T 1553/22 - Human-pig chimeras

Key points

• "Claims 3 [] of auxiliary request 2 read as follows: "3. A chimeric non-human blastocyst expressing human ETV2 and lacking expression of said non-human animal ETV2, wherein the blastocyst is porcine."
• "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"
• " claims 3 and 4 do not include language that would exclude chimeras having human cell participation in the brain or germ cells."
• The applicant is a university.
• "In the appealed decision, the examining division refused the application for ethical reasons pursuant to Article 53(a) in conjunction with Rule 26(1) EPC and Recital 38 of the Directive 98/44/EC of 6 July 1998 on the legal protection of biotechnological inventions (point 4.16 of the Reasons). "
• The Board: " The ethical dimension of patent law has found its expression in Article 53(a) EPC, together with the implementing regulations in Rules 26 to 29 EPC. These Rules were introduced in the EPC to align the EPC with the Directive 98/44/EC of 6 July 1998 on the legal protection of biotechnological inventions (the "EU Biotech Directive"). In order to achieve harmonised protection in the field of biotechnological inventions in Europe, the EU Biotech Directive provides a supplementary means of interpretation for the EPC (Rule 26(1) EPC). Thus, when the compliance of a biotechnological invention with ethical principles has to be assessed, the legal framework is a composite one, in the sense that the EPC provisions should be understood in the light of the EU Biotech Directive, also including considerations which are outside the strict patentability requirements."
• "Human-animal chimeras are not mentioned in Rule 28(1)(a) to (d) EPC, nor in the provision from which this Rule is derived, namely Article 6(2) of the EU Biotech Directive. However, specific forms of human-animal chimeras are mentioned in Recital 38, which relates to the illustrative list of exclusions for reasons of ordre public and morality provided in Article 6(2) of the EU Biotech Directive. Recital 38 includes the following wording:

"...whereas processes, the use of which offend against human dignity, such as processes to produce chimeras from germ cells or totipotent cells of humans and animals, are obviously also excluded from patentability;".

• "Recital 38 does not exclude chimeras as such, but specifically identifies processes to produce chimeras from germ cells or totipotent cells of humans. Since the present invention involves the use of pluripotent cells, which are distinct from totipotent cells and germ cells, it can be said that Recital 38 does not apply directly.
• This sets up the legal puzzle: if the EU legislator intentionally did not wish to exlcude human-animal chimeras in general (and, at the time of drafting, did not think of pluripotent cells, perhaps), what is excluded? Only the recited type of chemiras? Or some intermediate class?
• "The board takes the view that the exclusion of Article 53(a) in conjunction with Rule 28(1) EPC 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 Rule 26(1) EPC a further special case is added to the non-exhaustive list of Rule 28(1) EPC."
• Rule 26(1): "For European patent applications and patents concerning biotechnological inventions, the relevant provisions of the Convention shall be applied and interpreted in accordance with the provisions of this Chapter. Directive 98/44/EC of 6 July 1998 on the legal protection of biotechnological inventions shall be used as a supplementary means of interpretation."
• "the board finds 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. 
•  This reason is straightforward for chimeras including totipotent cells, which in view of their developmental capability to form an entire organism may form a brain with human-like cognitive abilities or human germ cells. 
• The Board finds it 'straightforward', but that may be a case of hindsight in solving a legal problem.
• "However the same reason applies to pluripotent cells, which despite lacking the ability to differentiate into totipotent cells or cells of the placenta, nevertheless have the ability to differentiate into neural cells or germ cells. Thus, if an invention relates to a situation where human cells might integrate into the chimera's brain, potentially giving the chimera human-like cognitive or behavioural capabilities, or into its germ line, potentially giving it the ability to pass on humanised traits, the board considers that the underlying rationale of Recital 38 of the Directive would be relevant and shall be taken into account in examining compliance with Article 53(a) in conjunction with Rule 28(1) EPC."
• "the board does 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 Article 32 Vienna Convention, the board finds 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."
• Article 32 Vienna Convention indeed limits the use of the preparatory documents to these two cases, though the EPC travaux are cited more freely by the Boards.
• "With regard to the present case it must therefore be established whether the invention defined in claims 3 to 5 includes embodiments that fall under the scope of Recital 38 [by analogy?], thus contravening the requirements of Article 53(a) EPC in conjunction with Rule 28(1) EPC. Specifically, it must be determined whether the claims define chimeras and methods of producing chimeras including embodiments where human cells participate in the brain or germ cells of the chimera."
• "Document D15 is a scientific article on research into ways of regulating the differentiation of the donor cells into the endodermal organs, in order to address concerns that human cells might be present in the germ line or participate in the brain of chimeras resulting from blastocyst complementation. These ethical concerns are set out prominently in the abstract of the document:"Blastocyst complementation, which exploits the capacity of PSCs to participate in forming chimeras, does not, however, exclude contribution of PSCs to the development of tissues - including neural cells or germ cells - other than those targeted ..."."
• "Even years after the date of filing of the application, these concerns remained undiminished, as evidenced by documents D9 and D10, which were made available to the public in 2019 and 2021 respectively."
• " On the basis of the documents on file and on the balance of probabilities, the board can 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 relevant date is the filing date, I understand: "14. The assessment of objections under Article 53(a) EPC, as well as under Rule 28(1) EPC, should be based on the understanding in the technical field at the relevant date of the patent application, although evidence arising after that date may be taken into account, provided it reflects the state of the art at the effective date (see decision T 315/03, Reasons 8.2, 9.5, 9.7 and 10.9)."
• Cf. G 2/08: "Rule 28(c) EPC (formerly Rule 23d(c) EPC) forbids the patenting of claims directed to products which - as described in the application -  at the filing date could be prepared exclusively by a method which necessarily involved the destruction of the human embryos from which the said products are derived, even if the said method is not part of the claims." (not cited in the present decision; and Article 83 EPC might be relevant here).
• "the appellant stressed also the dramatic importance of the present invention in the field of xenotransplantation, potentially the very first step to repair and replacement technology which was previously regarded as pure science fiction. This fact should be balanced against the unsupported ethical concerns raised by the examining division."
• "The board recognises the importance of the present invention. However, for the reasons stated above, balancing tests are irrelevant in the context of the categories of inventions which are excluded from patentability ipso facto. Considerations involving balancing the potential benefits of the invention for humanity/the medical benefit against prejudice to human dignity/animal suffering, are limited to the so-called "real" Article 53(a) EPC objections or to inventions related to the genetic modification of animals within the meaning of Rule 28(1)(d) EPC. Instead, where the legislator wanted to exclude inventions offending life and human dignity as such, there can be no room for manoeuvre (see also G 2/06, Reasons 31)."
  
  
• "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."

• As a comment, if these "technologies capable of preventing the presence of human cells in the brain and/or germ cells of the chimera" are now available and common general knowledge, the Art. 53(a) EPC objection can be addressed with an undisclosed disclaimer (G2/03), most likely, and Article 83 EPC is complied with by the availability of these preventive technologies (and appropriate reference to them in the application as filed).
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• Suppose the preventive technologies also work for the chimeras from germ cells or totipotent cells of humans and animals" are these then patentable (under a dynamic interpretation, perhaps)?

EPO 

The link to the decision can be found after the jump.

https://www.epo.org/en/boards-of-appeal/decisions/t221553eu1