CRISPR-Cas9: A Patent Contest

What is CRISPR-Cas9?

By weight, there are over 27 times more bacteria than all animals combined. The most numerous organisms on earth are by far the viruses that utilize these bacteria as hosts, called bacteriophages. As one researcher colourfully put it: there are “approximately a trillion phages for every grain of sand in the world”. These bacteriophages and their hosts have likely been engaged in an evolutionary arms race for 3 billion years. Both archaea and bacteria, which are prokaryotes, use a form of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and various CRISPR Associated Proteins (Cas) to defend against viral threats. The CRISPR-Cas9 system was derived from the study of prokaryotic defense mechanisms to phage viruses. The system allows bacteria and archaea to edit foreign DNA that might otherwise hijack their biology to replicate.

CRISPR’s History

The existence of naturally occurring CRISPR sequences was discovered back in 1987. Their function was first postulated in Spain in 1995. In the mid 2000s, this function was confirmed, and we began to study its mechanism of action. The first patent for CRISPR technology was granted in 2005 for “Use of a Cas Gene in Combination with CRISPR Repeats for Modulating Resistance in a Cell.” Around this time, Danisco, a bioproducts company, began to study using CRISPR. While CRISPR’s mechanism of action was not fully understood, Danisco introduced phage viruses into dairy cultures in laboratory experiments. The survivors of phage infection acquired immunity to future attack. This process led to an understanding of the CRISPR-Cas system’s mechanism of action, greatly improving yogurt production, and saving Danisco millions of dollars. The process was adopted across the industry within a few years. In 2008, the RNA sequence that enables the Cas to attack DNA was first described. By 2011, the only missing piece was an understanding of exactly how CRISPR-Cas targets and cuts target DNA at the right place.

Jennifer Doudna of UC Berkeley (Berkeley) and Emmanuelle Charpentier of Umea University in Sweden discovered the “genetic scissors” that would provide the key to “rewriting the code of life,” eventually sharing a Nobel Prize in Chemistry for this work. In 2012, they published a paper demonstrating that an entire functional CRISPR-Cas complex could be created in a lab. This set off a race to demonstrate functional editing in plants and animals. In January 2013, five separate research teams from different organizations each published papers in 2013 to this effect. Of these five, the two considered by many to be the best approaches were published in Science by George Church of Harvard University and Feng Zhang of the Broad Institute, respectively.

The Patent Race

Doudna and Berkeley quickly filed a patent jointly with UVienna and Charpentier as an individual inventor in May 2012 for use “in any living cell”. Zhang and the Broad Institute filed a patent in December 2012 for use in “eukaryotic cells (i.e., animal, plant and fungal cells)”, simultaneous with their paper being approved by Science. This later application was more specific and resulted in a patent being issued in April 2014. When Berkeley challenged the Broad Institute’s patent, the US Patent Trial and Appeal Board (PTAB) in February 2017 stated there no conflict between the patents: the Broad Institute received the patent for use in animal and plant cells and Berkeley for all other (i.e., bacterial and archaeal) cells. However, in the UK, the European Patent Office (EPO) revoked the Broad Institute’s patent for lack of novelty, granting Berkeley patent rights. As a result, there are a number of global licensing ambiguities that exist depending on whether the Broad Institute’s patent is recognized. Despite the uncertainty, licensing of both of these patents are being sold across the world. License holders include Caribou Biosciences/Intellia Therapeutics (UC Berkeley), CRISPR Therapeutics, ERS Genomics, Casebia Therapeutics (Charpentier) and Editas Medicine (Broad Institute). New CRISPR patents proliferate. There are now over 11,000 patent families for CRISPR technologies, some of which challenge the original patents in various ways.

Patent Decisions and Litigation

The different rulings by the EPO and the US Federal Court of Appeal (in conjunction with the PTAB) seem to hinge on two different parts of the test for patentability. Pivotal to the US Court of Appeal ruling was non-obviousness. Similar to the Canadian obviousness four-part test and considerations (Apotex Inc. v. Sanofi-Synthelabo Canada Inc., 2008 3 SCR 61), the four Graham factors in the US examine: the scope and content of the prior art; the differences between the claims and the prior art; the level of ordinary skill in the art; and objective considerations of non-obviousness. The Broad Institute argued that applying CRISPR to eukaryotic cells was in fact an inventive step. They essentially claimed that an ordinary person skilled in the art would have not enough knowledge to know that Berkeley’s patent extended from prokaryotic to eukaryotic cells because the cells have differing properties and scientific research is not presumptively or successfully translated from one to the other. Thus, the average skilled artisan would not have a reasonable expectation that CRISPR-Cas9 system would successfully apply to eukaryotic cells, even if such a test may be ‘obvious to try’ as the Canadian jurisprudence phrases it. In its decision, PTAB found that a person skilled in the art would expect a CRISPR-Cas9 system used on eukaryotic cells to need “its own set of unique conditions” to work. Further, there was evidence from Doudna herself that getting CRISPR-Cas9 to work in eukaryotic cells would be “a profound discovery” and could not be produced through ordinary skill alone. Therefore, the US Court of Appeal, in agreement with the PTAB’s original finding, ruled that a separate patent targeting these cells specifically required a degree of invention.

Opposite this decision, the EPO accepted Berkeley’s argument that the Broad Institute’s patent was not novel, failing disclosure. This was in part due to priority filing issues that arise because patent treatises do not automatically extend protection from one country to another (Casebook, 585). The Broad Institute was forced to revise authorship of their European patent, which changed their effective filing date. The Broad Institute argued that the EPO decision “does not involve the actual scientific merits of the patent application, but the interpretation of rules that dictate what happens when the names of inventors differ across international applications.” While this may be true, patent law regulates not only content but also process. In Europe, where first-to-file is strictly followed, the Broad Institute’s technical errors resulted in a failed priority status and their documents deemed as relevant prior art. In both Canada and the UK, prior disclosure invalidates novelty if it permits a skilled artisan to read, understand and apply the patent claims (Apotex Inc. v. Sanofi-Synthelabo Canada Inc., 2008 3 SCR 61). The disclosure, being publicly available from their US patent application, would necessarily do so and therefore, the EPO revoked the Broad Institute’s application. Berkeley could also argue that their revolutionary research provided sufficient motivation for the Broad Institute’s application to eukaryotic cells, which would justify their patent rights in Europe.

CRISPR-Cas9 in Canada

Ongoing litigation between Berkeley, the Broad Institute, and other patent holders, as well as the complexities of licensing between Europe and the US, has created what seems to be a standstill in Canada. A search of the Canadian Patent Database shows 5,460 pending applications for CRISPR applications, including several from both Berkeley and the Broad Institute. Most, if not all, of these applications, dating as far back as 2015, do not have a forecasted issue date associated with the application, likely indicating that the Canadian Intellectual Property Office (CIPO) is waiting to see how the subsequent disputes play out in international judicial decisions and commercial dealings. This legal uncertainty means that until the ownership of the CRISPR-Cas9 patent is established, interested companies cannot confidently license the technology for commercial use, which is the purpose of the patent framework. A patent is not “intended as an accolade or civic award for ingenuity. It is a method by which inventive solutions to practical problems are coaxed into the public domain by the promise of a limited monopoly for a limited time” (Apotex Inc v Wellcome Foundation Ltd., 2002 SCC 77). In waiting for a final US resolution to the patent dispute, the CIPO is preventing both commercial use and development, as well as the opportunity for Canadian legal development through litigation. Fortunately, basic research is permitted by both the patent regime and the prospective rights holders. There continues to be new innovations and developments built upon these foundational patents.

Joint Licensing Strategy – A Potential Outcome

With so many new CRISPR patents being added every year, a better solution than ongoing litigation could be a patent pool which provides a streamlined licensing system that simultaneously simplifies commercial applications and guarantees diverse rights holders incentives to continue innovating in the field. The Broad Institute has been advocating such a system for years, but is not willing to give Berkeley what they feel they are legally entitled to. So far, efforts toward this end have not been successful.

In the meantime, wherever you are, Berkeley’s foundational patent is required on top of whatever specific uses to CRISPR are being employed in a given product. Currently, the Broad patent is required to use CRISPR in higher life forms in the US, which includes what is considered to be the most lucrative applications. Perhaps the future of gene editing will look similar to the cell phone patent environment, with a thicket of lawsuits, many companies entering into cross-licensing deals and some applications requiring hundreds, or even thousands, of licenses.

CRISPR-Cas9: A Patent Contest

Communications Law

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