T 0197/22 (Delivery of mRNA II/TRANSLATE BIO) 22-03-2024

1. Admittance of arguments and documents

1.1 The patent proprietor's argument concerning the sufficiency of disclosure of first medical use claims

In the statement of grounds of appeal the patent proprietor argued that sufficiency of disclosure of a claim directed to the so-called first medical use of a composition under Article 54(4) EPC is to be acknowledged if the patent credibly discloses a specific therapeutic utility of the composition and that it is not required to demonstrate utility over the whole scope for any therapy and any disease.

Opponent 2 objected that this argument represented an amendment to the patent proprietor's case, which should not be admitted.

According to the minutes of the oral proceedings before the opposition division (see page 7, second paragraph) the patent proprietor maintained during the first instance proceedings that the claimed invention was sufficiently disclosed, because the patent described at least one way of performing the claimed invention. The Board considers that the patent proprietor's argument objected to by opponent 2 represents merely a further development of the argument mentioned in the minutes and has therefore acknowledged the argument to be part of the appeal proceedings under Article 12(2) RPBA.

1.2 Document A106

Document A106 was cited by the patent proprietor in response to documents D59 and D74 filed by opponent 2 under Rule 116 EPC during the first instance proceedings in particular to support the patent proprietor's argument that the discontinuation of a clinical trial does not imply a lack of efficacy. Opponent 2 contested the admittance of document A106 for it being late filed and lacking relevance. The Board considers that the filing of document A106 in the appeal proceedings is justified as response to the filing of documents D59 and D74 at a late stage during the first instance proceedings by opponent 2.

The Board has therefore admitted document A106 in the appeal proceedings under Article 12(4) RPBA.

1.3 Documents A107, A110 and A119

Documents A107, A110 and A119 were cited by the opponents in their replies to the appeal to support their arguments that contrary to the proprietor's submissions the lack of an effect of expressed mRNA on the hematocrit level in healthy mice reported in document D39 supported the objection of lack of sufficient disclosure.

The Board considers that the filing of documents A107, A110 and A119 in the appeal proceedings is justified as response to the proprietor's appeal and that their admittance is not detrimental to procedural economy.

The Board has therefore admitted documents A107, A110 and A119 in the appeal proceedings under Article 12(4) RPBA.

1.4 Documents A102-A105, A108, A109, A111-A115, A117, A118 and A120

In its communication pursuant Article 15(1) RPBA the Board expressed the preliminary opinion that documents A102, A103, A104, A105, A106, A114, A115, A117, A118 and A120 addressed issues possibly relevant to the appeal and that their admittance did not seem detrimental to procedural economy, but that the admittance of documents A108-A109 and A111-A113 did not seem justified.

In line with its preliminary opinion the Board admitted during the oral proceedings documents A102, A103, A104, A105, A106, A114, A115, A117, A118 and A120 and refused to admit documents A108-A109 and A111-A113.

Given the Board's findings on the issue of sufficiency of disclosure concerning the patent proprietor's main and auxiliary requests, which are not affected by the content of these documents (see sections 2 and 3 below), further details for the reasons regarding the admittance and non-admittance of these documents are of no relevance to the decision taken.

2. Main request - Article 83

2.1 The Board agrees with the patent proprietor that in case of a claim for a composition for use under Article 54(4) EPC it is not generally required for compliance with Article 83 EPC that a patent discloses the therapeutic suitability of the defined compositions in treatment of a plurality of diseases (see T 424/21, reasons 40).

However, as claim 1 of the main request 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 (see 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.

2.2 Claim 1 of the main request defines the composition to comprise mRNA encoding a functional protein or enzyme. The patent demonstrates in examples 7 and 8 with in vivo experiments in mice that mRNA encoding firefly luciferase (FFL) may be effectively transfected and expressed using a liposomal transfer vehicle as defined in claim 1 of the main request.

As recognized by the patent proprietor during the oral proceedings, 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 observes that claim 1 of the main request defines the encoded protein merely as a functional protein or enzyme and leaves the nature of the intended therapy still to be determined. The encoded protein FFL in examples 7 and 8 of the patent may well be considered as a functional protein as defined in the claim, yet the patent provides the skilled person no instruction for the therapeutic use of the mRNA encoding FFL when encapsulated in a transfer vehicle as defined in claim 1 of the main request.

2.3 Even if the term "functional protein or enzyme" in claim 1 of the main request is understood as functionally restricted to a protein with a feasible therapeutic utility, the Board considers 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.

2.3.1 The patent provides in Figures 2-5 results from the experiments of examples 7 and 8 in which mice were administered mRNA encoding FFL in a liposomal formulation as defined in claim 1 of the main request. Figure 2 presents results from bioluminescence assays which detect according to paragraph [0123] of the patent the preferential FFL expression in the liver of the treated animals. Figures 3 and 4 presents results from in situ hybridisation assays which indicate according to paragraphs [0124]-[0125] of the patent the detection of FFL-mRNA in the liver of treated animals. Figure 5 further presents results from immunohistochemical assays which indicate according to paragraph [0127] of the patent the detection of expressed FFL in the hepatocytes of the treated animals.

2.3.2 Document D14 is a review article on the prospects for mRNA gene delivery published one year before the priority date of the patent. As pointed out by the opponents, document D14 (see page 486, left column, second paragraph ) indicates that luciferase assays only provide an indirect measure of protein expression levels. During the oral proceedings, the proprietor maintained that the experimental results reported in the patent demonstrated the effective in vivo transfer and expression of FFL-mRNA, but acknowledged that the results reported in the patent do not quantify the actual expression of the transferred mRNA.

2.3.3 Document D64 represents prior art reporting the stable expression of antibodies at therapeutic levels after gene transfer using a viral vector. Document D64 states that most antibodies require high and sustained serum levels. According to document D64 the high antibody concentrations required for clinical efficacy rendered the development of antibody gene transfer technologies challenging, because gene transfer typically achieved only low expression levels (see D64, page 587, right column, second paragraph).

Document A106 represents a review of trends in clinical trials for the delivery of nucleic acid based therapeutics, which was published only shortly after the priority date of the patent. The document reports that as of December 2009 (corresponding to the priority date of the patent) there had been 1579 gene therapy clinical trials worldwide, of which about 25% involved non-viral vectors. In this context the document explicitly states (see page 39, left column, lines 9-14):

"Currently, delivery efficiencies of synthetic vectors in the clinic are too low to obtain therapeutic levels of gene expression."

As explained in section 2.3.2 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 main request without providing a basis for the quantification of this expression. Documents D64 and A106 indicate, however, that formulations 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. The Board therefore considers that documents D64 and A106 substantiate serious doubts that the patent provides the skilled person with a sufficient disclosure to generally achieve effective therapy using a formulation within the definition of claim 1 of the main request and thus carry out the claimed invention without undue burden.

2.4 The patent proprietor argued that FFL represented an established reporter gene for demonstrating effective gene transfer and that the experimental evidence in the patent provided thereby the crucial proof of concept for the suitability of the defined formulations in gene transfer therapy. Following this proof of concept, the skilled person was according to the proprietor 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 Board observes that in the prior art FFL has indeed been relied upon as an established reporter gene for investigating formulations intended for gene transfer application. For instance, document D20 describes in example 13 experiments with FFL to explore the effect of dose levels and time on the total luciferase extracted from muscle of mice injected with formulations comprising mRNA and DNA encoding FFL. Notably, the experiments involved quantification of the expression as measured in light units using a standard curve established by measuring the light units produced by purified FFL within control muscle extract (see D20, pages 62-62, bridging sentence). However, as explained in section 2.3.3 above, 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 documents D64 and A106 serious doubts prevail that such a formulation allows to generally achieve therapeutically effective levels of expression of the contained mRNA. The Board is therefore not convinced that the patent provides actual proof of concept regarding the suitability of the claimed formulations for use in therapy.

The patent refers in paragraphs [0042] and [0087] to parameters which may be modified to optimize transfection efficiency, including the selection of the lipids and their molar ratios as well as the size of the liposomal formulations. Such parameters had also been mentioned in textbooks such as document D15 for the optimization of transfer vehicles for nucleic acids in general (see D15, pages 249-251, section 9.3.5). The patent further indicates in paragraph [0081] that the compositions may be administered and dosed in accordance with current medical practice.

However, the Board considers that 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 based on documents D64 and A106.

2.5 The patent proprietor further argued that contrary to the finding in the decision under appeal the post-published document D39 did not indicate any lack of therapeutic efficacy, but actually confirmed the therapeutic utility of the claimed formulations.

Document D39 describes in its example 1 lipid nanoparticle compositions containing mRNA encoding human erythropoietin (hEPO), which comprise like the liposomes of claim 1 of the main request a cationic lipid, a non-cationic lipid and a PEG-modified lipid (see D39, pages 37-38, formulations 1-4). Document D39 reports in Table 1 the following observed serum levels of hEPO in CD-1 mice after the administration of these composition (see D39, page 41):

FORMULA/TABLE/GRAPHIC

Whilst document D39 indicates in Table 1 that only the "C12-200" composition provided sufficient expression of hEPO to increase hematocrit levels in the non-anemic CD-1 mice, even the least effective composition comprising the cationic lipid "DODAP" resulted in a serum concentration of hEPO of 4.1 ng/ml, which was according to document D39 still 30-fold over the normal physiological levels of EPO protein (see D39, page 41, lines 10-14). Document D48 reports the effects of the administration of recombinant hEPO (rhEPO) on renal anemia in adenine-treated mice. The results presented in document D48 indicate that the administration of rhEPO allowed for the recovery of hematocrit levels in these anemic mice (see D48, page 9, Figure 7A). The administered dose in the experiments of document D48 generated a serum level of rhEPO commensurate with the 4.1 ng/ml reported in Table 1 of document D39 for the "DODAP" composition (see D48, page 9, Figure 7J). Taking account of the information in document D48 the Board therefore agrees with the patent proprietor that the results concerning the effect on hematocrit levels in non-anemic mice reported in document D39 do not demonstrate a lack of therapeutic efficacy of the described "DODAP" composition and that the 30-fold increase over normal levels of EPO reported in Table 1 of document D39 rather suggests the therapeutic potential of this composition.

The opponents contended that the lack of an effect on hematocrit levels reported in Table 1 of document D39 nevertheless indicated a lack of therapeutic efficacy of the used compositions in view of documents A107, A110 and A119. However, document A107 describes the effects of the administration of mRNA encoding murine EPO (mEPO) on hematocrit levels in mice (see A107, page 2, Figures 2c and 2d) and thus concerns the effects of a different protein than the human EPO described in documents D39 and D48. Moreover, documents A110 and A119 describe experiments in anemic mice with a compromised response to EPO (see A110, page 2, final paragraph; see A119, page 126, left column), rather than a deficit in EPO production as in the mice used in document D48. Documents A107, A110 and A119 are therefore not considered to support the opponents' contention.

However, whilst document D39 thus may describe with the mentioned experimental results the in vivo expression of the administered mRNA encoding hEPO in a quantity which could indicate the described compositions to be therapeutically useful, the patent fails to disclose such a quantitatively adequate expression of mRNA from the compositions as defined in claim 1 of the main request. In accordance with the considerations in G 2/21 (see reasons 77) a lack of sufficiency of disclosure cannot be remedied by post-published evidence. The patent proprietor's argument relying on the post-published document D39 is therefore not considered persuasive.

2.6 Accordingly, the Board concludes that the main request does not comply with Article 83 EPC.

3. Auxiliary requests

3.1 Auxiliary request 1

Claim 1 of auxiliary request 1 more specifically defines with respect to claim 1 of the main request the therapeutic use of the defined composition in treating a disease which results from a protein or enzyme deficiency in a subject.

Auxiliary request 1 retains the definition of the mRNA as encoding a functional protein or enzyme of the main request. This definition of the mRNA results in the non-compliance of the main request with Article 83 EPC for the reasons as presented in sections 2.2 and 2.3 above. The additional specification of the therapeutic use in claim 1 of auxiliary request 1 does not change the definition of the mRNA. Auxiliary request 1 does therefore not comply with Article 83 EPC for the same reasons as the main request.

3.2 Auxiliary requests 2 and 3

Auxiliary requests 2 and 3 additionally define in claim 1 with respect to claim 1 of auxiliary request 1 that the subject has an underlying genetic defect leading to compromised expression of the protein or enzyme and that the mRNA in the composition encodes a functional version of the protein or enzyme.

Auxiliary requests 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 main request presented in section 2.2 above does therefore not apply.

However, as explained in section 2.3 documents D64 and A106 indicate, 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 auxiliary requests 2 and 3 remains of a general and purely functional nature documents D64 and D106 thereby also substantiate serious doubts that the patent provides the skilled person with a sufficient disclosure to generally achieve effective therapy using the mRNA encoding a protein or enzyme as defined in claim 1 of the auxiliary requests 2 and 3.

Auxiliary requests 2 and 3 do therefore also not comply with Article 83 EPC.