Originally posted on IPKat.
Empagliflozin (Jardiance) is approved in the US for reducing the risk of cardiovascular death in adults with type 2 diabetes (T2D) and established cardiovascular disease, and in Europe for reducing the risk of cardiovascular death and hospitalisation for heart failure in adults with heart failure. The recent decision in T 0251/25 nonetheless found Boehringer Ingelheim’s European patent for the cardioprotective use of empagliflozin to be insufficiently disclosed. The application as filed contained biomarker data from rats and from a small study in type 1 diabetic patients. The Board of Appeal found that neither the application nor the common general knowledge provided a credible link between these biomarkers and the claimed reduction in cardiovascular death and heart failure. The sufficiency of a second medical use claim is assessed on what the skilled person would have believed at the filing date, and not on whether the drug was subsequently shown to work.
Legal background: Credibility of a therapeutic effect
For a second medical use claim, the therapeutic effect is considered a functional technical feature of the claim. According to the established case law, the application as filed must therefore make it “credible” that the known compound is suitable for the claimed therapeutic application, unless this is already part of the common general knowledge. The EBA confirmed in G2/21 that this is a requirement that cannot be remedied by post-published evidence (r. 77).
However, the evidence standard for credibility at the EPO is generally considered to be relatively low. Clinical data are not always required, and in vitro data, animal data or a mechanistic explanation may be enough. Previous decisions have, for example, found a patent for the anti-cancer use of “fish juice” sufficiently disclosed on the basis of cell line and mouse data, and a patent for low-dose IL-2 in lupus sufficiently disclosed without any lupus data, based on a shared Treg mechanism. An Opponent attacking sufficiency must also normally raise serious doubts substantiated by verifiable facts (T 19/90). In T 0251/25, the Board of Appeal had to consider the situation where such doubts came from the common general knowledge (CGK) of the skilled person.
Case background: Empagliflozin and cardiovascular outcomes
The patent in question was EP 2981255, owned by Boehringer Ingelheim. Empagliflozin is an SGLT2 inhibitor, an antidiabetic that lowers blood glucose by increasing its excretion in the urine. Empagliflozin has been before the Boards of Appeal before for plausibility issues, see T 1437/21 on inventive step. In this case, claim 1 of the main request (and as granted) read:
“Empagliflozin for use in a method for preventing, reducing the risk of or delaying the occurrence of a cardiovascular event in a patient with type 2 or type 1 diabetes mellitus or with pre-diabetes comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient wherein said cardiovascular event is selected from cardiovascular death and heart failure requiring hospitalization.”
Cardiovascular disease is a well-known complication of diabetes. At the filing date, however, no antidiabetic drug had been shown to reduce cardiovascular mortality. The experience with rosiglitazone (Avandia) was fresh in the memory of the field. Rosiglitazone had been approved on the basis of its glucose-lowering effect and a perceived potential for cardiovascular benefit evidenced by improvements in surrogate markers. A 2007 meta-analysis then found that rosiglitazone significantly increased the risk of myocardial infarction and was associated with an increase in the risk of cardiovascular death of borderline significance. Rosiglitazone was ultimately suspended across Europe in 2010, the EMA having concluded that its benefits no longer outweighed its risks. In response to the failure of rosiglitazone, both the FDA and the EMA issued guidance, the FDA’s dating from December 2008, that raised the threshold for the approval of new antidiabetic drugs by requiring direct clinical evidence of cardiovascular safety.
The experimental data in the application relied on for the claimed cardioprotective effect showed that empagliflozin counteracted endothelial dysfunction and oxidative stress in a rat model of diabetic cardiomyopathy. It was further shown that empagliflozin reduced arterial stiffness in human patients with type 1 diabetes. However, the application did not contain any data on cardiovascular outcomes.
The patent was opposed by ten Opponents, including Teva. The Opposition Division maintained the patent on the basis of auxiliary request 1, finding that the data in examples, read together with a review article in the prior art, rendered the therapeutic effect credible, and that the Opponents had not substantiated serious doubts with verifiable facts. Nine of the Opponents appealed. Dr Reddy’s intervened in the appeal after being sued for infringement by Boehringer in the UK.
A missing mechanistic link
The Board of Appeal agreed with the Patentee that clinical data is not always required to support a therapeutic effect. The question then became whether it was then credible from the biomarker data in the application that improving these biomarkers would reduce cardiovascular death and heart failure. Importantly, the Board of Appeal found that “[n]othing can be inferred from the examples themselves about how these biomarkers are linked to the claimed therapeutic application” (r. 5.14.1). The description did state that endothelial dysfunction was associated with atherosclerosis and had prognostic significance for vascular events. The Board of Appeal noted that “no evidence for this postulated mechanistic link, such as experimental data or a reference to supporting scientific literature, is provided in the application as filed” (r. 5.14.4).
The Board of Appeal then considered whether the relevant therapeutic link was part of the CGK. Of the many documents relied on by the Patentee, only two review articles were accepted as representative of the CGK, and in both of these, the Board of Appeal considered, “the connection remains speculative and is not backed up by pertinent data” (r. 5.14.6). The remaining documents were original research articles, a type of document the Board of Appeal did not regard as representing the CGK (r. 5.14.7). The Board of Appeal concluded that “the missing mechanistic link appears to have been part of the common general knowledge as an unconfirmed hypothesis only […] Without supporting evidence, these speculative considerations cannot close the gap in relation to the link between the experimental data and the claimed therapeutic application” (r. 5.14.10)
Rosiglitazone and the regulatory guidance
The Opponents had provided evidence that rosiglitazone, like empagliflozin, improved endothelial function, reduced oxidative stress and reduced arterial stiffness, both in rats and in humans. Importantly, however, rosiglitazone had subsequently been found to increase cardiovascular risk. The Opponents’ evidence was therefore considered to weigh against there being a direct and unequivocal relationship between the effects reported in the application as filed and the claimed therapeutic effect (r. 5.16.7).
The Board of Appeal also found that guidance issued by regulatory agencies would have been part of the CGK of the skilled person in the pharmaceutical field (r. 5.17.3). It thus followed for the Board of Appeal that any additional cardioprotective benefit could not be conclusively shown by a positive effect on such biomarkers either.
Finally, given that the claimed therapeutic effect was not rendered credible by the application as filed and the common general knowledge, the Board of Appeal found that Patentee could not rely on the post-published outcome study and marketing authorisation, “as this would go beyond corroborating an established finding” (r. 5.22). The main request was therefore found to lack sufficiency. The decision under appeal was set aside and the patent revoked.
Burden of proof: Convincing arguments alone may be enough
At the EPO, each party bears the burden of proof for the facts it alleges, and in opposition proceedings an Opponent invoking Article 100(b) EPC initially bears the burden of proving that the patent does not disclose the invention in a manner sufficiently clear and complete for it to be carried out. For the objection to succeed, the Opponent has to show serious doubts substantiated by verifiable facts (r. 5.7, citing T 19/90, r. 3.3).
The Board of Appeal in this case also tied the burden of proof to the content of the application itself. Reading G2/21, r. 77, the Board of Appeal considered that where there is no conclusive experimental data in the application as filed, a different proof of the claimed therapeutic effect has to be provided by the applicant in the application as filed, for example by way of a theoretical or mechanistic explanation or by relying on the CGK (r. 5.7, citing T 853/22, r. 23). From this the Board of Appeal drew the consequence that “[t]he type and quality of this disclosure in the patent application determines what type and quality of submissions is required from an opponent. Depending on the circumstances, an opponent may discharge its burden of establishing insufficiency merely by submitting convincing arguments alone” (r. 5.7, citing T 63/06, r. 3.3.2 and T 1558/11, r. 2.7.1).
In other words, the thinner the evidential basis on which the Patentee’s case for credibility rests, the less an Opponent needs to bring in order to defeat it. Where credibility is said to follow from a mechanistic hypothesis rather than from data, reasoned argument that the hypothesis does not hold may be enough, and the Opponent need not come armed with experiments of its own.
Analysis
The decision in T 0251/25 is broadly in line with the existing case law that the application as filed must render the therapeutic effect credible, and that post-published evidence can only be used to corroborate what is already in the application. The decision is consistent with other recent decisions such as T 0883/23, in which a study protocol without results was found insufficient at the priority date, and T 0709/23, in which a Patentee’s own post-published data undermined the credibility of its antibody claims.
It is nonetheless somewhat uncomfortable that a patent for a therapeutic effect that has since been demonstrated in a large outcome trial, and that is now standard of care, has been revoked for insufficiency. In that trial, empagliflozin reduced the relative risk of cardiovascular death by 38% and of hospitalisation for heart failure by 35% in patients with type 2 diabetes and established cardiovascular disease, aligning with both limbs of claim 1. Those reductions were notably described at the time as “surprising“, which it could possibly support the Board of Appeal’s view that the effect would not have been credible from biomarker data alone at the filing date. Importantly, the Board of Appeal did not find that biomarker data can never support a cardiovascular outcome claim. The Board of Appeal instead found that the CGK at the time undermined the inference, and that most importantly, the application did nothing to address this.
Author: Rose Hughes
Rose is a biotech and pharmaceutical patent specialist with over a decade of experience in intellectual property. Rose is a patent attorney at Evolve, where she leverages our unique fractional in-house model to provide clients with deep patent law expertise combined with the strategic commercial oversight typically associated with senior in-house counsel.
With a PhD in Immunology from UCL, Rose applies her technical background to complex innovations in biologics, cell and gene therapies, and the rapidly emerging field of AI-assisted drug development. Previously, Rose held the role of Director, Patents at AstraZeneca, where she was responsible for global IP portfolios and IP strategy at every stage of the pharmaceutical pipeline, from platform development and on-market commercialization to SPCs and patent term extensions.
A recognized thought leader in the field, Rose has been a regular contributor to IPKat since 2018, offering practical insights into European patent law developments. She is also a frequent speaker on the epi podcast, a guest lecturer for the Brunel University IP law Postgrad Certificate, and a contributing author to published books A User’s Guide to Intellectual Property in Life Sciences (2021) and Developments and Directions in Intellectual Property Law (2023).
