The first month of 2022 has seen a slew of CRISPR IP deals, with several large pharmaceutical companies deepening their investments in cutting-edge gene-editing technologies. This is further evidence that licensing activity in the space is building momentum, despite ongoing patent litigation. Recent dealmaking also suggests that much of the value of CRISPR IP lies outside the high-profile Cas9 enzymes.

A highlight was Bayer’s agreement with CRISPR rights holder Mammoth Biosciences. The deal, in which the German company will pay an initial $40 million, could be worth over $1 billion more in regulatory and commercial milestone payments. In return, Bayer gets the right to use Mammoth’s Cas14 and Casɸ IP for the development of up to five in vivo CRISPR treatments for liver diseases.

This follows on from Mammoth’s first significant therapeutics partnership, which was struck with Vertex Pharmaceuticals in October last year. This also pertained to the use of the biotech’s Cas14 and Casɸ rights, which it holds from co-founder and Nobel Laureate, Jennifer Doudna of the University of California, Berkeley. In that deal, the rare disease specialist handed over a similar upfront fee, $41 million, with up to $650 million in milestones, plus tiered royalties to follow.

This month also saw Pfizer agree a $1.35 billion collaboration with CRISPR innovator Beam Therapeutics, whose base editing technology the Big Pharma seeks to use to create one-time treatments for genetic conditions. Focusing on liver, muscle and central nervous system targets, the partnership involved an initial $300 million payment, plus a potential $1.05 billion further fees, with Beam retaining the right to co-commercialise programmes produced by the collaboration.

On top of that, January witnessed a further $175 million investment in UCal spinout Metagenomi. The biotech, which seeks to harness CRISPR gene-editing for the creation of immuno-oncology cell therapies, and which recently sealed a deal with Moderna, will receive the additional cash injection from Bayer, Bristol-Myers Squibb and VC investors.

Moreover, in the early days of 2022, Intellia Therapeutics signed an exclusive licensing deal with Kyverna Therapeutics aimed at the development of an allogenic CD19 chimeric antigen receptor T-cell therapy for several autoimmune conditions. Kyverna will have the right to use the company’s ex vivo CRISPR Cas9-based allogenic platform for this task. Intellia will receive an equity stake in its partner as well as commercialisation and royalty rights.

This torrent of recent deals is part of a broader trend towards CRISPR-related dealmaking. Not only did Vertex strike a significant deal with Mammoth towards the end of last year, but earlier in 2021 it paid $900 million upfront to gain the rights to CRISPR Therapeutics’ clinical sickle cell disease therapy CTX001. It also agreed to pay as much as $1.2 billion for use of Arbor Biotechnologies’ CRISPR technology for the development of ex vivo therapies for up to seven diseases. Beam Therapeutics has also recently out-licensed its rights to Apellis Pharmaceuticals in a five-year collaboration.

Perhaps this ought not to be a surprise given the recent clinical successes of CRISPR-related treatments. In June 2021, Intellia Therapeutics announced positive first-in-human data for its in vivo Cas9-based Regeneron-partnered candidate, NTLA-2001. The company has at least three other treatments in the clinic. Vertex and CRISPR Therapeutics are hoping to file for regulatory approval of CTX001 late this year. Beam itself is putting its lead candidate, BEAM-101 into phase 1/2 clinical trials.

But some of this licensing is happening in the face of deep uncertainties regarding ownership of fundamental Cas9 IP rights due to the ongoing US patent dispute between UCal, the Broad Institute and ToolGen (see here for more analysis).

Indeed, Beam – whose base editing technology makes use of others’ proprietary enzymes – could be impacted by the outcome of the Cas9 dispute. It licenses Cas9 patents from parties on one side of that dispute, Harvard University and the Broad Institute. And its CEO, John Evans, has admitted to paying close attention to the ongoing spat. A recent SEC filing spells out the related risks in detail. However, the company also has rights to – or options on the rights to – a range of non-Cas9 IP, including for Cas13 and Cpf1.

Recent transactions remind us, however, that there is a great deal more to the CRISPR patent landscape than Cas9 rights. Cas14 and Casɸ have a great deal of potential value as the basis for in vivo gene-editing therapeutics due to their compact nature, and the fact that Cas14 is pathogen-sourced, which could have safety benefits. Arbor’s $1.2 billion deal was made partly on the back of the newly-discovered Cas13d protein.

Furthermore, CRISPR Cas12 has proved a useful diagnostic technology. Mammoth has struck diagnostics-based deals with MilliporeSigma, Hamilton Company, GlaxoSmithKline and Agilent Technologies. Its Cas12 diagnostic tool DETECTR received FDA emergency use approval as a covid-19 test in late-2020.