March 17, 2015

Summary

In International Stem Cell Corporation v Comptroller General (Case C-364/13) (“International Stem Cell Corporation”), the Court of Justice of the European Union (“CJEU”) held that a parthenote does not constitute a ‘human embryo’ if, in the light of current scientific knowledge, it does not, in itself, have the inherent capacity of developing into a human being.  As a result, stem cells derived from parthenotes are not necessarily excluded from patentability in Europe, as was thought to be the case following the CJEU’s earlier decision in Oliver Brüstle v Greenpeace (Case C-34/10)(“Brüstle”).

Directive 98/44/ED (the “Biotech Directive”)

Article 6(1) of the Biotech Directive provides that inventions are not patentable where their commercial exploitation would be “contrary to ordre public or morality”.  However, Article 6(1) does not seek to impose a universal standard across the EU for what may and may not be patentable on the basis of ordre public.  Indeed, Recital 39 of the Biotech Directive acknowledges that ordre public corresponds to particular ethical or moral principles recognised in a Member State, and thus envisages that different standards may be applied in different Member States.

Article 6(2) sets out a non-exhaustive list of inventions which are not patentable because their commercial exploitation would be contrary to ordre public or morality.  These examples of unpatentable inventions play an important role in defining a minimum standard across all EU Member States for biotechnological inventions which are to be excluded from patentability on the grounds of ordre public. 

It follows that an invention falling within one of the examples given in Article 6(2) will be excluded from patentability in all EU Member States.  However, if an invention falls outside the examples given in Article 6(2) it may yet be excluded from patentability under the general prohibition of Article 6(1), although the position may vary across the EU as a result of different standards being applied in different Member States.

One of the exclusions listed in Article 6(2) is “[the use] of human embryos for industrial or commercial purposes”.  However, the Biotech Directive does not define ‘human embryo’ and this has created uncertainty about what stem-cell related inventions fall within this particular exclusion.

Brüstle

The meaning of ‘human embryo’ was previously considered by the CJEU in Brüstle.  In that case the CJEU held that the term “must be understood in a wide sense”, and included any human ovum from the moment of its fertilisation “since that fertilisation is such as to commence the process of development of a human being”.

As regards parthenotes[i], the CJEU concluded that “any non-fertilised human ovum whose division and further development have been stimulated by parthenogenesis constitute[s] a human embryo”.  The CJEU’s reasoning was as follows:

“Although those organisms have not, strictly speaking, been the object of fertilisation, due to the effect of the technique used to obtain them they are, as is apparent from the written observations presented to the Court, capable of commencing the process of development of a human being just as an embryo created by fertilisation of an ovum can do so.”

International Stem Cell Corporation – UKIPO Proceedings

International Stem Cell Corporation (“ISC”) filed two patent applications at the UK Intellectual Property Office (“UKIPO”) relating to the generation of, and derivation of stem cells from, parthenotes and associated therapeutic applications.

ISC put forward evidence to demonstrate that parthenotes are not capable of developing into human beings due to the absence of paternal DNA, which is necessary for normal embryonic development in mammals because of genomic imprinting (i.e. the differential expression of certain genes depending on whether they derive from maternal or paternal DNA).  On this basis, ISC argued that the ruling in Brüstle should not be applied because it was based on an incorrect finding of fact that parthenotes are “capable of commencing the process of development of a human being”.

The central issue for the UKIPO to determine was what the CJEU meant in Brüstle by the phrase “capable of commencing the process of development of a human being”.  Is this test concerned only with whether a cell has the capacity to start the development process (i.e. going through cycles of cell division), regardless of whether it has the capacity to complete that process and produce a viable human being?  Or is the capacity to complete the development process (i.e. the capacity to produce a viable human being) an essential requirement of the test?

In considering this issue, the UKIPO took note of the factual findings of the referring court (the German Bundesgerichtshof) in Brüstle, which stated:

“Whether [parthenogenesis] is actually feasible and whether such a cell could develop into a complete individual, has not yet been absolutely clarified from a scientific perspective. Independent of this one point in favour of qualification as an embryo as defined in Art. 6 para. (2c) of the Directive could be the fact that such cells in any event in the first division stages go through the same development as a fertilised egg cell and therefore appear worthy of protection”.

The UKIPO also considered the opinion of the Advocate General in Brüstle (see here), which made a clear distinction between totipotent cells and pluripotent cells and recommended that the CJEU limit the meaning of human embryo to cells which have the capacity to develop into human beings (i.e. totipotent cells). With regard to parthenotes in particular, the Advocate General stated that “Unfertilised ova…whose division and further development have been stimulated by parthenogenesis are also included in the concept of a human embryo in so far as the use of such techniques would result in totipotent cells being obtained.”  

However, the CJEU did not follow the Advocate General’s clear distinction between totipotent or pluripotent cells, and instead appeared to focus its test on the start of the developmental process and the fact (put before it by the German Bundesgerichtshof) that in the early stages, the development of parthenotes and fertilised ova are the same.

As a result, despite accepting that parthenotes are not capable of completing the development process into human beings and that the test set out in Brüstle was open to an alternative interpretation, the UKIPO felt bound by the finding of the CJEU that parthenotes are to be treated as human embryos for the purpose Article 6(2)(c) of the Biotech Directive.

ISC’s Appeal to the Patents Court

On appeal to the Patents Court[ii], ISC argued that the phrase “capable of commencing the process of development of a human being” required both the capacity to start the process of development into a human being and the capacity to complete that process: cells which were not capable of producing human beings should not constitute a human embryo.  ISC maintained its position that the CJEU had based its ruling on a flawed factual finding (i.e. that parthenotes were capable of developing into human beings).

By the time the Patents Court heard ISC’s appeal, ISC had obtained copies of a number of the written observations that had been put before the CJEU in Brüstle. ISC’s submissions as to contents of these observations was summarised as follows at [40]:

“Prof. Brüstle equated parthenotes with fertilised ova but only up to day 14 and before implantation. Greenpeace sought to equate parthenogenesis with the development of human life but without providing any technical basis for its position. The Portuguese Government said that it was “reasonable to accept” that parthenogenetic embryos have the potential to create a human being, although it acknowledged that the viability of embryos to birth had not been unequivocally proven. The Swedish Government said that is [sic] was too early to decide whether parthenotes should be regarded as embryos given the early stage of scientific research in this area. The Commission said that it was not clear whether a parthenote could develop into a complete human being. The UK’s observations were at best equivocal as to the capacity for parthenotes to develop into human beings.”

The Comptroller agreed that there was no consensus in the written observations before the CJEU as to the ability of parthenotes to develop into human beings.

Henry Carr QC (sitting as a Deputy Judge of the High Court) considered that the CJEU was entitled to reach the conclusion it did on the basis of the submissions before it which highlighted the similarity between the initial development of parthenotes and fertilised embryos. However, he also agreed with the UKIPO that the meaning of “capable of commencing the process of development of a human being” was unclear and he referred the matter to the CJEU.

The CJEU’s decision in International Stem Cell Corporation

The question referred to the CJEU in International Stem Cell Corporation was the same as one of the questions referred to the court in Brüstle save that it included the clarification that “[parthenotes], in contrast to fertilised ova, contain only pluripotent cells and are incapable of developing into human beings”.

The CJEU decided that to satisfy the condition of being “capable of commencing the process of development of a human being”, a non-fertilised human ovum must have “the inherent capacity of developing into a human being”.  In other words, a parthenote will be regarded as a human embryo for the purpose of Article 6(2)(c) of the Biotech Directive only if it is capable of developing into a viable human being.  The fact that a parthenote might be capable of starting that process, or at least a closely analogous process, is not of itself enough to bring it within the meaning of a ‘human embryo’.

However, mindful of the possibility that the state of scientific knowledge may advance so that it may become possible to confer upon parthenotes the capacity to complete the development process and give rise to viable human beings, the CJEU conditioned the “inherent capacity” test to the “current state of scientific knowledge”.  The operative part of the CJEU’s decision therefore reads as follows:

Article 6(2)(c) of the Biotech Directive “must be interpreted as meaning that an unfertilised human ovum whose division and further development have been stimulated by parthenogenesis does not constitute a ‘human embryo’, within the meaning of that provision, if, in the light of current scientific knowledge, it does not, in itself, have the inherent capacity of developing into a human being, this being a matter for the national court to determine”.

Noting that this decision was at odds with the decision reached in Brüstle, the CJEU expressly distinguished Brüstle on the basis that in that case:

“it was apparent from the written observations presented to the Court that an unfertilised human ovum whose division and further development have been stimulated by parthenogenesis did have the capacity to develop into a human being.  This is precisely why, on the basis of those observations, the Court held, in that judgment, that, in order to define the term ‘human embryo’, within the meaning of Article 6(2)(c) of Directive 98/44, a non-fertilised human ovum whose division and further development have been stimulated by parthenogenesis should be treated in the same way as a fertilised ovum and, therefore, be classified as an ‘embryo’. By contrast, in the present case, all parties and the referring court agreed that parthenotes do not have such a capacity.”

Discussion

This case provides some welcome clarity for the stem cell research community.  It suggests that stem cells derived from cell bodies that are incapable of developing into human beings fall outside Article 6(2)(c) of the Biotech Directive and may be the subject of patent protection in the EU.  However, such inventions may still be excluded from patentability under Article 6(1), although exclusion on this basis may not be universal across all Member States of the EU.

It will be tempting to view this new test for ‘human embryo’ as providing an easy distinction between totipotent cells (which are likely to constitute human embryos) and pluripotent cells (which are unlikely to constitute human embryos).  However, the ruling is strictly speaking confined to unfertilised ova stimulated by parthenogenesis which will invariably involve only pluripotent cells.  Even if the reasoning underlying the decision can be extended to other methods of generating stem cells, the totipotent / pluripotent distinction should be viewed only as a rule of thumb.  The real test is whether the cell has the “inherent capacity to develop into a human being”, and as was expressly recognised, with further manipulation, it may be possible to confer upon pluripotent cells the ability to develop to term.

Indeed, the UKIPO cited two papers in which parthenotes had been subjected to further genetic manipulation, including the addition of exogenous genetic material, to overcome maternal imprinting and the absence of paternal imprinting.  Following such manipulation live born mice were reported to have developed from cells of parthenogenetic origin.  Similarly, some totipotent cells may, because of some abnormality, for example, an additional copy of the genetic material (triploidy), lack the ability to develop to term, but may be manipulated using micro-surgical techniques to remove the third copy of the chromosomes, thus restoring the cells’ ability to develop normally to term.

In view of the fact that it may be possible for cells which lack the inherent capacity to develop into a human being to be manipulated so as to confer upon them that capacity, it is likely to become routine to seek to exclude such manipulations from the scope of the claims.  Indeed, ISC sought to do this by limiting its claims to pluripotent cells lacking paternal imprinting.

While the departure from the CJEU’s earlier decision in Brüstle is to be welcomed, the basis for it seems unsatisfactory.  The CJEU distinguished its earlier decision in Brüstle on the basis that, in Brüstle, it was “apparent” from the written observations “that parthenotes had the capability to develop into human beings”.  This characterisation of the contents of the written observations in Brüstle is to be contrasted with the submissions made by the parties before the referring court: both ISC and the Comptroller agreed that while there was broad consensus to be found in the written observations before the CJEU in Brüstle for the proposition that parthenotes are analogous to fertilized ova in the early stages of development, there was no such consensus for the proposition that parthenotes could in fact develop into human beings.  If the latter reading of the written observations before the CJEU in Brüstle is correct, then it would suggest that the basis for the CJEU’s decision in that case was that parthenotes are capable of starting the process of development into human beings (and may be able to complete that process).  This would be consistent with the test enunciated by the CJEU in Brüstle namely, “capable of commencing the process of development of a human being”. 

On this basis the decisions in Brüstle and International Stem Cell Corporation can be reconciled as follows.  When Brüstle was decided, the evidence did not rule out the possibility that parthenotes had the inherent capacity to develop into human beings.  In these circumstances, a cautious approach which focused on the start of the developmental process (rather than on the ability to complete that process) appears to be justified. However, the evidence before the court in International Stem Cell Corporation ruled out such a possibility (save for instances where parthenotes are genetically modified to overcome the inhibition to the development process caused by genomic imprinting). Accordingly, the dignity and integrity of the person was, on the evidence, no longer at risk and the CJEU’s decision to exclude parthenotes from the definition of ‘human embryo’ can also be justified.  In other words, it seems that the key issue to be determined in these cases is whether the state of “current scientific knowledge” excludes the possibility that a particular cell body has the inherent capacity to develop into a human being.  This of course raises the following questions: (1) at what date is the state of scientific knowledge to be assessed; and (2) what level of consensus is required among the scientific community before the possibility that the cells in question could develop (without further manipulation) into a human being can be ruled out?

In relation to the first of these questions, it is noted that the priority dates of the patent applications at issue are, in Brüstle, 19 December 1997 and, in International Stem Cell Corporation, 21 October 2005 and 24 July 2006, and that the papers relied upon by ISC to confirm that parthenotes could not develop to term were published in 2007 and 2008[iii], albeit that genomic imprinting had been suggested as a mechanism for the failure of parthenotes to develop to term as early as 1984[iv].  From this it would appear that advances in scientific knowledge after the priority date may be taken into consideration.  While this approach may allow the ‘right’ answer to be reached in any given case, it creates a degree of uncertainty as to the patentability of certain stem cell inventions might change during the 20 year term as the science advances.

As for the second question, the CJEU referred to its earlier decision in Smits and Peerbooms (Case C-157/99) in which it held that scientific knowledge must be “sufficiently tried and tested by international medical science”.  The meaning of this however seems to be rather unclear, especially since, in the context of Article 6(2)(c) of the Biotech Directive, the scientific knowledge must prove a negative.

Finally, the inconsistency in the judgments of the CJEU and the referring court noted above highlights some of the more regrettable features of proceedings before the CJEU: the written observations are not generally available to the public and judgments are generally brief and do not include detailed reasoning.  As a consequence it is often difficult to properly scrutinise decisions of the CJEU and in certain instances, such as Brüstle, to decipher with certainty the basis upon which a judgment is made.  This can often cause difficulties for national courts in seeking to apply the guidance of the CJEU to a particular set of facts and can result in a proliferation of further references to the CJEU seeking clarification of essentially the same point.

Published with minor alternations in Bioscience Law Review Vol. 14, Iss. 3.

Footnotes:

[i] An unfertilised egg that has been artificially activated (by chemical or electrical means) to divide and develop.

[ii] [2013] EWHC 807 (Ch)

[iii] Revazova et al., Cloning and Stem Cells [2007] Vol 9 pp 432-449; Kastenberg et al., Transplantation Reviews [2008] Vol 22 pp 215-222; Brevini & Gandolfi, Cell Proliferation [2008] Vol 41 pp 20-30; Kim et al., Cell Stem Cell [2007] Vol 1 pp 1-7.

[iv] McGrath, J., & Solter, D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37, 179–183 (1984); Surani, M. A. H., et al. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308, 548–550 (1984).