MilliporeSigma said today its first CRISPR-related patent will be awarded in the U.S., as a result of the U.S. Patent and Trademark Office issuing a formal Notice of Allowance for MilliporeSigma’s application directed to its proxy-CRISPR technology.

Proxy-CRISPR is a new genome-editing technique designed to increase the efficiency, speed, flexibility, and specificity of CRISPR by opening the genome for modification of DNA. The technology can help scientists modify hard-to-access regions of the genome, according to MilliporeSigma.

“This is great news for researchers in the U.S., as they now have more gene-editing options that accelerate drug development,” MilliporeSigma CEO Udit Batra, PhD, said in a statement. “As a leading innovator of CRISPR technology, we will continue to collaborate with scientists around the world to ensure that the full potential of this powerful tool is realized, responsibly and ethically.”

MilliporeSigma’s proxy-CRISPR method uses two CRISPR systems designed to target the genome in proximity to each other and work together. One CRISPR system opens a regional “door,” pushing away blocking chromatin proteins, while the other walks through it to find the exact location for modification.

Because the resulting modification requires two CRISPR binding events, the proxy-CRISPR method can enable twice the specificity of individual CRISPR systems, MilliporeSigma said.

The U.S. patent allowance marks MilliporeSigma’s 13th CRISPR patent worldwide. The company has been granted patents for CRISPR-related technologies covering foundational and alternative genome-editing methods starting in June 2017 in Australia, then two months later in Europe. In Australia and Europe as well as in Canada, MilliporeSigma has received patents for its CRISPR paired nickase technology, which applies cleaving opposite strands of a chromosomal sequence to create a double-stranded break—as well as for CRISPR integration technology, which entails the chromosomal cutting of the sequence of eukaryotic cells and insertion of a DNA sequence.

Patents for the CRISPR integration technology have also been granted in Singapore, China, Israel, and South Korea.

MilliporeSigma said it is licensing its entire patent portfolio for all fields of use. MilliporeSigma is the name through which Merck KGaA’s Life Science business operates in the U.S. and Canada.

Addressing ethical concerns

In its statement announcing its first U.S. CRISPR patent, MilliporeSigma noted that its parent company, Merck KGaA, Darmstadt, Germany, has established an independent, external Bioethics Advisory Panel to provide guidance for research in which its businesses are involved—including research on or using genome editing. Merck KGaA has developed and published a six-page policy statement intended to address ethical as well as technological concerns concerning its use of CRISPR and other genome editing technologies in research and applications.

“Even if the questions around efficiency, specificity, and safety of genome editing can be resolved, there are also ethical issues to be considered. These issues include the consequences for the individual, their offspring, and the potential repercussions for society as a whole,” according to the policy statement.

The issues resurfaced late last year, following the uproar within the scientific community that followed the disclosure by He Jiankui, PhD, that he and colleagues had performed genome editing on human embryos using CRISPR-Cas9, resulting in the birth of twin girls. Jiankui has defended his research despite condemnation from a consensus of researchers and stakeholder institutions in genome editing, but was fired last month from his university, the Southern University of Science and Technology (SUSTech) in Shenzhen, China.

Speaking with GEN last month, Batra articulated Merck KGaA’s areas of emphasis in gene editing via CRISPR-Cas9. They include developing more specific methods of cutting and replacing relevant parts of the genome while avoiding off-target impacts; and developing better cell lines that more closely mimic human cells for in vitro toxicology studies—for example, using gene editing to modify Madin-Darby Canine Kidney (MDCK) cells to look more like the human gut, or to enhance bioproduction.

Merck KGaA has advanced into gene editing-based drug development in recent years through a series of collaborations and other initiatives. Last month, the company outlicensed to Vertex Pharmaceuticals a pair of DNA-dependent protein kinase (DNA-PK) inhibitors—one clinical, the other preclinical—for use in gene editing applications in six genetic disease indications. The licensing agreement, whose value was not disclosed, covers M9831 (formerly VX-984) and an additional preclinical compound—two of four compounds that Merck KGaA licensed from Vertex in 2017 for $230 million upfront.

In December, MilliporeSigma launched a strategic alliance with genOway by licensing to the French biotech exclusive rights to Merck KGaA’s foundational genome-editing patents to produce and sell rodent models designed to allow nonprofit and for-profit scientists to use Merck KGaA’s CRISPR/Cas9 technology.

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