Interestingly, whilst the Munich Central Division revoked EP 3666797B across the UPC member states in which it was in force for lack of inventive step, the EPO Opposition Division rejected the opposition.

Background and technology

Sanofi’s patent EP 3666797B granted with claim 1 directed 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 monoclonal antibody or antigen-binding fragment thereof was 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 low density lipoprotein receptor (LDLR).

The patent explains that PCSK9 is involved in regulating the levels of the LDLR, which is in turn important in the removal of low density lipoprotein cholesterol from the bloodstream into liver cells. Thus, the claimed antibodies have a cholesterol-lowering effect.

Inventive step assessment

The Central Division did not strictly follow the EPO’s problem-solution approach in the assessment of inventive step and instead referred to the approach used in NanoString Technologies Inc v 10x Genomics Inc (UPC_CoA_335/2023).

Although the approach applied by the Central Division possesses some similarities with the EPO’s problem-solution approach applied by the Opposition Division, there are also some key differences, particularly in the selection of the “realistic starting point” as opposed to “closest prior art” and formulation of the “underlying” technical problem rather than the “objective” technical problem. We consider these differences in more detail in our article on inventive step at the UPC (Inventive Step at the UPC: Two years on).

Despite these differences, both divisions considered Lagace (cited as C3 in the UPC proceedings and D5 in the EPO proceedings) as the starting point for the assessment of inventive step. This research article described the role of secreted PCSK9 in regulating LDLR protein levels in heptaocytes.

In fact, the divisions focused upon the same paragraph of Lagace: “If PCSK9 functions as a secreted factor as suggested by the current data, then additional approaches to neutralize its activity, including the development of antibodies to block its interaction with the LDLR or inhibitors to block its action in plasma, can be explored for the treatment of hypercholesterolemia.”

From this teaching it was held that the skilled person would have an incentive [Central Division] or motivation [Opposition Division] to pursue antibodies blocking the interaction, and only routine experimentation would be required to develop the antibodies. Therefore, both decisions were in line with established EPO jurisprudence on antibodies, where generating an antibody to a known target is considered routine work for the skilled person.

Similarly, both divisions considered that a difference with the claimed invention was that Lagace did not disclose any antibodies blocking the interaction between PCSK9 and LDLR for use in the treatment of hypercholesterolemia.

This brings us to the question of reasonable expectation of success.

Diverging approaches to reasonable expectation of success

Amgen provided extensive arguments in both sets of proceedings as to why the skilled person would lack a reasonable expectation of success.

The Central Division opened its discussion of reasonable expectation of success with the following comment: “The Central Division can leave undecided the question of whether or not under the circumstances of the present case, where there is an incentive in the prior art towards the claimed subject matter and the next steps would not amount to more than routine experimentation for the skilled person, a reasonable expectation of success is required to come to the conclusion that the claimed subject matter lacks inventive step”.

This comment could be considered surprising in the context of a second medical use claim, in which a claimed therapeutic effect is considered a functional technical feature of the claim under established EPO practice.

Indeed, the EPO’s Opposition Division stated in its decision that it “strongly disagrees” with the UPC court on the point quoted above. The Opposition Division went on to comment that: “While the reasoning provided by the UPC Court might be applicable for a product claim, the OD considers that in the case of a medical use claim, reasonable expectation of success plays a crucial role.”

Despite the initial comment provided by the Central Division that the requirement for a reasonable expectation of success could be left undecided, the Division goes on to provide its reasoning as to why the arguments presented by Amgen “must fail”. In particular, the Central Division held that Amgen did not demonstrate that the skilled person would have had any “serious doubts” that a therapeutic antibody could be developed. Serious doubts were defined as: “doubts of such a nature that these would have dissuaded the skilled person from pursuing an antibody approach to block the interaction…as suggested by Lagace”.

Accordingly, the Central Division considered that the skilled person would possess a reasonable expectation of success, such that the claimed subject matter lacked an inventive step.

By contrast, the Opposition Division held that: “While D5 [Lagace] provides a suggestion to use antibodies that block the interaction of PCSK9 to LDLR in the treatment of hypercholesterolemia, it does not provide the skilled person with a reasonable expectation of success that using said antibodies would be indeed therapeutically effective”.

Furthermore, Amgen presented an additional argument for lack of reasonable expectation of success in the EPO proceedings, based upon figure 6d of the prior art document Qian (cited as D24 and in the UPC proceedings as C6). Amgen argued that this figure shows a trend that (at physiologically relevant levels, 500 ng/ml) PCSK9 does not have an effect on cell surface LDLR levels. Based upon this evidence, the Opposition Division held that the skilled person would not have reasonably expected that an anti-PCSK9 antibody that prevents or reduces the binding of PCSK9 to LDLR could have a therapeutic effect.

Accordingly, the Opposition Division considered that the skilled person would lack a reasonable expectation of success based upon Lagace alone or Lagace in combination with Qian, such that the claimed-subject matter possessed an inventive step.

Final comments

These proceedings provide an indication that the EPO’s Opposition Division will not necessarily be swayed by a parallel UPC ruling by a Court of First Instance, although it remains to be seen whether the Opposition Division would diverge, and so openly, from a UPC Court of Appeal decision.

In its approach to reasonable expectation of success, the Central Division appeared to diverge from the established EPO practice in the context of second medical use claims. In particular, the Central Division appeared to set a lower bar for reasonable expectation of success for second medical use claims and placed the onus on the patentee to prove that a skilled person would not have expected the suggested antibody approach to succeed. This might be contrasted with established EPO practice for second medical use claims, in which a reasonable expectation of success plays a crucial role and the patentee must show that it was not obvious to try the suggested approach with a reasonable expectation of success.

Thus, these proceedings evidence that even small changes in the assessment of issues such as inventive step could result in significant divergence between the case law at the EPO and UPC.

Both of these decisions have been appealed, with the UPC Court of Appeal ruling expected to issue first this summer and oral proceedings before the EPO Board of Appeal already scheduled for April 2026. It will be interesting to see whether, and how, the Court of Appeal and Boards of Appeal address the diverging approaches to reasonable expectation of success in the context of second medical use claims in their respective decisions.

Any clarity on the assessment of inventive step for second medical use claims provided by the UPC Court of Appeal would be welcomed by users of the UPC system. We will be keeping a close eye, in particular, on any indications from the UPC Court of Appeal that the standard for assessing reasonable expectation of success in the context of second medical use claims will be lower in the UPC courts than under established EPO practice.

Case details at a glance

Decision level: Munich Central Division
Case: UPC_CFI_1/2023
Parties: Sanofi-Aventis Deutschland GmbH et al v Amgen Inc
Date: 16 July 2024
Decision: dycip.com/sanofi-amgen-jul24