Stem Cell Patenting in Europe

MORALLY ACCEPTABLE SOURCES OF HUMAN EMBRYONIC STEM CELLS (hESCs): EMBRYOS THAT NEVER WERE, OR COULD NEVER BE

The Advocate General’s Opinion in C 364/13, if followed, improves the position for pioneering inventions based on hESCs in Europe.

The scope for patenting stem cell-based inventions in Europe was dealt a blow by the judgement of the CJEU in Brüstle vs Greenpeace (C 34/10)1. The practical result of this judgement was that the earliest date from which the EPO would acknowledge that morally acceptable sources of human stem cells were available was 10 January 2008.

The search for earlier morally acceptable sources of human embryonic stem cells (hES cells) has continued. As foreshadowed in our previous articles2,3 there has been debate as to whether parthenotes, cells grown from a stimulated but otherwise unfertilised human egg, constitute human embryos. This is because a parthenote is biologically incapable of developing into a human being.

The Advocate General’s Opinion in response to a recent referral to the CJEU by the UK High Court in the case of ISCC vs Comptroller4 speaks to this issue and concludes that parthenotes are not embryos. We hope that the CJEU will follow the Advocate General’s Opinion. In our view the consequence for European patent practice of such a ruling should be that morally acceptable sources of hES cells will be considered to have been available from late 2005, and perhaps significantly earlier.

The Advocate General’s Opinion in response to a recent referral to the CJEU by the UK High Court in the case of ISCC vs Comptroller4 speaks to this issue and concludes that parthenotes are not embryos. We hope that the CJEU will follow the Advocate General’s Opinion. In our view the consequence for European patent practice of such a ruling should be that morally acceptable sources of hES cells will be considered to have been available from late 2005, and perhaps significantly earlier.

Background

The decision issued by the CJEU in respect of Brüstle vs Greenpeace and its practical application by the EPO severely narrowed the scope of sources of hES cells for use in patentable inventions. This was because the Brüstle decision stated “that the concept of ‘human embryo’ within the meaning of [the EU Biotech] Directive must be understood in a wide sense” [our emphasis added].

Following this reasoning, the CJEU held that “any human ovum must, as soon as fertilised, be regarded as a ‘human embryo’ within the meaning and for the purposes of the application of Directive, since that fertilisation is such as to commence the process of development of a human being.”

However, the phrase “commence the development of a human being” is controversial because not all cells described as being hES cells are capable of completing such development.

This has been noted and considered by the Advocate General in his Opinion and he finds that “commencing the development of a human” implies that whether this development has truly commenced depends on whether this development is biologically possible. In other words, if a structure alleged to be an “embryo” cannot possibly develop into a human being then can it ever be said to have “commenced the development of a human”?

Parthenotes

Consequently, a question arises about the patentability of pluripotent cells derived from sources that are known not to be able to develop into a human being. One such source is a parthenote – an unfertilised human egg cell that is stimulated to divide and grow. The cells in the colony/embryo resulting from this stimulation can differentiate into various cell types, including pluripotent cells, much as the cells of a fertilised egg would differentiate. Consequently, the current EPO practice following the Brüstle decision is that any non-fertilised human ovum for which division and further development are stimulated by parthenogenesis is considered to constitute a “human embryo”.

However, a parthenote cannot develop into a human. This is because it is essential for viability that half the chromosome complement of a human comes from an egg and half from a sperm cell. It is often said that the information encoded in the DNA that is held within every nucleated cell of a human being contains the total information required to build that particular human being. However, this is not so.

The DNA of the egg and the fertilising sperm are marked with further information as to their origin: egg or sperm. The DNA of each gamete is specifically imprinted, i.e. labelled, by a pattern of modifications to the DNA such that the activity of a large number of genes is defined by whether they come from the egg or the sperm. This information – this additional layer of genetic control – is essential for human development. In its absence, that is, in a parthenote where the whole genetic complement is derived from the egg, a human cannot result because an “embryo” lacking this imprinted information can never be viable.

ISCC vs Comptroller

The inventions developed by International Stem Cell Corporation (ISCC) considered by the Comptroller and Courts5, and now by the Advocate General are based on parthenogenetically produced cells. The Comptroller rejected their patentability following the Brüstle decision. However, ISCC appealed this decision to the High Court for the reasons summarised above.

In order to clarify the CJEU’s decision in Brüstle on this point the UK High Court referred this question to the CJEU (case no. C 364/13):

“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?”

The answer was supplied by Advocate General Cruz Villalón in his Opinion and is summarised in paragraph 80, which reads,

“Unfertilised human ova whose division and further development have been stimulated by parthenogenesis are not included in the term ‘human embryos’ […] as long as they are not capable of developing into a human being and have not been genetically manipulated to acquire such a capacity.”

Accordingly, the cell-containing structures derived from unfertilised ova that have been stimulated to divide parthenogenetically are not “human embryos” within the definition of Article 53(a) and Rule 28(c) EPC.

This finding is consistent with the observations made obiter dictum by Henry Carr QC when he gave the preliminary view of the referring court in stating:

“I agree with ISCC that if the process of development is incapable of leading to a human being, as the Hearing Officer has found to be the case in relation to parthenotes, then it should not be excluded from patentability as a 'human embryo.”

Additionally, this finding is consistent with the interpretation of the decision delivered by the German Bundesgerichtshof in the case of Brüstle vs Greenpeace e.V6 when they applied CJEU decision C 34/101. In this case, the judges held that the embryos from which the stem cells were extracted had, by the time they were extracted, lost the capability of commencing development of a human being. Consequently, the removal of such cells should not therefore be considered a use of embryos.

If The Opinion is Followed, When Would Acceptable Human Embryonic Stem Cell Lines Become Available?

The Advocate General is the former Chief Justice of the Constitutional Court of Spain. If his Opinion is followed by the CJEU we expect that the EPO will, in turn, declare that their practice will follow the CJEU’s decision. We believe that the consequent practical impact on the patentability of inventions based on hESCs should be to shift back the date of first availability of “human embryonic stem cells” from morally acceptable sources to late 2005 or early 2006. Currently, the EPO acknowledge 10 January 2008 as the earliest date on which hES cells from morally acceptable sources were available following the disclosure of Chung et al.7.

However, we mentioned above that the search for morally acceptable sources of hES cells has continued. We and others have been reviewing publically available literature for disclosures that define the earliest date from which morally acceptable stem cell lines were made available. We believe that we have two examples that support an earlier date of availability for acceptable hES cell lines.

Chromosomally Aberrant Embryos

First, in December 2005 Alikani and Munné8 disclosed that non-viable, pre-implantation human embryos were a suitable source for providing hES cells. We are grateful to Dan Wise and Annabel Strawson of Carpmaels & Ransford for telling us about this first example, which has a cover date of 1 December 2005. Indeed, it appears that the true date of availability may be earlier than this as we have also obtained slides from a PowerPoint presentation by one of the authors, which contains figures found in this paper, that is dated November 2005.

“Method 2” of Alikani and Munné discloses how hES cells with a normal complement of chromosomes can be obtained from “chromosomally abnormal embryos […] with no chance to develop into foetuses”.

The disclosure here is not about parthenotes but describes how hES cells can be obtained from embryos diagnosed with specific chromosomal abnormalities which are, similarly, incompatible with life. These chromosomally abnormal embryos were the result of normal fertilisation preceded by aberrant egg or sperm development; resulting in their cells having three copies of a particular chromosome rather than the normal complement of two copies of each chromosome. As a result, the fertilised eggs that gave rise to these embryos were incompatible with life from the outset. In this case cells taken from these abnormal embryos were cultured and Alikani and Munné found that some of the cultured cells self-corrected to yield a normal complement of chromosomes.

So, while the cells yielded by the method of Alikani and Munné are not parthenotes, they fall within the definition used by the High Court in its question to the CJEU, i.e. “in contrast to fertilised ova, [they] contain only pluripotent cells and are incapable of developing into human beings” [our emphasis].

It follows that, using the logic of the Advocate General set out above, cell lines produced by these methods are not derived from human embryos. Thus products and methods incorporating such hES cells are not excluded from patentability.

Furthermore, the cells obtained by this method are arguably equivalent to those considered by the Bundesgerichtshof in the case of Brüstle vs Greenpeace referred to above. In both of these cases, at the time that the cells were extracted the embryo was no longer capable of further development and therefore the extracted cells were morally acceptable because they were not capable of developing into a human being.

Another notable feature of this method is that the feeder cells used to support growth of these hES cells are mitotically inactivated mouse embryonic fibroblast cells. Therefore, in line with EPO Enlarged Board of Appeal decision G 2/06 (WARF), no destructive use of human embryos was required in order to culture these cell lines.

A Scandal Yielding Parthenotes

Our second example relates to hES cell lines derived from unfertilised, parthenogenetically stimulated human ova; that is to say embryos that never were. The cell lines were available as of 9 January 2006, and probably earlier.

In 2004 and 2005 the group of Korean researcher Hwang Woo Suk of Seoul National University published papers claiming to have made great strides in the cloning of human cells by utilising somatic-cell nuclear transfer (SCNT). In this infamous case, these claims were proved to be false.

The official investigation and report of Seoul National University on Dr Hwang Woo Suk9 led to his paper10 being retracted in a blaze of publicity.

However, the investigation resulting from this fraud revealed that the NT-1 cell line produced during this work was a parthenogenetically derived hES cell line. Furthermore, this hES cell line was lodged with the Korean Cell Line Bank for the purpose of obtaining a patent.

Thus, it is clear from the official report that the cell line NT-1 was available by January 2006 and probably prior to publication of the 2004 paper; our investigations as to the exact date are ongoing. Certainly the cell line was available to researchers prior to January 2006 because they were using it to investigate and verify the findings published by Hwang et al.

The official investigation confirmed NT-1 was derived from an unfertilised human ovum where its division and further development had been stimulated by parthenogenesis, i.e. these are precisely the circumstances considered in case C 364/13 and which are set out in the question referred to the CJEU by the UK High Court. Consequently, following the Advocate General’s Opinion cell line NT-1 is, arguably, an hES cell line from a morally acceptable source.

Similarly to the disclosure of Alikani and Munné above, the withdrawn paper describes methods of culturing hES cells using serum-free sequential medium. Therefore, the creation of cell line NT-1 did not require the destruction of human embryos. Consequently, its use in the working of a patented invention should be acceptable following decision G 2/06.

Conclusion

If the Opinion of the Advocate General is followed by the CJEU then hES cell lines consistent with the morality provisions of the EPC as defined in Article 53(a) and Rule 28(c) EPC, and as interpreted by the EPO following the WARF and Brüstle decisions, were arguably available at least as far back as November 2005, and probably earlier. This compares with the EPO current practice acknowledging that acceptable cells were available only from 10 January 2008. Consequently, the gloomy outlook for patenting early stem-cell based inventions appears to be brightening.

References

  • Oliver Brüstle vs Greenpeace e.V. (CJEU decision C 34/10)
  • Schlich, CIPA Journal 2012
  • Hill and Schlich, CIPA Journal 2013
  • Opinion of the Advocate General Cruz Villalón in CJEU case C 364/13 (International Stem Cell Corporation vs Comptroller at General of Patents)
  • Decision of the UK High Court [2013] EWHC 807 (Ch) (International Stem Cell Corporation vs Comptroller at General of Patents)
  • Decision of the German Bundesgerichtshof X ZR 58/07 (Brüstle vs Greenpeace e.V.)
  • Chung et al., Cell Stem Cell, 2008 February 7;2(2):113–7, Epub 2008 Jan 10, doi:10.1016/j.stem.2007.12.013.
  • Alikani and Munné, Stem Cell Reviews, v. 1, 2005
  • Investigation Committee Report, Seoul National University (SNU), 10 Jan. 2006. (Members: Chairman Myung-Hee Chung, SNU, Uhtaek Oh, SNU, Hong-Hee Kim, SNU, Un Jong Pak, SNU, Yong Sung Lee, Hanyang University, In Won Lee, SNU, In Kwon Chung, Yonsei University, Jin Ho Chung, SNU).
  • Hwang, W.S. et al., Evidence of A Pluripotent Human Embryonic Stem Cell Line Derived From a Cloned Blastocyst, Science 303, 1669 (2004).