Originally posted on IPKat.
For the multi-billion-dollar world of oncology combinations, getting this timing right can be a high stakes question. The recent Board of Appeal decision in T 0592/24, relating to Novartis’s blockbuster breast cancer combination of ribociclib and letrozole, offers innovators some welcome reassurance, at least for Europe. The Patentee was able to demonstrate sufficiency based on preclinical data in the application as filed whilst supporting inventive step with post-published data from the subsequent clinical trial (G2/21).
Legal Background: Inventive step and synergy
The patentability of combination inventions at the EPO relies on the established case law on synergy. Synergism is normally understood as an interaction of two or more technical measures that produces an effect greater than the sum of their separate effects (T 2773/17). Importantly, it is not enough that the features merely solve the same problem or that their effects are of the same kind and add up to an increased but otherwise unchanged effect (T 1054/05). The inventive step for combination inventions is arguably increasing, with the evidence required to demonstrate synergy over the whole scope of the claim increasing as the volume of patents in this space increases in-line with the pharmaceutical industry’s ever increasing interest in marketing new combinations of known drugs.
Case background: Oncology combinations
Combination therapies are big business in oncology. The present case related to the combination of Novartis’s multi-blockbuster ribociclib with letrozole. Ribociclib (KISQALI) has become one of Novartis’s fastest-growing products, generating some USD 4.8 billion in sales in 2025, a rise of 58% on the previous year, with US sales doubling. In Europe, KISQALI was approved in 2017 for the first-line treatment of postmenopausal women with HR+/HER2− advanced or metastatic breast cancer in combination with letrozole. This was the first approval for ribociclib, which has never been approved as a monotherapy. Letrozole is an old Novartis drug that is now generic.
The present case related to the Novartis patent (EP 3033086 B1) claiming this combination. The priority date of the patent was August 2013, 4 months before the start of the phase 3 clinical trial for the combination (NCT01958021). The patent was opposed by several generics, including Teva. The patent particularly claimed a pharmaceutical composition comprising a combination of ribociclib and letrozole, and its use for the treatment of hormone-receptor-positive breast cancer. The Opposition Division maintained the patent in amended form. The Opponents appealed on the grounds of, inter alia, lack of inventive step and sufficiency.
Inventive step for a combination therapy
The Board of Appeal had no trouble finding the patent sufficiently disclosed based on the preclinical data, on the grounds that the opponents had provided no substantiated doubt with respect to the effect of the claimed combination. This is in line with the EPO’s relatively low bar for sufficiency (Evolve Insights). The primary issue on appeal was inventive step starting from a prior art combination of the CDK4/6 inhibitor palbociclib and letrozole.
The claimed invention was found to differ from the closest prior art by the replacement of palbociclib with ribociclib (both CDK4/6 inhibitors). For inventive step of the new combination, the Patentee relied on in vitro data in the patent showing that the ribociclib combination achieved a higher synergy score than the palbociclib combination. The Patentee also submitted post-published clinical evidence from the phase 3 trial, demonstrating that the claimed combination provided a significant improvement in overall survival compared to the prior art combination.
The Opponents argued that the in vitro data did not establish a statistically significant improvement. The Opponents also argued that, based on G 2/21, the post-published clinical evidence could not be relied upon because an effect on overall survival was not explicitly mentioned in the application as filed.
The Board of Appeal was not convinced by the arguments of the Opponents. In particular, the Board of Appeal found that the in vitro data in the patent convincingly demonstrated an increased level of synergy for the claimed combination . The Board placed particular weight on the patent containing direct comparative data for both combinations generated using the same assay system, distinguishing earlier decisions such as T 512/02 and T 484/09 in which such comparative data were absent (r. 4.2.7).
Addressing the post-published evidence, the Board of Appeal applied the principles of G 2/21 and reviewed previous interpretations in cases such as T 1994/22 and T 1989/19. The Board of Appeal noted that the application as filed explicitly taught the utility of the combination in treating the specified cancers and provided outlines for clinical studies. For the Board of Appeal, this disclosure was enough for the skilled person to derive the technical effect of increased survival of patients in the clinic, as encompassed by the application as filed, particularly given the in vitro data of improved synergy compared to the prior art combinations (r. 4.2.11).
The Board of Appeal therefore found the claimed combination to possess an inventive step in view of the data provided in the application as filed, also taking into account the post-published evidence, which, notably, was not a head-to-head trial but a matching-adjusted indirect comparison between the separate MONALEESA-2 (ribociclib/letrozole) and PALOMA-2 (palbociclib/letrozole) trials. The appeals were therefore dismissed and the patent maintained.
Analysis
This decision is another data point to help in the perennial question in pharma IP strategy, when do you file on a clinical invention such as a combination therapy or new indication. We know from other recent Board of Appeal decisions that filing on just the protocol, without data, is not enough. At least some form of data is needed. However, T 0592/24 confirms that preclinical data that encompasses the technical effect later demonstrated in the clinic can be sufficient to support both sufficiency and inventive step.
Often it is necessary to file a patent application before entering the clinic, especially for inventions directed at new indications and combination of known drugs. The present case demonstrates that this is a viable strategy, so long as you have sufficient preclinical and/or mechanistic data that tell your inventive story and that this is included in the application as filed. Usually, this shouldn’t be too difficult, given that preclinical evidence and mechanistic justification will also be needed to support the regulatory submissions. However, combination inventions can be a difficult case in this regard. This is because, unlike patentability, synergy is not required to support a clinical trial for a combination. Where many patent offices will consider the “simple” combination of two known drugs as obvious, regulatory authorities require extensive clinical evidence of a positive benefit-risk to support an approval. However, the positive benefit-risk required by regulatory authorities does not have to be synergy. As such, the regulatory package supporting the clinical trial for the combination will not have to include synergy data.
For drug combination inventions relying on synergy as a technical effect, there is the further risk that the clinical trial readout may not actually demonstrate the synergy of a combination but may merely demonstrate an additive effect and positive benefit-risk. The post-published evidence may thereby actually undermine the inventive step of the patent (compare T 709/23 and T 816/22). As such, a wise patent strategy may both include preclinical synergy data and ensure the patent aligns with the regulatory strategy and looks beyond synergy as a technical effect of the combination. Regardless, as this case also demonstrates, the potential value of these cases means that it is always going to be worth a shot.
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).
