EP 3 318 248-B1 results from a divisional application of EP 2 506 857. It relates to the delivery of mRNA for the augmentation of proteins and enzymes in human genetic diseases.
Brief outline of the case
The proprietor filed a new MR in opposition. The MR and AR1-3 lacked sufficiency and the patent was revoked.
The board confirmed the revocation for lack of sufficiency.
The claims at stake
The MR was not linked to any specific disease and merely defined a pharmaceutical composition comprising at least one mRNA molecule encapsulated in a liposome having a size of less than 100 nm, …. and wherein said at least one mRNA encodes a functional protein or enzyme.”
AR1 related to a therapeutic use “for use in treating a disease which results from a protein or enzyme deficiency in a subject”.
AR2 related to a therapeutic use “for use in treating a disease which results from a protein or enzyme deficiency in a subject, …. the at least one mRNA encodes a functional version of the protein or enzyme”
AR3 related to a therapeutic use “for use in treating a disease which results from a protein or enzyme deficiency in a subject, …. wherein the underlying genetic defect results in (i) non-synthesis of the protein, (ii) reduced synthesis of the protein, or (iii) synthesis of the protein, wherein the protein lacks or has diminished biological activity; and the at least one mRNA encodes a functional version of the protein or enzyme.
The proprietor’s point of view
In line with the established jurisprudence as represented by T 424/21 it was in case of a claim defining a composition for use in therapy as covered by Art 54(4) – first medical use – not required to demonstrate utility over the whole scope of the claim for any therapy and any disease.
Firefly luciferase (FFL) represented an established reporter protein for demonstrating effective gene transfer and had been used for such purpose in a variety of documents on file.
The results from examples 7 and 8 in Figures 2-5 of the patent demonstrated with the effective in vivo expression of FFL in mouse hepatocytes that the used liposomes provided for the effective delivery and in vivo expression of the contained mRNA.
The effective delivery and expression of mRNA encoding a functional protein or enzyme by liposomes as defined in the claims of the main request allowed for the treatment of diseases in which the subject benefits from the provision of the functional protein or enzyme.
The proprietor argued that he made available a kind of proof of concept. Following this proof of concept, the skilled person was well able on the basis of the instructions in the patent and the common knowledge to optimize the lipid compositions and to adjust the administered dose to achieve the therapeutically required levels of the protein of interest.
The opponents’ point of view
The experiments of examples 7 and 8 of the patent merely demonstrated the unquantified in vivo expression in hepatocytes of mRNA for a reporter protein, namely firefly luciferase (FFL).
The patent did thereby not demonstrate any therapeutically relevant level of expression of mRNA nor the absence of unacceptable toxicity.
The board’s decision
Main request
The board agreed with the patent proprietor that in case of a claim for a composition for use under Art 54(4) it is not generally required for compliance with Art 83 that a patent discloses the therapeutic suitability of the defined compositions in treatment of a plurality of diseases, but it usually suffices to show that at least one medical use is credibly achieved. SeeT 424/21, Reasons 40.
However, as claim 1 of the MR defines a composition for use in therapy, the patent must provide the skilled person with sufficient instructions for applying the compositions within the scope of the claim in some form of therapy without undue burden.
In line with the considerations in G 2/21, Reasons 77, this requires that the patent must substantiate the therapeutic utility of the claimed composition if in the absence of experimental data it would not be credible to the skilled person that any therapeutic effect is achieved.
The patent demonstrates in examples 7 and 8 with in vivo experiments in mice that mRNA encoding FFL may be effectively transfected and expressed using a liposomal transfer vehicle as defined in claim 1 of the MR.
As recognized by the proprietor during the OP, the expression of FFL luciferase serves no purpose in any therapy. According to the proprietor, examples 7 and 8 provided nevertheless with the use of FFL proof of concept that the defined transfer vehicles allowed for the effective transfer and expression of therapeutically useful proteins.
The board considered that the patent does not provide the skilled person with a sufficient disclosure to generally enable the therapeutic use of the claimed formulation comprising the mRNA encoding for an accordingly defined protein.
The patent only provides evidence which indicates a detectable in vivo expression of mRNA encoding the reporter protein FFL using liposomes with a constitution as defined in claim 1 of the MR without providing a basis for the quantification of this expression.
This is the more so, since in literature it is noted that “Currently, delivery efficiencies of synthetic vectors in the clinic are too low to obtain therapeutic levels of gene expression.”
For the board, the mere detection of an unquantified level of expression of FFL using a particular formulation for gene transfer does not credibly disclose the general suitability of such a transfer vehicle for use in gene therapy, because in view of prior art documents serious doubts prevail that such a formulation allows to generally achieve therapeutically effective levels of expression of the contained mRNA.
Without substantiation of the suitability of a formulation for therapy to start with, these suggestions for optimization and dosing remain proposals for a research project which do not overcome the doubts regarding the suitability of the claimed formulations for use in therapy.
The AR
AR 1 retains the definition of the mRNA as encoding a functional protein or enzyme of the MR. This definition of the mRNA results in the non-compliance of the main request with Art 83 EPC for the same reasons
AR 2 and 3 thereby restrict the definition of the functional protein or enzyme encoded by the mRNA to the actual deficient protein or enzyme giving rise to the disease to be treated. The reason for non-compliance of the MR does therefore not apply.
However, prior art indicates, that systems for gene transfer which allowed for the generation of a detectable level of expression of a particular gene still failed to achieve the quantitatively adequate levels of expression required for effective gene therapy, whereas the patent only provides evidence for detectable in vivo expression of mRNA encoding the reporter protein FFL.
As the definition of the encoded protein or enzyme in AR 2 and 3 remains of a general and purely functional nature, the same prior art also substantiate serious doubts that the patent provides the skilled person with a sufficient disclosure to generally achieve effective therapy.
Comments
For a first medical use it might not be necessary to demonstrate utility over the whole scope of the claim for any therapy and any disease, but at least for one disease. It should however be “credible” for other diseases.
In case of gene therapy, the application as filed should indicate quantitatively adequate levels of expression of genes required for effective gene therapy,
In relation with G 2/21, the naughty word “plausible” has been replaced by “credible”.
https://www.epo.org/en/boards-of-appeal/decisions/t220197eu1
Comments
Leave a comment