Better Together? Patents on Combination Therapies at the EPO
Combination therapies refer to the use of two or more medicinal products or active ingredients together to achieve enhanced therapeutic effects, improve patient outcomes, or reduce side effects compared to monotherapy. Combinations may be delivered either by prescribing the individual medicines separately or by using fixed-dose combination products, in which two or more active ingredients are formulated together within a single dosage form. These approaches are commonly employed in areas such as oncology, infectious diseases, and chronic conditions, where the synergistic or complementary actions of multiple agents can offer significant advantages over single-drug treatments.
This article provides an overview of patent considerations for combination therapies at the European Patent Office (EPO), with an aim to equip applicants with a thorough understanding of the EPO’s approach to this field.
Novelty
Product Claims
In fields such as combination therapies, where the prior art is crowded, it is important to assess whether the combination itself is new or whether the core invention lies elsewhere. A new combination of active ingredients not previously disclosed together can create a new composition of matter. This can be claimed as product claim, which may take the form: “A composition comprising…”, “A combined product comprising…”, or “A kit comprising…”. From an infringement perspective, a claim that claims the two actives together expects that, at some point, the two actives will be together, for example, in a kit or a single pill or tablet. Importantly, one of these actives being sold could potentially infringe the claim as a contributory infringer.
Even if the prior art provides a generic indication that two or more compounds could be combined, such as through multiple lists of possible actives, a specific combination may still be considered new.[1] The EPO applies the same test for novelty as for basis; the claimed combination must be directly and unambiguously disclosed in the prior art to be novelty-destroying.[2]
A new formulation of a known combination of active ingredients can also create a new product.
For all claims in this area, it is important to take care with the breadth and clarity of functionally defined actives or actives defined by a “result to be achieved”.
Medical Use Claims
Even if a combination is known, it may still be possible to claim a new medical use. This can be achieved by specifying, for example, a new disease indication, a new clinical setting, dosage, treatment protocol, administration route, or patient population. Claims can be structured as “X for use in the treatment of disease Y by simultaneous or sequential administration with Z”. The phrase “sequential administration” is particularly important if the two actives will not be administered together. Another possible claim format is “a combination of X and Z for use in the treatment of disease Y”.
Again, care should be taken with the breadth and clarity of functionally defined diseases.
Inventive Step
Could Versus Would
The decisive criterion for inventive step is “not whether the individual elements of the combination were known from the prior art, but whether the state of the art would lead a skilled person to the particular overall combination of (possibly already known) features”.[3] If this were not the case, it would be impossible for a combination consisting exclusively of known individual features to involve an inventive step.
Surprising Technical Effect
If a combination comprises two known compounds which both interact with well-established biochemical pathways involved in the disease, it can be more challenging to show that merely combining these two compounds as a single therapy is inventive. However, such a combination can still be patentable if, for example, it is demonstrated that the combination provides an unexpected technical effect, as in case T 0009/81.
A merely arbitrary choice from a host of possible solutions cannot be considered inventive unless justified by a previously unknown technical effect that distinguishes the claimed solution from other solutions. In cases involving arbitrary selection, the prior art does not need to contain an incentive for the skilled person to select the particular solution claimed.[4]
Technical effects that can support inventive step include improved pharmacokinetics, improved bioavailability, improved half-life, improved patient compliance, reduced side effects, reduced dosage frequency, a different administration route, or overcoming specific challenges.
Synergy in Combination Therapies
Synergistic effects are, by definition, not foreseeable, as established in EPO Case Law of the Boards of Appeal.[5] In T 1054/05, two features interacted synergistically if their functions were interrelated and lead to an additional effect that went beyond the sum of the effects of each feature taken in isolation. In T 0926/11, it was not enough that the features solved the same technical problem or that their effects were of the same kind and added up to an increased but otherwise unchanged effect. Therefore, an additive effect generally is not considered synergistic. Whilst it is not necessary to prove synergy for establishing inventive step, synergy is beneficial because, by definition, it is inventive.
Improvement Compared to Monotherapy
Where synergy has not been demonstrated for the claimed combination, it is still possible to demonstrate an inventive step as discussed in Appeal Board decisions T 1642/07 and T 0790/11.
In T 1642/07, the combination therapy of a herpes simplex virus (HSV) and a chemotherapeutic agent was considered. Although monotherapies were already known to be effective, the prior art disclosed a combination of HSV with radiotherapy, not the claimed combination (Reasons 10 and 32). In view of the uncertainty relating to the different biological mechanism of action, and the possible drug interaction for the claimed combination, the Board concluded that an additive effect was sufficient to acknowledge an inventive step (Reasons 28-30).
In T 0790/11, a composition comprising a tosylate salt of sorafenib (an aryl urea compound) and a cytotoxic or cytostatic agent or pharmaceutically acceptable salt thereof was considered. The examples in the patent “describe in vivo studies in mice with tumour xenografts from various tumour lines”, showing that “an additive effect on tumour growth suppression is apparent” (Reason 5.4). In some examples, the effect was not merely additive, “but still considerably improved compared to administration of each of the agents alone”. The objective technical problem was formulated as “the provision of a composition for the treatment of cancer with improved solubility, and consequently bioavailability, and improved efficacy, while at the same time being well-tolerated”. The Board found that “the skilled person could not have reasonably expected that sorafenib tosylate in combination with cytostatic/cytotoxic agents would exhibit such a good balance between efficacy and tolerability.” (Reason 5.9.4).
The Role of Data in Combination Therapy Patents
If a claimed invention lacks reproducibility, this may become relevant under the requirements of sufficiency of disclosure or inventive step. If an invention lacks reproducibility because its desired technical effect as expressed in the claim is not achieved, this results in a lack of sufficient disclosure, which cannot be remedied with post-filed data. This is highly relevant for medical use claims and functionally defined products.
If the effect is not expressed in the claim but is part of the problem to be solved, there may be a problem of inventive step, which can sometimes be supported with post-filed data. This is more relevant for structurally defined product claims.
Data under inventive step
For inventive step, technical effects must be “encompassed by the technical teaching” and “embodied by the same originally disclosed invention”. It is important to ensure that potential unexpected technical effects are “conceptually comprised by the broadest technical teaching of the application as filed”, and that the skilled person, having the common general knowledge on the filing date in mind, and based on the application as filed, would not have “legitimate reason to doubt that the purported technical effect can be achieved with the claimed subject-matter” (T 0116/18).
“It is not sufficient that a technical effect can be achieved by a composition, which in terms of technical features, corresponds to compositions in the application as filed” (T 0887/21, Reason 2.15.4).
Data under sufficiency
For medical use claims, sufficiency is assessed based on the information provided in the patent application together with the common general knowledge, to determine whether it is credible that the claimed therapy would work. Once the enablement threshold has been met, post-published evidence may be taken into account to support the breadth of the claim.
Clinical Trials and Their Impacts on Patentability
Overall, a combination therapy will be novel over disclosures relating to monotherapies and over disclosures relating to the combination but without any data. The prior art effect of pre-clinical or clinical results for monotherapies, including press releases or journal publications, is fact dependent. However, it is unlikely to be enough to establish a reasonable expectation of success for a combination therapy, unless there is evidence to build expectation that the combination would be an effective treatment in terms of efficacy and safety. Additional features in a medical use claim, such as dosage, can further distance the claim from pre-clinical results.
A published clinical trial protocol for a combination therapy, without results, is unlikely to destroy novelty but can establish a reasonable expectation of success and destroy inventive step. This is fact dependent and might involve considering whether there is any prejudice or teaching away in the art, which would lead the skilled person to think that there is a hope to succeed, but no reasonable expectation of success.
Here we provide a selection of decisions of the EPO Boards of Appeal where the claims recite a combination therapy, and the prior art includes preclinical and/or clinical trial disclosures.
In T 1255/21, the claims were directed to co-therapy (a fragment of a wild-type RAS protein plus a pyrimidine analogue) for the treatment of cancer. The closest prior art was a phase I/II clinical trial protocol relating to the claimed treatment in patients. The difference between the protocol and the patent was that the latter disclosed that the therapeutic effect which the trial was set up to test, was actually obtained. Therefore, the claim was novel. The question was whether starting from the disclosure of the clinical trial protocol, the skilled person would have reasonably expected that putting the protocol into practice would result in an effective treatment. There was no “prejudice or teaching away” in the art which would have dissuaded the skilled person to put the clinical trial protocol into practice, so the claim was found to lack an inventive step. Of note, the Board considered that a reference in the protocol to the assessment of "the potential for interference” between the therapeutics used in the co-therapy would have been understood by the skilled person to be “a standard indication for any combination therapy, and as such it would not impart to the skilled person any particular prejudice against the proposed clinical trial”.
In T 2506/12, the claims were directed to the treatment of cancer by combination therapy employing ET-743 with PLD (Pegylated Liposomal form of anthracycline Doxorubicin). The prior art disclosed a phase I clinical trial protocol for the claimed combination in cancer patients but did not disclose results.
In relation to novelty, the Board noted that both efficacy and safety must be considered to determine whether an effective treatment is disclosed in the prior art. The Board considered that the skilled person would not have been able “to exclude the possibility that ET-743 and PLD might interact to produce unacceptable adverse effects, and in combination might reach dose-limiting toxicity before reaching the threshold of pharmacological efficacy”. Therefore, the claim was novel.
In relation to inventive step, the Board held that “the general consideration that any clinical trial might fail [is] not sufficient to establish an inventive step”. The Board considered that “drug compounds to be used in a clinical trial with human subjects are not selected based on a general ‘try-and-see’ attitude, but based on existing favourable scientific data, for both ethical and economical reasons. Thus, a clinical trial is not a mere screening exercise.” Since there was no other information that “would have discouraged the skilled person in the art from carrying out an experimental evaluation to confirm the usefulness of the combination treatment”, the Board found that the claimed subject matter was not inventive.
In T 2963/19, the claims were directed to a combination therapy for pancreatic cancer specifying a patient population and dosage regimen. The closest prior art disclosed a phase III clinical protocol corresponding to the claimed dosage regimen. The phase III protocol was also described in an example of the patent. Neither the example in the patent nor the prior art clinical protocol reported results of the described treatment. The Board held that to the extent that it is reasonable to predict from the protocol in the patent that the proposed therapy will be safe and effective, the same considerations apply when considering the prior art clinical protocol disclosure - a positive outcome for the described therapy could reasonably be expected. For this reason, the claim was found to lack inventive step.
In T 1853/16, the claims were directed to the treatment of metastatic breast cancer characterised by overexpression of ErbB2 (also known as HER2) with a combination of an anti-ErbB2 antibody and a taxoid. The claim also required that the combined administration has clinical efficacy as measured by determining time to disease progression (TTP).
The prior art disclosed that both paclitaxel (a taxoid) and rhuMAb HER2 (an anti-ErbB2 antibody) are individually therapeutically effective as monotherapies in humans having metastatic breast cancer overexpressing HER2. In addition, a synergistic effect had been shown in a mouse xenograft model for the combination of an anti-ErbB2 antibody and paclitaxel. Of note, the Board considered preclinical xenograft data to be a reliable indicator for clinical efficacy of the combination therapy because monotherapy results had been shown to translate into clinical efficacy in human patients. Finally, a phase III clinical study had been designed for paclitaxel or anthracycline in combination with humanised anti-HER2 antibody (rhuMAb HER2) in patients with metastatic breast cancer overexpressing HER2.
The Board found that the effects observed for the combination therapy in the prior art would have provided a reasonable expectation that TTP would increase compared to treatment with the taxoid alone, as there is an “unescapable link” between tumour growth and TTP, so the claim was not inventive.
In T 0209/22, the claims were directed to a once-daily combination therapy of vilanterol with an anticholinergic agent for the treatment of COPD and/or asthma.
The prior art was a phase I clinical study in healthy volunteers. The Board considered that the clinical trial in healthy volunteers could not have anticipated the claimed therapeutic effect “simply because the study subjects did not suffer from COPD or asthma”. Therefore, the claimed therapy was novel.
The patent provided results for each drug as monotherapy in COPD patients and for the combination in healthy volunteers. Accordingly, in relation to sufficient the Board considered that there was “a strong presumption” that the combination “would be effective in the treatment of asthma or COPD, and that a dosage regiment of once-daily administration would be feasible”.
Regarding inventive step, the question to be answered was whether, at the effective filing date, there was a direct route that would have led to the development of the claimed combination with a reasonable expectation of success. Both drugs were still in early stages of their pharmaceutical development, with only preclinical data available for the monotherapies in the prior art, and neither had progressed to the clinical stage. Therefore, the Board considered that there would not be a reasonable expectation of success of the claimed combination therapy, so the claims were found to be inventive.
Summary and Strategic Drafting Considerations
Applicants should not assume that they cannot patent a combination, nor should they assume that they can!
An entirely prophetic patent application covering a desired combination or formulation, without any indication of the likely mechanism or effect, is unlikely to be successful at the EPO. It is important to include data in the application or provide a credible scientific theory as to why the new combination or formulation provides an advantage over the prior art. Applicants should also be aware of the inventive step-sufficiency squeeze (as in T 2963/19) - prior published disclosures relied on for sufficiency will also be relevant prior art when assessing inventive step.
Applicants should consider the breadth of claims during the application drafting process, ensuring adequate basis for fallback positions.
Finally, Applicants should adopt a cautious approach with respect to information (not just data) that is put into the public domain before filing a patent application. This applies to regulatory submissions, press releases and journal publications, and also information shared with patients. For example, confidentiality agreements between the sponsor and the patients will be relevant.
[1] EPO Guidelines, April 2025 Edition, G-VI, 7. Selection inventions.
[2] For example, in T 0137/04, a claim directed towards the use of nateglinide (a short-acting hypoglycaemic agent) for the manufacture of a medicament to be used in combination with metformin (a long-acting hypoglycaemic agent) in the treatment of type 2 diabetes was found to add subject matter because this combination had not been directly and unambiguously disclosed in the application as filed. Consequently, the patent was revoked.
[3] EPO Case Law of the Boards of Appeal, 11th Edition, I.9.3.1.
[4] EPO Case Law of the Boards of Appeal, 11th Edition, I.D.9.21.9a.
[5] EPO Case Law of the Boards of Appeal, 11th Edition, I.D.9.9.6.
