Regulation and licensing: the CRISPR conundrum continues

In January 2018, The Wall Street Journal issued a fascinating report into clinical trials in China. Since 2015, the report said, scientists have used the now well-known CRISPR technology on at least 86 cancer patients. China is believed to be the first country in the world to test CRISPR on humans. According to doctors quoted in the article, 15 patients had died during the trials, but those deaths were caused by the diseases they were suffering from.

Helped by lower regulatory hurdles than in the US and Europe, China is leading the way on trialling CRISPR on humans. Perhaps it will be the first nation to find a cure for cancer. While some may point to the promise of the potentially revolutionary CRISPR—which allows scientists to cut and repair DNA—others may fear that the use on humans of a nascent and little-understood gene-editing tool should be taken extremely carefully.

Eric Williams, partner at Barnes & Thornburg in Indianapolis, says regulators in the US have taken a more cautious approach than those in China to approving use of CRISPR technologies on humans. He notes that a team of scientists from Oregon Health & Science University needed two years to receive ethical approval for editing human embryos using CRISPR.

“Similarly, it took two years for scientists at the University of Pennsylvania to win Food and Drug Administration approval to test a therapy using CRISPR technologies on 18 cancer patients, with a start date of late 2018,” he says.

According to technology blog Engadget, the University of Pennsylvania study will collect up to 18 patients with multiple myeloma, melanoma and/or two types of sarcoma, and the scientists will use CRISPR to delete two particular genes in patients’ T cells.

“The first, PD-1, can be manipulated by cancer cells to impede the immune system, while the second is an alarm-sounding receptor that will be removed and replaced with one engineered to alert the body to specific tumours,” the blog reported.

In Europe, regulators are still assessing proposals for testing CRISPR systems on human patients, although certain ex vivo approvals have managed to proceed, says Williams. For example, in February 2016, British scientists gained regulatory approval to use CRISPR and related techniques to genetically modify human embryos, but only for research purposes, he adds.

Williams argues that the cautious position of regulatory bodies in the US and throughout Europe appears to be sensible given the uncertain ability of CRISPR to make inheritable changes in human beings.

“CRISPR techniques could create mutations and undesirable side-effects in human germline cells (the genome that can be passed on via transmission to future generations).

“These safety concerns should be minimised before widespread testing begins to take place on human subjects, especially given reports of the relative ineffectiveness of the CRISPR/Cas9 system to edit some human cells,” Williams adds.

There is the added difficulty of how to properly institute informed consent of patients regarding the possible risks and effects of CRISPR treatment that could be passed on to future generations of the patients, he says.

“These complications are indicative of the several facets of risk present in gene-editing that must be balanced with the possible life-changing benefits.”

Patent boom

Amid the challenges around ethics and regulation—a separate but related issue to patenting—innovation in the CRISPR area has taken off and there are more than 1,700 applications for patent families in this area. IPStudies, a Switzerland-based IP consultancy, says it analyses and classifies 100 new families every month. CRISPR isn’t just intended for use in human therapeutics—it is being applied in agriculture and industrial contexts too.

Williams says while patent laws rarely intersect with those concerning ethical considerations such as regulatory processes, it is imperative that innovators continue to file patent applications worldwide “or they will risk losing patent protection in countries that subsequently change tactics on the process to regulate gene-editing”.

The major players in the CRISPR patent field are the Broad Institute of MIT and Harvard and the University of California (UC), Berkeley, which are locked in high-profile patent disputes in the US and Europe. These legal battles have revealed a burning desire to dominate what may be the leading gene-editing tool for years to come.

Kevin O’Connor, partner at Neal, Gerber & Eisenberg in Chicago, says several other entities have patents and patent applications that may be directed to fundamental aspects of CRISPR technology, including Vilnius University, ToolGen, MilliporeSigma, and Cellectis.

“The gene-editing technology in these early patents and patent applications is not necessarily specific to any gene or disease, but instead could potentially be used to edit any gene associated with any disease. Other, later-filed patent applications are often narrower and focused on particular modes of delivery and/or applying CRISPR technology to edit particular genes or treat particular diseases,” he explains.

Williams says innovation in the CRISPR field shows no sign of slowing down but it’s important for regulators to follow correct protocol given that the safety of the population and the planet is paramount.

“It is understandable if regulatory bodies prefer to ‘get it right’ from the beginning instead of trying to retrofit the current and sometimes archaic laws regarding genetically-modified organisms to cover the transformative technologies that gene-editing represent,” he says.

Freedom to operate

Another issue that must be ‘right’, but in a legal rather than a regulatory context, is freedom to operate (FTO). In the crowded and complex CRISPR patent landscape, companies should be clear on what authorisation they need in order to use the technology for themselves.

But, as O’Connor notes, identifying which patents are relevant to an FTO and then obtaining any necessary licences is highly inefficient, especially as there are several patent owners in the field and many potential licensees too.

“A patent thicket creates further complexities when considering commercialisation of a human therapeutic based on CRISPR technology. In certain industries, such as agriculture or industrial biotechnology, non-exclusive licences may be sufficient for companies to access the collection of patents needed to commercialise an application of CRISPR technology.

“However, development of a human therapeutic is often dependent upon some measure of exclusivity and, therefore, non-exclusive licences may not adequately protect the licensee’s investment in developing and commercialising the technology,” he adds.

O’Connor explains that at least two approaches have been proposed to simultaneously address the desire for widespread access to foundational CRISPR patents and for patent exclusivity for CRISPR-based human therapeutics.

The first is non-exclusive licensing of foundational, “target-agnostic” patents, coupled with subsequent patents directed to gene-specific or disease-specific applications for exclusivity. The second is exclusive licensing of foundational, target-agnostic patents on a target-specific or disease-specific basis.

In a potentially major development in the non-exclusive licensing area, in March 2017, licensing company MPEG LA called on patent owners to “solve the CRISPR IP conundrum” by forming a patent pool. In a statement at the time, the company said the pool’s “single, non-exclusive, cost-effective, transparent licence will allow the market to focus on the creation of new products and therapies that accelerate and expand CRISPR’s deployment”.

O’Connor says that so far, only the Broad Institute has revealed that it has submitted patents for evaluation by MPEG LA, “but there may be others since there was no requirement to publicly announce such submissions”.

The Broad Institute and UC Berkeley have also both adopted exclusive licensing models in the CRISPR field.

However, O’Connor says, in the current licensing environment, it is unclear whether a company desiring to commercialise a human therapeutic based on CRISPR could obtain, or would even need, licences from each of the many entities holding fundamental patents.

“There still seems to be an opportunity for a collaborative solution, such as by cross-licensing or a patent pool, for gaining access to the entire collection of fundamental patents needed to commercialise a human therapeutic based on CRISPR technology.

“The challenge in achieving this collaborative solution lies with the effective parsing of patents to identify those target-agnostic patents that are essential for development and ensuring that commercialisation of human therapeutics is adequately incentivised by providing commercialising licensees with patent exclusivity,” he adds.

Pools: the pros and cons

The main potential benefits of the pool would be to improve efficiency and reduce transaction costs by aggregating the necessary patents under a single licence or suite of licences, while the pool administrator could serve as the impartial party tasked with identifying the truly essential patents, O’Connor says.

One drawback for patent owners is having a third party assess the scope of their patents, says O’Connor, and “it’s possible that a patent owner may not agree with the pool administrator’s decision regarding the essentiality (or otherwise) of its patents”.

Another danger of pools is they can fall foul of competition law. In a 2014 report by the World Intellectual Property Organization, called “Patent Pools And Antitrust: A Comparative Analysis”, the authors said that while pools can encourage competition and innovation, they can also provide an opportunity for anti-competitive behaviour.

“They involve an inherent risk of collusive behavior,” the report said, and “may be regarded as a cartel”. It explained that there may be competition-related concerns regarding the licensing practices and restrictions they entail, adding that so-called patent thickets can lead to increased transaction costs and to “chilling effects on the development of new products”.

O’Connor says that in the CRISPR area, identification of the essential patents—and keeping non-essential patents out of the pool—is critical if the pool is to survive competition scrutiny.

In an article published on the LSIPR website in May, European academics Timo Minssen, Esther van Zimmeren and Jakob Wested wrote that in addition to the issue of competition law, UC Berkeley must also join the MPEG LA pool in order for it to be commercially successful. However, as the writers reminded us, “these two key players [Broad Institute and UC Berkeley] have been involved in patent litigation and might not be so eager to step into a joint licensing scheme”.

If this prevents the pool from operating effectively, another solution to the CRISPR conundrum will need to be found.

CRISPR fact file

• 1,700-plus applications for patent families in CRISPR

• 100 new families classified every month (IPStudies)

• 2015: human CRISPR trials began in China

• 15 patients have died, but because of their underlying illnesses