In brief

In the recent decision by the Patent Trial and Appeal Board (PTAB) of the United States Patent and Trademark Office in Interference No. 106,115, University of California v Broad Institute, the Broad Institute, the Massachusetts Institute of Technology, and Harvard University (together, Broad) were held to have had priority over the University of California, Berkeley (UC Berkeley), the University of Vienna, and Emmanuelle Charpentier (together, the CVC) in the invention of a single RNA CRISPR-Cas9 system that functions in eukaryotic cells. This decision places Broad’s US CRISPR-Cas9 patent landscape at an advantage over CVC’s at present, although additional interferences between each of Broad and CVC against each of ToolGen and Sigma-Aldrich are still pending.

Background

The CRISPR-Cas9 gene editing system is based on a naturally occurring endogenous genome editing system which functions as part of the immune response in bacteria. CRISPR is an acronym for clustered, regularly interspaced, short palindromic repeats. When the bacterial immune system is presented with viral DNA or plasmids, it extracts short fragments of these foreign DNA sequences and inserts them into one or more of the bacterium’s CRISPR loci. The loci containing the foreign DNA is then transcribed to produce short CRISPR RNAs (crRNAs). These crRNAs can recognise and attach very specifically to the foreign DNA sequences of the virus and direct the CRISPR-associated protein 9 (Cas9), a DNA nuclease, to cleave such sequences on the basis of sequence complementarity, thus inactivating the virus. The capability of the CRISPR-Cas9 system to precisely cleave genomic DNA makes it very versatile and effective for genome editing, for example, deleting sequences from the genome or permitting the introduction of foreign DNA sequences into the genome.

In 2012, researchers Jennifer Doudna (UC Berkeley) and Emmanuelle Charpentier (Helmholtz Centre for Infection Research in Germany) demonstrated the use of CRISPR-Cas9 system for genome editing in vitro. Their work led to the filing of a patent application (US 2013/032589) with claims encompassing numerous applications of the CRISPR-Cas9 system for a variety of cell types. The patent application claims a priority date of 25 May 2012.

Also in 2012 and in parallel to the activity of Doudna and Charpentier, researcher Feng Zhang (Broad Institute) developed a method of using the CRISPR-Cas9 system for genome editing in eukaryotic cells. This work also led to a patent application being filed which claims a priority date of 12 December 2012. The patent was granted as US 8,697,359 on 15 April 2014.

Since then both parties have filed a number of patent applications only to later realise that they had filed competing patent applications. In 2016, CVC and Broad initiated priority (or “interference”) proceedings (Interference No. 106,048) at the PTAB to be granted the exclusive rights to CRISPR-Cas9 technology. The outcome of this proceeding led to a ruling that eukaryotic CRISPR and other uses of the CRISPR-Cas9 system were separate inventions and patentable by Broad and CVC, respectively. CVC appealed the decision to the US Court of Appeals for the Federal Circuit (Regents of Univ. of California v. Broad Inst., Inc., 903 F.3d 1286 (Fed. Cir. 2018)), which denied its appeal.

Between April 2018 and February 2019, CVC filed a series of continuation applications that included claims to the application of the CRISPR-Cas9 system in eukaryotic cells. The applications claim priority to the original non-provisional filing which was at issue in Interference No. 106,048, and the series of provisional applications dating back to 25 May 2012. This led to the PTAB declaring a second interference (Interference No. 106,115).

Interference No. 106,115

The PTAB was required to determine which of the parties’ inventors were the first to invent a CRISPR-Cas9 system with a single guide RNA that is able to cleave or edit DNA to alter gene expression or modulate transcription of a targeted gene in a eukaryotic cell (the Invention). The focus of Interference No. 106,115, therefore, was to determine which party was the first to conceive of and reduce to practice the use of a CRISPR-Cas9 system for genome editing in eukaryotic cells.

During the preliminary motions phase of Interference No. 106,115, CVC was accorded the benefit of 28 January 2013 as the filing date of its provisional application (US 61/757,640), whereas Broad was accorded the benefit of 12 December 2012 as the filing of date its provisional application (US 61/736,527). The parties then filed motions claiming for dates of conception and reduction to practice of the Invention that were earlier than their respective accorded benefit dates.

CVC had argued before the PTAB that the CVC inventors had conceived of the Invention on 1 March 2012 and, by 9 August 2012, had reduced the Invention to practice. The evidence relied on by CVC included declarations from the CVC inventors, their lab notes, and email correspondence between members of the CVC inventors’ research teams. The basis of CVC’s claim that they had reduced the Invention to practice by 9 August 2012 was that experiments performed by that time had demonstrated CRISPR-Cas9 genome editing in zebrafish.

Broad, on the other hand, contended that by March 2012 CVC had yet to establish a definite plan and that, throughout 2012, the CVC inventors had encountered multiple failures when they attempted to use their CRISPR-Cas9 system in human cells and zebrafish embryos. Broad argued that these failures had prompted the CVC inventors to consider changing material aspects of the system in order to find a strategy that could work. It followed that such failures meant that the CVC inventors had not expressed their ideas in such clear terms to enable persons skilled in the art to make the Invention.

In respect of their claim to priority, Broad argued that the Broad inventors had reduced the Invention to practice by 5 October 2012, the date on which the Broad inventors submitted a manuscript to the journal Science. The manuscript included the Broad inventors’ results of successful experiments that demonstrated genome editing of eukaryotic genomes using the CRISPR-Cas9 system.

The PTAB determined from the parties’ arguments and evidence that the preponderance of the evidence supported the arguments submitted by Broad. The PTAB found that CVC did not have a definite and permanent idea of how to achieve the Invention in March 2012, let alone reduce it to practice by August 2012. In contrast, the PTAB was persuaded that the Broad inventors had achieved an actual reduction to practice of an embodiment of the Invention by 5 October 2012, based on Broad inventors’ submission of the manuscript to Science.

Key lessons

• In the US, under the old “first to invent” system (before the “America Invents Act”), clear and contemporaneous evidence in respect of conception of the subject matter claimed and reduction to practice is essential where there is a dispute over priority. This typically takes the form of laboratory notebooks and other records of experiments, including regarding experimental design, protocols and conditions, such as email correspondence.

• The patents on the revolutionary CRISPR-Cas9 genome-editing technology in eukaryotic genomes are a hotly contested space. Despite Broad’s present success over CVC, a number of interferences are still pending between Broad and each of ToolGen and Sigma-Aldrich.

• In Australia, a decision is currently pending in respect of an appeal by ToolGen in the Federal Court of Australia against a successful opposition in the Australian Patent Office by a “straw man” opponent.