On 15 February the USPTO announced its long-awaited decision regarding the CRISPR patent interference proceedings between the University of California Berkley (UCB) and the Broad Institute of MIT. The decision closes the door on an important chapter of the increasingly bitter dispute over who owns the fundamental IP protecting CRISPR technologies. In short, despite filing after UCB, the Broad's US patents have been held not to interfere with UCB's patent application, mainly because the judiciary panel believed that the implementation of the CRISPR system into eukaryotic cells did involve an inventive step. It is generally accepted that the outcome will not prevent the UCB from securing patent protection themselves, and thus the decision does not really address the central issue of who ultimately controls the right to exploit the technology in the US.
Nevertheless, the buzz surrounding the outcome marks the decision as another important landmark in the CRISPR story. What follows is an explanation of why CRISPR is considered to be such a revolutionary innovation and how the two sides will continue to push for global protection regardless of the USPTO's decision.
What is CRISPR?
In its native guise, the CRISPR/Cas system provides inheritable bacterial immunity to protect microbes against invading pathogens. It works by first recognising then cutting and pasting short segments of foreign DNA into a particular locus of its own genome. The corresponding RNA transcribed and processed from these short DNAs, known as CRISPRs, combine with the Cas protein to constantly survey the host for the DNA of the foreign pathogen. Once encountered, Cas compromises the invading species by cleaving the foreign DNA at the sequence complementary to the RNA, thus sparing the microbe from a potentially devastating infection.
CRISPR was first reported in the scientific literature in the late 1980s, and for the next two decades research in the area was confined to a relatively small but dedicated community of scientists. That all changed in August 2012, when a group from University of California Berkley (UCB) reported the revolutionary finding that CRISPR/Cas9 could be engineered to cleave targeted genetic sequences (Jinek et al, Science).
Of course, genetic engineering is not a novel idea, but gene editing techniques that pre-date CRISPR are cumbersome, and typically rely on the engineering of protein interfaces for the specific recognition and cleavage of target DNA sites. Such projects can take months, even years, and considerable expense to achieve, and there is no guarantee of success.
The beauty of CRISPR/Cas lies in its simple approach to gene editing: recognition and cleavage of the target DNA using a complimentary strand of RNA. Thus, a simple, relatively inexpensive molecule can be rapidly synthesized to target and cleave DNA sequences with high specificity. Moreover, CRISPR can be used to edit multiple genes simultaneously and can be modified for use in a variety of organisms. Unsurprisingly, therefore, the range of applications that can benefit from CRISPR/Cas is limited only by the imagination. Despite its relative infancy, CRISPR/Cas has already rapidly advanced research areas as diverse as human therapeutics, disease modelling, and agricultural science.
Opposing strategies for global protection
The excitement and potential of CRISPR is reflected in the world of IP. As of September 2016, more than 860 patent families relating to CRISPR technologies had been filed. The explosion of CRISPR-related filings illustrates why owning the foundational rights to CRISPR is such a lucrative commodity.
First and foremost, it is unclear what impact, if any, the USPTO's decision will have outside the US, particularly in jurisdictions such as Europe, which operates the first to file rule. Setting aside the decision for a moment, it is interesting to observe the different strategies each side has taken for protecting CRISPR in Europe and the UK.
Firstly, the European arm of the Broad portfolio (Figure 1) highlights a particularly aggressive strategy for securing patent protection. This has so far involved the filing of multiple applications and frequently requested expedited review. It is interesting to speculate as to the motive behind this approach. Perhaps the decision was influenced by Broad having to play catch-up by virtue of their later filing date. Nevertheless, the strategy could be considered a success, having resulted in nine granted EP patents and at least eight pending applications sharing up to 12 priority dates, the earliest of which is 12 December 2012.
Figure 1 The EP Broad portfolio of applications sharing the 12 December 2012 priority date. Blue lines indicate the priority year of individual PCTs, black represents the international phase and red the entry into the regional phase. Green indicates the granted EP patents, with numbers identifying the individual applications.
By contrast, UCB has a single application under examination at the EPO with an earliest priority date of 25 May 2012. The UCB team has also managed to acquire a granted ex-PCT GB patent covering CRISPR/Cas, as well as three branch-off German utility models (Figure 2). Strategically, the GB patent could become particularly important for safe-guarding protection in the UK in the event of the EP application failing to grant.
Figure 2 The UCB portfolio. This illustrates the contrasting approach UCB has taken to securing protection.
Looking more closely at the prosecution of the UCB EP application, it will come as no surprise that multiple third parties have filed observations attacking the patentability of the application. Although the observations are extensive, the main issue focusses on the entitlement of the UCB application to the earliest priority date of May 2012 (Figure 3 – P1). At least initially, several parties successfully argued that P1 did not provide an enabling disclosure by failing to explicitly disclose an essential feature of the CRISPR system. As a consequence, the earliest priority date shifted to October 2012, which although is still before the earliest priority date of the Broad patents, is after the publication of the Jinek paper, thus making UCB's own publication a novelty destroying disclosure (Figure 3a). Nevertheless, the most recent examination report issued by the EPO suggests that UCB has managed to successfully restore their original priority claim, raising hopes that the application will soon proceed to grant.
Figure 3 The UCB priority issue.
What next?
So, what with the recent outcome of the US interference proceedings and the impending grant of the UCB EP application, the dispute surrounding the ownership of CRISPR IP is gaining traction. However there still remains a long road ahead to establishing with any certainty who, if either, of the Broad or UCB, exclusively owns the foundational rights to CRISPR IP in any jurisdiction. One thing that is for sure is that the continuing investment and excitement surrounding CRISPR/Cas means there will be many observers keeping a keen eye on how the proceedings pan out, particularly prospective licensees, who must be looking forward to navigating the complex CRISPR licensing landscape to ensure they can properly work their inventions.
Reference
Jinek et al. (2012) Science, 337, 816.
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