to Regeneron Pharmaceuticals, Inc., titled "Lyophilized and reconstituted protein formulations".
  • Publication/Filing Date: Issued on August 20, 2002, from an application filed on March 27, 2001.
  • Brief Description: This patent generally describes lyophilized protein formulations that are resistant to degradation, aggregation, oxidation, and other degenerative processes. It highlights the use of lyophilization for long-term storage of proteins.
  • Potential Anticipated Claim(s): US 6,436,897 B1 broadly teaches the concept of lyophilizing proteins to achieve stability. While it does not specifically mention VEGF antagonists or intravitreal administration, it lays the groundwork for stable lyophilized protein formulations. Therefore, this patent could potentially anticipate aspects of claims in US11084865 related to the lyophilizable nature of the formulation and the stability achieved through lyophilization (e.g., claims 1, 26, and 51 regarding the native conformation of the protein after storage, if the method of achieving that stability is generally disclosed in the earlier patent). Specifically, the general principle that "the lyophilized protein is substantially resistant to degradation, aggregation, oxidation, and other degenerative processes while in the freeze-dried state" as mentioned in US11084865, references US 6,436,897.

• Holash et al. (2002) Proc. Natl. Acad. Sci. USA 99:11393-8

  • Full Citation: Holash et al. (2002) "VEGF-Trap: A VEGF blocker with potent antitumor effects," Proc. Natl. Acad. Sci. USA 99:11393-8.
  • Publication/Filing Date: Published in 2002.
  • Brief Description: This publication describes the "VEGF trap," a soluble VEGF-specific fusion protein antagonist. The VEGF trap described is the fusion protein that is the active ingredient in the formulations of US11084865.
  • Potential Anticipated Claim(s): This publication likely anticipates the core component of the claimed formulations—the VEGF antagonist fusion protein itself, particularly the general concept of a "VEGF trap" and potentially the specific sequence (or highly similar sequences) of SEQ ID NO:4, which is explicitly mentioned as the preferred VEGF antagonist in US11084865. Therefore, claims 1, 26, and 51, to the extent they rely on the novelty of the VEGF antagonist per se, could be anticipated.

• Kim et al. (2002) Proc. Natl. Acad. Sci. USA 99:11399-404

  • Full Citation: Kim et al. (2002) "The VEGF Trap: A novel antiangiogenic agent that inhibits ocular neovascularization," Proc. Natl. Acad. Sci. USA 99:11399-404.
  • Publication/Filing Date: Published in 2002.
  • Brief Description: This publication, similar to Holash et al., also describes the VEGF trap and its use as an antiangiogenic agent, specifically mentioning its ability to inhibit ocular neovascularization.
  • Potential Anticipated Claim(s): Similar to Holash et al., this reference could anticipate the VEGF antagonist fusion protein (SEQ ID NO:4) and its application in treating ocular conditions. The application of VEGF antagonists for ocular conditions directly relates to the "ophthalmic formulation suitable for intravitreal administration" language in the claims. Therefore, claims 1, 26, and 51, if they depend on the novelty of the VEGF antagonist or its general use for ocular indications, could be anticipated.

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.