28 August 2016

Can an Early-Stage Embryo Without a Father Be Considered ‘Human’?

BlastocystUnder subsection 18(2) of the Australian Patents Act 1990, ‘human beings, and the biological processes for their generation, are not patentable inventions’.  An account of the legislative history of this exclusion may be found in the Patent Office decision Fertilitescentrum AB and Luminis Pty Ltd [2004] APO 19 at [13]-[25], which demonstrates that it was essentially the result of a political compromise between a push to exclude all genetic material and life forms from patentability, and the status quo of having no express exclusions in the Act. 

The government of the day rejected a broad exclusion on the basis that ‘it is impossible to foresee what inventions there will be in the future’ and that ‘a Patents Act which is not flexible enough to deal with the unforeseen would not serve the inventors, the public or the Government.’ 

Included with ‘the unforeseen’, however, are scientific developments that challenge the very category of ‘human’.  A Delegate of the Commissioner of Patents has recently had to deal with the question of whether the creation of a blastocyst via parthenogenetic activation of a human oocyte falls within the exclusion of subsection 18(2): International Stem Cell Corporation [2016] APO 52

No need to worry if you did not understand that last sentence.  I have done the background reading, and here is what it means in plain English.  What the inventors at International Stem Cell Corporation (ISSCO) did was to:
  1. extract an immature human egg cell (an ‘oocyte’) from the ovary;
  2. employ a technique to artificially activate the oocyte without requiring fertilisation (a process known as ‘parthenogenesis’); and
  3. allow the activated oocyte to develop to an early stage of cell division called a ‘blastocyst’.
The point of all this is to enable the production of human stem cells matched to the woman from whom the oocyte was taken.  Therapies based on the use of stem cells are considered extremely promising for the treatment of various forms of degenerative disease, diabetes, heart disease and numerous other conditions. 

As ISSCO stated in its 2007 press release announcing the breakthrough, ‘parthenogenetic stem cell lines that are genetically related to the recipient may overcome rejection problems and thus may have the potential to give significant therapeutic benefit to patients.’  Furthermore, ‘parthenogenetically-derived stem cells provide an alternative to embryonic stem cells derived from fertilized embryos or from somatic cell nuclear transfer (SCNT) technology.’  These latter techniques are highly controversial, because they involve the use of potentially viable human embryos.

What, then, is the status of a parthenogenetic blastocyst?  If it qualifies as ‘human’, then it, and the processes by which it is created, fall within subsection 18(2), and are therefore unpatentable in Australia.  Fortunately for ISSCO, and for the many patients who may ultimately benefit from continued substantial investment in these types of biotechnology, the Australian Delegate found that this is not the case.

The Patentability Question

The principal issue that the Delegate was required to address can be understood by reference to claim 1 of ISSCO’s Australian patent application no. 2013205483:

A method of producing human stem cells comprising:
    (a) obtaining a blastocyst by cultivating an activated unfertilized oocyte at low O2 tension wherein the blastocyst is haploid or diploid and lacks paternal imprinting;
    (b) transferring the blastocyst to a layer of feeder cells, and culturing the transferred blastocyst in media under high O2 tension, wherein the blastocyst is haploid or diploid and lacks paternal imprinting;
    (c) mechanically isolating an inner cell mass (ICM) containing pluripotent cells of the ICM from trophectoderm of the blastocyst of stem (b); and
    (d) culturing the pluripotent cells of the ICM of step (c) on a layer of feeder cells in media under high O2 tension,
wherein the blastocysts are cultivated from an unfertilized oocyte that has been activated by contacting the oocyte with an ionophore at high O2 tension and then contacting the unfertilized oocyte with a serine threonine kinase inhibitor under low O2 tension and wherein the oocyte genome is haploid or diploid and lacks paternal imprinting.
The significance of the phrase I have bolded, ‘lacks paternal imprinting’, will become apparent.
The examiners of this, and other, claims filed by ISSCO rejected them under subsection 18(2) on the basis that (see paragraph [16] of the Delegate’s decision):
...the cultivation of an activated unfertilized oocyte as claimed represents the cultivation of a human embryo, and as such represents a biological process for the generation of a human being. While the method is not explicitly directed to a method of generating a human being, the method includes a step where a human being (ie a parthenogenically-activated oocyte) is produced, and therefore the subject matter of the claim is not patentable.
This form of objection raises two distinct questions:
  1. Does a method which, overall, is not directed to human beings, or the biological processes for their generation, fall foul of subsection 18(2) if it nonetheless involves one or more steps that might be characterised as such?
  2. Is a parthenogenetically-activated oocyte a ‘human being’?
Spoiler alert: the answers (according to the Delegate) are ‘yes’ and ‘no’.

‘Incidental’ Embryos

The first of the above questions is pretty easy to answer.  Clearly the exclusion in subsection 18(2) addresses moral and ethical concerns around the patenting of something that arguably amounts to human life, and to the provision of a patent incentive for the commercial development of such technologies.

That being the case, prohibiting the patenting of human beings, or the biological processes for their generation, while allowing the patenting of applications that essentially involve such subject matter would render the exclusion largely ineffective.  As the Delegate concluded (at [22]):

With regard to s18(2), the amendments to the Act were responsive to public concern regarding the patentability of human beings and reproductive technologies for producing human beings. ... I consider that the exclusion of biological processes where a (potentially human) entity is created, and is subsequently used (or even destroyed to allow the use of the cells produced) for another purpose, provides a clear representation of the type of mischief that Parliament was addressing. Put another way, it would be inconsistent with the intended purpose of s18(2) if the inclusion of additional steps following the production of a human being or human embryo resulted in the claim circumventing the s18(2) exclusion.

Is a Fatherless Embryo ‘Human’?

As highlighted in the claim above, a parthenogenetically-activated oocyte has no father, i.e. it carries no paternal genetic information and ‘lacks paternal imprinting’.

This is important because although there are many species in nature that can reproduce parthenogenetically, mammals are not among them.  On the contrary, mammals have evolved such that both maternal and paternal genetic material is essential to proper development.  Parthenogenetic mammals, lacking paternally imprinted genes, develop abnormalities are are generally considered non-viable.

The delegate characterised the second question above, i.e. ‘is it a human being?’ as ‘whether the entity produced at any point in the method claimed can reasonably claim the status of a human being. In other words, does the formation of a blastocyst via parthenogenic oocyte activation represent a “process that directly relates to the generation of a human being”’  (Delegate’s decision at [28]).

The Delegate found that it does not (at [30]-[31]):

In the context of the claimed invention, an early developmental structure, or blastocyst, is formed following activation of the oocyte. This structure is analogous to a blastocyst formed following fertilisation of an oocyte by a sperm, but it is not the same. ... [T]he entity produced following parthenogenic oocyte activation does not have the potential to lead to birth so does not lie on the pathway from fertilisation to birth, and thus cannot claim the status of a human being. At each point from oocyte activation to the formation of the blastocyst, as well as developmental stages further down the developmental path, the entity is not a human being.

A clear distinction between the two entities is that the blastocyst produced by parthenogenic oocyte activation contains only maternal DNA. As a result, these blastocysts do not contain a complete genome. They lack all the imprinted genes that would be provided by the paternal genome and are also incapable of developing the extraembryonic tissues that support embryogenesis .... Furthermore, as the mammalian oocytes activated in the claimed methods are not totipotent (i.e. they cannot divide and produce all of the differentiated cells of an organism), it is not possible for any subsequent entity to develop into a human being.

Accordingly, the blastocysts created in the course of performing the claimed methods do not qualify as ‘human beings’, and therefore do not fall foul of subsection 18(2).

Consistency With European Position

There is nothing especially unusual about Australia’s exclusion from patentability of biotechnologies involving ‘human beings’.  The European Biotechnology Directive – which authorises patenting of a broad range of biotechnology – also explicitly excludes such things, e.g. at Article 6(2):

...the following, in particular, shall be considered unpatentable:
(a) processes for cloning human beings;
(b) processes for modifying the germ line genetic identity of human beings;
(c) uses of human embryos for industrial or commercial purposes

As a result, ISSCO ran into difficulties in obtaining patents on its technology in the UK.  It appealed Patent Office rejections to the UK High Court, which referred a question to the European Court of Justice (CJEU) to assist it in reaching a decision.  That question was:

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 [The Biotechnology Directive] ...?

The CJEU answered this question as follows (Case no. C-364/13):

[The Directive] must be interpreted as meaning that an unfertilised human ovum whose division and further development have been stimulated by parthenogenesis does not constitute a ‘human embryo’, within the meaning of that provision, if, in the light of current scientific knowledge, that ovum does not, in itself, have the inherent capacity of developing into a human being, this being a matter for the national court to determine.

Following this ruling, it does not appear that the matter was required to return to the UK High Court for judgment.  I note, however, that the two UK applications at issue, GB0621068.6 and GB0621069.4, have both now resulted in granted patents.

Conclusion – A Human Embryo Needs a Mummy and a Daddy

Australia is currently embroiled in a debate as to whether or not we should make it legal for people who love each other and want to spend their lives together to marry, regardless of their individual genders.  This is, it should be noted, already the law in the US, the UK, Ireland, New Zealand, Canada and South Africa, among others.  This makes Australia an outlier and a laggard in our peer group which I, personally, think is a disgrace.  And since our politicians, whom we already elected to represent us, are incapable of agreeing to step up and take responsibility, it seems we are to be subjected to a costly and divisive plebiscite in order to tell them what they, in fact, already know, which is that a majority of Australians are in favour of removing this ugly and unnecessary form of discrimination.

And, just to be absolutely clear, it is also my view that children will thrive in any happy and supportive environment, regardless of the gender of their parents and/or guardians.  Equally obviously, there are many ‘traditional’ family environments in which children do not thrive... or worse.

There is no question, however, that biology is pretty critical to conception and successful development of a foetus.  As we see in this case, a blastocyst with one mummy and no daddies is not a viable human being.  Rather, it is the result of an extraordinarily clever and advanced development in biotechnology that could have significant positive implications for the future of healthcare, and benefit many future generations regardless of the genders of their parents – biological or otherwise.


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