Article first appeared in Intellectual Property Magazine - September edition
What constitutes a human embryo is important to determine the patentability of certain biotech inventions as under Article 6(2)(c) of the Directive on the Legal Protection of Biotechnological Inventions (98/44/EC), commonly referred to as the Biotech Directive, the use of human embryos for industrial and commercial purposes is excluded from patentability. The meaning of 'human embryo' under the Biotech Directive, has already been considered by the Court of Justice of the European Union (CJEU) in Oliver Brüstle v Greenpeace (Case C-34/10), when the CJEU adopted a wide interpretation and held that any organism "capable of commencing the process of development of a human being" must be regarded as a human embryo and this included parthenotes (unfertilised ova/oocytes activated by chemical or electrical manipulation to initiate the process of cell division and development).
Whether parthenotes can constitute human embryos is currently being re-considered by the CJEU in Case C-364/13 International Stem Cell Corporation v Comptroller General of Patents in circumstances where such parthenotes are incapable of developing into human beings. On 17 July 2014, Advocate General Cruz Villalón delivered his Opinion and concluded that parthenotes that are not able to develop into a human being and have not been genetically manipulated to acquire such capacity should not be considered 'human embryos' under the Biotech Directive. This Opinion will be generally welcomed by the biotech industry and it is hoped that the CJEU will follow the decision of the AG.
The limitation on patentability of biotech related inventions is a controversial area. Under the Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPs), to which all WTO members are signatories, although patents must be available for any invention in all fields of technology, this is subject to the proviso that members can exclude from patentability inventions on ordre public and morality grounds.
In July 1998, following significant developments in the biotech sector and a 10 year debate in the EU over how best to encourage biotechnology innovation in Europe while addressing ethical concerns, the EU finally adopted the Biotech Directive to harmonise patentability of biotech inventions. Article 6(1) of the Biotech Directive confirms that inventions whose commercial exploitation would be contrary to ordre public or morality are unpatentable. Article 6(2) goes on to provide a non-exclusive list of what is considered to be unpatentable and this includes "uses of human embryos for industrial or commercial purposes".
Equivalent exclusions to patentability were subsequently included in the European Patent Convention and the Implementing Regulations to the EPC which, although not EU legal instruments, are relevant in that all Member States are signatories and the prosecution of the majority of patents in Europe is managed by the European Patent Office (EPO). Indeed, in the WARF Enlarged Board of Appeal decision of November 2008, the EPO held that under the EPC it is not possible to grant a patent for an invention which necessarily involves the use and destruction of human embryos. The only exception to this were those inventions involving the use of pluripotent human embryonic stem cells (hESCs) (which can develop into some but not all cell types) and which could be generated by using cell lines which were publically available at the relevant filing date since destruction of human embryos to generate these cell lines was historical.
In Brüstle, the CJEU went one step further and held that inventions that required the destruction of human embryos, no matter when this may have occurred, are unpatentable. The case also for the first time attempted to define what is meant by a 'human embryo' for the purposes of Article 6(2)(c) of the Biotech Directive providing a wide interpretation which covered all of the early stages of human development and all other similar cells which have the capability of commencing the process of development of a human being, including parthenotes.
ISC reference to the CJEU
In the current case, ISC sought two patents from the UK IPO: a method of producing pluripotent hESCs and corneal tissue derived from such cells from parthenogenetically-activated oocytes (GB0621068.6) and a method of isolating pluripotent hESCs from parthenogenetically-activated oocytes (GB0621069.4). As these oocytes have not been fertilised the resulting parthenotes contain only half the amount of genetic material to that found in fertilised cells; they contain only maternally derived genetic material but lack paternal chromosomes. Due to "genomic imprinting" some genes are only expressed in paternal rather than maternal DNA and are therefore repressed in parthenotes while other genes which would normally be repressed may be abnormally expressed. As a consequence, parthenotes cannot develop into viable human beings. Thus the cells of a parthenote are pluripotent (capable of differentiating into embryonic but not extra-embryonic tissues, for which paternal DNA is required) and not totipotent (capable of differentiating into all human cell types including extra-embryonic tissues).
Following the broad interpretation of a 'human embryo' in Brüstle, the UK IPO felt bound to refuse ISC's patent applications on the ground that the organisms produced by the inventions are "capable of commencing the process of development of a human being" and therefore excluded from patentability by the Biotech Directive.
ISC appealed to the High Court . It did not consider it necessary to refer the matter to the CJEU for a preliminary ruling as, in its view, it was acte clair because the key question following the CJEU decision in Brüstle was whether an organism is capable of commencing the process of development which leads to a human being. ISC submitted that the Brüstle decision excluded parthenotes from patentability only to the extent that they are capable of giving rise to totipotent cells, each of which has the capacity to develop into a complete human being.
The Comptroller General of Patents did not consider the matter acte clair as it was unclear whether the CJEU had in mind a test whereby commencing the process of development of a human being sufficed or whether it needed to be a process that was capable of leading to a viable human being. Deputy Judge Henry Carr QC agreed that the matter was not clear and that it justified a further reference to the CJEU with the question:
“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 on the Legal Protection of Biotechnological Inventions?”.
On 29 April 2014, the CJEU held a hearing in which ISC, the UK, France, Sweden and the Commission made oral observations, having previously received written observations from each of them as well as from Poland and Portugal.
The Opinion of the Advocate General
In answering the question, Advocate General Villalón highlighted the previous CJEU reference made in the Brüstle case. He noted that the current reference is identical save that the ISC reference explicitly refers to unfertilised human ova containing only pluripotent cells which are incapable of developing into a human being.
Key to the Court's decision in Brüstle and therefore central to the interpretation of Article 6(2)(c) was the criterion of being "capable of commencing the process of development of a human being". AG Villalón rejected the view that this refers simply to the commencement of the first steps of development but rather it is the inherent capacity to develop into a human being which is determinative. In his view, the Court in Brüstle established a 'functional equivalence' between the inherent capacity of fertilised ova and parthenotes, which is now known to be scientifically inaccurate.
The AG considered the nature and extent of the list of prohibitions to patentability in Article 6(2). In particular he noted that the list should be regarded as a minimum 'no-go zone' for all Member States on which inventions should be considered unpatentable but it is non-exhaustive and merely illustrative as to which inventions would offend against ordre public or morality. Ultimately, however, a Member State could still decide to exclude parthenotes from patentability under Article 6(1) if the Member State in question decided that parthenotes offend their own standards of ordre public or morality.
The AG also dismissed the idea that a parthenote could offend Article 5 of the Biotech Directive, which excludes from patentability the human body at any stage of development or any 'elements isolated from the body'. He argued that parthenotes could not be classified as a human body or a stage of its formation; they were created from a technical process and Article 5 by itself does not prevent their patentability.
Observations were submitted to the CJEU in support of ISC's submissions that parthenotes should not be considered 'human embryos' in the sense of Article 6(2)(c) by France, Sweden, the UK, and the European Commission. Portugal was also in support of ISC's submissions but emphasised the risk of parthenotes acquiring the ability to develop into a human being through additional manipulation and suggested it should be up to the national court to ensure this capacity does not exist for the patent at issue. Poland, in contrast to all other submissions, argued that in the interest of safeguarding human dignity, the focus should be on the capacity to commence the process of development, regardless of whether that process is fundamentally ill-fated.
AG Villalón recognised that it may eventually be possible to genetically manipulate a parthenote so that it can develop into a human being. In his conclusion, he therefore caveated the patentability of parthenotes with the stipulation that they are "not capable of developing into a human being and have not been genetically manipulated to acquire such capacity”.
The exclusion from patentability of hESCs isolated from fertilised ova as well as the societal and ethical dilemmas it creates leaves an opening for cellular therapies based on alternative methods for obtaining stem cells. The use of parthenogenetic hESCs has huge potential to provide cells and tissue for developing new cellular therapies and for regenerative medicine, and are viewed as one of the most promising alternative sources of histocompatible (tissue-compatible) cells. In addition, hESCs derived from parthenogenetic embryos have the advantage over traditional methods of reprogramming somatic cells in terms of the cost and time required to produce clinical-grade cells. Recently discovered alternatives such as umbilical cord blood could be a promising source of cells for use in blood-related diseases but questions exist over their effectiveness for establishing treatments for non-blood related diseases. Research in parthenogenetic hESCs is still in its infancy but recent studies have shown promising applications, such as genetic screening in mammalian cells.
The Opinion is regarded by many, including the authors, as a sensible conclusion and would serve as a much needed carve-out to the Court's conclusions in Brüstle. It will no doubt come as welcome news to biotech companies who develop cellular therapies; if the CJEU follows the Opinion, the increased ability to secure patent protection across the EU would remove much uncertainty for investors and encourage investment in the field.
  EWHC 807 (Ch)