THE DEATH OF STEM CELL PATENTS? NO: A REGRETTABLE DECISION BUT AN EXAGGERATED RUMOUR
The Court of Justice of the European Union (CJEU) has issued its much anticipated ruling in the case of Brüstle v. Greenpeace e.V. (C-34/10). Ever since, a rash of hastily written stories has appeared in the news trumpeting the death of stem cell patents, lamenting their passing and predicting the destruction or exodus of stem cell research in Europe. Whilst there is bad news for some, meaning existing patents or applications may now contain no valid subject matter, these rumours of the demise of stem cell patents have been exaggerated. Perhaps, the resultant certainty coupled with today’s technology means the future for patenting stem cell inventions in Europe could not be better.
Brüstle v. Greenpeace e.V. (C-34/10) concerns a patent held by Professor Oliver Brüstle, who is the director of the Institute of Reconstructive Neurobiology at the University of Bonn. His research includes treating neurological disease by transplanting neural stem cells into patients. The patent in question was granted in 1999 and embraces neural progenitor cells (precursors of nerve cells), neuronal cells derived from these precursor cells and a method of producing them from human embryonic stem cell lines (hES lines).
In 2004 Greenpeace filed a request at the German Federal Patents Court that the German patent be revoked because the subject matter of the patent was contrary to ordre public or morality. The German Federal Patents Court found the patent to be partially invalid and all claims relating to cells derived from hES cells were deleted. Professor Brüstle appealed this decision to the German Federal Court of Justice who referred the case to the CJEU for a preliminary ruling on the interpretation of Article 6(2)(c) of the European Biotech Directive (Directive 98/44/EC; [the Directive]), which says that ‘uses of human embryos for industrial or commercial purposes shall be considered unpatentable on the basis that commercial exploitation would be contrary to ordre public or morality’. The central issue was that the Directive does not define what is a ‘human embryo’ nor what are ‘industrial or commercial purposes’. Consequently the questions the German court asked were:
- 1. What is meant by the term ‘human embryos’ in Article 6(2)(c) [of the Directive]?
- (a) Does it include all stages of the development of human life, beginning with the fertilisation of the ovum, or must further requirements, such as the attainment of a certain stage of development, be satisfied?
- Are the following organisms also included:
– unfertilised human ova into which a cell nucleus from a mature human cell has been transplanted;
– unfertilised human ova whose division and further development have been stimulated by parthenogenesis?
- (c) Are stem cells obtained from human embryos at the blastocyst stage also included?
- 2. What is meant by the expression ‘uses of human embryos for industrial or commercial purposes’? Does it include any commercial exploitation within the meaning of Article 6(1) of [the Directive], especially use for the purposes of scientific research?
- 3. Is technical teaching to be considered unpatentable pursuant to Article 6(2)(c) of the Directive even if the use of human embryos does not form part of the technical teaching claimed with the patent, but is a necessary precondition for the application of that teaching:
- – because the patent concerns a product whose production necessitates the prior destruction of human embryos,
– or because the patent concerns a process for which such a product is needed as base material?
We had some idea of the potential content of the judgement in March when the Advocate General (AG) issued his opinion (for comment thereon, see G. Schlich’s article in the April 2011 edition of the CIPA Journal [ref 1]). As it turns out the court did largely follow the AG’s opinion, but they did not adhere to it completely. Their final answers to the questions were as follows.
In answer to Question 1 the CJEU defined the meaning of the term ‘human embryo’, which was not defined in the Directive, as being:
“Any human ovum after fertilisation, any non-fertilised human ovum into which the cell nucleus from a mature human cell has been transplanted and any non-fertilised human ovum whose division and further development have been stimulated by parthenogenesis [constitute a ‘human embryo’]”
The CJEU went on to find that an invention that requires the destruction of an embryo is unpatentable and this assessment was to be made from the disclosure of the specification as a whole and not only the invention defined by the claims.
This appears to be in line with EPO decision G2/06 (WARF) but this judgement goes beyond WARF in considering that the definition of an embryo must be understood in a ‘wide sense’, as is demonstrated by the court’s answer to Question 3 and which is discussed below.
The judgement also further defines what fertilisation means in this context stating, ‘if that fertilisation is such as to commence the process of development of a human being’.
While the CJEU followed the AG’s opinion as to the definition of a human embryo, one aspect of the AG’s opinion that has not been confirmed by the CJEU and that has been referred back to the German court to decide upon is the question of whether each of the cells of the inner cell mass (ICM) of the blastocyst (see illustration) are also ‘human embryos’, i.e. whether, in the light of scientific developments, they are capable of commencing the process of development of a human being.
The AG’s view was that a cell of a human embryonic stem cell (hES) line derived from the ICM is pluripotent rather than totipotent, and that such a pluripotent cell in isolation cannot be regarded as constituting an embryo in itself because it is not capable of developing into a complete individual. In reaching this decision the AG considered the national law of some of the member states and concluded that most of them, including Germany and the UK, took the view that pluripotent cells are not human embryos. This seems reasonable scientifically as otherwise the ICM of an entity we normally regard as a single embryo would be deemed to contain multiple separate embryos. As mentioned above, this aspect of the AG’s opinion has not been confirmed by the CJEU.
In answer to the second question, the CJEU decided that ‘the use of human embryos for the purposes of research which constitutes the subject matter of a patent application cannot be separated from the patent itself’. As patents are necessarily commercial instruments, scientific research leading to a patent application is necessarily also commercial in nature. So, we can see nothing that falls outside the commercial or industrial exploitation referred to in the exemption wording apart from, as reaffirmed by the court, the concept that use ‘for therapeutic or diagnostic purposes which are applied to the human embryo and are useful to it’ remain patentable.
Regarding the answer to Question 3 of the decision, the WARF decision previously concluded that an invention would be unpatentable if it necessarily destroyed an embryo, and hence patentable stem cell-based inventions were restricted to those where carrying out the invention did not necessarily require the destruction of a human embryo. Most accepted it followed that inventions that were filed after hES lines became available were patentable, as there was no disclosure or necessity for further embryos to be destroyed.
On this question, the CJEU decided that ‘an invention must be regarded as unpatentable, even if the claims of the patent do not concern the use of human embryos, where the implementation of the invention requires the destruction of human embryos or their use as base material whatever the stage at which that takes place’. Therefore, the answer to Question 3 may be more restrictive than the WARF decision in that it will be argued that even if the destruction of the embryos occurs at a stage long before the implementation of the invention, such as in the production of an hES stem cell line which is maintained for months or even years before cells from the line are used for carrying out the invention, then the invention did historically destroy an embryo and is not patentable. This may therefore extend non-patentability of stem-cell based inventions to those that could have been worked at their filing date by using hES lines because these hES lines were originally generated by harvesting cells from a human embryo and this necessarily resulted in its destruction.
Furthermore, on the face of it the ruling against the patentability of inventions ‘where the implementation of the invention requires the destruction of human embryos […] whatever the stage at which that takes place’ would appear to have consequences outside the stem cell field. In use, do not both contraception (that prevents implantation) and in vitro fertilisation (IVF) (by the standard practice of producing multiple embryos) cause the destruction of ‘human embryos,’ as defined by the ruling?
Summary so far
We write as people who favour patenting of stem cell inventions. The decision expands the definition of ‘human embryo’, allows patentability only in the narrowest of circumstances (therapy on the embryo) and finds that everything that merits a patent application is commercial or industrial. So far, so bad?
We understand that the UKIPO is actively considering the impact of the Brüstle decision and will not be waiting for the German court to opine first. It seems the EPO too will not delay: Benoît Battistelli, EPO President, has posted an entry on the EPO blog [ref 2] saying that ‘If the judges rule in favour of a restrictive interpretation of biotech patentability provisions, the EPO will immediately implement it’.
Potential challenges to the decision
With such an emotive and potentially commercially important issue what prospects are there for challenges to finally clarify the boundaries of the exception to patentability? Might it be argued, for example that:
- Re: hES cell lines, if the embryos were to be destroyed imminently owing to being excess to requirements following IVF treatment then was it the process of cell line preparation that necessarily led to their destruction; was it not the fact the embryos were inevitably in excess?
- Re: any invention in particular, the embryo was not destroyed by that invention. If a single hES cell line provides material leading to 10 separate inventions, isn’t just the first one unpatentable?
It is clear that totipotent cells are not patentable as these can be considered to be human embryos. However, in line with the thoughts above, would an invention that utilises cells differentiated from a totipotent cell be patentable? Such cell lines have been created already by removing and culturing a single cell from an eight-cell embryo. This is an adaptation of pre-implantation genetic diagnosis (PGD), which is a diagnostic technique used during IVF treatment. PGD works by using the cell removed from the embryo to screen for genetic abnormalities before implanting the (not destroyed) now seven-cell embryo. However, this removed cell can be cultured to produce a stem cell line and necessarily the embryo is not destroyed (and can go on to develop fully) after the single cell is harvested. While the cells of this stem cell line are pluripotent, i.e. they can become any foetal or adult cell type, they are not individually able to implant or develop into a human. In this way they are similar to the individual cells of the blastocyst that the CJEU have requested that the referring court decide upon. Further rulings from national courts on the second part of Question 1 may clarify the legal status of cell lines produced in this way and the patentability of any pluripotent cells derived from them.
As we mentioned above, the Brüstle decision caused a certain amount of upset amongst stem cell scientists and researchers who felt that this was a regrettable decision that would impede progress in stem cell research in Europe by causing uncertainty and doubt amongst investors as to whether they would be able to protect their investment. The feeling seemed to be, ‘who will invest in Europe, in us, if you can’t patent here’ and ‘while Europe is the leader in stem cell research, can we really convince investors and researchers that the future of this research is in Europe when our inventions will have to be commercialised in other markets’? It appears to us that this angst is not necessary. A lot of this worry seems to arise from researchers and inventors having become used to the idea that patent protection is essential for any progress and that any reduction or change in scope will invalidate their efforts. Another concern raised in the media was that investment in stem cell research will not come to or stay in Europe. The decision does not affect patents outside Europe for European companies, and therefore they can still file for protection elsewhere, and either not seek patent protection within the European region or file in Europe expecting narrower or no protection.
However, we think this view is overly pessimistic because there is much less cause for concern than this, especially regarding new and ongoing investment. For new inventions, options for avoiding embryo-derived hES cells can now plausibly be used: induced pluripotent stem cells (iPS cells; pluripotent cells derived from differentiated adult or foetal tissue cells) and non-destructive methods of removing cells from an embryo and culturing them, for example.
In short, there are practical, patentable alternatives to the now non-patentable (embryo-destructive) hES cell line-derived technologies. The Brüstle decision gives us clarity as to what we can do to develop and exploit these. Investors tend to hate uncertainty and this decision removes a certain amount of uncertainty for them; they better understand now how they will be able to protect their investments and consequently there is probably less risk that investment will go outside Europe.
One further practical point is that stem cells are not a simple technology to bring to market. The regulatory hurdles to be cleared before gaining official approval are daunting but the benefit of these hurdles is that it is very difficult for a competitor to produce a generic version of a stem cell therapy for sale. Two reasons for this are: (i) the period of exclusivity for the data produced to gain regulatory approval is a significant barrier and the product produced has to be the same specific cell type which has been approved. This may be not easily reproduced or impossible to reproduce at all; and (ii) in order to reduce the risk of teratomas growing from implanted pluripotent stem cells, the stem cells used for therapy may be required to be supplied with other proprietary features and thus not available for copying or propagation by potential infringers.
Consequences in practice
The practical consequences for research and development being carried out today and in the recent past may actually be rather limited. Researchers will continue to use the most tractable experimental system that suits their research. Should this then turn out to be the hES cells derived from embryo destruction and that are available from cell-line repositories then they will use them. The technologies and products that will issue from this research will probably remain patentable because new versions of stem cell technologies, such as those using iPS or PGD-derived cells that are produced without destroying embryos, could be used to work the invention. In particular cases these alternatives will have not been used, but could have; the invention is patentable because embryo destruction was not inevitable.
Which patents are in trouble?
It seems clear that some patents filed during the initial rise of this new technology will not be enforceable. Patents and applications are on file disclosing inventions that use hES cells as the only starting material and having a filing date when there were no other plausible alternatives that did not inevitably destroy embryos. It will be argued based on the answer to Question 3 that these patents and applications are doomed.
Which patents are clearly OK?
In contrast there are filings that are clearly not going to be affected by the current ruling, such as inventions that are based on adult stem cells, foetal stem cells or iPS cells etc., i.e. those that have been produced without destruction of a human embryo.
And what of the grey area in between?
In between these two extremes is a twilight area. When, at the dawn of this new technology, did it become plausible that the skilled person could have used alternative techniques that did not necessarily involve embryo destruction at any stage in the past? Is the reference to ‘use as base material’ an even broader definition of use of an embryo that does not require destruction, just ‘use’ in some way? If an invention utilises hES cells where an embryo was destroyed in order to produce the cells or cell line but could reasonably have been carried out at the filing date by a non-embryo-destructive technique, such as those mentioned above, then the invention should remain patentable. As far as we know the earliest disclosure of iPS cells was published on 20 November 2007 [ref 3] and the earliest mention of hES cells derived from a PGD-type technique was published on 23 August 2006 [ref 4]. If any of our readers know of earlier disclosures we would, of course be delighted to hear from you.
As mentioned above, researchers will use the most tractable and eloquent experimental system available to them as this is the most likely to produce a workable invention for them. However the invention will be patentable if it is plausible that it can be worked using patentable embryonic stem cell types – if embryo destruction was not inevitable. Following the Brüstle decision we can envisage a scenario where a potential infringer will then use unpatentable hES cells to work an otherwise patented invention believing themselves to be outside the scope of patent protection; it appears to us that they will still infringe. Wilfully immoral infringement still constitutes infringement. A (contrary to morality) booby-trapped vehicle could not be patented itself but if it contains all features of a claim to a vehicle it still infringes that claim, as that claim is based on patentable subject matter. Why would the stem cell field be different?
This line of reasoning leads us to a situation that may not be immediately apparent. Today you could use experimentally tractable hES cells to produce an invention that would not, on its face, be patentable. However, recent advances in the art, such as those mentioned above, may very well make it plausible that this unpatentable invention can be worked by using patentable subject matter, thus conferring patentability. A third party using an unpatentable embodiment of the invention, however, will infringe.
Obviously, we are disappointed with the ruling in that it may restrict the patentability of historically filed stem cell based inventions still further than WARF and render some granted patents unenforceable. However, the consequences of the Brüstle decision for the future may, in fact, be positive. The ruling has yielded greater certainty for researchers and investors, and, in terms of investment and commercialisation of inventions, certainty is a good thing.
It appears to us that patents and applications relating to human embryonic stem cells fall into the following categories:
- Those using hES cells prior to the deposit of hES cell lines.
- Those filed after hES cell lines had become available, for which it may be arguable embryos were not necessarily destroyed for the purposes of the invention.
- Those filed after new sources of human embryonic stem cells became available, whose creation does not require destruction of an embryo and that may plausibly be worked by using them.
Thus, there is effectively a window of uncertainty in the middle. Only the fine interpretation of the decision will determine whether those caught in the middle retain patentable subject matter. Patentees caught in this window will inevitably be disappointed with the ruling and the European Patent Office will no doubt take an initial view that tends to deny patentability; it should expect challenges. It is a misconception, however, that later inventions can no longer be patented or enforced; this is simply wrong and in fact the opposite is true.
As regards investment going elsewhere, the skills base is strong in Europe and, while scientists are worried, it appears that patents for inventions utilising hES cells developed today and in the recent past will remain enforceable. In short we see no reason for concern about the future of the stem cell sector in Europe, it is however a shame about some of the past.
- Schlich, G.W. (2011) Stem cell patenting in Europe: a plea to the CJ. CIPA Journal April 2011.
- Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. (2007). Science Dec 21; 318(5858) 1917-20. (Published online 20 November 2007.)
- Klimanskaya I, Chung Y, Becker S, Lu SJ, Lanza R. (2006). Human embryonic stem cell lines derived from single blastomeres. Nature 444, 481-485. (Published online 23 August 2006.)