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T 1639/21 – Synergy and inventive step – Not necessarily linked

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The patent relates to a mRNA/anti-PD-1 combination vaccine comprising an isolated mRNA comprising an open reading frame coding for an antigen and an antagonistic antibody directed against PD-1.

Brief outline of the case

The OD found that a new MR filed during opposition was lacking N over D1 prior art under Art 54(3).

The proprietor and all five opponents appealed the OD’s decision to maintain the patent according AR1.

The board decided that the MR and AR1-4 were lacking IS.

The board also dismissed a request for a referral to the EBA by the proprietor.

The case is interesting in that it deals with the notions of reasonable expectation of success and synergy.  

The whole discussion between the proprietor and the opponents turned around the replacement of an anti-CTLA-4 antibody, as disclosed in the CPA=D13, by an anti-PD-1 antibody in combination with the mRNA vaccine.

The proprietor’s point of view

The claimed vaccine/inhibitor combination resulted in improved therapeutic effectiveness compared to the prior-art combination. due to a synergistic interaction between the mRNA vaccine and the antagonistic antibody directed against PD-1.

The unexpected synergistic effect could not have been anticipated by the skilled person, and when starting from D13, the skilled person did not have a reasonable expectation of obtaining an improved synergistic effect for several reasons. The proprietor referred to T 1814/11, T 2156/14 and T 2097/15.

There was no motivation for the skilled person to replace the anti-CTLA4 antibody because the potential safety issue in document D13 was resolved and the antibody was FDA approved.

For the proprietor, it was unpredictable if and how the individual components of the claimed combination would interact with each other. The mechanism which resulted in this interaction and thus allowed for a more than additive effect was still not understood. This was the case for both the combination in document D13 and the inventive combination according to claim 1.

A more than additive effect was generally considered remarkable since the exact mechanism, by which two components interacted to generate synergy, could typically not be explained, let alone expected..

The opponents’ point of view

In view of the known toxicity of CTLA-4, the technical problem could be formulated as the provision of an mRNA vaccine and inhibitor composition which had an improved safety profile in view of fewer and less severe side effects.

The prior art at hand showed that anti-PD-1 antibodies showed a series of advantages in their use.

This provided the motivation to the skilled person to replace the anti-CTLA-4 antibody of document D13 with an anti-PD-1 antibody with a reasonable expectation that the combination of an anti-PD-1 antibody and an mRNA vaccine would result in a synergistic immune response compared to the mRNA vaccine alone with fewer side effects.

Thus, the skilled person not only could but would have modified the vaccine/inhibitor combination disclosed in document D13 by replacing the anti-CTLA-4 antibody with an anti-PD-1 antibody.

There was no prejudice for using anti-PD-1 antibodies since the immune system checkpoint blockade was known to be an effect independent of the vaccine providing the antigen.

In view of the many positive indications in the prior art, the skilled person seeking an anti-PD-1/vaccine combination would also have adopted a “try and see” approach and would have replaced the anti-CTLA4 antibody with an anti-PD-1 antibody even if a synergistic effect was not certain.

The board’s decision

The board not only agreed with the parties that D13 was a suitable starting point for assessing IS, but that the difference was indeed the replacement of the anti-CTLA4 antibody by an anti-PD-1 antibody.

The board further agreed with the OD that an “improved therapeutic effectiveness” of the claimed vaccine/inhibitor combination in comparison with the vaccine/inhibitor combination disclosed in document D13 could not be acknowledged.

For the board, the mRNA vaccine elicits an immune response against the tumour, i.e. a therapeutic effect. The anti-immune checkpoint antibody, however, on its own, does not have a direct effect on the tumour; it only counteracts an inhibition of the immune response. Releasing this blockade can only have a therapeutic effect in combination with an existing immune response, which can either come from the immune system itself which recognises the tumour as “non-self” or be stimulated by a vaccine.

The board used the following image: releasing a brake alone does not move a car but allows a faster speed when the motor is on. The speed generated by the motor with the brake released will always be more than additive compared to the speed when the brake is on because the reduction of speed imposed by the brake will always be greater than zero.

The board concluded that the claimed combination and the combination disclosed in document D13 can be seen as showing a synergistic effect at least for mRNA encoding a tumour antigen.

D13 further points to possible shortcomings of blocking CTLA-4, which “is rarely associated with severe side effects as a result of the non-selective activation of autoimmune cells]”. These side effects are avoided in D13 by using a lower than previously reported dose..

In conclusion, the skilled person already knew from the disclosure of D13 that CTLA-4 blockade has known safety issues and that PD-1 is a further immune checkpoint protein which enhances the effect of cancer vaccines.

The board concluded from D13 and from review articles D14, D15, D31, D35, D37 and D54 that the skilled person starting from D13 would have considered PD-1 as a promising immune checkpoint target for an antagonistic antibody in combination with cancer vaccines.

For the board, it was undisputed that CTLA-4 and PD-1 immune checkpoint proteins reduce or block the T-cell response by different mechanisms but there was no evidence that there was a direct interaction between the mRNA vaccine and the antibody targeting an immune checkpoint protein, be it CTLA-4 or PD-1.

The board concluded that a synergistic effect of the components of the claimed vaccine/inhibitor combination does not arise by a direct molecular interaction but by an indirect interaction, namely the release of an immune checkpoint block which allows an effective immune response to the vaccination.

The board further concluded that three documents explicitly disclose a synergistic effect between anti-PD-1 antibody and cancer vaccines.

The skilled person had thus a reasonable expectation that anti-PD-1 antibodies achieve a synergistic effect when combined with an mRNA vaccine.

Safety issues brought forward by the proprietor were dismissed by the board as the skilled person is always interested in finding alternatives and improving existing products and processes. The solution to potential safety issues by limitation to a low dose in document D13 is thus not a reason for the skilled person not to look for alternatives which did not have this limitation, such as anti-PD-1 antibodies.

For the board, the skilled person would not have been dissuaded from replacing the anti-CTLA-4 antibody used in document D13 with an anti-PD-1 antibody.

The board also considered that the decisions cited by the proprietor do not lead to the conclusion that there is an “automaticity of inventive step” in presence of a synergy.


The case is interesting as it shows that a synergy was to be expected when replacing the anti-CTLA-4 antibody in D13 by an anti-PD-1 antibody with a reasonable expectation of success.

Synergy does not necessarily imply IS, as here a synergy was to be expected.

Although dealing with a biotech problem, the board did not hesitate to compare the effect at stake with releasing the brakes of a car. This is quite remarkable.


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