Amgen, Inc v Sanofi-Aventis Deutschland GmbH, Sanofi-Aventis Groupe S.A.Sanofi Winthrop Industrie S.A. & Regeneron Pharmaceuticals, Inc, UPC Court of Appeal, 25 November 2025, Appeal Nos. UPC_CoA_528/2024 & UPC_CoA_529/2024
The second panel of the UPC Court of Appeal (CoA) has held that Amgen’s patent EP 3 666 797 for PCSK9-inhibitor antibodies used for treating high cholesterol levels (hypercholesterolemia) is valid, overturning the earlier decision of the Munich Central Division (CD). The court reached the same decision as the EPO Opposition Division, although based on different reasoning. Offering more flexibility than the EPO’s strict problem-solution approach (PSA), the CoA emphasised a ‘holistic’ approach to obviousness, with the claimed solution deemed obvious when, at the relevant date, the skilled person wishing to solve the objective problem, and starting from a realistic starting point, would (not just could) have arrived at the claimed solution.
This decision was handed down on the same day as another CoA decision, in the Edwards v Meril medical device (prosthetic heart valve) dispute, in which the CoA’s first panel adopted the same guidelines. The present case, is, however, particularly relevant for the pharmaceutical and biotech sector because it considers the role of reasonable expectation of success in determining obviousness of medical use claims.
The decision also addresses added matter and sufficiency, but this article will focus only on the primary areas of disagreement with the Munich CD, namely construction of second medical use claims and inventive step.
Background
The global dispute between the parties concerns two products – Amgen’s evolocumab (brand name Repatha), and Sanofi’s and Regeneron’s alirocumab (Praluent). Both products are therapeutic monoclonal antibodies used to treat and prevent ailments caused by hypercholesterolemia, especially when patients do not respond adequately to changes in diet and treatment with statins. The antibodies target an enzyme called proprotein convertase subtilisin/kexin type 9 (PCSK9), which mediates the levels of lipoproteins, particularly low-density lipoproteins (LDL), in the body. By binding to PCSK9 and thereby blocking the PCSK9-LDL receptor (LDLR) interaction, these antibodies assist in lowering blood LDL concentrations.
The patent in issue is EP 3 666 797 B1. It relates to antigen binding proteins that bind to PCSK9 and methods of using and making the antigen binding proteins. The EPO Opposition Division upheld the patent as granted, although an appeal is pending before the Technical Board of Appeal.
The dispute led to many UPC firsts. The parties both filed on 1 June 2023, the first day of UPC operations, with Sanofi filing a revocation action in the Munich CD, and, on the same day, Amgen issuing an infringement action against Sanofi and Regeneron before the Munich Local Division (LD). Regeneron’s counterclaim for revocation was subsequently referred to the Munich CD and combined with Sanofi’s revocation action, resulting in a stay of the infringement action. On 16 July 2024, in the UPC’s first substantive revocation decision, the Munich CD found that the patent lacked an inventive step and revoked the patent in its entirety across all of the 17 UPC contracting member states in which it is in force.
The appeal focused on Amgen’s arguments that the Munich CD had applied the wrong approach to inventive step assessment (with Sanofi and Regeneron maintaining their arguments on inventive step, added matter and sufficiency).
Decision
The CoA allowed the appeal, and importantly set out a clear approach to inventive step assessment.
Claim construction
The CoA provided useful guidance on the construction of second medical use claims, such as claim 1 of the patent which provides: “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 for use in reducing the risk of a recurrent cardiovascular event related to elevated serum cholesterol levels; wherein the monoclonal antibody or the antigen-binding fragment thereof binds to the catalytic domain of a PCSK9 protein of the amino acid sequence of SEQ ID NO: 1, and prevents or reduces the binding of PCSK9 to LDLR.”
The Munich CD found that the skilled person would understand that the claimed treatment is not limited to a particular lowering of cholesterol levels as long as there is some measurable reduction in vivo and the therapy is safe. It adopted a broad interpretation of claim 1, finding that the claimed use encompasses the administration of the claimed antibodies together with at least one other cholesterol reducing agent, notably statins, as provided for by claims 6 and 7. It said that the skilled person would understand this to mean that a very small cholesterol reducing effect caused by the claimed antibodies can be “therapeutically effective”.
The CoA, however, took a stricter approach than the Munich CD to construing such claims, which played a critical role in determining obviousness (see below). For second medical use claims, the CoA confirmed that it is an inherent feature that the claimed product must be “therapeutically effective” in a meaningful way, by causing a noticeable improvement of the medical condition. In this case therefore, claim 1 required no set threshold for the level of cholesterol reduction (or binding of PCSK to LDLR), but it must bring about a therapeutic effect in a meaningful way, leading to a noticeable improvement in the patient’s condition, rather than just “any” lowering of cholesterol levels.
Further, the CoA found that the role of dependant claims in helping to interpret independent claims is limited to where they add an additional features which provides a more specific description of the independent claim. In this case, in contrast to the Munich CD, the CoA found that claim 1 had to be interpreted on the basis of its own features because the additional features of claims 6 and 7 may lead to a different interpretation of the level of therapeutic effect of the claimed antibodies. As such, the claimed antibodies must be therapeutically effective on their own.
As will be discussed below, the CoA’s narrower interpretation meant that the skilled person would need a reasonable expectation that the PCSK9-inhibitor antibodies would lead to a meaningful therapeutic effect.
Inventive step: the guidelines
At first instance, the Munich CD’s concluded that the patent was invalid due to lack of inventive step. The precise nature of the UPC’s approach to obviousness has led to much discussion following some differences in opinion of the local divisions. It was therefore perhaps timely that the CoA’s first decision on the merits led to clarity on this issue, with the court setting out the UPC’s framework for assessing inventive step (which, it said, could already be derived from its decision in 10x Genomics v Nanostring (UPC_CoA_335/2023 as rectified)). As will be seen below, while this more ‘holistic’ approach offers more flexibility that the EPO’s strict PSA, the court noted that all methods (including those adopted by European national courts), should, if applied correctly, lead to the same conclusion, perhaps mindful of the overarching desire to harmonise with the EPO.
The EPO’s PSA is well-known, with three established steps:
1. Identify the closest piece of prior art;
2. Identify the objective problem the patent is aiming to solve by comparing the relevant claim with the closest prior art; and
3. Determine whether the claimed solution would have been obvious to the skilled person starting from the prior art and having knowledge of the objective problem.
This is applied by courts in some European countries including France and The Netherlands, but contrasts with the more ‘holistic’ approach adopted in some European jurisdictions including Germany and the UK where the objective problem (in Germany) or the inventive concept (in the UK) is determined as a first step before being compared with the prior art.
The UPC’s approach can be framed as three questions, which appears closer to the holistic approach used by some of the national courts, as follows:
1. Identification of the objective problem
The first step is to identify the objective problem of the invention. The EPO requires this to be identified by comparing the relevant claim to the closest piece of prior art, which requires an assessment of the individual features of the claim. However, the UPC takes a more holistic approach, requiring that the objective problem is established from the perspective of the skilled person, with their CGK, as at the application or priority date, by determining what the invention adds to the state of the art, looking at the claim as a whole (rather than individual features), the technical concept and the skilled person’s understanding the technical effects achieved from the claimed invention. Importantly, however, the CoA emphasised that the objective problem should not contain pointers to the claimed solution to avoid hindsight.
2. Identify a realistic starting point
The second step is to identify a realistic starting point in the state of the art in the relevant field of technology. This of course, begs the question, what is a realistic starting point? According to the CoA, a starting point is realistic if its teaching would have been of interest to a skilled person who, at the relevant date, wishes to solve the objective problem. While this, in reality, is often likely to be the ‘closest prior art’ required for the EPO’s PSA, there is an element of flexibility built into this test which is positive for challengers, with the court emphasising that there can be more than one realistic starting point, thus distinguishing this holistic approach from the EPO’s strict PSA. However, the claimed invention must be inventive starting from each of them, so perhaps, in reality, there is less flexibility compared with the EPO’s PSA than might be initially envisaged.
3. Would the skilled person have arrived at the claimed solution?
Finally, the CoA determined that the claimed solution would be obvious when at the relevant date the skilled person, starting from a realistic starting point in the state of the art in the relevant field of technology, wishing to solve the objective problem, would (not just could) have arrived at the claimed solution. An invention would be obvious if the skilled person, who is uninventive and unimaginative, would take the next step prompted by a pointer or as a matter of routine, and arrive at the claimed invention.
In patents which relate to an antibody invention, such as the present case, this third step would be modified, requiring the skilled person, when prompted by a pointer or as a matter of routine, to take the next step to arrive at the claimed invention with a reasonable expectation of success.
Reasonable expectation of success implies the ability of the skilled person to predict rationally, on the basis of scientific appraisal of the known facts before a research project was started, the successful conclusion of that project within acceptable time limits. It may depend on multiple factors, including whether or not the technical field was unexplored, practical or technical difficulties, and the strength of any pointer in the direction of the claimed solution. However, the CoA highlighted that the fact that other teams may have been working on the same project at the same time did not necessarily imply a reasonable expectation of success, rather that it was an interesting research area with a “mere hope to succeed”.
Application to the facts
In applying these principles to the claims in issue, the CoA overturned the decision of the Munich CD, and concluded that the patent is valid.
The CoA firstly identified the objective problem as being to provide a therapeutically effective treatment or prevention of hypercholesterolemia or atherosclerotic disease or other conditions related to elevated serum cholesterol levels. It noted, however, that the provision of an antibody or the use of PCSK9 as a target to regulate LDLR levels should not be included in the objective problem because this points to the solution provided by the invention and would therefore introduce an element of hindsight in the inventive step assessment.
Second, the court agreed with the Munich CD that a realistic starting point for assessing inventive step was a publication entitled Lagace, “Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and livers of parabiotic mice”, which it said is directed towards a similar purpose to the invention and would have been of interest to the skilled person working in the relevant field i.e. to treat hypercholesterolemia and other conditions related to elevated serum cholesterol levels. Lagace clearly presented PCKS9 as a target of interest to the skilled person who wishes to develop a treatment for hypercholesterolemia and related diseases, as confirmed by expert evidence presented by both parties (for parallel Australian proceedings).
As such, the court agreed with the Munich CD that, at the priority date, the skilled person, starting from Lagace, would have had a strong incentive to block PCSK9 activity to reduce LDL levels in order to be able to treat hypercholesterolemia and similar diseases.
However, moving on to the third step, the CoA found that the skilled person would not have considered, as a next step, developing antibodies targeting PCSK9 with a reasonable expectation of success.
The skilled person would have understood that the prospect of developing antibodies to block PCSK9:LDLR binding and leading to a reduction in cholesterol levels, and its role as an effective treatment for hypercholesterolemia, would have depended on resolving several uncertainties. This included the assumption that PCSK9 acted through both an intracellular and extracellular pathway and the relative contributions of each, whether the extracellular pathway by which PCSK9 functioned would be sufficient to offer a therapeutically effective treatment (in contrast to the findings of the Munich CD which considered this as not relevant), and the need for and difficulty of further experiments (identified in Lagace) to clarify the contribution of this pathway. Experiments also showed weaker PCSK9:LDLR binding extracellularly (i.e. in plasma), raising doubts about whether the required level of binding would occur in vivo to have a therapeutic effect.
The CoA therefore concluded that the scientific research in the field of the mechanism of action of PCSK9, specifically the contribution of the extracellular pathway, had, at the priority date, not reached the stage where the skilled person could have reasonably predicted that an antibody that blocks the interaction between PCSK9 and LDLR would be therapeutically effective in treating or preventing the diseases referred to in claim 1 or of reducing the risk associated with such diseases.
As such, at the priority date the skilled person could not have reasonably predicted whether the antibody route would lead to a therapeutically effective treatment (i.e. a meaningful reduction of cholesterol levels rather than just any lowering), as required by claim 1 as construed (see above), for hypercholesterolemia or related diseases. While they could as a next step have developed antibodies binding to PCSK9 within the scope of the claim with the hope of finding a therapeutically effective treatment for hypercholesterolemia, it could not be said that they would have done so with a reasonable expectation of success.
The findings in relation to a reasonable expectation of success distinguish the CoA’s ruling from that of the Munich CD. As such, the CoA overturned the earlier decision and concluded that the patent is valid.
Conclusion
This decision aligns with the approach taken in the Edwards v Meril decision, handed down on the same day, demonstrating a clear coordination between the two UPC CoA panels to set out a framework for the UPC’s approach to inventive step, clearly intended to be applied by the lower courts going forward. However, a more thorough understanding as to how it applies to different claim forms, and different factual scenarios, will come from decisions of the lower courts, which will ultimately provide practitioners with guidance as to how to address the obviousness question. While the holistic approach builds in flexibility to enable the court to take a different view on the facts to the EPO, the CoA’s comments clearly indicate that it anticipates that, in most cases, outcomes will be aligned.
Certainly, this CoA decision brings the UPC back in alignment with the outcome at the EPO Opposition Division, although an appeal is pending, the outcome of which will be interesting and will inevitably lead to further discussion in this long running dispute.
