Grant Fisher v ToolGen Incorporated
[2018] APO 65
•18 September 2018
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Grant Fisher v ToolGen Incorporated [2018] APO 65
Patent Application: 2013335451
Title:Composition for cleaving a target DNA comprising a guide RNA specific for the target DNA and Cas protein-encoding nucleic acid or Cas protein, and use thereof.
Patent Applicant: ToolGen Incorporated
Opponent: Grant Fisher
Delegate: Dr Leslie F. McCaffery, Deputy Commissioner
Decision Date: 18 September 2018
Hearing Date: 21 May 2018, in Canberra (Supplementary submissions finalised 21 June 2018)
Catchwords: PATENTS – opposition to the grant of a patent under section 59 – Section 40(2)(a) and whether the specification is clear enough and complete enough for the skilled person to work the invention across the full scope of the claims – Section 40(3), clarity and support – Section 43 and priority – novelty – inventive step – opposition successful – opportunity to amend – costs awarded.
Representation: Counsel for the applicant: Patrick W. Flynn
Patent attorney for the applicant: Jones Day
Counsel for the opponent: Christian Dimitriadis SC and Clare Cunliffe
Solicitor for the opponent: Ashurst Australia
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2013335451
Title:Composition for cleaving a target DNA comprising a guide RNA specific for the target DNA and Cas protein-encoding nucleic acid or Cas protein, and use thereof.
Patent Applicant: ToolGen Incorporated
Date of Decision: 18 September 2018
DECISION
The opposition under Section 59 is successful.
Claim 19 lacks clarity.
Claims 1 to 8 and 10 to 18 lack novelty.
Claims 1 to 8, 10 to 18 and 21 lack inventive step.
The Applicant has 2 months from the date of this decision to propose amendments to overcome the issues.
As the opposition is successful, costs according to Schedule 8 are awarded against the Applicant Toolgen Incorporated.
REASONS FOR DECISION
1. Patent application 2013335451 was filed by ToolGen Incorporated (the Applicant) on 23 October 2013. The application claims earlier priority from several US provisional applications: 61/717324 which was filed on 23 October 2012 (hereinafter P1), 61/803599 which was filed on 20 March 2013 (hereinafter P2) and 61/837481 which was filed on 20 June 2013 (hereinafter P3).
2. Examination was requested on 21 August 2015. Following two adverse examination reports, the application was advertised as accepted on 15 September 2016. A notice of opposition was filed by Grant Fisher (the Opponent) on 15 December 2016.
3. The statement of grounds and particulars was filed on 15 March 2017 and set out the following grounds of opposition: novelty, inventive step, utility, and sections 40(2)(a) (sufficiency), 40(2)(aa) (best method), 40(2)(b) (definition) and 40(3) (clarity and support). A request to amend the statement to reflect the evidence in support provided by the opponents was filed on 13 July 2017, and allowed on 24 August 2017.
4. The matter was heard on 21 May 2018. The grounds of novelty, inventive step, sufficiency, clarity and support were pressed at hearing. The Applicant was represented by Mr Patrick Flynn and the Opponent by Mr Christian Dimitriadis and Ms Clare Cunliffe.
Standard of proof
5. The examination of the present application is governed by the Patents Act 1990 (the Act) as amended by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (the Raising the Bar Act). The standard of proof that applies to the examination of the present application is therefore the balance of probabilities – I must accept the present application if satisfied, on the balance of probabilities, that the application complies with the Act. If I am not so satisfied, then I can refuse the application.
Evidence
6. Evidence in support consisted of declarations by Mr Grant William Fisher dated 15 June 2017; Dr Marco Josef Herold dated 15 June 2017 (Herold 1); and Professor Paul Quinton Thomas (Thomas) dated 15 June 2017.
7. Evidence in answer consisted of a declaration by Associate Professor Ron Firestein (Firestein) dated 19 September 2017.
8. Evidence in reply consisted of a declaration by Dr Herold dated 17 November 2017 (Herold 2).
9. I will refer to the relevant parts of the evidence as required.
Background
10. The application relates to the use of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology in targeted gene editing in eukaryotic cells or organisms.
11. The specification provides a general background to CRISPR. These are loci containing multiple short direct repeats that are found in the genomes of bacteria and archaea and functions as a prokaryotic immune system, conferring resistance to exogenous genetic elements such as plasmids and phages.
12. Short segments of foreign DNA (spacers) are incorporated into the genome between the CRISPR repeats, and act to recognise and silence exogenous genetic elements in a manner analogous to RNAi in eukaryotic organisms. Cas9 is an essential protein component in the Type II CRISPR/Cas system and forms an active endonuclease when complexed with two RNAs termed CRISPR RNA (crRNA) and trans-activating crRNA (tracrRNA) thereby slicing foreign genetic elements in invading phages or plasmids to protect the host cells. crRNA is transcribed from the CRISPR element in the host genome, which was previously captured from such foreign invaders.
13. The specification states that “[u]ntil now, a genome editing and genotyping method using the RNA-guided endonuclease (RGEN) based on CRISPR/Cas system has not been developed”, and that the invention provides a “programmable RNA-guided endonuclease” that cleaves DNA in a targeted manner in eukaryotic cells and organisms.
Construction: legal principles
14. The principles of construction are well established. As Middleton J stated:
“It is well settled that the Court should, from the outset, approach the task of patent construction with a generous measure of common sense. The Court must place itself in the position of a person skilled in the relevant art, being the subject matter of the patent. From this perspective, the patent is to be read as a whole, in the context of the specification and in light of the prevailing common general knowledge and state of the relevant art at the priority date.”[1]
[1] Eli Lilly and Co Ltd v Apotex Pty Ltd [2013] FCA 214; 100 IPR 451 at 482 [139].
15. Middleton J went on to provide a useful summary of relevant principles:[2]
[2] Ibid at [143].
· a patent is a public instrument which must, if it is to be statutorily valid, define a monopoly which is not reasonably capable of being misunderstood;
· the Court, when reading the entire patent specification, must place itself in the position of a person who is skilled in the relevant art, given their general knowledge, and the common general knowledge and the state of the art that existed before the priority date of the patent;
· the words used in a specification, including the claims, are to be construed from this standpoint in a “commonsense” and not abstract manner;
· what is disclosed in the body of the specification will also assist the skilled person in the art to understand the claims, bearing in mind that a patent is a unilateral document and the patentee has chosen particular words to describe the invention;
· the claims define the monopoly claimed by the patent;
· terms which are unclear in the claims may be defined or clarified by reference to the body of the specification;
· language which has no positive meaning in the claims may become clear when the specification is used as a “dictionary” for the jargon in the claims; and
· that said, given the special function of the claims, it is impermissible to read into a claim an additional integer, or otherwise vary the scope of the claim by reference to the body of the specification.
16. Middleton J also cautioned that:
“It is clear from the above propositions (particularly the latter three points) that the use the Court can make of the body of a specification will vary from case to case. As Apotex submitted, there is a fine line between using the specification to construe the claim, and using the specification in such a way that adds an impermissible gloss to the claims.”[3]
[3] Ibid at [144].
17. These are the principles that I will apply in this determination.
The person skilled in the art
18. The specification is construed through the eyes of the person skilled in the relevant art. This is the hypothetical person to whom the specification is addressed.[4] This determination plays a central role in determining the validity of the patent:
“He is the person to whom the patent is addressed and who must construe it. He is the person whose knowledge will determine whether a patent is novel. He is the person who will judge whether a patent is obvious...”[5]
[4] General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (1971) 1A IPR 121 at 134.
[5] Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980; 49 IPR 225 at [70]-[71].
19. The person skilled in the art is assumed to be a skilled but unimaginative and non-inventive worker in the field of the invention.[6] One formulation describes them as “those likely to have a practical interest in the subject matter of [the] invention.”[7] Notably:
“The identification of the relevant field will, in its turn, determine the characteristics of the notional worker skilled in the art who must provide the answer to the question of whether the invention was obvious. Such characteristics will include the qualifications of the notional worker, the setting in which he or she operates and the practices and techniques that he or she will regard as commonplace and known.”[8]
[6] Minnesota Mining and Manufacturing Co & 3M Australia Pty Ltd v Beiersdorf (Aust) Ltd [1980] HCA 9; (1980) 144 CLR 253 at 293.
[7] Catnic Components v Hill & Smith Ltd [1982] RPC 183.
[8] Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59 at 153; (2002) 212 CLR 411 at 465.
20. As noted above, evidence was provided by Prof Thomas, Dr Herold, A/Prof Firestein and Mr Fisher. Mr Fisher’s evidence related to the publication date of the key prior art documents in the opposition. This evidence was not disputed and therefore requires no further reference in the decision.
21. Prof Thomas is a Professor of Biochemistry at the University of Adelaide. He is also the Director of South Australian Genome Editing and Head of the Developmental Genetics Laboratory at the South Australian Health and Medical Research Institute. His research has included the use of homologous recombination to manipulate the genome of embryonic stem cells in mice and knock out genes of interest.
22. Dr Herold is a Laboratory Head at the Walter and Eliza Hall Institute of Medical Research (WEHI). His postdoctoral research work focussed on genetic manipulation of rats using RNA interference (RNAi) technology, and particularly short interfering RNA (siRNA) and small hairpin RNA (shRNA), to silence particular genes. He subsequently applied RNAi techniques in his role at WEHI as part of his research into the molecular regulation of cancer cell growth and death.
23. A/Prof Firestein is the Head of the Centre for Cancer Research at the Hudson Institute of Medical Research and a consulting pathologist in molecular genetic pathology at Monash Health. He also has research experience in RNAi technology, including in cancer research.
24. Notably, all of the experts stated that they were generally aware of CRISPR being used in bacterial systems in 2012. However, it was not until after the publication of several important papers related to the use of CRISPR in eukaryotic cells, that they began using the technology in their own research. The importance of CRISPR as a research tool is indicated by Dr Herold as follows:[9]
“Our use of the Type II CRISPR/Cas9 system to develop novel mouse models has been immensely successful. For example, using old technologies, it took us around two years to develop a novel mouse model. In contrast we can develop a novel mouse model using the CRISPR/Cas9 technology in about 3 months on average.”
[9] Herold 1 at [33].
25. It was clear from the evidence that all three experts had extensive relevant experience in gene manipulation, and there was little dispute between the parties as to their suitability to provide expert evidence on the present matter. Submissions were made about the comparative experience of declarants, and where necessary I have taken such submissions into account in determining the weight I can give evidence.
Construction: the specification
26. The specification ends with 21 claims. These are given in an Annex to this decision. Claims 1 and 10 are independent claims defining compositions and methods respectively.
27. Claim 1 defines:
A composition comprising a Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas system for use in introducing a site-specific, double stranded break at a target nucleic acid sequence in a eukaryotic cell, said CRISPR/Cas system comprising (i) a nucleic acid encoding a Cas9 polypeptide comprising a nuclear localization sequence, and (ii) a nucleic acid encoding a guide RNA that hybridizes to a target nucleic acid, wherein the guide RNA is a chimeric guide RNA comprising a CRISPR RNA (crRNA) portion fused to a trans activating crRNA (tracrRNA) portion.
28. Claim 10 defines:
A method of introducing a site-specific, double-stranded break at a target nucleic acid sequence in a eukaryotic cell, the method comprising introducing into the eukaryotic cell a Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas system, wherein the CRISPR/Cas system comprises:
(a) A nucleic acid encoding a Cas9 polypeptide comprising a nuclear localisation signal, wherein the nucleic acid is codon optimized for expression in eukaryotic cells, and
(b) A nucleic acid encoding a guide RNA that hybridizes to the target nucleic acid, wherein the guide RNA is a chimeric guide RNA comprising a CRISPR RNA (crRNA) portion fused to a trans activating crRNA (tracrRNA) portion, wherein the target nucleic acid sequence comprises a first strand that binds to the crRNA portion and a second strand having a trinucleotide protospacer adjacent motif (PAM),
and wherein the Cas9 polypeptide and the guide RNA form a Cas9/RNA complex in the eukaryotic cell, whereby a site-specific double stranded break at the target nucleic acid sequence is introduced.
29. Dependent claims define specific sources of the Cas9 polypeptide, codon optimization, the nature of the target nucleic acid and the nature of the guide RNA. The opponent highlighted a number of features of the claims, mainly in relation to the breadth of the definitions in comparison with the disclosure but also in relation to the priority documents.
30. Before dealing with the substantive issues I will outline some of the relevant issues of construction.
“introducing a site-specific, double stranded break at a target nucleic acid sequence in a eukaryotic cell”
31. There was no apparent dispute between the parties as to this referring to a specific location of a DNA molecule. For example, Professor Thomas understood this phrase as referring to the introduction of a mutation at a specific, targeted region of the genome, and since RNA is typically single stranded and the specification does not discuss using the CRISPR/CAS9 system to target double stranded (folded) RNA complexes, the term “target nucleic acid” would be limited only to DNA.[10]
“nucleic acid encoding a Cas9 polypeptide”
[10] Quinton at [43].
32. The parties were largely in agreement as to this definition being directed to DNA and RNA sequences that encode Cas9 polypeptides.[11] None of the experts considered that this definition encompasses the use of the Cas9 protein itself.[12]
[11] Opponent’s submissions at [76].
[12] Herold 1 at [136]-[138], Thomas at [46]-[47], Firestein at [260].
33. There was some dispute between the parties as to whether or not the claims included the use of paired nickases. Wild-type Cas9 polypeptides introduce a blunt-ended double-stranded break. Paired nickases arise where the nuclease domains of the Cas nuclease are mutated to give a nickase that is capable of introducing a single stranded break. If one nickase is used together with another nickase then the system is capable of introducing a double stranded break comprising a nucleic acid overhang otherwise known as a “sticky end”.[13]
[13] Herold 1 at [78].
34. Dr Herold understood the term Cas9 polypeptide as including Cas9 polypeptides with endonuclease activity as well as paired Cas9 nickases.[14] However A/Prof Firestein stated that the term “Cas9 polypeptide” included only the singular form of the Cas9 nickase.[15] He noted that two nickases would be required to provide a double-stranded break – that is, the system would require two single stranded breaks – and therefore the claims did not include such pairs.
[14] Herold 1 at [136]-[142].
[15] Firestein at [356].
35. The specification states that the “Cas protein may be any Cas protein provided that it has an endonuclease or nuclease activity when complexed with a guide RNA.”[16] The specification further states that:
“The guide RNA and the Cas protein may function as a pair. As used herein, the term ‘paired Cas nickase’ may refer to the guide RNA and the Cas protein functioning as a pair. The pair comprises two guide RNAs. The guide RNA and Cas protein may function as a pair, and induce two nicks on different DNA strands.”[17]
[16] Specification at [158].
[17] Specification at [187].
36. The Applicant submitted that this paragraph does not compel an alternative construction of the term the Cas9 protein being an endonuclease, particularly since the above paragraph referred to paired Cas nickases and the claims do not use that terminology. This submission is also consistent with the evidence of Prof Thomas, who stated that:
“I understand ‘Cas9 polypeptide’ to include both the native sequence of Cas9 found in nature as well as what the Patent Application describes as ‘paired Cas nickases’. As stated above, an endonuclease is a molecule that makes a double stranded break in DNA. A nickase in this context is a modified Cas9 that does not make a double stranded break and instead cuts (or ‘nicks’) one of the two DNA strands. The Patent Application describes the Cas protein used in the system as an ‘endonuclease or nickase’ (paragraph 151). It discusses and provides examples of how paired Cas9 nickases (i.e. a Cas9 nickase with two different sgRNAs) may be used to make ‘staggered’ double stranded breaks…”[18]
[18] Thomas at [49].
37. On balance I am satisfied that the system defined in Claim 1 does not encompass the use of Cas9 nickases. The evidence suggests to me that the term “site-specific, double stranded break” would be read as a double stranded break introduced by an endonuclease, rather than two single stranded breaks as would be introduced by paired nickases. A similar definition is provided in Claim 10, and I consider that definition to also be limited to the use of an endonuclease and not a nickase.
“Cas9 polypeptide comprising a nuclear localization sequence or signal”
38. There was no apparent dispute between the parties as to the meaning of the term “nuclear localisation sequence”, or NLS. These are short peptides found in nuclear proteins that facilitate the transport of the nuclear proteins into the cell nucleus.[19]
“a nucleic acid encoding a guide RNA”
[19] Firestein at [124].
39. The parties were in substantial agreement that the term “a nucleic acid” includes DNA which encodes the guide RNA. However the parties differed as to whether the term nucleic acid also includes the guide RNA itself.
40. Dr Herold stated that in normal usage the term nucleic acid would refer to DNA, in the form of a vector or plasmid.[20] Prof Thomas stated that the term could not include in vitro transcribed guide RNA as this does not “encode” anything.[21] In contrast, A/Prof Firestein stated that he understood the term to further include the guide RNA itself, but did not provide any further detail as to why.[22]
[20] Herold 1 at [148].
[21] Thomas [53]-[56].
[22] Firestein at [262].
41. The specification describes the various ways by which the guide RNA may be transferred to the cell,[23] and clearly distinguishes between the guide RNA being delivered as naked guide RNA, or as DNA that encodes the guide RNA. Consistent with the terminology used throughout the specification I consider that Claim 1 defines DNA that encodes the guide RNA and not the naked guide RNA itself.
[23] Specification at [176]
42. In contrast to his interpretation of Claim 1, Dr Herold considered that dependent claims 9, 19, 20 and 21 indicated that the term “nucleic acid encoding the guide RNA” is intended to include in vitro transcribed guide RNA.[24] However terms are construed according to what the skilled person would have understood from the language the author used, rather than what they would have thought the author intended to say. To this end, Claim 9 defines that the guide RNA comprises two additional guanine nucleotides at the 5’ end. Dr Herold stated that this indicated to him that the guide RNA has been transcribed in vitro using a T7 promoter. The two guanine nucleotides allow for more efficient in vitro transcription of the guide RNA using the T7 promoter.[25] I note that this interpretation is consistent with the use of a T7 promoter in Example 6 for the in vitro transcription of guide RNA. However, there is nothing in the specification that implicitly or explicitly limits the two additional guanine nucleotides at the 5’ end to nucleotides that are only in vitro transcribed. As a consequence I see no reason why the scope for the claim should be extended to include the use of in vitro transcribed RNA.
[24] Herold 1 at [148]-[150].
[25] Herold 1 at [74] and [180].
43. Claim 19 defines that “the nucleic acid encoding the guide RNA is in vitro transcribed RNA”, even though the claims to which it is appended define the use of nucleic acid encoding the guide RNA. Even though this type of transcription may be possible, there is no apparent support in the specification for such matter. In my opinion there are two possible conclusions that can be drawn from Claim 19: firstly, an error has led to the inconsistency between Claim 19 and the other claims; or secondly, that the term “nucleic acid encoding the guide RNA” takes the broader meaning and includes the naked RNA. In this regard, the specification provides no indication that the term “nucleic acid” should take any meaning other than its plain meaning. This is also consistent with the use of the term nucleic acid in the definition of a “nucleic acid encoding a Cas9 polypeptide” as discussed above, and which was understood by all experts to be directed at DNA encoding the Cas protein and not to the Cas protein itself. I see no basis on which a different construction should be taken for the guide RNA.
44. I therefore consider that Claim 19 is directed towards guide RNA that is in vitro transcribed and introduced into the cell. This being the case, the skilled person would be unable to determine whether or not an act they carry out would infringe this claim because the claim is dependent on the use of a nucleic acid encoding the guide RNA in the method. I therefore consider that the claim lacks clarity.
“wherein the guide RNA is a chimeric guide RNA comprising a CRISPR RNA (crRNA) portion fused to a trans activating crRNA (tracrRNA) portion”
45. The opponent made submissions in relation to the breadth of this term in comparison with the description provided in the specification. This is further discussed below under sufficiency, but while the issue of breadth of the claims was raised in relation to this term I do not consider that the parties found any difficulty in understanding its meaning.
46. The specification states that the guide RNA may consist of separate crRNA and tracrRNA, or may be a single-chain (chimeric) RNA produced by fusion of an “essential portion” of crRNA and tracrRNA. However the definition used in the claims is clearly limited to the single-chain guide RNA.
47. The specification states that the crRNA is the targeting portion of the guide RNA and hybridises with the target DNA.[26] The tracrRNA is “invariable”, and binds to the Cas9polypetide. If using a Cas9 polypeptide from a particular species of bacteria then generally the tracrRNA from that bacterium would need to be used.[27]
“a nucleic acid encoding a Cas9 polypeptide …wherein the nucleic acid is codon-optimized for expression in eukaryotic cells”
[26] Specification at [173].
[27] Herold 1 at [73].
48. Codon-optimization is a well-established technique which involves modification of nucleotide bases in a DNA sequence in order to provide more efficient translation of the protein base.[28]
“the target nucleic acid sequence comprises a first strand that binds to the crRNA portion and a second strand having a trinucleotide protospacer adjacent motif (PAM)”
[28] Herold 1 at [66].
49. A PAM is a short coding sequence that acts as a recognition site for the Cas9 nuclease. Different Cas9 proteins may recognise different PAMs.[29] For example, one of the Cas polypeptides derived from S. pyogenes recognises and binds to a 5’-NGG-3’ PAM, wherein N represents any nucleotide and the GG represents two guanine nucleotides. A target gene may contain numerous PAMs having this sequence, but the nuclease will only unfold and cleave the target DNA when the PAM sequence is adjacent to a sequence which is complementary to the guide RNA.[30]
[29] Firestein at [157].
[30] Herold 1 at [63]-[64].
Clear enough and complete enough disclosure
50. Section 40(2)(a) requires that the complete specification must disclose the invention in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art. The provisions of section 40(2)(a) have recently been considered in detail in CSR[31] and Evolva.[32] I do not intend to repeat the detail of the considerations made in those decisions, but will simply refer to the conclusions.
[31] CSR Building Products Limited v United States Gypsum Company [2015] APO 72.
[32] Evolva SA [2017] APO 57.
51. In CSR the delegate adopted a three-step test for determining whether the specification provided a clear enough and complete enough disclosure of the claimed invention as follows:
· What is the scope of the invention as claimed?
· What does the specification disclose to the skilled person?
·Does the specification provide an enabling disclosure of all the things that fall within the scope of the claims?
52. An expanded approach was taken in Evolva, wherein the third consideration of enablement was assessed according to the following criteria:
·Is it plausible that the invention can be worked across the full scope of the invention?
·Can the invention be performed across the full scope of the claims without undue burden?
53. A point of contention between the parties in the present case related to the extent to which the disclosure of a document may be supplemented by common general knowledge. The applicant referred me to the statements of Kitchin J (as he was then) in Eli Lilly v HGS that “the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification.”[33] They further noted that the requirements of Sections 40(2)(a) and 43 were broadly the same and, consistent with the statements in Eli Lilly v HGS, it is permissible to supplement the information provided (particularly in the priority document) by the common general knowledge to arrive at embodiments that would not have been envisaged without the invention. The gist of the Opponent’s submissions on this point was that care should be taken in such considerations to ensure that the common general knowledge was being used to construe and to work the invention disclosed in the document, rather than supplementing the information to arrive at something new.
[33] Eli Lilly and Company v Human Genome Sciences Inc [2008] EWHC 1903 (Pat); [2008] RPC 29 at [239].
54. The Applicant referred me to a recent UK decision, Regeneron v Kymab,[34] in which Kitchin LJ considered sufficiency of disclosure in relation to an antibody and in particular the extent to which, and the manner in which, an invention must be enabled across the full scope of the claim. The invention in question related to genetically modified mice. The sufficiency issue arose because one of the examples involved the insertion of large sequences of DNA into the mouse DNA, but this could not be achieved at the priority date in the manner disclosed in the specification. The patentee argued, and the Court agreed, that the skilled person would recognise that the method could not be performed using larger DNA sequences and would reduce the size of the DNA inserts. The method employed minigenes, which were considered common general knowledge at the priority date. There was no specific disclosure in the specification of the use of minigenes– the consideration was whether these were common general knowledge in the art at the time and whether it was obvious for the skilled person, having recognised that the method described would not work, to make such a change to the method disclosed in the specification in order to enable the preparation of the desired antibodies.
[34] Regeneron Pharmaceuticals, Inc v Kymab Limited and Novo Nordisk A/S [2018] EWCA Civ 671.
55. Kitchin LJ first noted the corresponding provisions of the UK Act and the EPC in relation to permissible claim breadth and sufficiency. He considered several key principles were not in dispute:[35]
i. The sufficiency of the disclosure is to be assessed having regard to the specification as a whole, including the description and claims
ii. the disclosure is to be considered through the eyes of the skilled person or, as here, the skilled team to whom the patent is addressed; and
iii. the skilled person may use his or her common general knowledge to supplement the information contained in the specification.
[35] Ibid at [209].
56. Kitchin LJ first considered the issue of the degree of enablement, noting that EP and UK law had developed in the same way and that it was well-established that the skilled person must be able to perform the invention without undue effort.[36] He emphasised that:
“sufficiency of the description is a matter which must be assessed having regard to the nature of the invention, the character of the technical field in which the invention is made, and the abilities of the skilled team: see for example, Halliburton v Smith International Inc”[37]
[36] Ibid at [210]-[212] and references cited therein.
[37] Ibid at [213].
57. Kitchin LJ then turned to the issue of enablement across the full scope of the claim, considering a number of decisions of the EP Board of Appeal, as well as UK authorities. He noted that several of the Board of Appeal decisions[38] had been reviewed by the Court of Appeal in Novartis v Johnson & Johnson,[39] where Jacob LJ explained that the heart of the test is :
“Can the skilled person readily perform the invention over the whole area claimed without undue burden and without needing inventive skill.”
[38] T 0435/91 Detergents/Unilever, T 0694/92 Modifying plant cells/Mycogen, and T 1743/06 Amorphous silica/Ineos.
[39] Novartis AG and anor v Johnson & Johnson Medical Ltd and ors [2010] EWCA Civ 1039.
58. However Kitchin LJ considered that these decisions (and others of the Board of Appeal) made it clear that other factors were also important:
“231. First, it is not the law that a specification must necessarily enable the skilled person to make or perform all of the embodiments of a claimed invention. Were it otherwise, claims would be insufficient if they covered inventive improvements. But, as the decision in Polypeptide expression/Genentech I makes clear, in appropriate cases, a claim may embrace variants which may be provided or invented in the future and which achieve the same effect in a manner which could not have been envisaged without the invention.
232. Secondly, the assessment of insufficiency must be sensitive to the nature of the invention and the facts of the particular case. If the character of the invention is one of general methodology or is such that the invention is of general application then it may be permissible to claim it in general terms, even though the specification does not enable every way of arriving at its subject matter. Otherwise, as the Board explained in Modifying plant cells/MYCOGEN, no dominant patent could ever exist and each developer of a new method of arriving at that subject matter would be free of earlier patents. In many cases in the field of biotechnology, patent protection would then become illusory.
233. Thirdly, it is a general principle that the protection afforded by the claims must correspond to the technical contribution to the art made by the disclosure of the invention. The patentee is entitled to fair protection having regard to the nature and character of the invention he has described.”
59. I note here that in the Board of Appeals decision referred to in the first point, Polypeptide expression/Genentech I, the argument had been forwarded that the particular features defined should be limited to those available in the art at the particular point in time, and not include any that might be invented in the future or that were part of private collections that were not available to the public. The Board found that this argument had no basis in existing law. I will return to this point below.
60. Kitchin LJ drew other relevant points from the UK law:
i) The specification must enable the invention to be performed to the full extent of the monopoly claimed. But if the invention discloses a principle capable of general application, the claims may be in correspondingly general terms. A principle of general application is simply an element of a claim which is stated in general terms;
ii) If the patentee has found a new product which has a beneficial effect but cannot demonstrate there is a common principle by which that effect will be shared by other products of the same class, he will be entitled to a patent for that product but not for the class. But if he has disclosed a beneficial property which is common to the class, he will be entitled to a patent for all the products of that class even though he has not himself made more than one or two of them;
iii) There is more than one way in which the breadth of the claim may exceed the technical contribution to the art embodied in the invention. The patent may claim results which it does not enable, such as making a wide class of products when it enables only one of those products and discloses no principle which would enable others to be made. Or it may claim every way of achieving a result when it enables only one way and it is possible to envisage other ways of achieving that result which make no use of the invention;
iv) A claim containing such an element is sufficiently enabled if the skilled person can reasonably expect the invention to work with anything which falls within the general term; and
v) A particular form of an element of a claim may improve the way the invention works and be inventive. However, the patent is not insufficient simply because the specification does not enable that improvement. It is still a way (albeit an improved way) of working the original invention.
61. I consider that the statements by Kitchin LJ in Regeneron do not change but rather act to further clarify the principles underlying support and sufficiency which were applied in CSR and Evolva. However, two of the points made by Kitchin LJ have particular relevance in the present case and worth further elaboration: firstly that a claim may embrace variants which may be provided or invented in the future and which achieve the same effect in a manner which could not have been envisaged without the invention (from the Polypeptide expression/Genentech I referred to above), and secondly, that particular forms of an element in the claim may improve the working of the invention in an inventive manner.
62. I consider these points to be consistent with the principle that if the invention discloses a principle of general application then the claims may be drafted in correspondingly broad terms. There may indeed be subsequent developments in the art or further embodiments within the defined principle that could be considered inventive, but this would not necessarily render the claim lacking in sufficiency. A simple example of a situation of this type may be where a known class of receptor antagonists was used to treat a particular disease – in this case the technical contribution would be the identification of the link between the receptor and the disease. The use of subsequently discovered receptor antagonists for treatment of the same disease would fall within the scope of the claim, but not the antagonists themselves. The use of the new antagonists for the treatment of the disease could not have been envisaged without the technical contribution made by the invention. The fact that the claim did not enable the undiscovered compounds at the date of filing would not render the claim insufficient.
63. Furthermore, the situation in Regeneron appears to sit with the principle that the skilled person is construing the specification with a mind to working the invention as defined by the claims, and can be expected to undertake routine trial and experimentation using their common general knowledge in order to achieve this. The nature of the experiments undertaken in Regeneron appeared to be significant, but the evidence in that case established that they were part of the common general knowledge and would have been done as a matter of routine in order to work the claimed invention. I do not consider that Regeneron provides any basis for the skilled person to use common general knowledge to supplement the disclosure in any way that could be considered inventive. Ultimately the key consideration is whether the application provides a principle of general application that is plausible and that does not require an undue burden of experimentation. If these requirements are met then the specification will be sufficient.
64. Turning now to the present claims, a major aspect of the opponent’s argument was that if a third party was to develop another Cas polypeptide that recognised a different PAM sequence, or a different Type II CRISPR/Cas9 system utilising a sgRNA comprised of different crRNA and tracrRNA sequences derived from another species, and having targeted cleavage activity in eukaryotic cells, it would be covered by the claims. They submitted that this would be a considerable research project and as a consequence the invention was not enabled across the full scope of the claim. In my opinion the points discussed above in relation to Regeneron are directly applicable to these submissions, and I will apply the principles accordingly.
65. The Opponent noted Dr Herold’s evidence to the extent that the body of the specification does not disclose the breadth of what is claimed. Dr Herold identified several features in this regard: the NLS; the components of the guide RNA; the use of DNA to encode the guide RNA; and the use of Cas9 polypeptides other than that derived from S. pyogenes. I will deal with each of these in turn.
The nuclear localization signal (NLS)
66. The Applicant submitted that the specification provides a principle of general application, namely that a CRISPR/Cas9 system or composition for introducing a double stranded break at a target nucleic acid sequence in a eukaryotic cell which involves a sgRNA guided Cas9 endonuclease with an NLS. However despite the submission that the NLS is a key component of the principle of general application, the specification provides little detailed discussion of this particular feature. Indeed the only reference to NLSs occurs in the examples.
67. Prof Thomas stated that Claims 1 and 10 are not limited to the use of any particular NLS or where the NLS is in any particular region of the Cas9 polypeptide.[40] Dr Herold also stated that the position of an NLS may adversely affect the localisation and functioning of a protein and as a consequence the suitability of a particular NLS would need to be tested.[41] The only NLS identified and tested in the body of the application is the specific NLS “PKKKRKV”, [42] C-terminus of Cas9 for experiments in mammalian cells and the N-terminus for experiments in plant cells.[43]
[40] Thomas [51], [62].
[41] Herold 1 at [146]-[147].
[42] Herold 1 at [189].
[43] Opponent’s submissions for hearing at 83.
68. However, A/Prof Firestein stated that NLSs are well-known and are commonly used to induce nuclear translocations. They are typically located at either the N- or the C-terminal end so as to increase the availability of the localisation signal and reduce interference with protein function. It was routine in his opinion to test for alternative NLSs and locations.[44]
[44] Firestein at [126]-[127].
69. On balance, while I am concerned that so little discussion was given in the specification on a feature that has ultimately been identified as central to the principle of general application, I am satisfied that the skilled person would consider it plausible that other NLSs could be used. The use of an NLS in the manner described here, while a key aspect of the principle of general applicability, is not specific to the present DNA constructs, but rather is a widely used technique in the art for cellular delivery. Moreover the use of the term “NLS” itself implies the function of the species, and consequently in my opinion informs of a broader class. That aside, the application as filed provided a broad disclosure of various transfection techniques being used to introduce the Cas9 polypeptide into the cell, and the specific use of an NLS in the examples would have led the skilled person to understand that these could be used to achieve transfection. There would be no undue burden of experimentation for the skilled person to identify and utilise alternative NLSs as necessary.
The components of the guide RNA
70. Dr Herold stated that the claims are directed to chimeric sgRNA comprising crRNA portion fused to a tracrRNA portion, whereas the body of the application discloses chimeric sgRNA sequences that differ only in the 20 nucleotide part of the crRNA sequence complementary to the target sequence. In relation to the remaining part of the crRNA portion and the tracrRNA portion, the application discloses only sequences associated with Cas9 from S. pyogenes joined by a linker made up of four nucleotides (GAAA). The tracrRNA is used in two different lengths with no explanation of which length is preferred and why.[45]
[45] Herold 1 at [189].
71. A/Prof Firestein stated that he understood the specification to teach that the guide RNAs should retain the “essential portion” of the crRNA and the tracrRNA for any specified DNA site in order to exhibit activity. He considered that the essential portions of the crRNA and the tracrRNA sequences would be exclusive of the 20 base pair portion that is complementary to the DNA target site. He also stated (in relation to the similar issue with the disclosure in the priority document P1) that:
“While I agree that P1 does not delineate the boundaries of the crRNA and tracrRNA, in my opinion, I would not need this information to utilise the CRISPR/Cas9 technology with a single guide RNA. This is because P1 provides the information that is required to use the CRISPR/Cas9 P1 system in a programmable manner. This critical information comprises the guide RNA sequence necessary to construct a functional chimeric guide RNA sequence for any given gene (by swapping the 20 nucleotides corresponding to the 20 pair base pair target site…)”[46]
[46] Firestein at [310].
72. I find the Applicant’s submissions on this point persuasive. The guide RNA used in the present system is based on a paper by Jinek, which the application references and in which further information is provided as to the structural requirements of the guide RNA components.[47] Dr Herold’s evidence on this point does not provide sufficient information on the nature and extent of experimentation that would be required and essentially highlights the difference between the claimed subject matter and the specific examples. On the other hand the steps in programming a chimeric guide RNA as set by A/Prof Firestein appear plausible and do not appear to require an undue burden of experimentation. On balance I consider that this aspect of the invention is sufficient.
Nucleic Acids encoding the guide RNA
[47] M. Jinek et al., Science 337, 816 (Aug 17 2012).
73. The Opponent submitted that the claims are directed to DNA encoding the guide RNA, whereas the experimental detail in relation to DNA encoding the guide RNA is very limited.[48] The gist of the submission on this point was that nearly all the examples use naked RNA, and very little information is provided in relation to DNA encoding the guide RNA. For example, plasmids encoding chimeric guide RNA are referred to in Examples 1-3 and 6, but there are no details as to how these are made.[49]
[48] Herold at [189].
[49] Herold at [151].
74. As an initial point I note that the Opponent refers to the information as being very limited. That is not the statutory test. A/Prof Firestein stated that the selection and use of plasmids (including the selection of promoters) to express guide RNA in a mammalian cell, were routine prior to October 2012.[50] I consider this to be consistent with the principle that it is permissible for the skilled person to supplement the information in a document with their common general knowledge in order to enable the claimed invention. The nature of the experimentation required to enable the disclosure provided in the specification is well known in the art. In this case I am satisfied that the skilled person would implement such techniques without an undue burden of experimentation to provide the claimed invention.
The Cas9 polypeptide
[50] Firestein at [360].
75. The opponent noted that claims 1 and 10 are not limited to any specific site for the double stranded break, and that the specification states that the system can be designed to target any DNA sequence. The claim includes the use of the system in any eukaryotic cell.[51] The opponent contrasted this with the disclosure in the specification that specific PAM sites are required adjacent to the target nucleic acid sequences and that each target DNA sequence is cut three nucleotide bases upstream of the specific PAM sequence, namely 5’-NGG-3’ or 5’-NAG-3’.
[51] Opponent’s submissions at [73].
76. However the opponent also noted that there was no limitation in the claims as to the bacterial species from which the Cas9 polypeptide is derived,[52] but the system described and used in the examples was S. pyogenes strain M1 GAS.[53] Neither Prof Thomas nor Dr Herold was aware of Cas9 polypeptides from any other bacterial species or strain being used in eukaryotic cells prior to October 2012.[54]
[52] Herold 1 at [139], Thomas at [48].
[53] Herold 1 at [140].
[54] Thomas at [48], Herold at [141].
77. Dr Herold considered the engineering of Cas9 polypeptides from S. pyogenes to recognise a different PAM sequence, or the design, testing and use of a Cas9 polypeptide from another species would require significant work,[55] and that such work is not routine.[56] He was aware that Cas9 nucleases from different species recognise different PAM sequences, but was not aware of the specifics of what PAM sequence is recognised by Cas9 of any given species.[57] However Dr Herold provided little detail as to the nature of the experiments that would be required and why these would be considered undue.
[55] Herold 1 at [197].
[56] Herold 2 at [16(a)].
[57] Herold 2 at [14].
78. A/Prof Firestein stated that he would not attempt to engineer a new Cas9, but would outsource this work to a laboratory specialising in protein engineering.[58] While Dr Herold questioned this approach, I do not consider this a significant issue since it is consistent with the principle that the skilled person can comprise a team having members of different knowledge and skills. In any case, when asked whether he could identify the PAM sequence given a Cas9 protein from another species or an engineered variant that, like the present Cas9 protein would cleave a DNA target with a triplet target “NNN” downstream of a 20bp target site, A/Prof Firestein provided a description of alternative means of generating such variants:[59]
[58] Firestein at [303].
[59] Firestein at [157].
(a) generate a DNA target site template encoding different combinations of A, C, G and T immediately downstream of the 20 base pair target sequence;
(b) either generate PAM variant (triplet “NNN”) or use site-directed mutagenesis to introduce a variation in the PAM nucleotides where the DNA target site is encoded in a plasmid form; and
(c) then assess the ability of all potential PAM triplet sequences (which he calculates to be 64) to affect CRISPR/Cas9 cutting using the in vitro DNA cleavage assay described in the application.
79. On balance I consider the processes set out by A/Prof Firestein to be plausible and not to require an undue burden of experimentation in this art. The evidence provided by Dr Herold on this point does not shift the balance of this consideration. I am satisfied on the evidence before me that the skilled person would be able to identify other members of the Cas9 polypeptide family for use in Type II CRISPR/Cas systems without an undue burden of experimentation.
Conclusion on sufficiency
80. I consider in view of my determinations above that the specification describes the invention in a manner that is clear enough and complete enough for the person skilled in the art to work the invention across the scope of the claim. In particular, I consider that the invention sets out a principle of general application which is plausible and does not require an undue burden of experimentation. This ground of opposition has not been made out.
Support
81. Section 40(3) requires that the claim or claims must be clear and succinct and supported by the matter disclosed in the specification.
82. The test for determining whether the claims are supported by the matter disclosed in the specification is as set out by the Delegate in CSR:
(a) Construe the claims to determine the scope of the invention as claimed;
(b) Construe the description to determine the technical contribution to the art; and
(c) Decide whether the claims are supported by the technical contribution to the art.[60][60] CSR, supra.
83. The scope and meaning of the terms in the claim are given above under Construction.
84. I am satisfied that the technical contribution to the art can be summarised as “a Type II CRISPR/Cas9 system for introducing a double stranded break at a target nucleic acid sequence in a eukaryotic cell which uses a nucleic acid encoding a sgRNA guided Cas9 endonuclease with an NLS.”[61]
[61] Applicant’s submissions for hearing at [261].
85. The opponent’s submissions on this point were essentially the same as those given for sufficiency, and are largely related to the relatively broad scope of the claims compared to the specific examples. For similar reasons to those given under sufficiency I see no basis for narrowing the technical contribution to only the exemplified matter. I consider that the claims are supported by the disclosure.
Conclusions on Section 40
86. Claim 19 lacks clarity.
87. The specification describes the invention in a manner that is clear enough, and complete enough, for the person skilled in the art to work the invention across the scope of the claim.
88. The claims are supported by the matter disclosed in the specification.
Priority
89. The Opponent’s arguments in relation to novelty and inventive step relied heavily on the applicant’s priority claim being found invalid.
90. The relevant provision, Section 43, was amended by the Raising the Bar Act and has received limited judicial consideration, particularly in relation to the specific issues in question here. There was no apparent dispute between the parties that section 43 requires a similar consideration to that required under section 40(2)(a). However the parties differed as to how Section 43 should be applied in the present case. I will therefore firstly consider the relevant law before considering the facts of the case.
Relevant law
91. The priority date of a claim is determined according to Section 43 of the Act, and by Division 2 of the Regulations. Section 43 of the Act requires that:
(1) Each claim of a specification must have a priority date.
(2) The priority date of a claim is:
(a) If subsection (2A) applies to the claim – the date determined under the regulations;
(b) Otherwise – the date of the filing of the specification.
(2A) This section applies to a claim if:
(a) prescribed circumstances apply in relation to the invention defined in the claim; and
(b) a prescribed document discloses, or a prescribed set of prescribed documents considered together disclose, the invention in a manner that is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art.
92. Thus the priority date of a claim is the date of filing of the specification unless the two conditions given in section 43(2A) apply. The first of these conditions is that prescribed circumstances apply in relation to the invention defined in the claim. Regulations 3.13A sets out the prescribed circumstances applying to the determination of priority for PCT applications. For clarity I have limited the cited sections to those that are relevant in the present case:
(1) This regulation applies to a claim if:
(a) the circumstance mentioned in subregulation (2) (a prescribed circumstance for paragraph 43(2A)(a) of the Act) applies to the invention defined in the claim; and
(b) either:
(i) a document mentioned in subregulation (4) (a prescribed document for paragraph 43(2A)(b) of the Act) clearly discloses the invention in the claim; or
(ii) 2 or more of those documents (a prescribed set of prescribed documents for paragraph 43(2A)(b) of the Act), considered together, clearly disclose the invention in the claim. [Emphasis added]
Circumstance
(2) For paragraph (1)(a), the circumstance is that the specification containing the claim that defines the invention was filed for a PCT application, and:
(a) …
(i) the PCT application claims the priority of an earlier application under Article 8 of the PCT; and
(b) …
(iii) the earlier application is a basic application that was the first application made in a Convention country in relation to the invention, and:
(A) the earlier application was made no more than 12 months before the filing date of the PCT application;…
93. The circumstances given in subregulation 3.13A(2) above – that the PCT application claims priority from an earlier application, and that application was made no more than 12 months earlier than the filing date of the PCT application – do not appear to be in dispute and accordingly I will assume that these have been satisfied.
94. The second condition of section 43(2A) is that a prescribed document (or set of prescribed documents taken together) disclose the invention in a manner that is clear enough and complete enough for the invention to be performed by a person skilled in the art. Regulation 3.13A (1)(b) above refers to subregulation 3.13A(4) in identifying these documents:
Documents
(3) For paragraph (1)(b), the documents are the documents filed for the earlier application at the time the application was made.
95. As set out above in paragraph (1)(b), there is also a threshold requirement that the basic document clearly disclose the invention in the claim in order for Regulation 3.13A to apply. Regulation 3.12 provides a definition of this term as follows:
(4) In this division, a document, or a set of documents considered together, clearly discloses an invention if the document, or set of documents, discloses the invention in a manner that is clear enough, and complete enough, for the invention to be performed by a person skilled in the relevant art.
96. Provided the prescribed circumstances apply and the prescribed documents clearly disclose the invention in the manner required, then the priority date is determined as follows:
Priority date
(5) Subject to regulation 3.12, the priority date is:
(a) the date when the earlier application was made; or
(b) if there is more than one earlier application—the date the earliest of those applications was made for which paragraph (1)(b) is satisfied.
97. The Applicant submitted that section 43 requires only a single consideration – namely that the priority document enable the invention as claimed. They noted the statements of Perram J in Encompass that section 40(2)(a) has no requirement that the specification disclose the nature of the invention:[62]
“… the new form of s 40(2)(a) contains a requirement as to a clear disclosure but it is expressed to be ‘clear enough and complete enough’ for a particular purpose viz ‘for the invention to be performed by a person skilled in the relevant art’. I cannot see that any part of the wording of the new s 40(2)(a) which lends itself to be interpreted as containing a further requirement that the nature of the invention be made plain. Even if, which I do not accept, there was some peg in the language of s 40(2)(a) upon which such an interpretation might be hung, I do not see how it could be rescued from the purposive effect of the phrase ‘for the invention to be performed by a person skilled in the relevant art’.”
[62] Encompass Corporation Pty Ltd v InfoTrack Pty Ltd [2018] FCA 421 at [162] to [167].
98. Perram J made similar comments in relation to section 43(2A)(b).[63] The applicant further submitted that the similar approach for enablement in relation to priority and internal disclosure meant that the skilled person is also permitted to use their common general knowledge to supplement the information contained in the priority documents in order to enable the invention. These submissions were based on the statements of Kitchin LJ in Regeneron, which I have discussed above.
[63] Ibid at [184].
99. The Opponent submitted that the consideration of priority requires a two-step approach, and that the application would only be entitled to claim earlier priority if the priority documents:
(a) “disclose the invention” claimed in the application; and
(b) Do so “in a manner that is clear enough, and complete enough” for the invention to be performed by a skilled addressee.
100. The gist of their argument was that if only enablement and not disclosure was required then this would have been reflected in the legislation, which could have simply required that a prescribed document enable the invention rather than requiring that it disclose the invention in manner that enabled the invention. The Opponent considered that caution should be taken in relation to supplementing the information in a document by common general knowledge. They noted that the focus of most Australian and UK cases relating to section 40(2)(a) is on enablement because the disclosure requirement is generally satisfied by the presence of claims. They argued that, reductio ad adsurdum, if an invention once known could be implemented by a skilled person using only his or her common general knowledge then it would be possible to file a blank description as a priority document and obtain priority. In effect the test for priority claim would be lower, rather than higher, than it was under the old (fair basis) law.
101. However, the Applicant noted that Perram J had addressed a similar submission in Encompass as follows:
“The Respondent submitted that removing the requirement of making the nature of the invention plain would hardy be raising the bar. There may be some rhetorical force in that flourish. Nevertheless, it seems to me that whilst the Explanatory Memorandum clearly demonstrates that its authors were aware of the former requirement of making the nature of the invention plain, it is silent on what they intended for the former requirement to continue. The entire discussion of the authors is given over to the second requirement of enablement.”
102. I agree with the Applicant’s submissions that there is no requirement that the nature of the invention be made plain in the provisional application. However, the legislation refers to the earlier applications “clearly disclosing” the claimed invention. The legislation qualifies the disclosure for both section 40(2)(a) and 43 in that it must be of a manner that is clear enough, and complete enough, for the invention to be performed by the person skilled in the art. The term “a manner” suggests that there is no specific means by which the disclosure must be provided – as long as the particular disclosure is sufficient. The question therefore arises as to what was envisaged by the changes to the legislation brought about by the RTB Act, and in particular the manner of disclosure that is required by an earlier application in order for a specification to validly claim priority from that earlier application.
103. The Explanatory Memorandum to the RTB Act explained the changes to section 40(2)(a) as follows:
“The item is intended to modify the wording of paragraph 40(2)(a) of the Act so as to require enablement across the full scope of the claims, while adopting language that is consistent with that used in other jurisdictions. The wording in the amendment is similar to s 14(3) of the UK patents legislation, which has been interpreted as imposing this requirement. The wording is also similar to art 83 of the European Patent Convention, which has been interpreted with similar effect. The intention is that paragraph 40(2)(a) be given, as close as practicable, the same effect as the corresponding provisions of UK legislation and the European Patent Convention.
A specification that provides a single example of the invention may satisfy the requirements, but only where the skilled person can extend the teaching of the specification to produce the invention across the full width of the claims, without undue burden, or the need for further invention.
However it is expected to be more likely that, where the claims are broad, the specification will need to give a number of examples or describe alternative embodiments or variations extending over the full scope of the claims. This ensures that the monopoly extends only to that which could reasonably be said to be disclosed and no further.
If, on its face, the specification would appear to the skilled person to lack sufficient disclosure, the onus of establishing that the invention is described in enough detail lies with the applicant.”
104. The Explanatory Memorandum to the RTB Act provided the following explanation of the amendments to Section 43:
“Item 10 aligns the requirement for securing a priority date from an earlier filed application with the requirement for disclosure in a complete application (see item 8 above)…
The item is intended to achieve two objectives:
First, the amendment is intended to maintain consistency between the requirement of subsection 40(2) and the requirement for priority. Applicants should not be able to secure a priority date on the basis of a disclosure in a provisional or other relevant application that is less complete than required in a complete specification. Otherwise the applicant is in a position to deter competitors before they have fully realised the invention. Since an enabling disclosure will be required, the amendment will also align the requirements for securing a priority date with most other major patent jurisdictions.
Secondly, the amendment is intended to increase the transparency of the Act. The priority date is fundamental to the validity of a patent. Accordingly, it is more appropriate that the key aspect (‘clear and complete enough’) of such an important test for priority is explicit in the Act. However, the less crucial procedural details of how the test is to apply are prescribed in the Regulations. This will permit the other aspects of the existing priority date test to be re-made in the Regulations.” [Citations omitted].
105. As indicated by the Explanatory Memorandum, Section 40(2)(a) is intended to ensure the scope of the claims corresponds to the technical contribution the patentee has made to the art. The corresponding provision in the UK Act has been said to deter speculative claiming by “armchair inventors.”[64] In a similar manner, I understand that section 43 is intended to ensure that priority is not secured on the basis of a speculative assertion in a priority document, even if that assertion is subsequently enabled in the complete application. The Explanatory Memorandum refers to this as the applicant being in a position to deter competitors before they have fully realised their invention, or obtaining priority on the basis of a disclosure that is less than that required of a complete application.
[64] Warner Lambert Company LLC v Generics (UK) Limited (trading as Mylan) and ors [2016] EWCA Civ 1006 at [46].
106. At hearing the opponent drew on UK case law in support of their submissions, and in particular on Unilin v Berry.[65] In response the Applicant noted that while Australia has adopted the language of the UK Patents Act in relation to internal disclosure, it has not done so in relation to priority. In particular Section 5(2)(a) of the UK Patents Act states that:
“if an invention to which the application in suit relates is supported by matter disclosed in the earlier relevant application or applications, the priority date of that invention shall instead of being the date of filing the application in suit be the date of filing the relevant application in which that matter was disclosed, or, if it was disclosed in more than one relevant application, the earliest of them”
[65] Unilin Beheer BV v Berry Floor NV [2004] 2004 EWHC Civ 1021 at [48].
107. They argued that, as set out in Unilin v Berry, this section has been interpreted by the UK Courts in accordance with Article 87 of the European Patent Convention which provides:
“(1) A person who has duly filed in or for any State party to the Paris Convention for the Protection of Industrial Property, an application for a patent or for the registration of a utility model or for a utility certificate or for an inventor’s certificate, or his successor’s in title, shall enjoy, for the purpose of filing a European patent application in respect of the same invention, a right of priority during a period of twelve months from filing of the first application.”
108. The Court in Unilin v Berry noted that requirement for the ‘same invention” has been interpreted by the Enlarged Board of Appeal of the European Patent Office and applied by the UK courts as follows:[66]
“The requirement for claiming priority of ‘the same invention’, referred to in Article 87(1) EPC, means that priority of a previous application in respect of a claim in a European patent application in accordance with Article 88 EPC is to be acknowledged only if the skilled person can derive the subject-matter of the claim directly and unambiguously, using common general knowledge, from the previous application as a whole.”
[66] Unilin v Berry, ibid at [41] to [42].
109. The Applicant highlighted that the language of “directly and unambiguously derivable” was very different to the language in section 43, and despite the opportunity to mirror the wording of the European or UK law the Parliament had decided to align the priority requirement with the language of section 40(2)(a).
110. I note that the Explanatory Memorandum to Section 40(2)(a) indicates that the similarity of the language with the corresponding European and UK provisions is intended to ensure that it is to “be given, as close as practicable, the same effect as the corresponding provisions of UK legislation and the European Patent Convention.” In contrast and as noted by the Applicant, Section 43 uses very different language to the corresponding overseas provisions. However, the Explanatory Memorandum indicates that in practice the provision set out in section 43 will align the requirements for a claim to priority to those of foreign jurisdictions. I understand this to mean that even though the language of the corresponding provisions are different, the outcomes are intended to be similar.
111. In this regard, I note the comments of Kitchin J (as he then was) in Abbott v Evysio:
“So the important thing is not the consistory clause or the claims of the priority document but whether the disclosure as a whole is enabling and effectively gives the skilled person what is in the claim whose priority is in question. I would add that it must 'give' it directly and unambiguously. It is not sufficient that it may be an obvious development of what is disclosed.” [67]
[67] Abbott Laboratories Ltd v Evysio Medical Devices plc [2008] EWHC 800 (Pat); [2008] RPC 23 at [228].
112. I consider this to be consistent with the statements of Perrin J in Encompass in relation to there being no need to state the nature of the invention (akin to the consistory statement) but rather that the requirement is that the disclosure be enabling. In my opinion, the approach stated by Kitchin J above would provide substantially the same outcomes despite the differences in wording between the corresponding legislation. Consistent with the policy intents given in the Explanatory Memorandum I consider that UK and EPO law is relevant in this consideration.
113. A useful summary of the UK law on priority was provided by Carr J in Hospira v Cubist:
“General principles to be applied in respect of entitlement to priority were summarised by Kitchin LJ in Medimmune Ltd v Novartis Pharmaceuticals UK Ltd [2012] EWCA Civ 1234; [2013] RPC 27. In particular:
i) A claim to priority of the ‘same invention’ is referred to in Article 87(1) of the European Patent Convention. Section 5(2)(a) of the Patents Act 1977, which provides for entitlement to priority, is to be interpreted as having the same effect as Article 87(1), pursuant to section 130(7) of the Act; Medimmune at [151].
ii) The requirement for the ‘same invention’ means that priority is to be acknowledged only if the skilled person can derive the subject matter of the claim directly and unambiguously, using common general knowledge, from the priority document as a whole; G 2/98 Same invention [2001] OJ EPO 413; [2002] EPOR 167.
iii) The approach is not formulaic: priority concerns technical disclosure, explicit or implicit. The question is whether there is enough in the priority document to give the skilled person the same information as forms the subject of the claim and enables him to work the invention in accordance with that claim; Unilin Beheer v Berry Floor [2004] EWCA (civ) 1021; [2005] FSR 6 at [48].
iv) The important thing is not the consistory clause or the claims of the priority document, but whether the disclosure as a whole is enabling and directly and unambiguously gives the skilled person what is in the claim whose priority is in question. It must ‘give’ this disclosure directly and unambiguously. It is not sufficient that it may be an obvious development from what is disclosed; Abbott Laboratories Ltd v Evysio Medical Devicesplc [2008] EWHC 800 at [228].
v) Plausibility, as part of the requirement of an enabling disclosure, applies to issues of priority as well as sufficiency; Hospira UK Ltd v Genentech [2014] EWHC 1094 at [149].”[68]
[68] Hospira UK Limited v Cubist Pharmaceuticals LLC [2016] EWHC 1285 (pat).
114. In HTC v Gemalto, Floyd LJ had regard to the cited passages from Abbott v Evysio and Unilin v Berry before concluding that:
“The skilled person must be able to derive the subject matter of the claim directly and unambiguously from the disclosure of the priority document. Mr Tappin stressed that the question was one of what was disclosed to the skilled person, not what was made obvious to him by the priority document, for example in the light of his common general knowledge. I agree that, as the above passage shows, that is the correct approach. That does not mean, however, that the priority document should be read in a vacuum. The question of what a document discloses to a skilled person takes account of the knowledge and background of that person. A document may mean one thing to an equity lawyer and another to a computer engineer, because each has a different background. The document still only has one meaning because it is only the relevant skilled person’s understanding which is relevant. What is not permissible is to go further than eliciting the explicit or implicit disclosure and take account of what a document might lead a skilled person to do or try, or what it might prompt him to think of.”[69]
[69] HTC Corporation v Gemalto S.A. [2014] EWCA Civ 1335, [2015] RPC 17.
115. I will draw as appropriate on the principles given in the above cases in making the present determination.
116. Before turning to the specifics of the case, there is a further relevant consideration: that is for the purposes of section 40(2)(a), enablement is generally required across the full scope of the claim. However this is not necessarily a consideration for the determination of priority. In particular, Section 43(3) provides that:
“Where a claim defines more than one form of an invention, then, for the purposes of determining the priority date of the claim, it must be treated as if it were a separate claim for each form of the invention that is defined.”
117. Thus, provided a claim defines separate forms of the invention then the claim can be afforded multiple priority dates according to the date of filing of the specification, or the date of filing of an earlier application (or applications considered together) that clearly discloses the particular form of the invention. Guidance in determining whether a claim defines a single form of an invention or multiple forms was provided in AstraZeneca v Apotex[70] where a claim was determined to define only a single form of the invention, and in Nichia v Arrow[71] where the claim was found to define multiple forms of the invention.
[70] AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99 at [251].
[71] Nichia Corporation v Arrow Electronics Australia Pty Ltd, [2015] FCA 699 at [58] to [70].
118. My understanding is that if a claim is interpreted as defining only a single form, then the priority date will be determined to be either the filing date of the specification or the earliest date on which the invention is enabled across the full scope of the claim by an earlier application. Enablement could be from a single earlier application or from several earlier applications considered together, with the date of the latest application in the combination providing the priority date for the particular form of the invention.
119. Accordingly I consider that the determination of priority will essentially involve a process wherein:
- The earlier application is construed to determine the matter for which it provides an enabling disclosure.
- The claim in question is construed to determine the scope of the invention defined and whether the claim defines more than one form of the invention.
- One or more priority dates is assigned corresponding to the date of filing of the specification, or to the date of filing of the earlier application if that application clearly discloses the invention, or one or more forms of the invention defined by the claim.
120. Of course this will not necessarily be a rigid process of following the three steps – for example a consideration could involve iterative considerations of one or more aspects of the priority document and claims. Turning to the present case, for the purposes of this determination, I can limit the consideration to the first and second priority documents (P1 and P2).
What does the priority document P1 disclose?
121. As an initial observation, the priority document is written in the style of a journal article and appears to correspond to an article published in late January 2013 by the present inventors.[72] The body of the document provides sections titled Abstract, Summary of the Invention, Main Text, References, Figure legends and Materials and Methods. The Opponent commented that the priority document reads “more like an unfinished scientific paper suggesting some tentative conclusions and proposals for further work.” The document states that:
“Recently, Jinek et al. elegantly demonstrated that a single chain chimeric RNA produced by fusing an essential portion of crRNA and tracrRNA could replace the two RNAs in the Cas9/RNA complex to form a functional endonuclease, raising the possibility of using this system for genome editing in cells and organisms. Here we present the first evidence that RGENs can indeed induce site specific genome modifications in mammalian cells at high frequencies.”
[72] Cho et al., Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease, Nature Biotechnology 31, 230-232 (2013).
122. It also concludes that:
“Taken together, these findings indicate that RGENs are a new member in the family of genome editing tools that have revolutionized basic and biomedical research but with their own unique features that make them an ideal platform in many applications. We propose that RGENs should find broad utility in research, biotechnology, and medicine in the post-genomic era.”
123. At first blush P1 does indeed appear to describe a relatively early “proof of concept”, based on the earlier work of Jinek, of the development of CRISPR/Cas9 technology for use in eukaryotic cells. However the Applicant argued that a priority document need not contain any claims, nor make any express legal statement that uses the term “invention”. I agree with this submission – the key consideration under section 43 is what the document discloses in a clear enough, and complete enough, manner for the person skilled in the art to work the invention.
124. The Applicant submitted that P1 discloses a principle of general application, namely a CRISPR/Cas9 system or composition for introducing a double stranded break at a target nucleic acid sequence in a eukaryotic cell which involves a sgRNA guided Cas9 endonuclease with an NLS. I acknowledge that P1 does indeed disclose subject matter that clearly falls within this principle. However in order for the applicant to claim priority for this principle as articulated, it would need, as a whole, to be clearly and unambiguously derivable and enabled by the disclosure. It would not be fatal for priority purposes if P1 does not enable the principle as a whole, but the priority date of P1 would only be valid for the matter which does meet the enablement requirements.
125. The Opponent’s submissions in relation to the priority document, and the extent to which it enabled the invention, were largely the same as their submissions in relation to the application – in short, that the priority document either does not disclose the later claimed features or alternatively discloses specific embodiments from which no principles of general application may be drawn. They specifically noted that:
· P1 does not disclose a nucleic acid encoding a guide RNA.
· P1 only discloses S. pyogenes Cas9 recognising a PAM of 5’-NGG-3’.
· P1 does not disclose paired nickases.
· P1 only discloses the use of one specific NLS at the C-terminus of Cas9.
· P1 only discloses crRNA and tracrRNA associated with S pyogenes.
126. I will deal with each of these in turn.
Nucleic acid encoding a guide RNA
127. Dr Herold stated that P1 discloses only in vitro transcribed guide RNA,[73] and the Opponent submitted that there was no reference whatsoever in P1 to the concept of a nucleic acid encoding a guide DNA, including vector or plasmid delivery of the guide RNA.[74] The Opponent submitted that P1 in fact teaches that the use of in vitro transcribed guide RNA is an advantageous aspect of the CRISPR/Cas9 system disclosed in P1:
“In this regard, RGENs[75] based on Cas9 could provide useful options for genome editing. Compared to ZFNs[76] and TALENs,[77] RGENs can be more readily customized because only the synthetic RNA component is replaced to make a new genome-editing nuclease: No sub-cloning steps are involved to make customized RGENs.”[78]
[73] Herold 1 at [205].
[74] Opponent’s submissions for hearing at [142].
[75] RNA-guided Cas9 endonucleases
[76] Zinc-finger nucleases
[77] Transcription activator-like effector nucleases
[78] P1 at page 5, lines 10 to 14.
128. When asked how he would have used the CRISPR/Cas9 system described in P1, A/Prof Firestein provided an example of how he would have proceeded at that time.[79] In particular his research interests included the CDK8 gene. He stated that:
“I would have understood, based on my own experience in the field of molecular biology, that I could employ a number of methods to generate guide RNAs targeting the CDK8 gene, namely in vitro transcription (which is expressly referred to in P1), chemical synthesis of RNA, and cloning of the DNA form of the RNA into an expression vector, each of which, in my opinion, was a well known technique in October 2012.”
[79] Firestein at [161]-[163].
129. A/Prof Firestein stated that he would have selected the third method since in October 2012 this method was the most commonly used technique to express RNA in mammalian cells.[80] At first blush, this evidence is quite persuasive. However I note that A/Prof Firestein’s evidence also provided a description of some previous research in which he used a CRISPR/Cas9 system to knock out the CDK8 gene in the HCT-116 cell line.[81] This involved similar cloning techniques to those he subsequently referred to in his evidence on the disclosure in P1. This in itself would not necessarily suggest that his evidence was tainted by hindsight, but a perusal of the document in which this research is described states that the technique followed the method of Mali (D2).[82] D2, which as an aside I note was published after the earliest priority date claimed by the present application, made use of cloning techniques to introduce the guide RNA. As a consequence I consider that this significantly lessens the weight that I can give A/Prof Firestein’s evidence on this point.
[80] Firestein at [167].
[81] Firestein at [24].
[82] Mali et al., “RNA-Guided Human Genome Engineering via Cas9” (2013) Science 339 (6121) pp 823-825.
130. A significant point of difference between the experts was in the meaning of the term “sub-cloning” which was used in the passage referred to by Dr Herold as cited above. Dr Herold considered that this term includes cloning of the DNA form of the guide RNA into an expression vector.[83] In contrast A/Prof Firestein did not consider cloning of the guide RNA into an expression vector to be sub-cloning. He provided an overview of the insertion of foreign DNA into a vector, which included a description of sub-cloning as taking a section of DNA from another clone.[84] The Applicant argued that Dr Herold’s interpretation was a “wholly unsound basis upon which to find that P1 impliedly directs the person skilled in the art away from what, in A/Prof Firestein’s uncontradicted evidence, was the most commonly used method in 2012 to express RNA in mammalian cells.”
[83] Herold 1 at [77].
[84] Firestein, Exhibit RF-6.
131. Notably P1 describes methods for the construction of Cas9 encoding plasmids in which 1-kb fragments are assembled and cloned into a T-vector. The Cas9-encoding DNA segment from the T vector is then sub-cloned into p3s (another vector).[85] The Applicant also referred to dictionary definitions of cloning and sub-cloning in support of these submissions:[86]
“molecular cloning or DNA cloning the isolation in a bacterial cell of a fragment of any heterologous DNA in covalent linkage with a replicon (plasmid, phage, etc.) in order to obtain a homogeneous population (i.e. clone) of DNA molecules from the progeny of such a cell. The DNA to be cloned may be a fragment of genomic DNA obtained by restriction endonuclease digestion, or a complementary DNA (cDNA). The foreign DNA is inserted into the cloning vector, which has been cleaved with a restriction enzyme; the gaps between vector and insert DNA are sealed with DNA ligase. In cloning using plasmid vectors, plasmids are then reintroduced into host cells by transformation; markers on the cloning vector allow selection of plasmid-containing cells and identification of those cells that contain recombinant plasmids (rather than ‘empty’ vectors). …
subclone to clone into a new vector a subfragment of part of a larger cloned DNA, after excising the required fragment using restriction endonucleases.”
[85] Applicant’s submissions at hearing at [131]
[86] Oxford Dictionary of Biochemistry and Molecular Biology (Oxford University Press, 2nd ed. 2006).
132. The Applicant also submitted that the “nucleic acid encoding a guide RNA” is one component of the CRISPR/Cas9 system, and in both claims 1 and 10 is a “product integer” rather than a “method integer”. They argued that the important matter to the person skilled in the art seeking to perform the claims 1 and 10 is that a nucleic acid encoding a guide RNA is available, not how it was generated.[87] I do not dispute this submission, but consider that it is a secondary consideration to that of whether the priority document clearly discloses a nucleic acid encoding a guide RNA at all.
[87] Applicant’s submissions for hearing at [136].
133. In my opinion the key consideration here is whether a nucleic acid encoding a guide RNA can be derived, impliedly or explicitly, from the disclosure in P1. I do not consider that this equates to a consideration of what would have been obvious to the skilled person, but rather what the document directs the reader to do. This aligns with the principle set out by Unilin v Berry that priority concerns technical disclosure, explicit or implicit and whether there is enough in the priority document to give the skilled person the same information as forms the subject of the claim and enables him to work the invention in accordance with that claim. Pursuant to this principle, I consider little weight can be given to the Applicant’s submission that cloning was a well-known technique at the time of filing, particularly if the document directs away from using such techniques.
134. To this end, I agree with the Applicant’s interpretation of the terms “cloning” and “sub-cloning”. However I note that in P1, the section entitled “Abstract” states that “unlike ZFNs and TALENs, which are widely used in research and biotechnology, RGENs are customized without any cloning step, making them a broadly useful, scalable and expeditious platform for genome engineering in cells and organisms” [emphasis added]. This is inconsistent with the later statement that no sub-cloning steps are involved to make customized RGENs.
135. This leads to the question of whether one or the other of these references is incorrect. In the ordinary course of events, an abstract in a patent document serves the purpose of providing a summary of the subject matter in the document for searching purposes. If there is an inconsistency between the abstract and the body of an application the abstract would generally be taken to be incorrect. However in the present case the “Abstract” here is an integral part of the information given in P1 as a basis for the priority claim. I consider there is otherwise no indication in P1 that could be used as a basis to conclude that there is an implicit disclosure of a nucleic acid encoding a guide RNA. To the contrary I consider that the benefits provided in P1 such as scalability suggest the use of in vitro transcribed guide RNA.
136. Despite the Applicant’s submissions to the contrary and in the absence of a clear indication otherwise I therefore consider that there is no disclosure in the priority document of a nucleic acid encoding a guide RNA. I acknowledge this is a different outcome to my determination in relation to section 40(2)(a) for the complete application, but note that additional information was given in the application that contributed to the specification meeting the requirements for sufficiency.
Cas9 polypeptides other than S. pyogenes Cas9 recognising a PAM of 5’-NGG-3’
137. The consideration here is similar to that given above under sufficiency. I see no reason to come to a different conclusion. Indeed P1 acknowledges that:
“[T]he specificity of DNA recognition by RGENs is somewhat limited by the requirement for a 5’-GG-3’ dinucleotide in the PAM sequence. This motif is recognized by the Cas9 protein but not by the guide RNA. Thus, RGENs can be designed to cleave DNA once per 8 bp (= 4x4/2) on average. This limitation might be relieved by engineering Cas9 or employing Cas9 derived from other species.”[88]
[88] P1 at page 5, lines 18 to 22.
138. This is consistent with the approach A/Prof Firestein stated he would use to generate other Cas9 polypeptides. I therefore consider that the use of Cas9 polypeptides other than S. pyogenes Cas9 recognising a PAM of 5’-NGG-3’ is enabled by P1.
Paired nickases
This is a moot point in view of my determination that the claims do not encompass paired nickases. In any case there was no apparent dispute between the parties that the priority document P1 does not enable paired nickases.
The use of different NLS
140. The consideration here is similar to that given under sufficiency. While the general description of different means of transfection is not provided in P1, I consider the term NLS would implicitly inform of a broader class than just the single example provided. I therefore consider that P1 enables the use of NLSs other than the single example provided in P1.
crRNA and tracrRNA other than those associated with S pyogenes
141. This consideration was the same as that given above under sufficiency. I see no reason to come to a different conclusion on this issue.
Conclusion on the disclosure provided by P1
142. The priority document does not disclose the use of nucleic acids encoding the guide RNA in a manner that is clear enough, and complete enough, for the skilled person to work the invention.
Disclosure in the priority document P2
143. P2 discloses a method of RFLP genotyping using the RGEN system. Dr Herold stated that P2 does not disclose what is claimed in the complete application because:
(a) It appears that the experiments used Cas9 as the protein itself, not as a nucleic acid encoding the protein; and,
(b) The experiments used separate crRNA and tracrRNA, not chimeric sgRNA.
144. A/Prof Firestein did not comment on P2. Prima facie the assertions made Dr Herold appear sound, and I therefore conclude that P2 does not disclose, either itself or in combination with the disclosure in P1, the claimed invention in a manner that is clear enough, and complete enough, for the skilled person to work the invention.
Conclusion on priority
145. I note that for priority purposes a consideration will be whether the claim defines different forms of the invention and whether different priority dates are required to be assigned to each form. This is a moot point in the present case. With the exception of Claim 19 which I have found to be unclear in scope, all of the claims require a nucleic acid encoding the guide RNA. I have found that neither P1 nor P2 disclose this feature in a manner which is clear enough and complete enough for the person skilled in the art to work the invention. The claims are therefore not entitled to the earlier priority dates provided by P1 and P2.
146. The other priority document post-dates the publication date of the citations raised by the Opponent. There is no need for me to consider this particular document further – the earliest possible priority date is the date of filing of P3 (20 June 2013).
Novelty
147. Under subsection 7(1), an invention is taken to be novel unless it is not novel in the light of the prior art base. Information in a document forms part of the prior art base for the purposes of novelty if it was published before the priority date of a claim.
148. It is well established that the general test for anticipation is the reverse infringement test. The classic formulation of this test is that given by Aicken J:
“The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement.”[89]
[89] Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19; 137 CLR 228 at 235.
149. This test is satisfied if the alleged anticipation discloses all the essential features of the invention claimed.[90] Furthermore, in order to meet this requirement, the prior art:
“must contain clear and unmistakeable directions to do what the patentee claims to have invented... A signpost, however clear, upon the road to the patentee’s invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee.”[91]
[90] Nicaro Holdings Pty Limited v Martin Engineering Company [1990] FCA 40; 16 IPR 545 at 549.
[91] The General Tire& Rubber Company v The Firestone Tyre and Rubber Company Limited (1971) 1A IPR 121 at 486.
150. In some cases a prior publication may not explicitly disclose all of the features of the invention, but could still deprive the claimed invention of novelty if the missing information or feature is inherent:
“If the prior inventor’s publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent, the patentee’s claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor’s publication will inevitably result in something being made or done which, if the patentee’s patent were valid, would constitute an infringement of the patentee’s claim, this circumstance demonstrates that the patentee’s claim has in fact been anticipated.
If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee’s claim, but would be at least as likely to be carried out in a way which would not do so, the patentee’s claim will not have been anticipated, although it may fail on the ground of obviousness.”[92]
[92] The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited ibid at 485 to 486.
151. Pursuant to the earliest priority dates being found invalid, the Opponent cited 3 documents in relation to novelty against the claims indicated as follows:
D1. Cong et al., “Multiplex Genome Engineering Using CRISPR/Cas Systems” (2013) Science 339 (6121) pp 819-823 (and supplementary materials published with the document). Claims 1 to 8 and 10 to 18.
D2 Mali et al., “RNA-Guided Human Genome Engineering via Cas9” (2013) Science 339 (6121) pp 823-825 (and supplementary materials published with the document). Claims 1 to 8 and 10 to 18.
D3 Wang et al., “One Step Generation of Mice Carrying Mutations in Multiple Genes by CRISPR/Cas Mediated Genome Engineering” (2013) Cell 153 pp 910-918 (and supplemental materials published with the document). Claims 1 to 20.
152. The Applicant provided no response to the Opponent’s submissions on novelty, and no evidence was adduced by A/Prof Firestein on this ground. However the Applicant submitted that even if the claims of the application are only entitled to take priority from the filing date of the application that the Opponent has made no case that Claim 21 is anticipated.
153. I agree with the Opponent’s submissions in relation to D1, D2 and D3 each disclosing matter falling within the scope of Claims 1 to 8 and 10 to 18. However I disagree with the Opponent’s assessment of Claims 9, 19 and 20. I consider these are novel in view of D3 as there is no disclosure of a nucleic acid encoding a guide RNA that comprises two additional guanine nucleotides at the 5’-end. Dr Herold understood that Table S3 in D3 describes the oligonucleotides used to add the T7 promoter to the sgRNA template for in vitro transcription of the sgRNA. This in vitro transcription process does not fall within the scope of the present claims.
154. In summary Claims 1 to 8 and 10 to 18 lack novelty in view of D1, D2 and D3.
Inventive step
155. Subsections 7(2) and 7(3) set out that an invention is taken to involve an inventive step unless it would have been obvious to the person skilled in the art in the light of the common general knowledge, either considered alone or together with the prior art. The prior art is information that the skilled person could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant.
156. The test for whether an invention is obvious is whether it would have been a matter of routine to proceed to the claimed invention.
“The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not.”[93]
[93] Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12; 148 CLR 262 at 286.
157. In Alphapharm,[94] the High Court accepted the approach taken by Graham J in Olin Mathieson,[95] where he posed the reformulated Cripp’s question:
“Would the notional research group at the relevant date, in all the circumstances, ... directly be led as a matter of course to try [the claimed combination] in the expectation that it might well produce a [useful or better result]?”
[94] Aktiebolaget Hassle v Alphapharm Pty Ltd [2002] HCA 59; (2002) 212 CLR 411.
[95] Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd[1970] RPC 157 at [187].
158. Where the invention involves a combination of integers, obviousness is to be determined by reference to the combination as a whole and not each integer individually. As stated in Alphapharm at [41]:
“The claim is for a combination, the interaction between the integers of which is the essential requirement for the presence of an inventive step. It is the selection of the integers out of ‘perhaps many possibilities’ which must be shown by Alphapharm to be obvious, bearing in mind that the selection of the integers in which the invention lies can be expected to be a process necessarily involving rejection of other possible integers.”
159. The Opponent’s submissions on obviousness were that the claims which were not anticipated by D1, D2 and D3 were obvious. The remaining claims in question are Claim 9, 20 and 21. I have found that Claim 19 lacks clarity, and I have not considered this claim further in the present determination.
160. Claims 9 and 20 define that the guide RNA comprises 2 additional guanine nucleotides at the 5’-end. Dr Herold stated that the addition of two guanine nucleotides at the 5’ end indicated that a T7 promoter was used to transcribe the RNA molecule in vitro. The two guanine nucleotides allow for a more efficient in vitro transcription of the guide RNA using the T7 promoter.
161. However I have construed the claims as not including in vitro transcribed guide RNA. Dr Herold’s evidence was predicated on it being obvious to incorporate two additional guanine nucleotides at the 5’-end in order to improve in vitro transcription. I find this of little relevance in determining the inventiveness of the claims as I have construed them. Example 6 describes the use of guide RNA incorporating such a change, which is said to affect mutation frequencies at on-target and off-target sites.[96] No evidence has been adduced that would enable me to conclude that such effects are only provided by in vitro generated guide RNAs. As a consequence I consider that Claims 9 and 20 are inventive.
162. Claim 21 defines methods in which the nucleic acid encoding the Cas9 polypeptide is introduced into the eukaryotic cell before introducing the nucleic acid encoding the guide RNA into the eukaryotic cell. Dr Herold stated that:
“I understand the benefit of first introducing the nucleic acid encoding the Cas9 polypeptide is to allow time for transcription and translation of the Cas9. This reduces the risk of the guide RNA disappearing while the Cas9 protein is being expressed.
The language of this claim therefore indicates to me that the "nucleic acid encoding the guide RNA" includes in vitro transcribed guide RNA. If "nucleic acid encoding the guide RNA" referred only to DNA encoding the guide RNA, there would be no need to introduce the nucleic acid encoding the Cas9 polypeptide first in order to reduce the risk of the guide RNA disappearing while the Cas9 protein is being expressed.”[97]
[96] Specification at [438].
[97] Herold 1 at [187]-[188].
163. Dr Herold appeared to assume that the serial transfection approach would only be necessary if naked RNA was used. A/Prof Firestein did not directly address this issue, and the Applicant’s submissions at hearing were directed to serial transfection where a naked RNA was employed. However Dr Herold’s evidence on the use of serial transfection using DNA encoding the guide RNA suggests to me that the skilled person would not be led to the claimed process because it would be an unnecessary and less efficient means of carrying out the process. It does not suggest to me that they would be led away for any perceived technical prejudice. Incorporating a redundant or even disadvantageous feature in a claim does not make a claim inventive.
164. On balance I am satisfied that the evidence establishes that Claim 21 lacks inventive step.
165. In summary Claims 1 to 8, 10 to 18 and 21 lack inventive step in view of each of D1, D2 and D3. Claims 9 and 20 are inventive. I have not considered the inventiveness of Claim 19 because I have determined it lacks clarity.
Conclusion
166. The opposition is successful. Claim 19 lacks clarity. Claims 1 to 8 and 10 to 18 lack novelty. Claims 1 to 8, 10 to 18 and 21 lack an inventive step.
167. Given that I have found Claims 9 and 20 to be valid, the issues may be overcome by amendment. I allow the Applicant 2 months from the date of this decision to propose appropriate amendments to the specification.
Costs
168. Costs generally the event and the parties agreed to such an approach. I award costs according to Schedule 8 against the Applicant.
Dr Leslie F. McCaffery
Deputy Commissioner of Patents
Annex: Claims
1. A composition comprising a Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas system for use in introducing a site-specific, double stranded break at a
target nucleic acid sequence in a eukaryotic cell, said CRISPR/Cas system comprising (i) a nucleic acid encoding a Cas9 polypeptide comprising a nuclear localization sequence, and (ii) a nucleic acid encoding a guide RNA that hybridizes to a target nucleic acid, wherein the guide RNA is a chimeric guide RNA comprising a CRISPR RNA (crRNA) portion fused to a trans activating crRNA (tracrRNA) portion.
2. The composition of claim 1, wherein said Cas9 polypeptide is a Streptococcus Cas9 polypeptide.
3. The composition of claim 2, wherein said Cas9 polypeptide is a Streptococcus pyogenes Cas9 polypeptide.
4. The composition of any one of claims 1-3, wherein said nucleic acid encoding a Cas9 polypeptide is codon-optimized for expression in eukaryotic cells.
5. The composition of claim 4, wherein said nucleic acid encoding a Cas9 polypeptide is codon-optimized for expression in mammalian cells.
6. The composition of any one of claims 1-5, wherein said nuclear localization sequence is located at the C terminus of the Cas9 polypeptide.
7. The composition of any one of claims 1-5, wherein the target nucleic acid is an endogenous target nucleic acid.
8. The composition of any one of claims 1-5, wherein the guide RNA is in the form of a vector.
9. The composition of any one of claims 1-5, wherein said guide RNA comprises 2 additional guanine nucleotides at the 5' end.
10. A method of introducing a site-specific, double-stranded break at a target nucleic acid sequence in a eukaryotic cell, the method comprising introducing into the eukaryotic cell a
Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas system, wherein the CRISPR/Cas system comprises:
a) a nucleic acid encoding a Cas9 polypeptide comprising a nuclear localization signal, wherein the nucleic acid is codon-optimized for expression in eukaryotic cells,
and
b) a nucleic acid encoding a guide RNA that hybridizes to the target nucleic acid, wherein the guide RNA is a chimeric guide RNA comprising a CRISPR RNA (crRNA) portion fused to a trans activating crRNA (tracrRNA) portion, wherein the target nucleic acid sequence comprises a first strand that binds to the crRNA portion and a second strand having a trinucleotide protospacer adjacent motif (PAM),
and wherein the Cas9 polypeptide and the guide RNA form a Cas9/RNA complex in the eukaryotic cell, whereby a site specific, double stranded break at the target nucleic acid sequence is introduced.
11. The method of claim 10, wherein the Cas9 polypeptide is a Streptococcus Cas9 polypeptide.
12. The method of claim 11, wherein the Cas9 polypeptide is a Streptococcus pyogenes Cas9 polypeptide.
13. The method of any one of claims 10-12, wherein the nucleic acid encoding the Cas 9 polypeptide is codon-optimized for expression in mammalian cells.
14. The method of any one of claims 10-13, wherein the nuclear localization signal is located at the C terminus of the Cas9 polypeptide.
15. The method of any one of claims 10-14, wherein the eukaryotic cell is a mammalian cell.
16. The method of claim 15, wherein the mammalian cell is a human cell.
17. The method of any one of claims 10-16, wherein the target nucleic acid sequence is a genomic sequence located at its endogenous site in the genome of the eukaryotic cell.
18. The method of any one of claims 10-16, wherein the nucleic acid encoding the guide RNA is a vector.
19. The method of any one of claims 10-16, wherein the nucleic acid encoding the guide RNA is in vitro transcribed RNA.
20. The method of any one of claims 10-16, wherein said guide RNA comprises 2 additional guanine nucleotides at the 5' end.
21. The method of any one of claims 10-16, wherein the nucleic acid encoding the Cas9 polypeptide is introduced into the eukaryotic cell before introducing the nucleic acid encoding the guide RNA into the eukaryotic cell.
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