The past few decades have seen major progress in the fields of medicine and molecular biology, leading to the filing of numerous patent applications involving (among other things) human stem cells and gene sequences. The ethical, economic and scientific considerations arising from these controversial patents have been hotly debated from the start.
The EU Biotech Directive (98/44/EC) forms the legal basis for biotechnological inventions involving the patenting of stem cells and genes. The Biotech Directive was adopted in light of the growing economic importance of molecular biology and genetic engineering technologies, increasing the need for harmonisation of member states’ national laws. However, implementation of the Biotech Directive has triggered fierce debate in many member states; in Germany and France, the directive was adopted in a more restricted form which excludes product protection of gene sequences and limits the claim scope. That said, the directive has in general been transposed into the national patent laws of all EU member states.
The principles of patenting stem cells and gene sequences are regulated in Articles 5 and 6 of the Biotech Directive:
1. The human body, at the various stages of its formation and development, and the simple discovery of one of its elements, including the sequence or partial sequence of a gene, cannot constitute patentable inventions.
2. An element isolated from the human body or otherwise produced by means of a technical process, including the sequence or partial sequence of a gene, may constitute a patentable invention, even if the structure of that element is identical to that of a natural element.
3. The industrial application of a sequence or a partial sequence of a gene must be disclosed in the patent application.
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.
Although the European Patent Office (EPO) is not an organisation of the European Union, it has incorporated the criteria and definitions set out in the Biotech Directive into the European Patent Convention (EPC) Implementing Regulations (Rules 26 to 29) and Guidelines for Examination (Part G, II.5.2).
This chapter reviews the current legal situation concerning the patenting of stem cells and genes in Europe.
Patenting stem cells
According to Article 6(2)(c) of the Biotech Directive and Rule 28(c) of the EPC Implementing Regulations, European patents cannot be granted to inventions that use human embryos for industrial or commercial purposes. No further definition of the term ‘embryo’ is provided, which has caused significant confusion. However, a series of EPO and European Court of Justice (ECJ) decisions has brought much-needed clarity.
“Applications relating to human embryonic stem cells are considered patentable only if, at the filing date, at least one method for providing such cells was available which did not necessitate the destruction of an embryo.”
Decision G 2/06 (November 2008) of the Enlarged Board of Appeal was based on an application relating to a cell culture comprising primate embryonic stem (ES) cells (Primate embryonic stem cells/WISCONSIN ALUMNI FOUNDATION). The board held that subject matter relating to products (ie, stem cells) which on the filing date can be exclusively prepared by methods necessarily involving the destruction of human embryos from which said products are derived is not patentable under the EPC. This applies even if the destructive method is not explicitly part of the claims. In assessing the exception of patentability for human embryos, technical developments after the filing date are irrelevant.
Nevertheless, even after Decision G 2/06, the EPO took the view that inventions relating to human ES (hES) cells are patentable if evidence can be provided that suitable hES cells are publicly available. For example, if a hES cell line can be purchased at the filing date of an application, any downstream products, uses or methods derived therefrom are not excluded from patentability.
In Brüstle (C-34/10, October 2011) the ECJ dealt with a submission from the German Federal Court of Justice. The ECJ had to consider for the first time the term ‘uses of human embryos for industrial or commercial purposes’ within the meaning of Article 6(2)(c) of the Biotech Directive. The case was based on a German patent relating to neural cells which were derived from hES cells. The ECJ decided that according to the Biotech Directive, inventions are excluded from patentability where the technical teaching that is the subject matter of the application 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. Moreover, the term ‘embryo’ was broadly interpreted to cover all stages of human development after fertilisation of a human egg, as well as cells “capable of commencing the process of development of a human being”.
In line with Brüstle is EPO Decision T 2221/10 (Culturing stem cells/TECHNION) (February 2014). This case was based on an application referring to methods maintaining hES cells in culture in an undifferentiated state, as well as a cell culture comprising hES cells. The applicant argued – in line with previous EPO practice – that methods using commercially or otherwise available hES cell lines are not excluded from patentability because no de novo destruction of human embryos is necessary to perform them. The board disagreed. Referring to Decision G 2/06, it pointed to the fact that the Enlarged Board of Appeal had not distinguished between either steps carried out by the inventor or any other person or steps accomplished in direct preparation of the experiments leading to an invention and steps carried out at a point in time further remote from those experiments. Therefore, the board held that inventions which make use of hES cells obtained by the de novo destruction of human embryos or of publicly available hES cells which were initially derived by a process resulting in the destruction of human embryos are excluded from patentability under the EPC.
The very broad definition of ‘embryo’ used in the above decisions was limited by the ECJ decision in Case C-364/13 (December 2014), which had been referred from the UK High Court. The underlying application related to stem cells derived from unfertilised human eggs that had been parthenogenetically activated to stimulate cell division, therefore falling within the ECJ’s ‘embryo’ definition of 2011 (ie, “capable of commencing the process of development of a human being”). However, contrary to the previous decision, the court held that an unfertilised human egg whose division and further development has been stimulated by parental genesis does not constitute a ‘human embryo’ within the meaning of the Biotech Directive. In light of current scientific knowledge, it does not, in itself, have the inherent capacity to develop into a human being. In other words, according to the decision, the term ‘embryo’ covers only cells that have the capacity to develop into a human being. EPO Decision T 1808/13 (Embryonale Vorläuferzellen/BRÜSTLE, February 2015) is in line with this ECJ judgment.
A further relevant decision, Decision T 1441/13 (Embryonic stem cells, disclaimer/ASTERIAS, September 2014), was based on an application directed to a method of producing differentiated cells from primate pluripotent stem cells which, according to the description of the application, included human embryonic stem cells. The board concluded that at the 2001 filing date of the patent in suit, the known and practised method for achieving cultures of human ES cells (ie, the starting material of the claimed method) necessarily included preceding steps that involved the destruction of human embryos. Another source of pluripotent cells was not specified in the application.
The board stated that a first public disclosure of a method for obtaining human embryonic stem cells without destroying a human embryo was disclosed by Chung et al (January 2008). It further concluded that even disclaimers in applications filed before January 2008 excluding the use of human embryos are not admissible and that such disclaimers are admissible only in cases where non-destructive methods were available at the filing date.
“The case law shows that the EPO has not been concerned with ethical questions of patenting genes. Patentability of a naturally occurring nucleic acid sequence may be acknowledged if the claimed sequence is inventive – that is, the application as filed provides credible evidence for the solution of a technical problem and is industrially applicable”
Applications relating to hES cells are considered patentable only if, at the filing date, at least one method for providing such cells was available which did not necessitate the destruction of an embryo.
Accordingly, the EPO may allow claims relating to hES cells when they have a priority or filing date of January 2008 or later, as they can rely on the first non-destructive methods of obtaining stem cells from human embryos as described by Chung et al. Moreover, parthenogenetically activated hES cells seem patentable. The cut-off date of January 2008 is based on the assumption that no earlier method was available. This may change if earlier publications become more relevant. In cases filed before January 2008, a disclaimer relating to methods destroying embryos cannot be used, as non-destructive methods were not available. In contrast thereto, regarding applications filed after January 2008, disclaimers may be used to disclaim any products, methods or uses that require the destruction of a human embryo.
In light of the discovery that a destruction of cells can be reprogrammed to become induced pluripotent stem cells, it seems that embryos are no longer required to produce stem cells.
In June 2013 the US Supreme Court ruled that human genes cannot be patented because DNA is a “product of nature” (Association for Molecular Pathology v Myriad Genetics Inc). On the other hand, the Supreme Court found that DNA sequences different from naturally occurring sequences are patent eligible. In 2015 the High Court of Australia ruled that an isolated nucleic acid does not qualify as proper subject matter for patent protection (D’Arcy v Myriad Genetics Inc).
In the wake of these decisions, a large number of previously granted patents on gene sequences in the United States and Australia have been invalidated.
In Europe, according to Article 5(2) of the Biotech Directive and Rule 29(2) of the EPC Implementing Regulations, a naturally occurring gene sequence as such may be patentable if an industrial application thereof is disclosed.
The following are exemplary decisions of the Technical Boards of Appeal relating to the patenting of genes.
Decision T 1213/05 (Breast and ovarian cancer/ UNIVERSITY OF UTAH, September 2007) was based on a patent claiming an isolated nucleic acid comprising a coding sequence for the human BRCA1 gene. Oppositions against the patent grant were filed by the Swiss Social Democrat Party, Greenpeace eV and the government of the Netherlands (among others). The board rejected the opponents’ argument that the claimed subject matter was contrary to public order or morality. Further, the board pointed out that the EPO did not have competence to take into account the economic effects of granting patents and accordingly restrict certain fields of patentable subject matter. The board also rejected the necessity to interpret the EPC in light of the national legislation of its member states – in particular, the ethical concerns reflected in the French and German legislation calling for purpose-bound protection. The board acknowledged industrial applicability, since the claimed sequences were useful for diagnostic purposes and could thus be used commercially to detect the presence of BRCA1 alleles predisposing individuals to breast cancer. As the claimed sequence of the BRCA1 gene was erroneously depicted in a particular priority document, the patent could claim priority only from a later document. For this reason, the claims had to be substantially limited.
A further decision, Decision T 898/05 (Hematopoietic receptor/ZYMOGENETICS, July 2006), was based on a patent application claiming a polynucleotide encoding a ligand-binding receptor polypeptide. The application did not contain functional data and the presumed biological function was based only on computer-assisted sequence alignment. However, the board accepted that the claimed invention had a “sound and concrete technical basis” based on the disclosure of the application.
In Decisions T 0870/04 (BDP phosphatase/MAX-PLANCK, May 2005), T 0641/05 (GPCR-like receptor/PHARMACIA, November 2006) and T 1452/06 (Serine protease/BAYER, May 2007), industrial applicability was not acknowledged on the grounds that, even though the structure of the claimed nucleic acid sequence was given, the function was undetermined, obscure or only vaguely indicated. The board considered that no actual information regarding the function of the claimed nucleic acid molecule had been made credible in the application as filed. Thus, no “immediate concrete benefit” could be recognised for the claimed nucleic acid sequences and the patent applications were rejected. In Decision T 1329/04 (Factor-9/ JOHNS HOPKINS, June 2005), an application claiming a polynucleotide encoding a gene product was rejected as lacking inventive step. The board concluded that mental data in the application did not prove that a technical problem had been solved.
A recent case (T 1285/13, miR-1/MAX-PLANCK-GESELLSCHAFT, October 2016) related to an application claiming a micro RNA molecule. In the application, the structure of the claimed micro RNA and its precursor, as well as its differential expression during the development of Drosophila embryos, was disclosed. As for possible function, the micro RNAs were described as “molecules associated with physiological regulatory mechanisms”. Taking into account this disclosure, the board was convinced that the claimed subject matter had industrial applicability and solved a technical problem, thereby fulfilling the inventive step requirement.
The case law shows that the EPO has not been concerned with ethical questions of patenting genes. Patentability of a naturally occurring nucleic acid sequence may be acknowledged if the claimed sequence is inventive – that is, the application as filed provides credible evidence for the solution of a technical problem and is industrially applicable (ie, the application has a “sound and concrete technical basis” and discloses an “immediate concrete benefit”).
At present, a gene sequence isolated from the human body constitutes patent-eligible subject matter in Europe. Patentability of claims directed to gene sequences is determined only by applying ‘classical’ criteria for patentability – that is, novelty, sufficiency and (in particular) inventive step and industrial applicability. Ethical considerations play no prominent role.
However, this situation might change in future if political or social groups opposing the patenting of human genes gain greater political influence. In such case, either the European Union (by means of a new Biotech Directive) or the EPO (by amending its Guidelines for Examination) could adopt a more restrictive approach that prohibits the patenting of human genes and thus more closely resembles the present situation in the United States.<- Back to: ニュース