T 0197/22 - First medical use claims

Key points

• "in case of a claim for a composition for use under Article 54(4) EPC [first medical use claim] 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)."
• A totally uncontroversial statement until you compare it with the May 2024 PTAB USPTO decision  (APR pane) Ex parte Chamberlain, Appeal 22-1944 where a claim directed to " a method of treating a patient by administering an anti-C5 antibody [, said antibody] comprising ..." was considered and found to be invalid as lacking sufficient support by the description". Moreover, the decision comes directly from the USPTO Director, along with the Commissioner for Patents and the Chief Administrative Patent Judge. (Patently-O).
• "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."
• "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."
• "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. "
• " 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."
• "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.  Accordingly, the Board concludes that the main request does not comply with Article 83 EPC."
• The composition defined in the claim was as follows: " at least one mRNA molecule ...  encapsulated in a liposome having a size of less than 100 nm, wherein said liposome comprises one or more cationic lipid(s), one or more non-cationic lipid(s), and one or more PEG-modified lipid(s)," 
• EPO 

The link to the decision and an extract of it can be found after the jump.

https://www.epo.org/en/boards-of-appeal/decisions/t220197eu1

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.