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Stem cell patents in Europe

21 November 2017

Summary

Stem cells are able to differentiate into specialised cell types and therefore have great potential as tools for therapeutic tissue and organ regeneration. As a result, they are the focus of a considerable amount of academic and industrial research. The use of human embryos to obtain stem cells is controversial, and European Union (EU) legislation, specifically the Biotechnology Directive, restricts patentability of inventions relating to human embryos. This article summarises the relevant legal provisions of the Biotechnology Directive; how they have been interpreted by the Court of Justice of the EU (CJEU) and national courts of the EU Members states, and by the EPO; and areas of remaining uncertainty. Technologies involving pluripotent stem cells, including human embryonic stem cells or parthenotes, are in principle patentable in Europe if the cells are derivable without destruction of a human embryo. The existence of suitable established methods for obtaining human pluripotent stem cells should create greater freedom for patenting new stem cell technologies in Europe. However, it remains uncertain whether induced totipotent stem cells derived from non-embryonic human tissue would be eligible for patent protection.

Relevance and Provisions of the EU Biotechnology Directive
 
The Biotechnology Directive (Directive 98/44/EC on the legal protection of biotechnological inventions1) is the most important piece of legislation relating to the patentability of biotechnological inventions in Europe.  It has been enacted into the legislation of the EU Member states and is enforceable throughout the EU. In interpreting the provisions of the Biotechnology Directive, national courts from the EU Member states may refer questions to the Court of Justice of the EU (CJEU), which has ultimate responsibility for interpreting EU law.
 
The Biotechnology Directive has also been adopted into the legal provisions of the European Patent Convention (EPC), and therefore applies to European patents granted by the European Patent Office (EPO).  Notably, European patents may cover territories which are not EU Member states, such as Switzerland.  Therefore, the interpretation of the Biotechnology Directive is of fundamental importance in governing the patenting of human stem cell technologies throughout Europe, including in both EU and non-EU Member states.  
 
Article 1(1) of the Biotechnology Directive provides that EU Member states must protect biotechnological inventions under national patent law.
 
Exclusions from patentability are provided by Articles 5 and 6.
 
Article 5(1) states:
 
“The human body, at the various stages of its formation and development, and the simple discovery of one of its elements ... cannot constitute patentable inventions.”
 
Article 6 provides that:
 
“1. Inventions shall be considered unpatentable where their commercial exploitation would be contrary to ordre public or morality; however, exploitation shall not be deemed to be so contrary merely because it is prohibited by law or regulation.
 
2. On the basis of paragraph 1, the following, in particular, shall be considered unpatentable:
.
.
(c) uses of human embryos for industrial or commercial purposes...”
 
The Brüstle case - CJEU decision C-34/102
 
Greenpeace sought revocation of a German patent in the name of Professor Oliver Brüstle that concerned neural precursor cells which may be produced from embryonic stem cells. The German court referred three questions to the CJEU, relating to the meaning of the terms “human embryos” and “uses of human embryos for industrial or commercial purposes”; and the patentability of inventions which require the prior destruction of human embryos to provide starting materials for a claimed product or process.
 
The CJEU answered the first question by defining a human embryo as:                      
 
“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”.
 
The reasoning defined each of the specified organisms as a human embryo because they were considered to be “capable of commencing the process of development of a human being”. The definition of human embryo does not include totipotent stem cells, which are capable of differentiating into any other cell type of the body.  The CJEU therefore appears to have left open the possibility that totipotent stem cells might be excluded from the definition of a human embryo, potentially leaving the door open for the patenting of technologies based on induced totipotent stem cells, if and when this technology is realised. This topic is discussed further below. 
 
The decision also stated that:
 
“...it is for the referring court to ascertain, in the light of scientific developments, whether a stem cell obtained from a human embryo at the blastocyst stage constitutes a ‘human embryo”.
 
The answer to the second question confirms that the exclusion covers the use of human embryos for purposes of scientific research. Only use for therapeutic or diagnostic purposes which is applied to the human embryo and is useful to it is held to be patentable.
 
In considering the third question, the reasoning highlighted the fact that destruction of an embryo may occur at a stage long before the implementation of the invention, as in the case of the production of embryonic stem cells from a lineage of stem cells that had been produced by destruction of a human embryo. 
 
The decision stated that inventions are excluded from patentability if their technical teaching:
 
“requires the prior destruction of human embryos or their use as base material, whatever the stage at which that takes place and even if the description of the technical teaching claimed does not refer to the use of human embryos”.                                            
It is not entirely clear whether the exclusion is intended to relate to the use of destroyed human embryos as base material, or any use of human embryos as base material, including non-destructive use.  The reasoning for the decision highlights the impermissibility of destruction of the human embryo, rather than its use per se, suggesting that the exclusion relates only to destructive use. 
 
In applying the CJEU’s ruling, the German Federal Court of Justice (BGH) decided that the neural precursor cells could be produced without destruction of a human embryo, and upheld the patent with the proviso that subject matter involving the destruction of embryos was removed from the claims using an ‘undisclosed disclaimer’ (a negative limitation absent from the specification).
 
Furthermore, in the opinion of the BGH, the use of human embryonic stem cells cannot be qualified as a use of an embryo within the meaning of the Biotechnology Directive, because embryonic stem cells are not capable of commencing the process of development of a human being. Embryonic stem cells are “pluripotent”, meaning they are capable of differentiating into many, but not all, other cell types of the body.
 
The BGH appears to have interpreted the CJEU’s ruling as not excluding patent protection for an invention which requires non-destructive use of a human embryo as base material.  Thus, patent protection in the field of stem cell research is possible as long as the needed embryonic stem cells are not obtained from the destruction of a human embryo.
 
The International Stem Cell Corporation case - CJEU Decision C-364/133 
 
This case concerned a UK patent application in the name of International Stem Cell Corporation, covering a process in which unfertilised ova are stimulated to divide and reach a stage in development where stem cells may be isolated. The Brüstle decision concerning the scope of the meaning of “human embryos” would exclude the process from patentability as pertaining to “a non-fertilised human ovum whose division and further development have been stimulated by parthenogenesis”. Therefore, the application was refused by the UK Intellectual Property Office (UKIPO) and the Applicant appealed against the decision at the English High Court. 
 
Since Brüstle, new scientific knowledge established that while an ovum can be stimulated to produce all of the cell types found in a human, in the absence of paternal DNA it cannot develop into a human. In considering the appeal, the High Court referred the following question to the CJEU:
 
“Are unfertilised human ova whose division and further development have been stimulated by parthenogenesis, and which, in contrast to fertilised ova, contain only pluripotent cells and are incapable of developing into human beings, included in the term 'human embryos' in Article 6(2)(c) of Directive 98/44/EC on the legal protection of biotechnological inventions?"
 
The CJEU answered the question as follows:
 
“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.”
 
In applying the ruling of the CJEU, the UKIPO granted the patent to International Stem Cell Corporation.
 

EPO practice relating to stem cells 

The EPO has implemented the Biotech Directive via Article 53 and Rule 28 of the European Patent Convention (EPC), and the interpretation has been considered in 2008 by the Enlarged Board of Appeal in Decision G 2/06. The EPO has updated its Guidelines for Examination in relation to application of Rule 28, in light of the Brüstle decision, to provide the following:

“A claim directed to a product which at the filing date of the application could be exclusively obtained by a method which necessarily involved the destruction of human embryos from which the said product is derived is excluded from patentability under Rule 28(c), even if said method is not part of the claim (see G 2/06). The point in time at which such destruction takes place is irrelevant (T 2221/10).
 
When examining subject-matter relating to human embryonic stem cells under Art. 53(a) and Rule 28(c), the following has to be taken into account:
 
  1. the entire teaching of the application, not only the claim category and wording, and
  1. the relevant disclosure in the description in order to establish whether products such as stem cell cultures are obtained exclusively by the use, involving the destruction, of a human embryo or not. For this purpose, the disclosure of the description has to be considered in view of the state of the art at the date of filing”.
(emphasis of the Guidelines)
 
The Guidelines also note that Judgments of the CJEU on the interpretation of EU Biotechnology Directive, whilst not binding on the EPO, may be considered as persuasive.
 
According to Technical Board of Appeal Decision T 1441/13, Chung et al., 2008, Cell Stem Cell, Vol. 2 Issue 2, pages 113-117 (online publication date 10 January 2008), for the first time has allowed the provision of human embryonic stem cell cultures (cell lines) without destroying a human embryo in any production step.  According to the Chung method, single blastomeres were removed from embryos, and the biopsied embryos were subsequently grown to the blastocyst stage and then frozen. Thus, in view of T 1441/13, the Guidelines should be interpreted as excluding from patentability inventions involving human embryonic stem cells if their patent application filing date is before 10 January 2008.
 
The EPO has recently started to apply the earlier cut-off date of 5 June 20034, which is the date of publication of WO03046141, which discloses methods for deriving human embryonic stem cells from parthenotes.  This new practice appears to follow the CJEU’s determination in C364/13 that parthenotes are not human embryos, and hence their use to obtain human embryonic stem cells is not prohibited. 

The status of totipotent stem cells 
 
It has for some years been possible to create pluripotent stem cells from fully differentiated adult cells (so called “induced pluripotent stem cells” [iPS cells]). However, the only practical source of totipotent stem cells was embryonic tissue. The generation of induced totipotent stem cells [iTS cells] from non-embryonic tissue is a subject of intensive research effort around the world, and particularly in Japan. In October 2016, a team from Kyushu University reported the generation of fully potent mature mouse oocytes in culture from embryonic stem cells and from iPS cells derived from both embryonic fibroblasts and adult fibroblasts5. This work has been praised by the international scientific community, although it cautioned that there may be many further hurdles to be overcome before it might be replicated with human cells.  
 
The possibility of producing iTS cells from adult cells could abolish the current need to use embryos to obtain totipotent cells, thereby removing many ethical concerns associated with this field of research, and perhaps allow the engineering of recipient-derived tissues that are insusceptible to transplant rejection.  Hence, there is interest in whether patent protection may be available for iTS cell technologies in order to allow their development into mature, practical tools.
 
As noted above, the Brüstle decision did not include totipotent cells within its definition of “human embryos”.  As is normal practice, a preliminary opinion on the issues to be decided by the CJEU was published by an attorney general (AG) of the CJEU in advance of the Brüstle hearing.  This preliminary opinion did include totipotent stem cells in the definition of “human embryos”.
 
It is unclear in view of the Brüstle decision whether human totipotent cells would fall to be excluded from patentability.
 
The UKIPO has interpreted the Brüstle decision as implying that the term “human embryo” must be interpreted broadly to include any organism that is “capable of commencing the process of development of a human being” consistent with Article 5 of the Biotechnology Directive.
 
As such, the UKIPO guidance for UK patent examiners states that:
 
“Human totipotent cells have the potential to develop into an entire human body. In view of this potential, such cells are not patentable because the human body at the various stages of its formation and development is excluded from patentability”.
 
Such guidance would be followed by UK patent examiners, but is not binding on UK courts.  Whether or not human iTS cells might be eligible for patent protection could ultimately fall to be decided by the CJEU if a court of an EU Member State were to consider the issue sufficiently unclear to require guidance from the CJEU.  In my opinion, it appears more likely that a court faced with the issue would consider human iTS cells to fall within the definition of human embryo, and thus be excluded from patent eligibility.    

Conclusion
 
Whilst the decisions of the CJEU, and the decisions of national courts and the EPO pertaining to patentability of human stem cells might at first seem quite restrictive, it is important to remember that they largely concerned technologies developed at a time when the possibility of obtaining human embryonic stem cells without destruction of a human embryo was impossible or at least debatable. These restrictions would not apply to new technologies that could be implemented using embryonic stem cells obtained non-destructively from human embryos, or from human parthenotes. However, uncertainties remain concerning possible future developments, particularly in respect of induced human totipotent stem cells.  
 
 
1 Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 on the legal protection of biotechnological inventions; http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:31998L0044
2 Judgment of the Court (Grand Chamber) of 18 October 2011. Oliver Brüstle v Greenpeace eV. Case C-34/10. European Court Reports 2011 I-09821; http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A62010CJ0034
3 Judgment of the Court (Grand Chamber), 18 December 2014. International Stem Cell Corporation v Comptroller General of Patents, Designs and Trade Marks. Case C‑364/13; http://curia.europa.eu/juris/celex.jsf?celex=62013CJ0364&lang1=en&type=TXT&ancre
4 The European Patent System: Patentable subject matter related to health sciences and prior art search possibilities, Enrique Molina Galán, Director of Biotechnology at The Hague, November 2016; http://www.vpb.lt/files/Europos_patentu_sistema_patentuojami_objektai_susije_su_gyvybes_mokslais.pdf
5 Hikabe et al (2016) Nature 539:299-303. doi: 10.1038/nature20104.
 
 
 
 

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