Last summer, we reported on the UPC's first ever revocation decision, UPC_1/2023, which concluded that Amgen's patent (EP 3666797) lacked an inventive step. Although the UPC's Central Division revoked EP 3666797, during recent EPO opposition proceedings, the same patent was found inventive. This highlights the possibility of divergent outcomes for inventive step assessments at the UPC and the EPO, at least at first instance.
Background
The decision of the Opposition Division is the latest development in the long-standing global dispute between Amgen and Sanofi/Regeneron in the anti-PCSK9 antibody space. Sanofi and Regeneron market the drug Praluent®, while Amgen market the drug Repatha®.
PCSK9 triggers the degradation of low-density lipoprotein receptors (LDLRs) on liver cells, which means these cells have reduced capacity to remove LDL cholesterol from the blood. By binding to PCSK9 and blocking the interaction with LDLR, anti-PCSK9 antibodies assist in lowering blood LDL concentrations, thereby reducing the amount of cholesterol circulating in the bloodstream.
Amgen's patent EP 3666797 ('797) is part of a large family comprising 13 divisional applications. The original parent patent granted with a main claim directed to an antibody binding to human PCSK9 that competes with specific reference antibodies and having neutralising activity. This product claim was invalidated for lack of inventive step by the EPO during appeal proceedings and the patent was ultimately maintained with sequence-based claims directed to specific antibodies.
In the '797 patent, claim 1 refers to a monoclonal antibody or an antigen-binding fragment thereof for use in:
- treating or preventing hypercholesterolemia or an atherosclerotic disease related to elevated serum cholesterol levels; or
- reducing the risk of a recurrent cardiovascular event related to elevated serum cholesterol levels.
The antibody or antigen-binding fragment in claim 1 is also functionally defined as binding to the catalytic domain of a PCSK9 protein of the amino acid sequence of SEQ ID NO: 1, and preventing or reducing the binding of PCSK9 to LDLR.
Assessment of inventive step
In its revocation decision, the UPC Central Division followed the framework set out by the Court of Appeal in UPC_CoA_335/2023 (NanoString/10x Genomics) for assessing inventive step. Whilst this framework does not strictly follow the EPO's problem-solution approach, there are significant similarities between both approaches. Indeed, in this case both the UPC's Central Division and the EPO Opposition Division agreed that Lagace et al., 2006 ("Lagace") was the starting point for assessing inventive step. Lagace is a journal article that describes the role of secreted PCSK9 in regulating the level of LDLR. The Central Division and the Opposition Division in fact both noted the same passage in Lagace which suggested that antibodies developed to block the interaction between PCSK9 and LDLR could be explored for the treatment of hypercholesterolemia.
Based on this passage of Lagace, the Central Division and the Opposition Division both took the position that the skilled person would have been motivated to pursue antibodies to block the PCSK9-LDLR interaction.
However, the Opposition Division noted that Lagace failed to actually disclose any antibodies that could block the interaction between PCSK9 and LDLR for use in the treatment of hypercholesterolemia, and so a question in the context of the claimed medical use remained as to whether there was a "reasonable expectation of success" for the skilled person to arrive at the claimed medical use on the basis of Lagace.
Assessment of reasonable expectation of success for the claimed medical use as part of the determination of inventive step appears to be the main point of divergence between the reasoning of the Central Division and that of the Opposition Division.
A reasonable expectation of success?
In their assessment of inventive step, the UPC's Central Division followed the well-established position at the EPO that the development of antibodies to a known target is considered routine in the absence of any technical difficulties in producing such antibodies. In response to Amgen's arguments as to why the skilled person would not have had a reasonable expectation of success in relation to the therapeutic use, the Central Division concluded that the various alleged unknowns and uncertainties were not clearly voiced in the prior art, and in any event did not outweigh the clear incentive provided by Lagace.
The Opposition Division agreed that the skilled person would have been able to find antibodies falling within the scope of claim 1. However, the Opposition Division openly disagreed with the Central Division's dismissal of considerations relating to therapeutic efficacy. The Opposition Division held that there was a lack of direct evidence in Lagace that blocking the binding of PCSK9 to LDLR would be effective in treating hypercholesterolemia. The indirect evidence in Lagace was not considered enough to make a therapeutic effect plausible. At best, Lagace was considered to provide a hope to succeed.
The Opposition Division also stated that a reasonable expectation of success (or lack thereof) plays a "crucial role" in assessing whether a medical use claim has an inventive step. The Opposition Division took the position that Lagace provided a suggestion to use antibodies that block the interaction of PCSK9 with LDLR in the treatment of hypercholesterolemia, but did not provide the skilled person with a reasonable expectation that using such antibodies would be therapeutically effective. In the EPO proceedings, Amgen argued that a particular prior art document (D24) showed that targeting PCSK9 would not have an effect on LDLR at physiological PCSK9 concentrations. The Opposition Division considered that D24 taught away from the invention and in fact provided evidence that "casts serious doubts" that direct inhibition of the binding of PCSK9 to LDLR would result in a successful therapy under physiological conditions.
In their reasoned decision, the Opposition Division also commented specifically on the UPC's decision, disagreeing with the UPC's conclusion that a reasonable expectation of success is not required where there is an incentive in the prior art and where the next steps would not amount to more than routine experimentation.
The Opposition Division did though note that the reasoning provided by the Central Division's decision might be applicable for a claim to the antibody per se.
Final points
The facts of this case demonstrate how relatively minor differences in the test used to assess inventive step can, in some instances, lead to divergence in outcomes at the EPO and the UPC. This case also shows that an EPO Opposition Division will not necessarily follow the judgement of a UPC Court of First Instance on the same patent.
It should of course be noted that the Central Division and Opposition Division decisions are both first instance decisions, and so there is still a chance that the final outcomes in regards to inventive step could align on appeal. Indeed, Amgen have appealed the Central Division's decision, with a stay granted on the parallel infringement proceedings until the revocation action has been finally decided by the UPC Court of Appeal. Meanwhile, at the EPO, Sanofi and Regeneron have appealed the Opposition Division's decision and the Technical Board of Appeal has already summoned the parties to oral proceedings in April 2026.
Possible differences in approach between the UPC and EPO in consideration of "reasonable expectation of success" when determining inventive step could be particularly relevant for inventions in the biotechnology and life sciences sector. It remains to be seen if the divergent UPC and EPO assessments of inventive step for the present patent may be indicative of a more general difference in approach.
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