Last Tuesday, April 23, 2019, the U.S. Patent and Trademark Office granted (at long last) to the University of California/Berkeley, the University of Vienna, and inventor Emmanuelle Charpentier a patent corresponding to the application-in-interference with the Broad's patent estate, as U.S. Patent No. 10,266,850, to its CRISPR technology (where CRISPR is an acronym for Clustered Regularly lnterspaced Short Palindromic Repeats). The interference between the Broad Institute and the University of California/Berkeley over patents directed to CRISPR technology has been in the spotlight over the past few years (see "CRISPR Interference Declared"; "PTAB Decides CRISPR Interference -- No interference-in-fact"; "PTAB Decides CRISPR Interference in Favor of Broad Institute -- Their Reasoning"; "University of California/Berkeley Appeals Adverse CRISPR Decision by PTAB"; and "Berkeley Files Opening Brief in CRISPR Appeal"); the claims granted in the '850 patent correspond to those patentably distinct from the Broad's claims.
The claims issued to Berkeley et al. as U.S. Patent No. 10,266,850 include the following:
1. A method of cleaving a nucleic acid comprising contacting a target DNA molecule having a target sequence with an engineered and/or non-naturally-occurring Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) system comprising a) a Cas9 protein; and b) a single molecule DNA-targeting RNA comprising i) a targeter-RNA that hybridizes with the target sequence, and ii) an activator-RNA that hybridizes with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment, wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides, wherein the single molecule DNA-targeting RNA forms a complex with the Cas9 protein, whereby the single molecule DNA-targeting RNA targets the target sequence, and the Cas9 protein cleaves the target DNA molecule.
2. An engineered and/or non-naturally-occurring Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) system comprising a Cas9 protein or a nucleic acid comprising a nucleotide sequence encoding the Cas9 protein, and a single molecule DNA-targeting RNA or a nucleic acid comprising a nucleotide sequence encoding the single molecule DNA-targeting RNA; wherein the single molecule DNA-targeting RNA comprises i) a targeter-RNA that is capable of hybridizing with a target sequence in a target DNA molecule, and ii) an activator-RNA that is capable of hybridizing with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment, wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides, and wherein the single molecule DNA-targeting RNA is capable of forming a complex with the Cas9 protein, whereby hybridization of the targeter-RNA to the target sequence is capable of targeting the Cas9 protein to the target DNA molecule.
4. A method of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded thereon, the method comprising contacting a target DNA molecule having a target sequence with an engineered and/or non-naturally-occurring Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) system comprising: a) a single molecule DNA-targeting RNA comprising i) a targeter-RNA that hybridizes with the target sequence, and ii) an activator-RNA that hybridizes with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment, wherein the targeter-RNA and the activator-RNA are covalently linked to one another with intervening nucleotides; and b) a Cas9 protein, wherein the single molecule DNA-targeting RNA forms a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule, whereby said target DNA molecule is cleaved or edited or transcription of at least one gene encoded by the target DNA molecule is modulated.
40. An engineered and/or non-naturally occurring Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) system comprising a) a Cas9 protein, or a nucleic acid comprising a nucleotide sequence encoding said Cas9 protein; and b) a single molecule DNA-targeting RNA, or a nucleic acid comprising a nucleotide sequence encoding said single molecule DNA-targeting RNA; wherein the single molecule DNA-targeting RNA comprises: i) a targeter-RNA that is capable of hybridizing with a target sequence in a target DNA molecule, and ii) an activator-RNA that is capable of hybridizing with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment, wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides; and wherein the single molecule DNA-targeting RNA is capable of forming a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule, whereby said system is capable of cleaving or editing the target DNA molecule or modulating transcription of at least one gene encoded by the target DNA molecule.
Berkeley, Vienna, and Charpentier have had three previous patents granted in its CRISPR portfolio (see "Whither CRISPR? University of California/Berkeley Granted Another CRISPR Patent" for a summary of the previously granted patents). Like the other granted patents, the newly issued '850 patent claims are not limited to the type of cell in which the CRISPR reaction occurs (nor, indeed, are limited to any cell at all). The subject matter eligibility of the claimed RNA molecules is presumably supported by limitations to "non-naturally occurring" (reminiscent of limiting transgenic animals to "non-human" embodiments) as well as by including the limitation "wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides," rendering them altered from how they are found in nature.
While the Broad was successful in getting the Federal Circuit to affirm the PTAB's decision that there was no interference-in-fact between the parties' claims (see "Regents of the University of California v. Broad Institute, Inc. (Fed. Cir. 2018): Federal Circuit Affirms PTAB in Appeal of CRISPR Interference") and there have been reports of the outcomes of other skirmishes between the parties in the meantime (see "The CRISPR Chronicles -- Broad Institute Wins One and Loses One"), questions remain about how the rights to this technology will be apportioned between the parties, and how useful, reliable patent licenses will be granted to permit robust development and fulfillment of the many promises of CRISPR in a wide variety of genetic contexts. The patent situation remains somewhat murky, at least with regard to which entity, or both, or another, will ultimately have sufficiently strong or comprehensive patent protection to give licensees confidence in their rights to develop CRISPR technology to fulfill its great promise.
