Unified Patent Court issues first ruling on infringement of ‘second medical use’ patents

The decision of the UPC’s Düsseldorf Local Division (LD) relates to a long-running, multi-jurisdictional dispute over cholesterol-lowering medications: evolocumab, which is sold by Amgen under the brand name Repatha; and Sanofi’s and Regeneron’s alirocumab, sold under the brand name Praluent.

The parties were involved in filing the very first dispute before the UPC, and Amgen’s European patent No. EP 3 666 797 was revoked by the Munich Central Division in the UPC’s first substantive revocation decision. 

The present dispute relates to European patent No. EP 3 536 712 (‘EP712’), which is owned by Regeneron and of which Sanofi is the exclusive licensee. The patent is in force in Belgium, France, Germany, Italy and the Netherlands. Although it is the subject of pending European Patent Office opposition proceedings, a preliminary opinion that the patent is likely to be valid was issued in August 2024.

Sanofi and Regeneron issued infringement proceedings against Amgen before the Düsseldorf LD, and Amgen counterclaimed for revocation in this high-stakes dispute, with the value of the infringement action set at €20 million and the revocation action at €25m.

Both Rapetha and Praluent are monoclonal antibodies used to treat and prevent ailments caused by high cholesterol levels, especially when patients do not respond adequately to changes in diet and treatment with statins. They 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 and various studies have suggested they have positive effects on treating cardiovascular disorders.

EP712 relates to the administration of PCSK9 inhibitors to reduce the levels of serum lipoprotein (a) (‘Lp(a)’) in a particular patient group. Elevated serum Lp(a) has been shown in various studies to correlate with a variety of atherosclerotic and thrombotic disorders, and therefore therapeutic reduction of serum Lp(a) levels has been suggested as a means for treating or reducing the risk of cardiovascular disorders. 

The patent at the centre of the dispute before the Düsseldorf LD was a ‘second medical use’ patent. Such patents are typically used to protect the use of a known compound or substance for a new medical purpose, and can therefore be highly valuable for the repurposing of known medicines for new diseases. 

In its decision, the Düsseldorf LD noted that while the UPC’s legal framework for the assessment of (direct) patent infringement is set out in article 25 of the UPC Agreement (UPCA) and article 69 of the European Patent Convention (EPC), there are no statutory provisions regarding the infringement of second medical use claims and, at present, there is no established, relevant UPC case law.

As a result, the Düsseldorf LD became the first UPC division to set out its stall on the approach to infringement of such claims. It said that there is a two-stage process for a finding of infringement of a second medical use patent claim.  First, the alleged infringer must offer or place the medicinal product on the market in such a way that it leads to, or may lead to, the claimed therapeutic use according to the patent – referred to as the “objective” part of the test. Second, it must be shown that the alleged infringer knows, or should reasonably have known, of such use – the “subjective” part of the test.

The court emphasised that these requirements cannot be defined in an abstract manner, but instead require an analysis of all relevant facts and circumstances of the case. Relevant factors that may be taken into consideration in this analysis include, but are not limited to, the extent or significance of the allegedly infringing use; the relevant market, including what is customary on that market; and the market share of the claimed use compared to other uses. The court also said that the actions the alleged infringer has taken to influence the respective market should be taken into consideration, either “positively” – effectively  encouraging the patented use – or “negatively”, by taking measures to prevent the product from being used for patented use.

The court also said that the manufacturing of the product, in particular the package insert and Summary of Product Characteristics (“SmPC”), can be important, but are not always the only decisive factor to be taken into consideration when assessing whether a defendant is ultimately liable for patent infringement. The extent to which the alleged infringer knows or should have known that the product will be used for the claimed purpose is relevant.

Charlotte Weekes, a life sciences patent litigation expert at Pinsent Masons, said: “In setting out the test, the court noted that as an objective element, ‘there must be either a prescription in order to lower Lp(a) levels, or there must be at least circumstances showing that such a use may be expected to occur’”.

“This is useful guidance as to what is required in order to meet the first stage of the test. It is not surprising that the test also has a subjective element and it remains to be seen how this knowledge aspect will be evidenced in second medical use infringement cases,” she said.

“It is also very useful that the UPC has indicated it will be interested in actions an alleged infringer has taken to influence the market – both positively to use in an infringing way or negatively to prevent such use – but it appears it was unnecessary to get into this in this case.”

On the facts, the Düsseldorf LD found the patent to be valid, and dismissed the infringement action. 

It was undisputed that Amgen’s Repatha used a PCSK9 inhibitory antibody, but the court found that Sanofi and Regeneron failed to meet the first part of the two-stage test. Specifically, they did not show that the placement of Amgen’s product on the market led, or even may lead, to the claimed use, of lowering Lp(a) levels and treating hypercholesterolemia in the relevant patient group. The court also found that Sanofi and Regeneron had failed to show that any of Amgen’s marketing efforts were aimed at ‘selling’ the drug for the claimed use. Repatha is also not approved for the claimed use as a treatment to lower Lp(a) levels, but is instead approved for lowering LDL-C and mixed hyperlipodemia. The court went on to note that Sanofi and Regeneron had failed to provide any evidence to support the likelihood that physicians will prescribe Amgen’s product for use in reducing Lp(a) levels, noting in particular that the expert evidence did not support such allegations.

James Marshall, an expert in patent litigation at Pinsent Masons, said: “The case provides important focus on what is likely required in terms of evidence to establish infringement in the UPC of a second medical use patent, particularly when the infringing use is ‘off label’.” 
“It should be remembered too, when preparing cases, the UPC will not usually have the benefit of the type of extensive cross-examination of experts typical in the UK on important issues where their opinions conflict, as they did here.”

“In this case, the evidence of the Sanofi and Regeneron’s expert that it was expected that elevated Lp(a) level is often also taken into consideration when deciding to prescribe a PCSK9 inhibitor for LDL-C level treatment, i.e. concomitantly, and this was in fact their own practice, assuming the patient will benefit from the reduction in Lp(a), were considered insufficient to establish a sufficient likelihood of physicians actually doing so, in the face of the quoted written evidence of two experts for Amgen to the effect that they and their colleagues, when prescribing a PCSK9 inhibitor for lowering LDL, were in fact not also aiming to lower Lp(a) in those patients where it was elevated.”

Sarah Taylor, an expert in patent litigation at Pinsent Masons, said: “The UPC’s approach to infringement of a second medical use claim is interesting. While it contains some similarities to the tests deployed by some national courts, it is notable that the Düsseldorf LD has not directly applied the approach of the German national courts. Almost two years after the UPC opened, the early myth that the local divisions of the UPC would generally follow the existing jurisprudence of their respective European national courts has largely been dispelled, with the court developing its own approach to such matters.” 

“However, although the decision offers useful learnings on how the UPC may deal with second medical use infringement actions, it is only one decision of one local division. An appeal is highly likely, and the Court of Appeal’s insight would be welcome,” she said.

Life sciences companies should pay particular attention to the court’s findings, said Charlotte Weekes: “As a first decision on infringement of second medical use claims, this suggests the UPC may take a similar approach to that which some national courts have taken where this issue has arisen. Evidence will be key and the mere fact a product could have the same use or result as that claimed will not be enough alone to show infringement”.

“Potential infringers will need to think about additional steps they can take to reduce the risk of their product being used in an infringing way, in addition to carving out a patented therapeutic indication from the SmPC. They’ll also be tested on what they know or should reasonably know about how medical professionals throughout the UPC territory will use the product,” she said.