Regeneron v. Celltrion et al., decided March 5, 2025

Case Name and Citation: REGENERON PHARMACEUTICALS, INC. v. MYLAN PHARMACEUTICALS INC., AMGEN USA, INC., BIOCON BIOLOGICS INC., SAMSUNG BIOEPIS CO., LTD., FORMYCON AG, AMGEN INC., Defendants CELLTRION, INC., Defendant-Appellant, United States Court of Appeals for the Federal Circuit, Nos. 2024-2058, 2024-2147, Decided March 5, 2025 (Nonprecedential).

Subject: Appeal of a preliminary injunction barring Celltrion from launching its biosimilar version of Regeneron's EYLEA® (aflibercept) based on infringement of U.S. Patent No. 11,084,865 (the "'865 patent").

Key Issue: Did the District Court err in granting a preliminary injunction against Celltrion, specifically regarding whether Celltrion raised a "substantial question of invalidity" of the ’865 patent based on obviousness-type double patenting (ODP) in light of U.S. Patent No. 9,340,594 (the "'594 patent")?

Holding: The Federal Circuit affirmed the District Court's grant of the preliminary injunction, finding that Celltrion did not raise a substantial question of invalidity of the ’865 patent.

Main Themes and Important Ideas/Facts:

1.    Affirmation Based on Prior Decisions: The Federal Circuit explicitly states that this decision builds upon and incorporates the analyses from two previous appeals involving similar preliminary injunctions against other biosimilar manufacturers (Samsung Bioepis and Formycon) concerning the same Regeneron patents. The court notes a "substantial overlap in facts and district court analyses in this appeal and the SB and Formycon appeals" and therefore avoids repeating previously addressed information.

2.    Personal Jurisdiction and Nexus Conceded: Celltrion initially challenged the District Court's personal jurisdiction over it and the nexus between alleged infringement and irreparable harm. However, during oral argument, Celltrion "conceded that the SB Opinion controls on this issue" and "conceded that the nexus issue is also controlled by the SB Opinion." As a result, the Federal Circuit upheld the District Court's findings on these matters, stating that Celltrion's conduct satisfies the minimum-contacts requirement for personal jurisdiction in West Virginia and intends to distribute its biosimilar nationwide, including West Virginia. The court also rejected Celltrion's nexus argument as it presented no new arguments.

3.    Focus on Obviousness-Type Double Patenting (ODP): The central remaining issue on appeal was Celltrion's argument that the District Court erred in finding no substantial question of invalidity of the ’865 patent due to ODP over claim 5 of the ’594 patent. Celltrion specifically challenged the District Court's determination that the differences between the claims constituted patentable distinctions.

4.    Key Claim Differences Identified by the District Court: The District Court identified three key differences between the asserted claims of the ’865 patent and claim 5 of the ’594 patent:

·       The stability requirement of "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" (in the ’865 patent).

·       The requirement that aflibercept is glycosylated (in the ’865 patent).

·       The use of a vial (potentially implied in the ’594 patent, contrasted with a pre-filled syringe).

a.    Federal Circuit's Focus on the Stability Limitation: The Federal Circuit ultimately based its affirmance on the District Court's finding that the stability limitation in the ’865 patent is patentably distinct from the "stable for at least 4 months" requirement in claim 5 of the ’594 patent. The court stated, "it suffices for us to conclude that one claim difference—the stability limitation—renders claim 5 of the ’594 patent patentably distinct from the asserted claims of the ’865 patent."

b.    Rejection of Celltrion's Claim Construction Arguments on Stability: Celltrion argued that the District Court incorrectly construed "stable" in the ’594 patent and that the 98% native conformation limitation was inherent in the ’594 patent. The Federal Circuit rejected these arguments:

·       c. Construction of "stable": The court agreed with the District Court that "'stable' has a broader meaning than the particular SEC measurements of aggregation and threshold levels (98%) to which Celltrion attempts to limit the term." The court highlighted that the ’594 patent specification describes multiple aspects and methods of determining stability beyond just the 98% native conformation measured by SEC. The District Court observed that the ’594 patent even preferred "'at least 90%' non-aggregated protein is preferred, thereby confirming that levels of non-aggregation below 98% in the patent’s formulations are not only permissible, but desirable."

·       d. Inherency: The court agreed with the District Court that the 98% native conformation was not necessarily present in the compositions of claim 5 of the ’594 patent. The District Court correctly stated, "That the practice of ’594 claim 5 sometimes results in 98% native conformation is insufficient; inherency requires that the 98% native conformation limitation be present necessarily, not just possibly or probably."

·       The Federal Circuit also rejected Celltrion's argument that the "'at least 98%'" limitation in the ’865 patent merely defines a rate of aggregation, stating that "Celltrion’s argument contradicts the plain claim language, which states that ‘at least 98% of the VEGF antagonist is present in native conformation following storage . . . for two months’ as measured by SEC."

5.    Obviousness of the Stability Limitation Not Established: The Federal Circuit found no clear error in the District Court's conclusion that the 98% native conformation limitation would not have been obvious to a person of ordinary skill in the art based on claim 5 of the ’594 patent. The District Court relied on expert testimony indicating a lack of motivation to achieve and a reasonable expectation of achieving that specific stability level.

6.    Glycosylation Argument Not Decided: While the District Court found that the glycosylation requirement in the ’865 patent provided another distinction (noting that aflibercept has "at least thirty possible glycosylated forms of aflibercept . . . in addition to the nonglycosylated form," thus not a "very small genus"), the Federal Circuit did not reach a decision on this argument because the stability limitation was sufficient to affirm the preliminary injunction. Regeneron's counsel conceded during oral argument that if the stability finding was affirmed, the appeal would end.

Quote of Importance:

• Regarding the overlap with prior decisions: "Because of the substantial overlap in facts and district court analyses in this appeal and the SB and Formycon appeals, this opinion does not repeat those facts or analyses that were already addressed in the SB and Formycon Opin-ions."

• Regarding the inherency argument: "That the practice of ’594 claim 5 sometimes results in 98% native conformation is insufficient; inherency requires that the 98% native conformation limitation be present necessarily, not just possibly or probably."

Regarding the sufficiency of one patentable distinction: "As we ex-plained in the SB Opinion, it suffices for us to conclude that one claim difference—the stability limitation—renders claim 5 of the ’594 patent patentably distinct from the as-serted claims of the ’865 patent."

Conclusion: The Federal Circuit affirmed the preliminary injunction against Celltrion, primarily based on the finding that Celltrion failed to raise a substantial question of invalidity of the ’865 patent due to obviousness-type double patenting. The court determined that the stability limitation recited in the ’865 patent claims is patentably distinct from the claims of the ’594 patent. This decision reinforces the earlier preliminary injunctions granted against other biosimilar manufacturers seeking to market versions of EYLEA®, highlighting the strength of Regeneron's intellectual property position at this preliminary stage.