Elementary Claim: Sherlock Gains Patent Rights for Cas12 in Diagnostics

Sherlock Biosciences has gained U.S. rights to a patent for diagnostic use of a CRISPR system based on the smaller Cas12 enzyme as single RNA-guided endonuclease.

Sherlock—whose co-founders include CRISPR pioneer Feng Zhang, PhD, of the Broad Institute—says its exclusive U.S. rights to U.S. Patent No. 11,584,955, which covers a method for detecting target nucleic acid molecules, leveraging the collateral cleavage activity of a Cas12 protein. Sherlock says the technology has shown in tests the potential to deliver flexible, high-accuracy, low-cost Cas12-based detection of diseases, including malaria, tuberculosis, and COVID-19.

Sherlock boasts that the patent, combined with rights to additional patents issued to the Broad, places the company “at [the] apex of CRISPR-based diagnostics” based on targeting double-stranded DNA through Cas12 and targeting single-stranded RNA through another enzyme, Cas13.

CRISPR diagnostics designed to apply Cas12 and Cas13 is an area where Sherlock has competed head-on with another diagnostic developer—Mammoth Biosciences, co-founded by another CRISPR pioneer, Nobel laureate Jennifer Doudna, PhD. Mammoth has incorporated Cas12 and Cas13 into its proprietary toolbox of novel Cas enzymes—a toolbox that includes Cas14, which targets single-stranded DNA; and Casɸ, which is encoded exclusively in the genomes of huge bacteriophages.

Mammoth has exclusively licensed foundational IP around novel CRISPR Cas12, Cas13, Cas14, and Casɸ systems from the University of California, Berkeley. The systems were discovered in Doudna’s lab.

To use Cas12 within its toolbox, Mammoth would need to license the enzyme from his company, Sherlock president and CEO Bryan Dechairo, PhD, told GEN Edge.

“The patent that’s been issued is something that has very broad claims of amplification with CRISPR-based detection for diagnostics, and has the earliest filing date in the U.S. So based upon that, if people would like to use Cas12 with amplification of DNA, then they would need a license from Sherlock Biosciences,” he said.

Mammoth responded this week through a company statement to GEN Edge that noted: “We have several issued worldwide patents related to Type V and Type VI CRISPR systems that include Cas12, Cas13, Cas14 enzymes, and beyond. More generally, we have a broad and differentiated CRISPR-based IP portfolio across multiple fields of use.”

“We are not currently looking to license IP from third parties in the diagnostics space and we are open to discussions with parties that can leverage Mammoth’s pioneering innovations to benefit patients,” Mammoth added.

Focus on therapeutics

Over the past year two years, Mammoth has evolved into developing both CRISPR-based diagnostics and therapeutics, with growing emphasis on the latter. Late in 2021, Mammoth inked an up-to-$695 million collaboration with Vertex Pharmaceuticals to develop in vivo gene-editing therapies for two undisclosed genetic diseases using Mammoth’s CRISPR systems. And in January 2022, Bayer agreed to use those systems to develop in vivo gene-editing therapies, through a collaboration that could generate more than $1 billion for Mammoth.

The collaborations have already paid off for Mammoth, which received $31 million upfront from Vertex, according to Vertex’s Form 10-K annual report for 2022, and $40 million upfront from Bayer that was disclosed by the pharma giant.

Mammoth is building a pipeline of CRISPR therapies, and has identified several potential therapeutic areas for those treatments—including autoimmune diseases, cardiovascular, hematology, immuno-oncology, liver disease, neurology and neuromuscular diseases, and ophthalmology.

“We’ll start in the liver, and then we’ll move on to other tissues. Some areas that we’re really excited about include muscle and CNS,” Mammoth’s co-founder and CEO Trevor Martin, PhD, told GEN Edge last month.

Martin would not disclose details about the Bayer and Vertex collaborations. The CEO did say that Mammoth has set its first area of therapeutic focus on the liver because genome editors have been shown to be successfully transported to cells through delivery modalities that include adeno-associated viruses (AAVs) and some lipid nanoparticles (LNPs).

Mammoth and Sherlock received FDA emergency use authorizations (EUAs) for CRISPR-based COVID-19 diagnostics during the pandemic. Mammoth applied Cas12 in its COVID-19 diagnostic effort that culminated in the SARS-CoV-2 RNA DETECTR Assay, a COVID-19 diagnostic for which UCSF Health Clinical Laboratories was granted an FDA Emergency Use Authorization (EUA) in August 2020.

“We’re not focused on commercializing COVID testing as a company,” Martin said. “First and foremost, we’re a biotech company focused on therapeutics. Beyond that, CRISPR diagnostics is a brand-new method of molecular detection, I think it has exciting applications beyond COVID and respiratory testing, although obviously it has uses there. We’re thinking about it more holistically on the platform side.”

Three months earlier in May 2020, Sherlock became the first company to receive an EUA from the FDA for a COVID-19 diagnostic, namely its Sherlock CRISPR SARS-CoV-2 Kit.

“That’s a nice milestone for CRISPR, but that test did not really compare to PCR,” said Dechairo, who before helming Sherlock served as executive vice president of clinical development with Myriad Genetics during a career in which he held numerous roles at diagnostic as well as therapeutic developers. “For 30 years I spent my whole career in PCR. So, while [the kit] was a great demonstration that CRISPR had the accuracy of PCR, and it could be FDA cleared, it didn’t meet any real target product profile.

“So, when I came to Sherlock, we said, where is CRISPR unique vs. PCR? Where CRISPR’s unique compared to PCR is the ability to decentralize the technology at a very low cost of goods, where anybody else can use it,” Dechairo said. “And that’s when I pivoted the company towards being focused on over the counter, and really decentralizing and democratizing diagnostics around the world.”

Expanding collaboration

The patent covering Cas12 use in diagnostics was applied for by, and is assigned to, Shanghai Tolo Biotechnology, which in 2020 granted Sherlock exclusive U.S. rights to its CRISPR Cas12 (including Cas12a and Cas12b) diagnostic technology. In return, Sherlock granted Tolo exclusive rights to the CRISPR Cas13 SHERLOCK diagnostic platform in Greater China.

Last November, Sherlock and Tolo expanded their collaboration, by granting each other co-exclusive rights to Cas12 and Cas13 CRISPR diagnostic methods in areas of the world outside of the U.S. and Greater China. At the time, Sherlock said the expansion also allowed healthcare practices and others to sublicense rights to the technology for use by labs and hospitals.

The value of the 2022 and 2020 agreements has not been disclosed.

Sherlock says access to both Cas12 and Cas13 enables the company to detect both DNA and RNA

“When we licensed Cas12 from the Broad, we were just saying, ‘Well who has the earliest filing days?’ We found out it wasn’t the Broad—it was Tolo. So we went out and acquired the IP from Tolo, because they had that earliest filing date.”

The technology that Sherlock licenses from the Broad and from Tolo marries amplification with CRISPR detection, and is one of four amplification methods for which Sherlock holds IP rights, Dechairo said.

The other three are:

• A strand displacement amplification technology, an isothermal application method that works around 50 °C and enables healthcare providers to swab, amplify, engage a lateral flow strip, and read out results in under 15 minutes. Sherlock obtained the technology by acquiring Sense Biodetection for an undisclosed price, a deal announced February 1.
• An ambient temperature amplification method developed by the lab of Jim Collins, PhD, at the Wyss Institute for Biologically Inspired Engineering at Harvard University. The technology can run at room temperature and offer results in under an hour, Dechairo said. Collins is a co-founder and board member of Sherlock.
• A synthetic biology approach also developed by Collins’ lab at the Wyss Institute that enables users to detect DNA and RNA and convert it into synthetic proteins. These can then bind on multiple different bands on a lateral flow strip, allowing for highly multiplexed readouts from a single operation.

“The pairing of proprietary amplification technology from the Wyss Institute, as well as the rapid molecular amplification chemistry gained through our recent acquisition of Sense Biodetection, puts us on track to become a global health leader,” Collins said in a statement.

Dominant and defensible

“This dominant and defensible patent position will allow us to establish the necessary market foothold in the U.S. before we bring our rapid, point-of-need diagnostic tests to the rest of the world,” Collins added.

Given its access to other amplification methods, why did Sherlock pursue IP for CRISPR detection?

“When you amplify things isothermally, you often amplify up a lot of the raw materials, so, you lose some specificity. When you do that at colder and colder temperatures—because we can do that at room temperature—you actually start getting even more background, noise,” Dechairo explained.

“A CRISPR enzyme with its guide RNAs can come in read through all that background, and only read out what is what is positive,” he continued. “When those Cas enzymes 12 and 13 find their target, they then activate, and they start to cleave any nucleic acid in the surrounding liquid, which allows us to use that as a readout for detection, whether that is fluorescently or lateral flow.”

The Sense acquisition, Dechairo noted, also gave Sherlock access to the Cambridge, U.K., company’s Veros platform, which has a lateral flow readout. Veros is a low-cost, instrument-free, disposable device that has been through clinical trials and according to Sherlock has shown very high accuracy and isothermal chemistry.

That device, Sherlock reasons, can help it deliver affordable over-the-counter testing with superior accuracy.

“We have a whole team of AI scientists who have made machine-learning algorithms to develop CRISPR-based diagnostic assays. We’re putting all of that AI into a software package, so that not just Sherlock scientists, but the world’s scientists can design their own CRISPR-based diagnostics and bring them to the market,” Dechairo said.

Sherlock has named its program for that purpose “Rosalind” in tribute to Rosalind Franklin (1920-1958), the British structural biologist whose pioneering work producing x-ray images of DNA was crucial in the discovery of its structure by Francis Crick and James Watson in 1953.

By year’s end, Dechairo said, Sherlock will make the Rosalind software available to scientists worldwide so they can design their own CRISPR assays using the company’s AI software.

Zhang and colleagues at the Broad have been challenged for nearly a decade over patents for CRISPR-Cas9 technology by the University of California (UC), the University of Vienna, and CRISPR pioneer and Nobel co-laureate Emmanuelle Charpentier, PhD, in a bitter battle royal over who invented the gene-editing technology in eukaryotic cells.

Last year, Zhang and the Broad survived a second challenge to their CRISPR-Cas9 patents when the Patent Trial and Appeal Board (PTAB) of the U.S. Patent and Trademark Office (USPTO) decided that the Broad, MIT, and President and Fellows of Harvard College had priority over the Regents of the UC, University of Vienna, and Charpentier in the invention of a single RNA CRISPR-Cas9 system that functions in eukaryotic cells. Charpentier is director and scientific member at the Max Planck Institute of Infection Biology, Berlin.

The post Elementary Claim: Sherlock Gains Patent Rights for Cas12 in Diagnostics appeared first on GEN – Genetic Engineering and Biotechnology News.

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