The European Patent Office (EPO) has quietly adopted a dramatic change in itspractice regarding the patentability of inventions relating to human embryonic stem cells (hESCs).  The EPO had previously held the opinion that hESCs could only be obtained via morally acceptable methods from February 2008.  Therefore, any patent applications relating to hESCs filed before that date were objected to under the EPO’s morality provisions as being directed to excluded subject matter.  However, the EPO now seems to be satisfied that hESCs could be obtained via morally acceptable methods as early as 5 June 2003.  Consequently, Examination Reports have started to issue on patent applications filed after 5 June 2003 indicating that they do not contravene theEPO’s morality provisions.  This is good news for applicants with pending applications filed after 5 June 2003.

Background information is provided in items 1-3 below, so readers familiar with this subject may scroll straight to item 4.

1. Sources of hESCs

Traditionally, hESCs are derived from human embryos.  However, as discussed below, the concept of what constitutes a human embryo or a hESC is far from straightforward.  Initial methods for the isolation of hESCs from embryos involved the removal of a cell from the embryo in the blastocyst stage, with the concomitant destruction of the blastocyst [1].  More recent methods allow the isolation of a hESC from a blastocyst without destroying it [2, 3].  Once isolated by any of these methods, a hESC may be used to set up a hESC line.  This is an in vitro culture of hESCs which may be propagated in a laboratory to provide an essentially unlimited supply of hESCs. Over 200 hESC lines are now available to the public. 

A further approach for generating pluripotent cells is to stimulate an unfertilised human ovum (the female “egg”) by parthenogenesis to divide and develop into multiple cell types [4].  Another alternative is somatic cell nuclear transfer (SCNT), wherein the nucleus of an adult cell is introduced into an unfertilised ovum that has had its nucleus removed [5].  There has been some debate over whether these methods generate an ‘embryo’ and whether cells isolated therefrom are truly hESCs.

2. Morality provisions

The patentability of biotechnological inventions in the European Union (EU) is governed by the Biotech Directive [6]. The Biotech Directive states that inventions are not patentable if their commercial exploitation would be contrary to morality, and it specifically prohibits the use of human embryos for commercial or industrial purposes.  The EPO has implemented the Biotech Directive via Article 53 and Rule 28 of the European Patent Convention.

However, there is no consensus as to what the term ‘human embryo’ encompasses or what acts constitute the ‘use of a human embryo’.  In particular, there has been a significant debate as to whether the parthenogenesis or SCNT processes mentioned above yield an embryo.  It has even been suggested that individual hESCs might be considered to represent an embryo. The Biotech Directive does not provide any guidance in this regard, nor does it explain whether there are any uses that may be considered to be non-commercial and therefore outside of the exclusion from patentability.

It has therefore been left to patent offices and courts to determine how to interpret and apply the morality provisions.  The Court of Justice of the EU (CJEU) has twice been called upon to provide guidance in this regard.

3. Evolving interpretation of the scope of the morality exclusion

In 2008, the Enlarged Board of Appeal, the highest authority of the European Patent Office (EPO), held that inventions which necessarily require the destruction of a human embryo are excluded from patentability [7]. Nevertheless, European patents could be obtained for inventions which from the filing date of the patent could be worked using an existing hESC line. 

However, in 2011, the CJEU held in case C34/10 that it is immaterial how far removed the destruction of a human embryo is from the invention [8].  Thus, according to the CJEU, the ‘use of human embryos’ exclusion applies not only to those inventions which directly involve the destruction of an embryo, but also to those requiring the use of a hESC which was originally derived through the destruction of an embryo. 

Consequently, excluded from patentability were any methods or products which involve as their base material cells taken from an established hESC line which was originally obtained through the destruction of a human embryo, no matter how long ago the hESC line was established.  The EPO followed this approach in T2221/10, as reported here.

The CJEU also considered the meaning of the term ‘embryo’ in C34/10.  It was held that this term encompasses any fertilised ovum from the moment of fertilisation, including all subsequent stages during the development and formation of the human body, including the blastocyst stage from which hESCs are typically retrieved, as well as any other cell capable of commencing the process of development of a human being, such as the products of SCNT or parthenogenesis (‘parthenotes’).  The CJEU left it to the national courts to ascertain whether a hESC itself should be considered to be a human embryo.

However, the notion that a parthenote constitutes a human embryo because it is capable of commencing the process of development of a human being was successfully challenged in case C364/13[9].  It was noted that the written observations lodged with the CJEU in case C34/10 may have inaccurately presented the scientific and technical background relating to parthenogenesis.

In C364/13, the CJEU was satisfied that according to current scientific knowledge mammalian parthenotes can never develop to term.  This is because, in contrast to a fertilised ovum, they do not contain any paternal DNA, which is required for the development of extra-embryonic tissue.  Consequently, in December 2014 the CJEU ruled that parthenotes do not constitute a ‘human embryo’, with the proviso: “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. 

4.  Changes to EPO practice

The EPO is not bound by Decisions of the CJEU.  Nevertheless, the EPO’s Guidelines for Examination were updated to reflect Decision C34/10 and the Appeal Board has indicated in Decision T2221/10 that it found Decision C34/10 to be persuasive.  

Until very recently, the EPO took the view that the first report of a non-destructive method of isolating hESCs published in February 2008[3], and that inventions involving hESCs are excluded from patentability if their patent application filing date is before February 2008.

Thus, for example, in February 2014 an application filed 7 October 2003 was refused (T2221/10).

However, the EPO now appears to be following the CJEU’s determination in C364/13 that parthenotes are not human embryos, and that the use of parthenotes to obtain hESCs is therefore morally acceptable.  The EPO has recently started to issue Examination Reports that indicate that applications filed after 5 June 2003 do not contravene the morality provisions of the European Patent Convention.  The EPO’s reasoning seems to be that methods of deriving hESCs from parthenotes are disclosed in WO03046141, a patent application that published on 5 June 2003.  Based on the teaching provided in WO03046141, the EPO considers that the skilled person would have been able to generate parthenotes and derive hESCs from them from that publication date. 

Curiously, this momentous change of practice has not been well publicised. 

5. Outlook

The change of practice is good news for applicants with patent applications that were filed after 5 June 2003 and are still pending.  Any applicants who recently received a Decision refusing an application filed after 5 June 2003 for contravening the EPO’s morality provisions should urgently check whether there is still time to file an appeal.  Regrettably, if the deadline for filing an appeal has passed, no recourse seems to be available. 

This development also illustrates that a further shift in the EPO’s approach is conceivable.  C364/13 establishes that a parthenogenically-generated blastocyst that does not, in itself, have the inherent capacity of developing into a human being, does not constitute a human embryo.  It would seem to follow therefore that anyblastocyst which does not, in itself, have the inherent capacity of developing into a human being, does not constitute a human embryo. 

Can it therefore be concluded that using non-viable embryos with chromosomal abnormalities to isolate hESCs (without abnormalities) is outside of the scope of the prohibition [10]?  A further question is whether a blastocyst that has been rated as being of poor quality (and that is therefore deemed by IVF experts to be unsuitable for implantation) does in fact have the capacity to develop into a human being [11]. If not, then there seems to be a good argument that any hESC lines derived from such a blastocyst should be deemed not to have been obtained by destroying a human embryo.  It may therefore be important to determine what the quality was of the blastocysts from which any of the existing hESC lines were generated. 

It is uncertain whether it is in fact possible to determine with a sufficient degree of certainty whether a particular blastocyst has (or did have, prior to having been used to generate a hESC line) the capacity to develop into a human being.  However, given how much is at stake for businesses trying to protect their inventions, the 5 June 2003 date will no doubt be the subject of further challenge based on such arguments.