The complexities of patenting new uses for known medical substances were recently considered by the Düsseldorf Local Division in the UPC’s first decision on second medical use claims. The case of Sanofi v Amgen (UPC_CFI_505/2024) specifically addressed the novelty and infringement standards applicable to second medical use claims. The case is part of the long-running dispute between Sanofi and Amgen relating to PCSK9 antibodies across multiple jurisdictions and involving multiple patent families.
Case Background
The dispute in this case centred on Regeneron’s anti-PCSK9 antibody second medical use patent EP 3536712 B1, exclusively licensed to Sanofi. The patent claimed a pharmaceutical composition comprising a PCSK9 inhibitor for use in reducing lipoprotein(a) (Lp(a)) levels in a specific patient population at risk of cardiovascular or thrombotic occlusive disease. Amgen markets the PCSK9 inhibitor Repatha (evolocumab) for lowering LDL-C. Sanofi alleged that the sale of Repatha infringed their patent.
The value of second medical use patents
The most valuable patent protection for a drug product is generally considered to be the composition of matter (CoM) patent that protects the drug substance. The CoM patent is considered the most likely to prevent generic or biosimilar competition and to be most robust to challenge. For this reason, the CoM patent is often used to establish the loss of exclusivity date. Additional, later filed, patents may provide upside beyond the loss of exclusivity date, particularly those covering dose and formulation aspects and second medical use cases. Of these, second medical use patent often provide the longest upside, as they are the last to be filed, but also present unique enforcement challenges.
Validity of second medical use patents
From the validity perspective, second medical use patents may face inventive step attacks that require the patentee to demonstrate that the new use was not obvious for the skilled person to try in view of the drugs known efficacy and safety in other diseases. The greatest chance of success in upholding a second medical use patent is when the targeted disease is particularly difficult-to-treat such that there is a low expectation of success that any therapeutic will be effective in clinical trials. According to recent EPO Board of Appeal decisions on this legal standard, a hope to succeed should not be confused with an expectation of success.
Enforcement of second medical use patents
Enforcement difficulties further complicate second medical use patents. The protection of second medical use patents, by definition, is limited to a particular therapeutic use. It is therefore possible in many jurisdictions for competitors to avoid claims of infringement by carefully crafting their labelling to exclude the patented indication whilst still making the drug available for other uses. The value of second medical use patents is therefore determined by how much of the market it can protect. A second medical use patent that only covers a use that makes up a low percentage of overall marketed sales may be of limited value if the main therapeutic use of the drug is off patent.
“Skinny labelling” presents a significant challenge to innovator companies seeking to enforce second medical use patents. Generic manufacturers may strategically omit patented indications from their product labels while still marketing the same active ingredient for non-patented uses. This practice creates a complex enforcement landscape where the burden falls on the patent holder to prove that the generic product is knowingly being prescribed and dispensed for the patented indication despite its absence from the label. Courts across jurisdictions have struggled to establish consistent standards for addressing indirect infringement in skinny label cases, with some requiring evidence of active encouragement toward the patented use, while others focus on whether the generic manufacturer knew or should have known their product would be used for the patented indication regardless of labelling. This regulatory and legal grey area often allows generics to effectively circumvent second medical use patents, undermining the exclusivity innovators hoped to maintain through indication-specific patent protection.
UPC considers the novelty of second medical use claims
From the legal perspective, second medical use claims occupy a special position in patent law as purpose limited product claims established under Articles 54(4) and 54(5) EPC. As summarised by Court in this case, these provisions create a “notional novelty” by virtue of a legal fiction for substances or compositions for a specific new use that were already part of the prior art. As the Court explained in Headnote 3: “The sole reason why such claims can still be patented is the novelty (and inventiveness) of the new use.” Thus, for the Court, “the relevant question for assessing the novelty of second medical use claims is whether the therapeutic use as claimed is directly and unambiguously disclosed in the prior art” (para. 123).
In this case, Amgen argued that the patent in question lacked novelty since the prior art disclosed PCSK9 inhibitory antibodies for treating patients at risk of cardiovascular disease by reducing LDL-C. Amgen argued that lowering Lp(a) was an inherent effect of these antibodies, and therefore prior use in patients with CV disease to reduced LDL-C levels should be considered novelty destroying. However, the Court rejected this argument as “legally flawed” in that it ignored the notional novelty of second medical use claims as afforded by Article 54(5) EPC (para. 123). Importantly, the Court interpreted the claimed use of reducing Lp(a) levels “as a therapeutic intervention of its own right (albeit with the ultimate or overarching goal of treating or reducing the risk of cardiovascular disorders)” (para. 103). The Court found that no prior art document directly and unambiguously disclosed the use of an anti-PCSK9 antibody for lowering Lp(a) levels in the claimed patient population.
The Court’s interpretation of the law with respect to the novelty of second medical use claims is in line with the EPO approach. In the recent decision T 0558/20, for example, the Board of Appeal rejected the argument that there should be a higher bar for the novelty of second medical use features. The usual novelty test of whether the prior art included a clear and unambiguous disclosure of the use should be applied. The Local Division’s reasoning is also worth comparing to the recent decision in T 0209/22, in which the Board of Appeal similarly concluded that a novelty-destroying disclosure of a second medical use requires a clear and unambiguous disclosure in the prior art.
UPC considers the inventive step of second medical use claims
For inventive step, the Court focussed on the question of whether a skilled person would have been motivated to implement the claimed solution as their next step in developing the prior art. The Court approached inventive step from a “could-versus-would” perspective. As explained in Headnote 4: “A motivation to implement may be absent or negated if the skilled person is faced with many uncertainties or expected difficulties. If there is no motivation at all or a negated motivation, the subject matter of the claim is not obvious and involves an inventive step.”
The Court considered several potential starting points for inventive step analysis, including a prior art disclosure which evaluated treatment modalities to decrease elevated Lp(a) levels. Whilst the prior art mentioned that PCSK9 inhibitors “may also decrease Lp(a) concentration”, the Court found that the skilled person would not have been motivated to implement this as their next step. On the contrary, the Court identified several factors in the prior art that would have negated the skilled person’s motivation to use PCSK9 inhibitors for reducing Lp(a) levels, including the fact that Lp(a) was not thought to be cleared via the LDL receptor (LDLR), which is the target of PCSK9 inhibitors.
The Court concluded that these negations would have prevented the skilled person from being motivated to use PCSK9 inhibitors specifically for reducing Lp(a) levels, rendering the claimed invention non-obvious.
UPC considers the alleged infringement of second medical use claims
Despite upholding the validity of the patent, the Court went on to find no infringement by Amgen’s Repatha. The Court suggested some principles for assessing infringement of second medical use claims, requiring evidence that 1) the product is offered or placed on the market in such a way that it leads or may lead to the claimed therapeutic use, and 2) the alleged infringer knows or reasonably should have known this.
The Summary of Product Characteristics (SmPC) for Repatha mentioned that reduced Lp(a) in clinical trials. However, the Court found that this was merely “the objective report of an outcome effect of a clinical study which is comparable to background information.” Critically for the Court, Repatha was not specifically approved for lowering Lp(a) levels, but rather for lowering LDL-C and mixed hyperlipidaemia. The Court found that Sanofi failed to demonstrate that physicians would prescribe Repatha specifically for reducing Lp(a) levels. For the Court, the competing expert opinions submitted by the parties, did not establish a likelihood of such use. The Court also noted that any off-label prescription would face regulatory hurdles, including “the special need for medical justification and the risk of a refusal of reimbursement or recourse by the health insurance funds.”
The Court summarised the key principles for infringement of second medical use claims in Headnote 2: “For a finding of infringement of a second medical use claim, the alleged infringer must offer or place the medical product on the market in such way that it leads or may lead to the claimed therapeutic use of which the alleged infringer knows or reasonably should have known that it does” (emphasis added).
The Court was thus content to ignore both the inherent Lp(a) lowering effect of prior art PCSK9 inhibitory antibodies for the purposes of novelty assessment and the inherent Lp(a) lowering effect of the alleged infringing product (as acknowledged in the products own label) for the purposes of the infringement analysis. As the Court concluded with respect to infringement, any bonus effect of Repatha in reducing Lp(a) levels when used to reduce LDL-C levels was not relevant.
Parallel EPO proceedings
The patent in this case has also been opposed at the EPO. A key arguments at opposition was whether the claimed Lp(a) lowering effect should be considered a new therapeutic use or merely represented a further mechanism underlying already known treatment of LDL-C lowering. The Opposition Division rejected the opposition and upheld the patent, finding that Lp(a) lowering was a new treatment effect, and rejected the novelty attack based on the prior art use of PCSK9 inhibitory antibodies to lower LDL-C. So far, the EPO and UPC appear aligned on this case. Amgen has filed an appeal.
Final thoughts
The present case is just one amongst many in the long-running PCSK9 antibody patent dispute between Amgen and Sanofi, which reached all the way to the Supreme Court in the US. The US Supreme Court decision and other cases between Amgen and Sanofi before the UPC have related to the novelty and inventive step standard for antibody inventions. The US Supreme Court found that a broadly defined genus of antibodies in the claim lacked enablement, whilst the UPC found that a specified antibody sequence was merely the result of routine experimentation. The present decision is not a major win for either party in the dispute, given that the patent was found valid but not infringed, and that the patent also only relates to a section of the market for PCSK9 inhibitors.
It is always challenging to predict the outcome of cases involving second medical use claims, as evidence and expert opinions are usually highly influential to the outcome. However, if the approach of the Local Division in this case is followed by the rest of the UPC it could create a hurdle for patentees seeking to enforce second medical use claims, particularly when the claimed use is not an approved indication for the drug. In this case even the explicit mention of a claimed effect in the product information in this case was insufficient to establish infringement without evidence of actual or likely off-label prescribing practices. As this is one of the first UPC decisions addressing second medical use claims in depth, it could be influential in shaping the approach of the UPC and national courts to these types of claims.
We await to see if the decision of the Local Division will be appealed.
