Regeneron v. Mylan, decided March 14, 2025

Case Name and Citation: REGENERON PHARMACEUTICALS, INC. v. MYLAN PHARMACEUTICALS INC., decided March 14, 2025 (United States Court of Appeals for the Federal Circuit, Appeal No. 2024-2351)

Date of Briefing: October 26, 2023

Issue: Did the District Court for the Northern District of West Virginia err in denying Regeneron's motion for a preliminary injunction against Amgen for alleged infringement of U.S. Patent No. 11,084,865 (the "'865 patent")? The central question revolves around the claim construction of the '865 patent, specifically whether the claimed "VEGF antagonist" and "buffer" must be separate and distinct components in the pharmaceutical formulation.

Regeneron's Patent and Product:

• The '865 patent claims pharmaceutical formulations of aflibercept, a fusion protein (VEGF antagonist) used in Regeneron's biologic product EYLEA®.

• EYLEA® is used to treat angiogenic eye disorders and contains 40 mg/ml aflibercept, a buffer (sodium phosphate), and other excipients at a pH of 6.2.

• Claim 1 of the '865 patent, considered representative, recites a vial comprising an ophthalmic formulation with: "a vascular endothelial growth factor (VEGF) antagonist, an organic co-solvent, a buffer, and a stabilizing agent."

• The patent claims that at least 98% of the VEGF antagonist remains in its native conformation after storage.

• Amgen's Biosimilar (Pavblu) and Alleged Infringement:

• Amgen filed an abbreviated Biologics License Application (aBLA) for ABP 938, a biosimilar of EYLEA® now branded as "Pavblu," which was subsequently approved.

• A key difference between Amgen's formulation and EYLEA® is that ABP 938 does not contain a separate buffer component. Amgen formulated aflibercept in a way that the protein itself provides sufficient buffering capacity ("self-buffering").

• Regeneron sued Amgen alleging infringement of claims 2, 3, 27, and 28 of the '865 patent based on Amgen's aBLA filing.
  

The Central Claim Construction Dispute:

• The core of the dispute is whether the '865 patent claims require the "VEGF antagonist" (aflibercept) and the "buffer" to be separate and distinct components of the formulation.

• Regeneron argued that the aflibercept itself could also satisfy the "buffer" limitation in the claims.

• Amgen argued that the separate listing of "VEGF antagonist" and "a buffer" in the claims implies they must be distinct components, and since ABP 938 lacks a separate buffer, it does not infringe.
  

Application of the Becton Precedent:

• The District Court relied on the Federal Circuit's precedent in Becton, Dickinson & Co. v. Tyco Healthcare Grp., LP, which states, "[t]here can be no literal infringement where a claim requires two separate structures and one such structure is missing from an accused [product]."

• Becton also established the principle that "[w]here a claim lists elements separately, the clear implication of the claim language is that those elements are distinct components of the patented invention."

• The Federal Circuit in this appeal affirmed the District Court's application of Becton, finding that claim 1 of the '865 patent plainly recites a formulation comprising four separately listed components, including "a VEGF antagonist" and "a buffer," thus triggering the implication of distinctness.
  

Regeneron's Arguments Against Becton's Applicability:

• Regeneron argued that the District Court erred by not starting with the ordinary meaning of "buffer" and by failing to consider a prior District Court construction of "buffer" in separate litigation against Formycon.

• In the Formycon Decision, the District Court construed "buffer" to include "proteins like aflibercept." Regeneron argued this prior construction made the Becton implication inapplicable.

• The Federal Circuit rejected this, stating that the claim construction inquiry under Becton (distinct components) is different from the scope of "buffer" (what substances can function as a buffer). The court noted that the Formycon Decision did not address the distinct component issue raised by Amgen.
  

Overcoming the Implication of Separateness:

• The Federal Circuit considered whether the intrinsic and extrinsic evidence overcame the Becton implication.

• Intrinsic Evidence (Claims and Specification):The court found that the claims themselves reinforce the separateness by listing the VEGF antagonist and buffer with "different concentrations and different units of measurement" (e.g., mg/ml for aflibercept and mM for the buffer).

• The specification consistently describes the "VEGF antagonist" and the "buffer" as "separate and distinct components" throughout its description and examples.

• The specification explains that a "VEGF antagonist" blocks VEGF and that a "buffering agent, may be, for example, phosphate buffer."

• The specification language, such as "comprises a pharmaceutically effective amount of the VEGF antagonist . . . [and] can also comprise one or more pharmaceutically acceptable carriers, buffers..." suggests these are distinct elements.

• All eight example formulations and twenty-two embodiments in the specification describe aflibercept plus a separate buffer.

• The specification does not provide any examples of a single component performing both the VEGF antagonist and buffer functions.

• Extrinsic Evidence:Regeneron argued that extrinsic evidence showed proteins containing histidine (like aflibercept) were known buffers in the art.

• The District Court considered the extrinsic evidence but found it did not demonstrate that aflibercept could function as a buffer in a pharmaceutical formulation as of the '865 patent's filing date.

• The Federal Circuit saw no clear error in this finding, noting that intrinsic evidence is primary and that the District Court reasonably determined a cited publication (Gokarn) might even suggest self-buffering proteins were not well-known prior to the patent.
  

Likelihood of Success on the Merits:

• Because the Federal Circuit affirmed the District Court's claim construction requiring a separate buffer, and Amgen's ABP 938 does not contain one, the court concluded that "there is at least a substantial question of noninfringement."

• Therefore, Regeneron failed to establish a likelihood of success on the merits of its infringement claim, and the denial of the preliminary injunction was not an abuse of discretion.
  

Waiver of Remand for Damages:

• Amgen waived its right to a remand for calculation of damages related to the temporary injunction during oral argument.
  

Conclusion of the Federal Circuit:

The Federal Circuit affirmed the District Court's decision denying Regeneron's motion for a preliminary injunction against Amgen. The court agreed with the District Court's claim construction that the '865 patent requires the "VEGF antagonist" and "buffer" to be separate and distinct components, based on the plain language of the claims and consistent support from the patent specification. Because Amgen's biosimilar ABP 938 does not contain a separate buffer, Regeneron did not demonstrate a likelihood of success on its infringement claim.

Implications:

This ruling is a significant win for Amgen, potentially allowing its biosimilar of EYLEA® (Pavblu) to remain on the market without facing a preliminary injunction based on the '865 patent. The case highlights the importance of clear and consistent claim drafting in patents, particularly when listing multiple components in a formulation. The Federal Circuit's emphasis on the Becton precedent reinforces the idea that separately recited claim elements are presumed to be distinct unless the patent specification clearly indicates otherwise. This decision may also impact ongoing or future patent litigation involving biosimilars and the interpretation of pharmaceutical formulation claims.