A significant divergence has emerged between the European Patent Office (EPO) and the Unified Patent Court (UPC) regarding the validity of Amgen's PCSK9 antibody patent, with the two tribunals reaching opposite conclusions despite evaluating the same patent and grounds of challenge.
The EPO Opposition Division recently upheld Amgen's patent EP 3666797, finding it inventive, while the UPC Central Division had previously revoked the same patent for lacking inventive step. This marks the first major case demonstrating how relatively minor differences in inventive step assessment can lead to divergent outcomes between these two key European patent forums.
Patent Background and Clinical Significance
The disputed patent is part of the ongoing global litigation between Amgen and Sanofi/Regeneron in the anti-PCSK9 antibody space. Amgen markets Repatha®, while Sanofi and Regeneron market Praluent®, both PCSK9 inhibitors that have revolutionized cardiovascular treatment.
PCSK9 triggers the degradation of low-density lipoprotein receptors (LDLRs) on liver cells, reducing their capacity to remove LDL cholesterol from the blood. By binding to PCSK9 and blocking its interaction with LDLR, anti-PCSK9 antibodies help lower blood LDL concentrations, thereby reducing circulating cholesterol levels.
The patent's main claim covers a monoclonal antibody or antigen-binding fragment for treating or preventing hypercholesterolemia or atherosclerotic disease related to elevated serum cholesterol levels, or reducing the risk of recurrent cardiovascular events. The antibody is functionally defined as binding to the catalytic domain of PCSK9 and preventing or reducing PCSK9's binding to LDLR.
Areas of Agreement
Both the EPO and UPC reached similar conclusions on several validity challenges. They agreed that the patent did not extend beyond its original filing, finding that the focus on binding the PCSK9 catalytic domain was supported by disclosures in the priority documents. Neither tribunal found fatal flaws in the patent's instructions for producing and screening appropriate antibodies, accepting that techniques from immunization to phage display provided adequate guidance.
Both bodies also agreed on novelty once the patent's early priority date was secured, and both identified the same starting point for inventive step assessment: the Lagace et al. 2006 journal article describing PCSK9's role in regulating LDLR levels. Both noted the same passage in Lagace suggesting that antibodies blocking the PCSK9-LDLR interaction could be explored for treating hypercholesterolemia.
The Critical Divergence
The fundamental disagreement centered on the assessment of "reasonable expectation of success" for the claimed medical use. Both tribunals agreed that skilled persons would have been motivated to pursue antibodies blocking the PCSK9-LDLR interaction, but they differed significantly on whether success was reasonably expected.
The UPC Central Division followed the established EPO position that developing antibodies to a known target is routine absent technical difficulties in production. The Central Division concluded that various alleged unknowns and uncertainties were not clearly voiced in the prior art and did not outweigh the clear incentive provided by Lagace.
In contrast, the EPO Opposition Division openly disagreed with the Central Division's dismissal of therapeutic efficacy considerations. The Opposition Division held that Lagace lacked direct evidence that blocking PCSK9-LDLR binding would effectively treat hypercholesterolemia, with indirect evidence insufficient to make therapeutic effect plausible. At best, Lagace provided only "hope to succeed."
EPO's Emphasis on Therapeutic Uncertainty
The Opposition Division took the position that reasonable expectation of success plays a "crucial role" in assessing medical use claims' inventive step. While Lagace suggested using PCSK9-blocking antibodies for hypercholesterolemia treatment, it did not provide reasonable expectation of therapeutic effectiveness.
The EPO also considered prior art document D24, which Amgen argued showed that targeting PCSK9 would not affect LDLR at physiological concentrations. The Opposition Division found that D24 "taught away" from the invention and "cast serious doubts" that direct inhibition of PCSK9-LDLR binding would result in successful therapy under physiological conditions.
The Opposition Division specifically disagreed with the UPC's conclusion that reasonable expectation of success is not required where prior art provides incentive and next steps involve only routine experimentation, though it noted this reasoning might apply to antibody per se claims.
Implications for Biotechnology Patents
This case demonstrates how different interpretations of "obvious to try" versus "reasonable expectation of success" can yield opposite outcomes. The EPO placed weight on uncertainties regarding pH conditions, specificity, and in vivo efficacy that made success less predictable, while the UPC concluded these were routine challenges not constituting barriers to obviousness.
The divergence may be particularly relevant for biotechnology and life sciences inventions, where questions of plausibility and therapeutic efficacy are central to patent validity assessments.
Ongoing Appeals
Both decisions represent first-instance rulings, leaving room for alignment on appeal. Amgen has appealed the Central Division's decision, with parallel infringement proceedings stayed until final UPC Court of Appeal resolution. At the EPO, Sanofi and Regeneron have appealed the Opposition Division's decision, with Technical Board of Appeal oral proceedings scheduled for April 2026.
The case underscores that strategic patent planning must account for each jurisdiction's approach to evidence evaluation and nuanced plausibility questions, as seemingly minor variations in inventive step interpretation can result in dramatically different outcomes for high-stakes biotechnology patents.
