CRISPR has arrived Down Under

4 May 2019

The multi-party battle over CRISPR patent domination that has captivated post-grant challenge in the U.S. and Europe and elsewhere, has finally hit Australian shores in Grant Fisher v ToolGen Incorporated [2018] APO 65, albeit in a somewhat abbreviated fashion.

 

Grant Fisher launched opposition proceedings against the grant of Australian Patent Application No. 2013335451 to ToolGen Incorporated. At the time of the opposition filing and proceedings, Mr Fisher was a solicitor at Ashhurst Australia. Subsequent to issuance of the decision, Mr Fisher left Ashurst Australia and transferred his rights in the opposition to A.C.N. 004 552 363 Pty Ltd, seemingly a deidentified party being used to protect the identity of the true party behind the contentious proceedings. Such oppositions where the identity of the true party behind the proceedings are unknown as “straw man oppositions”, which are permitted under Australian practice before the Australian Patent Office.

 

Australian Patent Application No. 2013335451 is an Australian national phase entry of PCT/KR2013/009488. This PCT application is the originating application for the pivotal ToolGen CRISPR patent family embroiled in the broader CRISPR dispute to establish first/early filing rights of CRISPR/Cas9 platform in eukaryotic cells. The Australian application claimed priority from three (3) U.S. provisional applications, with the earliest priority date being 23 October 2012. The grounds of opposition that were pressed at hearing were novelty, inventive step, and section 40 issues of sufficiency, and clarity and support. Perhaps as a sign to deference of the importance of this decision or as a harbinger of litigation, the hearings officer was Deputy Commissioner of Patents.

 

The opposed application is broadly directed to compositions and methods related to Type II CRISPR, and notably use of CRISPR in eukaryotic cells. The application has 21 claims including independent Claims 1 and 10 defining compositions and methods respectively. Claim 1 is reproduced below:

 

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.

 

Under Australian practice, “for use in” does not limit the claim to the specified use and as such, Claim 1 is construed as a composition claim that is suitable for the specified use.

 

Claim 10 is directed to a method of introducing site-specific, double-stranded breaks in a target nucleic acid in a eukaryotic cell using Type II CRISPR compositions which includes which many of the elements of Claim 1.

 

The Delegate found the claims to be sufficient and supported, although Claim 19 was deemed to lack clarity. Claims 9 and 20 were found novel and inventive. The opposition was successful insofar as Claims 1-8, 10-18, and 21 were found to lack novelty and an inventive step. The allegation regarding novelty and inventive step made by the Opponent was reliant upon invalidation of the Applicant’s priority claim.

 

Though there were many issues of construction under contention, a single construction had a crucial bearing on the outcome of the opposition. The decision regarding the validity of the earliest priority date, and by extension novelty and inventive step, turned on the Delegate’s preferred construction of the “a nucleic acid encoding a guide RNA” recited in Claims 1 and 10. 

 

It was common ground between the parties that the term “a nucleic acid” includes DNA which encodes the guide DNA, but the parties disagreed as to whether the term “nucleic acid” should be construed more broadly to include the guide RNA itself.

 

The Delegate referred to the expert evidence regarding a skilled addressee’s understanding of the term “nucleic acid”. The Opponent’s first expert declared that “nucleic acid” refers to DNA in the form of a vector or plasmid, whilst their second expert was of the view that the term could not include in vitro transcribed guide RNA as this form did not “encode” anything. The Applicant’s expert declared that he understood the term to include the guide RNA itself, but did not elaborate as to why. The Delegate seemed to be influenced by the absence of a rationale by the Applicant’s expert.

 

In a short statement at [41], the Delegate provided the following rationale for his adopted construction of this feature:

 

The specification describes the various ways by which the guide RNA may be transferred to the cell, 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.

 

Thus, the Delegate limited the scope of this feature to DNA encoded guide RNA and thus excluded in vitro transcribed RNA and the guide RNA itself.

 

The consideration of the validity, or otherwise, of a priority date is made under section 43 of the Patents Act 1990 as amended by the Raising the Bar Act 2012 (“RTB Act”). Each party presented submissions as to the path that should be followed by the Delegate for a determination pursuant to section 43. The Applicant advocated that the section 43 question requires a single consideration as to whether the priority document/s enables the invention as claimed (at [97]). The Opponent proposed a two-step consideration in which the priority document/s must disclose the invention as claimed in the Application (either expressly or impliedly), and if that threshold is satisfied, the disclosure must be clear and complete enough for the invention to be performed by a person of skill in the art.

 

As the Delegate noted, judicial determination of section 43, as amended, is scant. Having reviewed limited authority and relying heavily upon the Explanatory Memorandum to the RTB Act in which IP Australia made a substantial contribution, the Delegate applied the following approach to determination of priority pursuant to section 43, noting that rigid adherence to this three-step process was not mandatory ( [119] to [120]):

 

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.

 

Using this approach, the Delegate turned to consideration of two priority documents having the earlier priority dates, namely P1 and P2. P1 is not an orthodox provisional patent application but rather a journal article filed as US Provisional Application No. 61/717324 filed on 23 October 2012. The article was subsequently published by the inventors in January 2013. P2 is US Provisional Application No. 61/803599 filed on 20 March 2013.  P1 discloses in vitro transcribed guide RNA only, and in the Delegate’s opinion a nucleic acid encoding a guide RNA as construed (ie. DNA encoded guide RNA) could not be derived, impliedly or explicitly, from the disclosure of P1. The Delegate found that neither P1 nor P2 disclosed “a nucleic acid encoding the guide RNA” as construed in a manner which is clear enough and complete enough for the person skilled in the art to work the invention.

 

With this finding, the priority date of the application became the filing date of P3, namely 20 June 2013, and as such three well-known and seminal publications relied upon by the Opponent became relevant prior art (see footnote). The Delegate ultimately found that each of these documents anticipated Claims 1 to 8 and 10 to 18.

 

Claims 1 to 8, 10 to 18 and 21 were found to lack inventive step in view of each of each of the prior art publications in light of common general knowledge.

 

It is noteworthy that ToolGen did not make submissions regarding the relevance or otherwise of the alleged prior art, novelty and/or inventive step, presumably for reasons of estoppel that may be invoked in other jurisdictions, noting that prosecution history estoppel is not applicable under Australian patent jurisprudence.

 

Neither party was content with the outcome of the opposition and the decision has been appealed to the Federal Court of Australia. Unsurprisingly, ToolGen alleges inter alia that the Delegate erred with construction of "a nucleic acid encoding a guide RNA” and the approach by the Delegate to consideration under section 43. The submission by the Opponent (whoever that really is) claims, inter alia, that the Delegate erred in finding that the specification is sufficient and supported, and also took umbrage with the Delegate’s construction of “a nucleic acid encoding a Cas9 polypeptide” and consequently findings on novelty and inventive step.

 

An appeal of an Australian Patent Office decision to the Federal Court of Australia is a hearing de novo. The outcome of this trial will not only be interesting from a commercial perspective, but also the point of law regarding section 43 that will be considered by the Court.

 

On 10 April 2019, the Australian government announced that use of gene-editing techniques (including CRISPR-based techniques) in plants, animals and human cell lines that do not introduce new genetic material will not be subject to government regulation. Prior to this amendment, this type of gene editing was under the same regulatory constraints as conventional genetic modifications, which require approval from a biosafety committee. Gene editing that uses a template to direct the repair or those that insert foreign DNA into the genome remains under government oversight. This position on gene editing places Australia between heavily regulated countries (such as Europe and New Zealand) and lenient jurisdictions such as the USA and Brazil. Perhaps this change is a signal to patent owners of the emerging commercial market opportunity for CRISPR-based gene editing techniques in Australia.

 

 

Footnote:

 

  1. Cong et al., “Multiplex Genome Engineering Using CRISPR/Cas Systems” (2013) Science 339 (6121): 819-823.

  2. Mali et al., “RNA-Guided Human Genome Engineering via Cas9” (2013) Science 339 (6121): 823-825.

  3. Wang et al., “One Step Generation of Mice Carrying Mutations in Multiple Genes by CRISPR/Cas Mediated Genome Engineering” (2013) Cell 153: 910-918.

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