International Stem Cell Corporation
[2016] APO 52
•16 August 2016
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
International Stem Cell Corporation [2016] APO 52
Patent Application: (1) 2012216371
(2) 2013205483
Title:(1) Synthetic cornea from retinal stem cells
(2) Parthenogenic activation of human oocytes for the production of human embryonic stem cells
Patent Applicant: International Stem Cell Corporation
Delegate: S. Calanni
Decision Date: 16 August 2016
Hearing Date: Written submissions filed on 11 March 2016
Catchwords: PATENTS - examiner objection – s18(2) – methods that incorporate a step where a potential human being is produced – parthenogenic activation of human oocytes – invention does not represent a biological process for producing a human being
Representation: Freehills Patent Attorneys
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: (1) 2012216371
(2) 2013205483
Title:(1) Synthetic cornea from retinal stem cells
(2) Parthenogenic activation of human oocytes for the production of human embryonic stem cells
Patent Applicant: International Stem Cell Corporation
Date of Decision: 16 August 2016
DECISION
The s18(2) objection in relation to 2013205483 has been overcome. Pursuant to regulation 13.4(1)(g), the application will not lapse for failure to gain acceptance until 3 months from the date of this decision.
The same reasoning extends to the s18(2) objection in relation to 2012216371, however that application has lapsed. In this instance the final date for acceptance cannot be altered because the request for examination for this application was filed before 15 April 2013.
REASONS FOR DECISION
Patent applications 2012216371 (the ‘371 application) and 2013205483 (the ‘483 application) were filed by International Stem Cell Corporation (the Applicant). The applications are divisional applications of 2006346492 and 2006304788, respectively, both of which lapsed through failure to gain acceptance within the prescribed period.
The Applicant requested examination of the ‘371 application on 27 February 2013, so the substantive amendments of the Patents Act 1990 (the Act) brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 do not apply to this application. In contrast, examination was request on 13 June 2014 for the ‘483 application, thus the above-mentioned amendments to the Act do apply to the ‘483 application.
The applications received first examination reports on 24 April 2014 and 2 June 2015 respectively. The sole outstanding objection in relation to the ‘371 application is that claims 1-30 define subject matter not patentable under s18(2). For the ‘483 application the outstanding objections are that claims 1 to 35 define subject matter not patentable under s18(2) and that claim 35 does not comply with subsection 40(3A). The present decision relates to the s18(2) matters only.
The matter was set for hearing on 31 March 2016. The applicant filed written submissions on 11 March 2016, however the hearing was vacated on 24 March 2016. Following further discussion and consideration of the written submissions, it was decided to proceed with the hearing based on the written submissions alone.
Although the ‘371 application was filed earlier, the technology referred to in that application is an extension of the technology described in the ‘483 application. For that reason, in the following consideration, I will first consider the ‘483 application.
The '483 application
The application is entitled ‘Parthenogenic activation of human oocytes for the production of human embryonic stem cells’. The specification states that parthenogenic activation of mammalian oocytes may be used as an alternative to fertilisation by sperm or nuclear transfer to prepare oocytes for embryonic stem cell generation.
At [0054] the specification defines parthenogenesis as a process by which activation of an oocyte occurs in the absence of sperm penetration, and refers to the development of an early stage embryo comprising trophectoderm and inner cell mass that is obtained by activation of an oocyte or embryonic cell, e.g. blastomere, comprising DNA of entirely female origin. In a related aspect, a ‘parthenote’ refers to a cell obtained by such activation. In another related aspect, a ‘blastocyst’ refers to a cleavage stage of a fertilized or activated oocyte comprising a hollow ball of outer trophoblast cells surrounding an inner cell mass (ICM).
The specification indicates that, while parthenogenesis is not an uncommon form of reproduction in nature, mammals are not known to be capable of this form of reproduction. Oocytes from placental mammals can be induced to undergo parthenogenesis in vitro; however embryonic development from parthenogenesis is not successful. In mammals, induced parthenotes develop to different stages after oocyte activation, but following transfer of an activated oocyte into a surrogate mother there is only limited embryonic survival. The failure of embryos to develop from mammalian parthenotes is a consequence of genetic imprinting and the requirement for genes from both the maternal and paternal genome in the control of embryonic growth and development, including development of the placenta [0055]-[0057].
The '371 application
The application is entitled ‘Synthetic cornea from retinal stem cells’. The invention described in the application relates to a process for obtaining synthetic cornea, specifically a method where retinal stem cells are obtained from a parthenogenically-activated human oocyte. Oocyte activation and the production of human stem cells are according to the methods described previously in the '483 application.
The Claims
10. The method defining the invention described in the '483 application is represented by claim 1 as follows:
1. 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.
11. A second independent claim specifically defines the method of activating the oocyte as follows:
11. A method of activating a human metaphase II oocyte comprising:
(a) incubating a human metaphase II oocyte in in vitro fertilisation (IVF) media;
(b) incubating the cell of step (a) in IVF media comprising an ionophore;
(c) incubating the cell of stem (b) in IVF media comprising a serine-threonine kinase inhibitor; and
(d) incubating the cells of stem (c) in fresh IVF medium until blastocyst formation,
wherein the incubating steps (a) and (b) are carried out under high O2 tension, and wherein an inner cell mass (ICM) obtained from the blastocyst at step (d) produce culturable stem cells.
12. The '483 application includes additional independent and dependent claims that essentially define methods incorporating the features of claims 1 or 11, as well as stem cells, cell lines and differentiated cells obtained according to these methods.
13. In the '371 application, the method defined by claim 1 essentially reflects the invention described in the application and is as follows:
1. A method of producing a synthetic cornea, cornea tissue or cornea cell comprising:
(a) obtaining blastocytes (sic) by cultivating an activated pluripotent, unfertilized oocyte at low O2 tension until blastocyst formation, wherein the blastocytes are haploid or diploid and lack paternal imprinting;
(b) transferring the blastocyst to a layer of feeder cells, and culturing the transferred blastocyst under high O2 tension, wherein the blastocytes are haploid or diploid and lack paternal imprinting;
(c) mechanically isolating an inner cell mass (ICM) containing pluripotent cells from trophectoderm of the blastocyst of stem (b); and
(d) culturing the pluripotent cells of the ICM to step (c) on a layer of human feeder cells under high O2 tension, wherein non-embryonic pluripotent stem cells are identified in the culture by human embryonic cell markers (hES) and neuron specific markers, and allowing synthetic cornea, corneal tissue or a corneal cell to develop; and
wherein the blastocysts are cultivated from a pluripotent, unfertilized oocyte that has been parthenogenically activated by contacting the oocyte with an ionophore at high O2 tension and then contacting the pluripotent, 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.
14. The ‘371 application includes additional independent and dependent claims relating to an isolated synthetic cornea, cornea tissue or cornea cell obtained by the method, and uses thereof.
The examiner's objections
15. During examination of the present applications, as well as the parent applications, objections were raised against the claims as a whole for defining subject matter that is not patentable under s18(2) of the Patents Act.
The position taken by the examiners in each instance was that the claimed methods include a step where an oocyte is activated to produce a parthenogenic embryo. Specifically, part (a) of claim 1 in each application represents a method step where a blastocyst is produced by cultivating an activated unfertilized oocyte at low O2 tension.
16. It was considered that 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.
Do the provisions of subsection 18(2) extend to methods that include a step producing a potential human being?
17. s18(2) of the Patents Act 1990 states that:
‘Human beings, and the biological processes for their generation, are not patentable inventions.’
18. The applicant submitted that there is no legal basis for the examiner to adopt an approach where an objection under the provisions of s18(2) is extended to a claim merely because a step of the claim is unpatentable. There is no basis for applying a different standard to s18(2) compared to other grounds of validity.
‘when considering the patentability of a claim under s18(1), s18(1A) and s40, the claim is considered in its entirety. A claim is not deemed to lack novelty for example when one integer of the claim lacks novelty’.
19. Further, the applicant submitted that:
‘...the drafting of s18(1) and (2) clearly demonstrates that Parliament, in defining the scope of patentable inventions, deliberately defined a patentable invention very broadly as including any invention that met the requirements of s18(1), but subject only to a specific exclusion in s18(2). In such a circumstance, there is no basis for reading the exclusion more broadly such that a part of an invention renders the entire invention unpatentable. Had Parliament intended that s18(2) would apply to any part of an invention, it would have easily added suitable words into the exclusion to make it clear.’
20. However, I consider there are clear limitations in applying a purely literal approach to the interpretation of the provision as suggested by the applicant. This is particularly the case in a situation where the state of the technology is changing and it is unlikely that Parliament could foresee the possibilities in that technology. For example, in 1990, when subsection 18(2) was introduced, mammalian reproductive cloning technology was in its infancy and embryonic stem cells were yet to be discovered. It is therefore not surprising that Parliament would use a broad exclusion because it would be difficult for them to anticipate or predict future developments in a rapidly changing technology.
21. In seeking to interpret subsection 18(2) of the Act, I am guided by the Acts Interpretation Act 1901, Section 15AA which provides the following:
‘15AA Interpretation best achieving Act's purpose or object
In interpreting a provision of an Act, the interpretation that would best achieve the purpose or object of the Act (whether or not that purpose or object is expressly stated in the Act) is to be preferred to each other interpretation.’
22. Thus, when interpreting s18(2), I must apply the interpretation that would best achieve the purpose of the Act. In doing so, I may consider the mischief that Parliament was trying to solve. 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. The history of the provision is laid out fully in Fertilitescentrum AB and Luminis Pty Ltd [2004] APO 19 (Fertilitescentrum) at [13]-[25]. Having regard to the deliberations described therein, 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.
Can blastocysts produced by parthenogenesis be considered human beings?
23. Having decided that processes that include a step that creates a human being are also excluded from patentability, the key issue in the present applications is whether a parthenogenic blastocyst (or parthenote) produced by the activation of an oocyte can be considered a human being.
24. In addressing this question I must consider the principles set out in the two decisions by the Deputy Commissioner relating to s18(2) of the Act, namely Fertilitescentrum and Woo-Suk Hwang [2004] APO 24 (Hwang).
25. At [37]-[38] of Fertilitescentrum the Deputy Commission held that:
‘The prohibition of `human beings' in my view is a prohibition of patenting of any entity that might reasonably claim the status of a human being. Clearly a person that has been born is covered by this exclusion. But to the extent that there is a process of generation of a human being that lasts from fertilisation to birth, I consider that a fertilised ovum and all its subsequent manifestations are covered by this exclusion’ (emphasis added).
The prohibition of `biological processes for (the generation of human beings)' clearly covers all biological processes applied from fertilisation to birth - so long as the process is indeed one that directly relates to the generation of the human being. I also consider the exclusion of biological processes includes the processes of generating the entity that can first claim a status of human being (emphasis added). For example, processes for fertilising an ovum; processes for cloning at the 4-cell stage by division; processes for cloning by replacing nuclear DNA.
26. Subsequently, in Hwang, the Deputy Commissioner decided that the exclusion of biological processes for the generation of human beings extended to methods where an ovum had been artificially activated and that inclusion of mitochondrial DNA that was bovine did not take away the essentially human characteristic of the embryo [8]-[9].
‘In natural reproductive processes, the activation of an ovum arises as a direct result of the fertilisation process. However it is clear that fertilisation by a sperm is not the only way in which an ovum can be activated. In my view, an ovum that has been artificially activated is in principle no different to an ovum that has been fertilised by natural means (noting of course that the DNA content of the ovum will be different). Accordingly the fact that the claimed method uses postactivation of the ovum does not remove the process from the ambit of s.18(2).
The embryo produced by the claimed process has both human and bovine DNA present. It is clear that the nuclear DNA is intended to be entirely human DNA. The mitochondrial DNA, which essentially is relevant to the energy use of the cell, is entirely bovine. The primary physical characteristics of mammals are governed by the nuclear DNA of the cells. In my view, the presence of the bovine mitochondrial DNA does not take away the essentially human characteristic of the embryo that is determined by the nuclear DNA. That is, the embryo that is produced by this method - while being hybrid - is properly considered human.’
27. Turning to the present applications, the methods claimed relate to the use of an activated human oocyte that necessarily contains human nuclear DNA. Thus, a simple application of the principles set out in Hwang leads to two conclusions:
1. The developmental entities formed following activation of the oocyte can be properly considered of human origin; and
2. The use of oocyte activation to produce a blastocyst does not automatically remove
the process from the ambit of s18(2).
28. The important remaining question to consider is 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’ (emphasis added)?
29. The Applicant has submitted that blastocysts formed via parthenogenic activation of unfertilised human oocytes do not have potential to become a human being (Applicant submissions [33]-[45]). In support of these submissions, the Applicant has referred to a number of scientific publications that examine and substantiate the notion that a blastocyst formed following oocyte activation does not have the potential to become a human being (Kastenberg, Z. J. et al, Transplantation Review, 2008, 22:215-22 (Annexure 12); Brevini et al, Cell Proliferation, 2008, 41:20-30 (Annexure 13); and Surani, M. A., Nature, 2001, 414:122-128 (Annexure 14)).
30. 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. The parthenogenic blastocyst has the same general morphology (a trophectoderm region and inner cell mass) as a blastocyst produced following normal fertilisation, and also progresses through early development in a manner that mirrors cell division following fertilisation. However, the 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.
31. 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 (Applicant submissions [35]-[38]). 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.
32. As such, based on the evidence provided, I am satisfied that the claims of the present applications do not fall within the ambit of `biological processes for the generation of human beings’ as proscribed by s18(2).
Conclusion
33. I conclude that the objection under s18(2) to the '483 application has been overcome. Pursuant to regulation 13.4(1)(g), the application will not lapse for failure to gain acceptance until 3 months from the date of this decision.
34. The '371 application lapsed prior to the filing of the written submissions in relation to this decision. As the request for examination for this application was filed before 15 April 2013, the final date for acceptance cannot be altered. I note, however, that a divisional application (2016200394) was filed on 22 January 2016.
S. Calanni
Delegate of the Commissioner of Patents
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