Human embryonic stem cell (hESC) related technologies evolve rapidly, with significant potential for medical benefits for human patients. EU patent law relating to stem cell technologies is a complex and contentious area, as exciting medical prospects collide with ethical considerations. Following a recent European Court of Justice (ECJ) decision (C-364/13) which held that parthenotes are not considered to be embryos, the EPO now seems to be satisfied that hESCs could have been generated by morally acceptable means as early as June 5 2003, replacing the former cut-off date of January 10 2008. This is good news for applicants with pending stem cell applications filed after June 5 2003.
The patentability of biotechnological inventions in the European Union is governed by the EU Directive on the Legal Protection of Biotechnological Inventions (98/44/EC), which states that inventions are not patentable if their commercial exploitation would be contrary to public order or morality. Particularly, it explicitly excludes from patentability the use of human embryos for industrial or commercial purposes. The Biotech Directive is not legally binding on the European Patent Organisation itself; it instructs EU member states to adapt their laws to achieve the results specified in the directive. However, the European Patent Organisation (although not a member of the European Union) has implemented the Biotech Directive in Article 53 of the European Patent Convention and associated rules. In particular, Rule 28(c) of the European Patent Convention prohibits the use of human embryos for industrial or commercial purposes.
The ever-more complex development of stem cell technology and associated patenting efforts have given rise to questions as to what constitutes a human embryo and which acts constitute uses of a human embryo that would trigger the exemption and preclude patentability. Both questions have been addressed in decisions of the European Patent Office (EPO) Enlarged Board of Appeal and the ECJ. Interestingly, the exemption was initially construed remarkably broadly.
To clarify the issue at hand, a brief overview of the generation of hESCs follows.
Scientific background to hESCs and parthenotes
hESCs are pluripotent stem cells which can give rise to all cell types of the body except extra-embryonic tissue. They are traditionally derived from the inner cell mass of a blastocyst, an early-stage pre-implantation embryo consisting of approximately 50 to 150 cells. hESCs may be used to establish cell lines providing an unlimited supply of hESCs for therapeutic or research purposes. To date, several hundred hESC lines are available to the public.
As the technology previously stood, the blastocyst would be concomitantly destroyed in the process of generating hESCs. However, recently developed methods allow the generation of hESC cell lines from a blastocyst without destroying it. An alternative method for generating pluripotent hESCs is to stimulate an unfertilised human ovum by chemical or electrical stimuli in order to trigger the ovum to divide and develop into multiple cell types (parthenogenesis), resulting in a parthenote.
Definition of ‘human embryo’
The Biotech Directive provides no guidance as to what exactly constitutes a human embryo; nor does it explain whether any uses exist that may be considered non-commercial and therefore outside the exclusion from patentability. It has therefore been left to patent offices and courts to determine how to interpret and apply the morality provisions.
Great variability exists among EU member states as to how a human embryo is defined. In Germany, the Act for the Protection of Embryos came into force in 2001, and Section 8 defines an ‘embryo’ as:
“[T]he human egg cell, fertilized and capable of developing, from the time of fusion of the nuclei, and further, each totipotent cell removed from an embryo that is assumed to be able to divide and to develop into an individual under the appropriate conditions.”
Accordingly, blastocysts and any totipotent cell derived therefrom constitute a human embryo in Germany. By contrast, parthenotes originate from an unfertilised egg and cannot develop into an individuum and may therefore not be encompassed by the definition provided in Section 8.
The Enlarged Board of Appeal, the highest authority of the EPO, held in G2/06 (Use of embryos/Wisconsin Alumni Research Foundation) that the term ‘embryo’ should not be given any restrictive meaning (eg, by requiring a minimum age). That broad definition of a ‘human embryo’ includes the blastocyst and its totipotent cells. Consequently, the generation of cell lines derived from a human blastocyst wherein the blastocyst is concomitantly destroyed constitutes the destruction of a human embryo, and is thus exempt from patentability due to contravening public order. Nevertheless, European patents could be obtained for inventions which at the filing date of the patent could be worked using a previously existing hESC line.
In C-34/10 (Brüstle/Greenpeace) the ECJ defined a ‘human embryo’ in even broader terms and held that “[a]ny human ovum after fertilization… and any non-fertilized human ovum whose division and further developments have been stimulated by parthenogenesis constitute a ‘human embryo’” (Paragraph 38).
The ECJ’s reasoning for including parthenotes in the definition was that parthenotes are “capable of commencing the process of development of a human being” (Paragraph 36). In compliance with C-34/10, and without distinguishing between cells derived from blastocysts or parthenotes, the EPO then considered an invention excluded from patentability not only if it directly involves the destruction of an embryo, but also if it required, the use of a hESC that was originally derived through the destruction of an embryo. Only applications filed after the cut-off date of January 10 2008 were considered to be allowable, since the patentee could rely on a paper published in Cell Stem Cell (CSC, 2:113-117, 2008) which disclosed the single blastomere process whereby a stem cell could be removed from an embryo without concomitantly destroying said embryo (confirmed by the Technical Boards of Appeal in T2221/10, T1441/13 and T1836/10).
Challenging the equation of parthenotes with human embryos
However, the notion that parthenotes constitute human embryos (as held in C-34/10) because they are capable of commencing the process of developing into a human being was successfully challenged in ECJ Case C-364/13 (International Stem Cell Corporation (ISC)/Comptroller General). ISC sought two patents from the UK IP Office: one directed to a method of producing pluripotent hESCs and corneal tissue derived from such cells using parthenotes (GB0621068.6), and another directed to a method of isolating pluripotent hESCs from parthenotes (GB0621069.4). As mentioned above, parthenotes are unfertilised eggs that are triggered to divide by chemical and electrical stimuli. Importantly, they can successfully develop into the blastocyst stage, but cannot develop further due to lack of parental DNA, which is required to form extra-embryonic tissues such as the placenta.
The UK applications were rejected. However, on appeal the High Court asked the ECJ whether parthenotes are included in the term ‘human embryos’ in Article 6(2)(c) of the Biotech Directive, which excludes the use of human embryos for industrial or commercial purposes from patentability. On December 18 2014 the ECJ confirmed (C-364/13) that parthenotes are not embryos per se and therefore are not excluded from patentability. In particular, the ECJ made a crucial distinction between embryonic stem cell technologies based on fertilised human ova and those based on unfertilised human ova stimulated by parthenogenesis (ie, parthenotes). The court indicated that a parthenote does not constitute a ‘human embryo’ within the meaning of the directive; thus, cells derived from such unfertilised human ova stimulated by parthenogenesis are patentable.
The ECJ stated in C-364/13 that the principle of Brüstle must be taken to mean that in order to be classified as a human embryo, a human parthenote must have the “inherent capacity of developing into a human being” (Paragraph 28), thereby stressing that the question to answer is whether parthenotes can develop into a human being, not whether they can commence that developmental process. Finally, the court held that according to the current scientific standard, human parthenotes do not possess the inherent capacity to develop to term and thus do not constitute a human embryo.
The failure of parthenotes to develop to term is due to genomic imprinting, in which a gene is expressed in a monoallelic, parental-specific expression pattern. In contrast to a fertilised ovum, human parthenotes lack paternal DNA – which is required for the development of extra-embryonic tissue, such as placenta – rendering them incapable of developing to term. The ECJ added the proviso: “[A parthenote] does not constitute a ‘human embryo’... if, in the light of current scientific knowledge, [the parthenote] does not, in itself, have the inherent capacity of developing into a human being, this being a matter for the national court to determine.” The proviso was added because the court considered that it may in future become possible to genetically manipulate parthenotes to give them the capacity to develop into a human being.
Ramifications of C-364/13
Even though the EPO is not bound by decisions of the ECJ, as a result of the ruling in C-364/13 that parthenotes are not human embryos and that the use of parthenotes to obtain hESCs is therefore morally acceptable, the EPO again changed its practice and recently started to allow applications which use human stem cells that, at the time the application was filed, did not require the destruction of a human embryo. The cut-off date that the EPO currently uses is June 5 2003 – the date of publication of WO03046141, which discloses methods for deriving hESCs from parthenotes in an enabling manner. Based on the teaching provided in WO03046141, the EPO considers that a skilled person would have been able to generate human parthenotes and derive hESCs therefrom at that publication date at the earliest. Accordingly, applications filed after June 5 2003 relying on hESCs do not contravene the morality provisions of the European Patent Convention.
This change of practice is good news for applicants with pending patent applications and a filing date after June 5 2003. Further, the new practice is now being applied in office actions. Applicants that recently received a decision refusing an application filed after June 5 2003 for contravention of the EPO’s morality provisions should urgently check whether there is still time to file an appeal. Regrettably, if the two-month period for filing an appeal (and reinstatement into that period) has passed, no recourse seems to be available.
Interpretation of C-364/13
This recent development emphasises that the key question to address is whether a stem cell, parthenote or blastocyst has the inherent capacity to develop into a human being. If that question can be answered in the negative, the stem cell, parthenote or blastocyst in question does not constitute a human embryo. Following this line of thought, the question arises as to whether cells derived from non-viable embryos with chromosomal aberrations or from blastocysts generated for in vitro fertilisation procedures that are of poor quality and deemed to be unsuitable for implantation are exempt from patentability.
Rigorously applying the reasoning of C-364/13, the answer might be that all of the above are not considered human embryos. However, it might not be feasible to determine with sufficient certainty whether said stem cell, parthenote or blastocyst has or had (before having been used to generate hESCs) the inherent capacity to develop into a human being.
Patenting genes and DNA under the European Patent Convention
Historically, the EPO applied a stricter standard regarding granting patents on biotechnological inventions than the US Patent and Trademark Office (USPTO), exempting certain biotechnological inventions as not patentable in Europe (eg, methods of treatment on the human or animal body or uses of human embryonic stem cells). By contrast, the right to seek protection for “anything under the sun that is made by man” used to be a central tenet of the US patent system (Diamond v Chakrabarty, US Supreme Court).
A June 2013 Supreme Court ruling altered the patent eligibility of human genes in the United States. The court held in Assoc for Molecular Pathology v Myriad Genetics that DNA that has been isolated from the human body is no longer patentable in the United States. It ruled that “a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated”, further pointing out that “what is patented must be made different by human hands”. Interestingly, complementary DNA was deemed to be patentable.
Since Myriad, isolated genomic DNA is no longer patentable in the United States as such. The USPTO guidance also seems to exclude from patentability other natural products ‘isolated’ from their natural environment (eg, bacterial cells, cell populations, enzymes and human antibodies), unless they are ‘markedly different’ from their natural counterparts.
European Patent Organisation
In the EPO inventions related to gene sequences can be patented provided that the industrial application of the sequence is disclosed in the application. Further, in contrast to the United States, claims to isolated genomic DNA and other natural products isolated from their natural environment are patentable before the EPO according to Rule 29(2) of the European Patent Convention, which states: “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.”
Germany has restrictions on patenting human genes, but they apply only to national patents – that is, patents obtained directly in Germany (not to be confused with European patents that are validated in Germany). Further, Section 1(a) of the Patent Act expressly provides for the patenting of isolated human genes (Paragraph 2), but requires a use restriction in the claims (Paragraph 4). Importantly, the German restrictions are limited to human genes, while the Myriad decision is unlikely to draw a distinction between human genes and genes from other organisms.
In summary, the European Patent Convention and Biotech Directive, as well as the German Patent Act, clearly allow patenting of isolated naturally occurring materials. For human genes, certain restrictions apply – that is, that at least a certain industrial application is disclosed in the application as originally filed (according to the EPO) and at least one use is included in the claims (in Germany). Thus, following Myriad, it seems that the scope of natural products such as genes that are deemed patentable is broader under the European Patent Convention than in the United States, benefiting the pharmaceutical industry, inventors and – ultimately – patients.
Sun Jin Lee, Heike Vogelsang-Wenke
This article first appeared in IAM. For further information please visit www.iam-media.com.