The CRISPR patent war

Research into genome-editing technologies has progressed to a point where we can read the strains of DNA that exist in almost every cell of our bodies as if they were on a word processor and take faulty, disease-causing genes out of a sequence and replace them with functioning ones.

The latest method of this so-called gene-editing technology is called CRISPR-Cas9. CRISPR-Cas9 gets its name from the clustered, regularly interspaced, short palindromic repeats (CRISPRs) in the DNA sequence, and the CRISPR-associated protein 9 (Cas9), which makes cuts in the specifically chosen locations in the strand.

Dubbed a ‘search and replace’ function for DNA, CRISPR-Cas9 allows researchers to easily make precise changes to a DNA sequence.

The therapeutic possibilities are exciting. Researchers have already used the method to treat haemophilia in mice, and eventually it could be used to treat a host of genetic diseases in humans.

The main players

There is a battle for the rights to the technology. Two groups of inventors are claiming priority to the invention of the CRISPR-Cas9 system, and whichever ultimately lands the patent rights and emerges victorious could have a drastic impact on CRISPR’s future.

In this battle, first blood was to Feng Zhang of the Broad Institute of Harvard and MIT, who received a patent covering the technology last April. The patent is broad, and could grant Zhang exclusive rights to use the technology commercially.

Zhang’s opponents are Jennifer Doudna of the University of California, Berkeley and Emmanuelle Charpentier of the Helmholz Centre for Infection Research, who also have a history of working with CRISPR-Cas9.

Their patent application, which claims a priority date of May 25, 2012, includes 155 claims and covers many applications for the technology for different cell types.

Zhang’s patent, called “CRISPR-Cas systems and methods for altering expression of gene products”, has a later priority date of December 12, 2012.

There are many other patent applications related to the CRISPR system. A paper from Nature Biotechnology says that as of March 2015, more than 12 new patents related to the system have been issued, and that there are more than 100 patent applications claiming or describing applications for CRISPR-Cas9.

According to that paper, eight of the issued patents belong to Zhang. Many of these have broad claims, although others are directed to specific applications, such as use of the platform to treat Huntington’s disease.

Zhang licenses at least his first CRISPR patent to Massachusetts-based biotech Editas Medicine, while Doudna licenses at least one pending patent to Intellia Therapeutics, also based in Massachusetts.

The major issues

Many companies engaged in CRISPR-Cas9 research have thrown their hats into the patent ring in an effort to secure a slice of this potentially revolutionary technology. However, there are specific characteristics of the technology itself which will affect how it is decided who gains rights to the invention, how the resulting licensing landscape will look, and how it will have an impact on the technology’s development.

For example, the technology is relatively easy to practise. Perhaps because of this, there is a hefty body of prior art that could make determining ownership of the system problematic. Even after patents are issued, inconsistencies in different countries’ licensing laws could create problems later in the technology’s life cycle.

Also, as the invention relies on a law of nature to be practised, the laws on what aspects of the technology are patent-eligible in different jurisdictions are likely to vary.

Kevin Noonan, a partner at McDonnell, Boehnen, Hulbert & Berghoff in Chicago, notes that because the CRISPR technology exploits a biological phenomenon, all that would be patentable in the US would be methods for exploiting the phenomenon.

While many companies have “claimed ownership” of the CRISPR-Cas9 invention, from a patent perspective there are many inventions underpinning the development of the technology, says James Legg, a patent attorney at Boult Wade Tennant in Cambridge, UK.

“It is therefore hardly surprising that the patent environment surrounding CRISPR-Cas and its many applications is complex.”

Legg notes that co-pending patent applications that have an earlier effective filing date but were published after the effective filing date of a patent application may be relevant to determining whether a patent is granted.

“In the rapidly advancing area of CRISPR-Cas, such co-pending applications are likely to have a significant limiting effect on the scope of patents granted,” Legg adds.

Commercialisation of a wide range of the technology’s applications may depend on licensing agreements between the main players of the CRISPR field.

Noonan suggests that different right owners might come together and offer licences to third parties, although adds this tends to happen more in telecommunications than in biotech.

Legg continues: “Patent transactions—licences, for example—offer the patent owner great flexibility to control the use of an invention to its benefit and also provide opportunities for third parties to obtain rights limited to their specific requirements.”

He explains that licences may be exclusive or non-exclusive, for certain territories but not others, or for specified purposes, for example, limited by therapeutic indication.

However, he adds, this aspect of patent strategy is “fraught with complexity”, particularly in agreements where the patent at issue has more than one owner.

In the US, a licence may be granted with the consent of just one co-owner of the patent, whereas in Europe consent of all co-owners is required, he explains.

“Therefore, a licence granted by only one co-owner without the consent of other co-owners would not be valid in Europe,” he says.

“Furthermore, a company, believing that it is in possession of a licence, could inadvertently walk into an infringement action brought by a co-owner who has not provided consent.”

Challenging patents

“The complex prior art background for CRISPR-Cas technologies is likely to provide considerable scope for third parties to challenge granted patents,” Legg says.

If Doudna and Charpentier’s patent application is rejected, they may mount an interference proceeding at the US Patent and Trademark Office against Zhang’s first-issued CRISPR patent, US number 8,697,359.

The Broad Institute paid for Zhang’s patent to receive a ‘fast-track’ examination, so it would be issued more quickly. But could this move make his patent more vulnerable to attack? Noonan doesn’t think so.

“The so-called ‘fast-track’ pathway is just a procedure for an applicant to get prioritised examination, which requires prompt responses from the applicant and a willingness to ‘take what the examiner is willing to give you’,” he says.

However, Richard Williams, a partner at HGF in London, says that in Europe at least, getting patents granted more quickly opens patent filers up to “central attack in opposition before the European Patent Office.”

Legg recommends that companies developing CRISPR-Cas technologies adopt a patent strategy that involves a combination of obtaining and defending their own patent rights, while licensing certain rights and challenging others.

“It is important that all these aspects are properly considered in formulating a patent strategy,” he says.

Bigger fish to fry?

Towards the end of March, before the first CRISPR patent had even celebrated its first birthday, a group of scientists, including Doudna herself, published a pair of commentaries in the journals Nature and Science, recommending how the technology can be used safely and ethically.

The authors, concerned that advances in gene-editing technology have now made it easier to make modifications to the human germline, call for a discussion about gene-editing as the phenomenon of genetically engineered human beings becomes a real possibility.

“Genome-editing technologies have made it easy for anyone with basic molecular biology training to insert, remove, and edit genes in cells, including sperm, eggs, and embryos, potentially curing genetic diseases or adding desirable traits,” an introduction to the article in Science says.

“Rumours are rife that scientists in China have already used CRISPR on human embryos. Researchers fear that publicity surrounding such experiments could trigger a public backlash that would block legitimate uses of the technology,” it added.

It’s difficult to predict what is in store for the CRISPR patenting landscape. “Some technical areas just flare up into litigation,” says Williams. “For example, there were the ‘gene chip wars’ involving Affmetrix and OGT some time back now.”

However, other areas don’t result in litigation, he adds. “About ten years ago there was a four-way race before the patent offices for patent rights protecting essential components of the human papilloma virus vaccine.”

Williams concludes: “For Cas9, yes, if the commercial pressure on the players doesn’t favour deal making, and there is sufficient return on investment at stake, and if well-funded parties are involved or employ proxies, then the chances of litigation happening are increased.”

With new CRISPR licensing agreements happening on an ever more frequent basis, and researchers continuing to develop this potentially revolutionary technology, it’s almost certain that the players are going to have a fight on their hands.