Mechanistic insights supporting the sufficiency and inventive step of a therapeutic use (without clinical data) (T 1601/22)

At the EPO, it is perfectly possible for a therapeutic invention to survive without clinical data. The recent decision in T 1601/22 confirmed this sometimes surprisingly low bar for sufficiency in Europe for therapeutic invention. The case was however also an illustration that whilst the sufficiency bar may be low, the hurdle for proving that a new dose is non-obvious remains high. Success in defending a second medical use invention in Europe generally requires the patentee to tell an inventive story that clearly articulates the technical challenges overcome and the rationale behind specific selections. The evidence standard may be low, but it must be the right type of evidence. 

Legal background: Inventive step and sufficiency

Reading up on immunological mechanisms

Demonstrating that a new dose is non-obvious can be a challenge. The EPO often views the selection and optimisation of a dose as a routine process for the skilled person. To succeed, a Patentee must clearly identify a surprising technical effect associated with the dose that counteracts the narrative that finding a safe and effective amount is merely routine. This often involves showing that the prior art depicted a landscape of complexity and trial-and-error rather than a clear path to success.

Conversely, the sufficiency bar for second medical use claims in Europe can often seem surprisingly low. Clinical trials are not necessarily required to satisfy Article 83 EPC. Instead, the requirement may be met by preclinical in vitro data, animal models, or early clinical data that makes the therapeutic effect credible (IPKat).  

Case background

The case related to EP 3443979. The patent related to the use of Interleukin-2 (IL-2), specifically human IL-2 or aldesleukin, for treating systemic lupus erythematosus (SLE) in human subjects. The primary focus of the invention was a low-dose therapy, specifically administering between 1 MIU/day and 3 MIU/day. This dosage was intended to stimulate regulatory T cells (Tregs), which suppress undesirable immune responses, without substantially inducing effector T cells (Teffs) that could aggravate the disease. The Strawman Opponent argued that the patent lacked novelty, inventive step, and sufficiency of disclosure.

Credibility of the therapeutic mechanism

The Opponent argued on appeal that the clinical studies in the patent did not prove efficacy in SLE because the data related to other conditions, such as HCV-related vasculitis and type 1 diabetes. However, the Board of Appeal found that the application identified a common mechanism of action for the claimed drug, the selective amplification of Treg cells. The application as filed particularly set out that IL-2 was known to play a major role in the survival and function of Tregs, and that the invention sought to increase the Treg/Teff ratio. The Board of Appeal noted that "the experimental results provided in the examples are acknowledged as proof of concept that is also valid in the case of SLE" (r. 6.13). In particular, the examples showed that low-dose IL-2 led to a marked increase in Tregs and Treg/Teff ratio, which the Board of Appeal found was enough to support sufficiency. In the present case, the Board of Appeal was satisfied that the extrapolation to SLE was credible because SLE was known to be characterised by a deficiency in Tregs (r. 6.13). 

Lack of direct and unambiguous link (Novelty)

The Opponent argued that the subject-matter lacked novelty over a prior art international application which disclosed mucosal administration of IL-2 for treating inflammatory conditions, including SLE. This prior art proposed a broad dose range from 1 IU to 3 MIU/day. However, the Board of Appeal noted that the prior art stated the effective dose would depend on the type and stage of the condition and the activity of the agent. The Board of Appeal concluded that "the dose of 3 MIU/day, or any particular dose within the claimed dosage range, was not directly and unambiguously linked in [the prior art] with the therapeutic indication SLE and with the administration of human IL-2 or aldesleukin" (r. 8.3). In other words, the skilled person would have had to select and combine disclosures from multiple lists with a specific pointer to do so. Novelty was therefore acknowledged (r. 8.4). 

Inventive step and standardised versus unstandardised units

The assessment of inventive step focused on a prior art document that reported two case studies of IL-2 treatment for SLE using doses of "500 units". The Opponent argued that the claimed range was either anticipated by or obvious in view of this disclosure. Importantly, however, the discloses were very old, dating back to 1987. The the Board of Appeal thus found that it was not possible to confirm if the dose units described were established according to the modern International Units (IU) standard determined by the World Health Organization (WHO). The Board of Appeal noted that the activity of the molecule could vary from one preparation to another and the International Units standard had only been established after the priority date of the prior art. The Board of Appeal observed that "the use of un-standardised 'units' and the vague description of the dosage regimen applied in the reported clinical cases does not permit any conclusions with regard to the dosage levels proposed, or the actual dosages used in the clinical cases" (r. 9.13).

The reasoning here is interesting in the context of the recent EBA decision in G 1/23. Whilst G 1/23 confirmed that a commercial product cannot be excluded from the state of the art solely due to non-reproducibility, it also explicitly distinguished a non-reproducible commercial product from "defective or speculative disclosure". The Board of Appeal in T 1601/22 essentially found that the vague disclosure in the prior art, with its unstandardised units and lack of reproducible dosages, fell into a similar category of information that could not be used as a reliable starting point. This confirms that whilst G 1/23 removed the "legal fiction" that non-reproducible products don't exist, it did not remove the practical reality that you cannot modify what has not been disclosed (or what cannot proven to have been disclosed). 

The absence of a mechanistic link

The Board of Appeal was also of the view that the prior art provided no guidance for selecting a suitable dosage or any link between a selected dose and an immunoregulatory effect. The Board of Appeal observed that the general range proposed in the prior art was very broad and lacked any rationale to guide a skilled person. In contrast, the claimed range was not selected arbitrarily because higher doses were known to stimulate Teffs, leading to undesirable effects. The technical problem was thus defined as providing a treatment of SLE that ensured a reproducible therapeutic effect. This problem was found to be solved by the claimed range which achieved preferential stimulation of Tregs without substantial stimulation of Teffs. The Board of Appeal concluded that this would not have been obvious based on the prior art, which was interested in IL-2 for its ability to stimulate Teffs in combination therapies rather than Treg stimulation as a monotherapy. The decision under appeal was set aside and the case remitted with the order to maintain the patent based on an auxiliary request. 

Interestingly, a case in the same family relating to the low-dose IL-2 for the treatment for T1D, was also found sufficiently disclosed and inventive (T 1048/21). 

Final thoughts

The decision on sufficiency in this case is thus a reminder that it is not always necessary to support a therapeutic invention with actual clinical data (IPKat). In this case, mere mechanistic data that could be extrapolated to the claimed indication in view of the CGK was considered enough to render the treatment effect credible. 

Similarly, the lack of a clear mechanistic link in the prior art may undermine an inventive step attack. The decision in T 1601/22 therefore also reinforces the principle that identifying a specific, surprising technical effect is crucial for defending dosage regimen patents. This decision thus once again highlights the importance of providing a reliable path to success that distinguishes the invention from routine trial and error. The success of this appeal shows us that for a therapeutic invention, it is important for the inventive story to be clearly outlined in the application as filed. For this type of invention, it is often not enough to merely provide some clinical data (IPKat). Instead, the patentee must be able to articulate the technical challenges that were overcome and the rationale behind the specific selections made.

It is consequently possible in Europe for a patent to provide high-quality late-stage clinical data demonstrating the safety and efficacy of a dose invention to still fall down for inventive step. By contrast, a claimed invention that outlines a surprising mechanistic link not hinted at in the prior art may withstand both inventive step and sufficiency attack. 

Further reading

• When does pre-clinical data plausibly support a therapeutic effect? (T 966/18) (July 2021)
• The criteria for the novelty and inventive step of pharmaceutical selection inventions (T 1356/21) (13 Dec 2023)
• Inventive step of treating a subpopulation of patients in view of prior art reporting a positive phase 3 clinical trial (T1437/21) (29 Mar 2024)
• Fishy evidence: Do we have the right sufficiency standard for therapeutic use? (T 1057/22) (06 Aug 2024)
• Plausibility as a moving target: Phase III clinical trial results sink second medical use patent (T 0816/22) (22 Jan 2025)