EP 3 264 891 A1, filed as PCT application PCT/US2016/020768 relates to Etv2 genes and uses thereof.
The application concerns the generation of pig-human chimeric animals with the aim of using them as a source of human vasculature and blood.
The chimeric pigs are obtained by methods involving “blastocyst complementation“. This involves creating a non-human (host) blastocyst lacking one or more genes involved in the development of the cells of interest.
This creates a so-called “niche” which is complemented by introducing into the blastocyst human pluripotent (donor) cells having those lacking genes. Specifically, in the application, the host blastocyst lacks the Etv2 gene, whose function is to promote hematoendothelial development.
Brief outline of the case
The ED refused the application under Art 53(a) and the applicant appealed.
In a communication under Art 15(1) RPBA, the board indicated, inter alia, that the claims of AR 2 which became the MR in appeal, encompassed ways of implementing the invention which were regarded as offensive to human dignity, contrary to the requirements of Art 53(a) and that the sole purpose of the OP would be to hear the applicant on this objection.
Furthermore, the board referred to Kobayashi et al, Stem Cell Dev. 24(2), 2015, 182-189, published September 2014 and supplied a copy to the applicant.
The ED’s decision
The ED refused the application for ethical reasons pursuant to Art 53(a) in conjunction with R 26(1) and Recital 38 of the Directive 98/44/EC of 06.07.1998 on the legal protection of biotechnological inventions.
It also concluded that, although the invention was directed to the genetic modification of animals, the exclusion under R 28(1,d) was not applicable because the outcome of the so-called “balancing test” developed in the jurisprudence for an objection under this provision, which could be seen as favourable for the invention.
The applicant’s point of view
The ED’s approach to chimeras was unduly restrictive and was not in line with the requirements of Art 53(a) or R 26(1), which provided that Directive 98/44/EC be used as supplementary means of interpretation for patent applications concerning biotechnological inventions.
While Recital 38 of the Directive 98/44/EC referred to the exclusion of chimeras involving human totipotent cells or germ cells from patentability, the claims in suit were directed to blastocysts and methods which involved pluripotent cells.
Moreover, the purpose of the invention was to provide humanised vasculature in swine, suitable for transplantation, rather than providing chimeric animals in which human cells would be found in multiple organs.
Art 53(a) was to be construed narrowly. It was the intended exploitation of the invention that was to be taken into account when analysing compliance with the requirements of Art 53(a). The proprietor referred to T 356/93, T 866/01 and T 315/03.
It was the ED’s duty to substantiate an objection under Art 53(a), cf. T 356/93, Reasons 18 to 18.6). Such a substantiation required conclusive evidence, as opposed to hypothetical scenarios.
However, the ED did not provide evidence that human cells could be found in the claimed chimera other than in the niche corresponding to the deleted porcine gene.
Documents cited by the ED did not provide conclusive evidence of human cells outside the niche and even indicated that human cells did not participate in the chimera’s brain or germ cells.
The ethical concerns raised in the cited documents were not part of the conclusions drawn from the work reported. Far more they amounted to additional thoughts and were mere speculation.
Only established facts were relevant to the decision to be taken under Art 53(a). These facts included other documents which provided examples of chimeras in which the cells of the donor species were not found in brain or germ. Moreover, a document cited by the applicant demonstrated that human cells did not contribute to a cell lineage outside the niche.
Human cells were either not present outside of the niche or if present would be in insufficient numbers to give rise to offensive characteristics in the chimera. Human cells were at distinct disadvantage in a pig embryo and would not survive, inter alia because of the pig’s immune system.
Said same document did not show that the chimeric embryo would have human characteristics because in fact it did not contain much information on human cells. Especially, it was not possible to conclude whether the human cells would survive in the embryo, because it merely showed the results at 2 days after injection of the human cells into the blastocyst.
Further documents also disclosed the usefulness of the invention.
Any concern that human cells would contribute to an organ where they were not desired could be mitigated by further modifying the human cells before introduction into the pig blastocyst.
The board could exercise discretion towards the applicant in view of the usefulness of the invention to provide humanised vasculature for transplantation.
The board’s decision
The board reminded that ethical dimension of patent law has found its expression in Art 53(a), together with the implementing regulations in R 26 to 29 . These Rules were introduced in the EPC to align the EPC with the “EU Biotech Directive” 98/44/EC.
In the jurisprudence of the EBA and of the BAs it was stated that Art 53(a), due to its general wording, embodies overriding legal and ethical norms. Accordingly the concepts of ordre public and morality have been identified for instance by reference to constitutional principles, to the ECHR, and to the Charter of Fundamental Rights of the EU.
The board took the view that the exclusion of Art 53(a) in conjunction with R 28(1) may extend to other chimeras, where the rationale underlying the examples identified in Recital 38 is also applicable to the chimeras concerned. Thus, by means of R 26(1) a further special case is added to the non-exhaustive list of R 28(1).
When considering the possible rationale underlying the specific exclusions of Recital 38, the board found that the reason why the chimeras identified in Recital 38 are regarded as offensive against human dignity is due to concerns that, in chimeras including human germ cells or totipotent cells, these human cells may integrate into the brain and/or develop into germ cells and result in a chimera with human or human-like capabilities.
The board did not consider it necessary to refer to the preparatory work to the EU Biotech Directive. Whereas the recourse to the preparatory work is possible as supplementary means of interpretation under Art 32 VCLT, the board found that in the present circumstances there is no ambiguous or obscure meaning in the wording of the exclusions in Recital 38 which needs to be clarified, nor does the interpretation on account of its object and purpose lead to a result which is manifestly absurd or unreasonable.
On the basis of the documents on file and on the balance of probabilities, the board could only conclude that there is no technical reason to dismiss the ethical concerns, raised in the relevant literature, that human cells may be present in the brain or germ cells of a chimera according to the present invention.
These concerns are relevant for chimeras resulting from the method defined in claim 5, as well as for the chimeras as defined in claims 3 and 4. This conclusion also takes into account that the method defined in claim 5 has no limitations as regards either the number of human cells injected in step (c) and that claims 3 and 4 do not include any limitations as to the number of human cells or exclude their presence in the brain or germ line.
The board noted that the claims under examination were not drafted to exclude embodiments in which human cells are present in the brain and/or germ cells of the chimera.
Conclusive evidence based on scientific publications available at or before the priority date shows that the consensus was that creation of chimeras that give rise to ethical concerns were not regarded as merely hypothetical, but were seen as a genuine possibility.
Furthermore, since the claims were not drafted to exclude embodiments where human cells are present in the brain and/or germ cells of the chimera, for instance by the inclusion of features based on technologies capable of preventing the presence of human cells in the brain and/or germ cells of the chimera, the board did not have to decide on the patentability of such subject-matter.
The board concluded that the claims of AR2 do not fulfil the requirements of Art 53(a).
Comments
That Art 53(a), like all rules for exceptions, ought to be constructed narrowly is not at stake.
The ED considered that the “balancing test” could not be applied, but nevertheless refused the application.
The board introduced by means of R 26(1) a further special case to the non-exhaustive list of R 28(1). It is to be expected that this non-exhaustive list will become longer.
The invention might in the eyes of its proprietor’s be useful, but producing chimeras including human germ cells or totipotent cells, is ethically not acceptable.
As it cannot be excluded that the human cells involved in the chimera integrate into the brain and/or develop into germ cells of the chimera, and result in a chimera with human or human-like capabilities, this invention is indeed incompatible with human dignity.
All what I scientifically possible, is not necessarily a progress.
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