Panel Advances Key Public Interest Issues In Gene Editing Technology

WASHINGTON, DC — The still-emerging breakthrough CRISPR gene editing tool has the potential to transform the field and do enormous good for humankind. But let’s make sure we understand it better and ensure the public interest before launching into using it too widely. Meanwhile, companies and researchers are actively licensing the technology. That was a message of a set of panellists working close to CRISPR’s development, speaking at a recent event in Washington, DC. 

The 15 September workshop was entitled, “Patents, the Public Interest and Two New Medical Technologies: Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), Chimeric Antigen Receptors Technologies (CAR T).” The event, organised by Knowledge Ecology International (KEI), was held in the Kaiser Permanente Center for Total Health, adjacent to Capitol Hill.

The archived webcast of the event is available here. The webcast included panels on CAR T, and looking at ways ahead. This article will focus on the CRISPR panel.

KEI recently wrote to the US Department of Health and Human Services (HHS) asking them to adopt a policy on the licensing of federally-funded CRISPR patented inventions.

Speakers on the panel included: Diana Singhroy, scientific and technical advisor at Knowledge Ecology International; Prof. Jacob Sherkow, associate professor of law at the Innovation Center for Law and Technology at New York Law School; Prof. Jorge Contreras, professor at the College of Law at the University of Utah; Issi Rozen, chief business officer at the Broad Institute of Harvard University and the Massachusetts Institute of Technology (MIT); and Kristin Neuman, executive director of biotechnology licensing at MPEG LA. The panel was moderated by William New, Director and Editor-in-Chief of Intellectual Property Watch.

“What CRISPR can do is, it is kind of like a molecular scissors,” Singhroy said in introducing the technology, which was discovered as part of the immune system of bacteria. “It can cut and paste text in the manual that is your genome.”

CRISPR is a game-changer, particularly because it takes the process of editing genes from years of breeding to get mice with the right genes down to weeks. “As a scientist, it blows your mind,” Singhroy said. And for silencing certain characteristics, it can bring the process down from months to days, she said, adding that research would be greatly sped up if you can start to get results “by the end of the week.” It is precise and versatile, and can be used across any species, she said, and infrastructure is still needed but it is cheaper.

“We don’t have Jurassic Park yet,” nor “designer babies,” she remarked, and are “not going to have Gattaca tomorrow” (referring to the 1997 sci-fi movie on the theme).

That’s because “we have the book, but don’t really know how to read all the pages,” Singhroy said, though this is being worked on as CRISPR gets refined. An example of its use might be to correct germline cells so that a hereditary disease does not get passed down. Another application of CRISPR is eliminating malaria in mosquitoes. Rather than removing a food source for birds and others by killing the mosquitoes, it would eventually make the population resistant because the offspring of even one resistant insect will have the resistance, she said. And work is being done on HIV to be able to cut it out and silence it, she said.

The possible benefits and dangers of gene editing continue to be widely debated, but one element came clear from the panel: if everyone cannot access the resulting benefits it will be problematic for all. Lack of access for some would dampen the progress of research, said Singhroy.

Sherkow guided the audience through the history of the development of CRISPR and the patent litigation that followed. It began with Watson and Crick’s discovery of DNA in 1953 and was punctuated in 2012 by the publication of an article by Jennifer Doudna and Emmanuelle Charpentier containing the “holy grail” of how to edit genes. He said that a researcher at the Broad Institute at Harvard, Feng Zhang, then came up with other advances, and that all of them were preceded by Prof. Virginijus Siksnys from the Vilnius University Institute of Biotechnology in Vilnius, Lithuania, who received a patent in May.

For the patent landscape, all of the researchers filed patents on CRISPR technologies, and inevitably, a major patent fight broke out. Siksnys filed first, in March 2012, followed in May 2012 by Doudna. Zhang’s application came later.

So there are three groups controlling the foundational aspects of CRISPR technology. Sherkow looked at the ethical, social and legal aspects of that. He previously wrote about the US Patent Trial and Appeal Board (PTAB) ruling earlier this year in favour of the Broad Institute “in the most monumental biotech patent dispute in decades” as he called it: a patent “interference” trial over foundational patents covering CRISPR-Cas9.

The University of California, Berkeley and the Broad Institute of MIT and Harvard were “at war” over foundational patents covering CRISPR-Cas9, he said. “UC Berkeley filed a patent application covering the basic contours of CRISPR-Cas9, while the Broad Institute’s later patent applications – which matured into real, issued patents – described in further detail how to use the technology in the cells of higher organisms, i.e., ‘eukaryotic’ cells. At the request of Berkeley, this triggered an ‘interference’ proceeding at the PTO, a trial over, essentially, who invented what first,” Sherkow wrote. And the PTAB ruled that the Broad Institute’s patents do not interfere with Berkeley’s patent application, an application that is still languishing, he noted last week.

Exclusive and Non-Exclusive Licences

Some universities have taken substantial equity interest in the work of their researchers in this area, who have established companies. Another option is to passively receive royalties, he said.

Sherkow and Contreras have written about [pdf] the situation of the universities’ licensing, raising the possibility that it could lead to a bottleneck in the use of CRISPR technology to discover and develop useful human therapeutics. Contreras likened CRISPR to a microscope, a basic tool that every researcher needs and that should be made widely available and accessible.

They note that the National Institutes of Health issued guidelines in 1999, and that a number of major research universities in 2007 signed the “Nine Points” set of core licensing values, including that universities should make patented research tools as widely available as possible.

For CRISPR, the universities have set up surrogates. UC Berkeley has an exclusive licence with Caribou Biosciences, (Doudna), the Broad Institute has an exclusive licence with Editas, and Charpentier has licensed with CRISPR Therapeutics.

Rozen explained that public interest is a firm guide for the Broad Institute’s management of its CRISPR assets. A recent announcement explained it thus:

“The Broad Institute, MIT, Harvard, and Rockefeller [University] hold 22 key CRISPR-Cas9 patents in the United States and Europe. The institutions already make CRISPR tools freely available to the academic and nonprofit communities and issue non-exclusive licenses for most types of commercial research, including agriculture. For human therapeutics, the Broad Institute places limits on exclusivity through its Inclusive Innovation model, which offers one licensee exclusive use for a defined period (two years), followed by an open call for applications by other groups. In the case of CRISPR-Cas9, the two-year exclusive period has already ended. Parties interested in licensing the technology are invited to apply through the Broad website.”

Rozen said the licensing schemes of the Broad Institute and UC Berkeley are “vastly different.” He noted that administrative issues such as the intellectual property ownership among researchers from different places have already been worked out in the partnership. The number one principle of the institute’s efforts is to maximise health impact, not profit. Everything is put in the public domain, there are no trade secrets, he said. And any non-profit or university can use Broad technology without a licence, no strings attached. The complexity arise with industry, he said. It plays a key role in the process. Industry works with their scientists and at some point take a licence.

Even with commercial licensing, their most important criterion is public benefit. But there are cases where a non-exclusive licence is a death sentence, Rozen said, for instance in getting the private sector to invest the hundreds of millions of dollars in clinical trials. It is hard to imagine a company that would invest the $800 million minimum to develop a new drug without every immediately being able to take it and make it for a fraction of the price. Shareholders would be very unhappy.

He clarified that the licensing of Broad and UC Berkeley are different, because the latter licences in all fields exclusively to Caribou, which is a surrogate. “We have not done that,” Rozen said. Instead, they parsed out the licensing of CRISPR. “We do believe licensing tools should be non-exclusive,” he said. “As a research tool, it should be available to the world.”

To date, they have done over 60 non-exclusive licences, he said. Many companies are coming directly to Broad to get licences, not going through Editas.

But with human therapeutics, “this is where we struggled significantly,” he said. They decided to go with an exclusivity to drive investment, but they limited it through an approach they called an “inclusive innovation” model. Under this model, Broad exclusively licensed to Editas to “targets of its choosing for the development of genomic medicines.” But after two years, other companies can apply to licence CRISPR for uses Editas is not interested in.

So if Broad gets approached by a company it does not have to share it with Editas but it has to ask Editas if it is already working on this gene target. If Editas says yes, he says “the world is served because Editas is developing it.”

If Editas is not working on the gene of interest – “and chooses not to fund and launch a new program of its own within the period, the IP is available for licensing by Broad, Harvard and MIT to the third party,” Rozen said in his presentation.

Some have raised concern that Editas may say it is working on a gene and let it languish, denying the world new research in that area. But Rozen says the two-year safety valve addresses that.

CRISPR Patent Pool

Meanwhile, a group with a strong background in setting up patent pools has launched a pool for CRISPR that could help get around potential blockages to innovation.

MPEG LA issued a call for CRISPR Cas9 patent holders to “solve the CRISPR IP conundrum.”

“MPEG LA’s CRISPR Cas-9 Joint Licensing Platform will give technology owners the opportunity to share in mass-market royalties from their CRISPR technology while enjoying, with other developers, broad access to other important CRISPR technologies,” it said. “As a voluntary market-based business solution to the patent access problem tailored to balance, incentivize and resolve competing market and public interests, an independently managed patent pool is the best hope for unleashing CRISPR’s full potential for the benefit of humanity.”

The Broad Institute joined the MPEG LA patent pool in July. But so far UC Berkeley has not.

Patent thickets – too many patents getting in the way of innovation – are a potential problem, the experts said.

What’s to stop foreign companies creating patent thickets in their countries? “That’s the thing we’ve got to kind of worry about.” Sherkow said. “The situation in Europe is rapidly going to become complicated.”

International bodies that might play a role in harmonising approaches to CRISPR might include the European Patent Office, which addresses questions of who owns a patent, and the World Intellectual Property Organization, which is can encourage countries to harmonise their patent laws.

Neuman said the patent pool MPEG LA is proposing is a self-regulating, self-governing solution, and is not going to be reliant on a government institution. The power there is that private patent holders can come together and figure things out in a way that will benefit themselves and the world, she said.

Discussion and Debate

In the question and answer period, Contreras said the issues go beyond just intellectual property. As the technology comes to fruition and we start to see more therapies, institutions like World Health Organization will take interest and become involved, he said. The Organization for Economic Cooperation and Development (OECD) is another one, and it has a significant IP charter, he added.

Rozen said the “silver lining” is that the uncertainty over who owns what has not stopped anyone from using the technology. “When I talk to companies – and I talk to companies a lot – everybody’s using CRISPR.” That’s because it is too important to hold off, so they trust that it will get worked out. “I think that’s the right attitude. It has not stopped research, people have not gotten paralyzed, and are investing in it heavily.” The field is “moving at a rapid pace,” he added, and many new CRISPR technologies are being developed.

Contreras said there are “many, many” other enzymes being developed with CRISPR.

“Really, I think everybody who has spoken today is shooting for the same goal: the broad adoption of what could be a supremely valuable technology for human health,” he said. But the lawyers working on the cases are talented (he used to work with them), he added, and in Broad’s case, it might be difficult to use the “escape valve” it created.

For both the patent pool and whether Broad can authorise others to use the technology, in a practical way, the proof is “going to be in the pudding,” said Contreras. It will depend on what actors do. A company could come up with a new use for gene X and tell Broad it is going to licence with Editas but that may not be enough to control its use.

Rozen clarified that “it is not enough to tell us. They have to raise the funding, show us the funding, send regular reports with the commercial activities, and if they don’t, they lose it.” So there are mechanisms to prevent abuse.

Contreras replied that he would still ask whether the ability for an Editas to take an idea and run with it, is that going to chill others from investing the money in the idea in the first place.

Contreras also raised that patent pools in the life sciences have “been hard,” unlike pools for communications technologies or other tech areas. Can have holdouts, major companies can refuse to join. When will there be critical mass, he asked.

And he raised a question about crossing the research “valley of death” of getting funding to bring an idea to commercial fruition, where exclusivity is a key attraction for investment.

Neuman responded that human therapeutics might be difficult to address, but agriculture and biotechnology are examples of “low-hanging fruit” where such investment is not needed to bring a product to market. Wouldn’t be nice if any company who has the wherewithal to start a little company to start working on these problems, could get access to the basic patent rights they need, she asked.

She cited a famous case in which a core discovery related to RNA by researchers Cohen and Boyer led to patents that were made available for licensing on a non-exclusive basis and by many accounts (for instance here) literally led to the rise of the biotech corridor in Silicon Valley south of San Francisco that led to many global blockbuster products. The key was that the ground layer technologies were made available to anyone and only the more specific technologies they developed were held exclusively (and still earned them tremendous revenues).

This would be a better model than the approach of Broad to hold an exclusive licence, Neuman suggested. And she said there’s an argument to be made for CRISPR human therapy patents to be put in the pool as well as there will be plenty of patents to follow.

A question was also raised about why the editing mechanism is appropriate for exclusive rights over the broader product, such as why if I own the microscope (a basic tool) do I also own leukaemia. And a question was asked about the fact that much of the research was publicly funded so how is that reflected in the public access to affordable products.

Sherkow said on the public funding aspect what the public paid for was the academic research into this area. He mentioned a company called Addgene, which makes the DNA to allow CRISPR work, and uses material transfer agreements.

“I think the public is far and away getting bang for its buck on the research side,” he said. “The public is not paying for clinical trials to do this (as the government does not conduct those).

Contreras said there was a “normal” amount of public funding invested in the development of CRISPR and no one knew at the time it would be so important. He also noted that the National Institutes of Health, which typically has a roughly $30 billion budget to invest in R&D, has a duty to consider the commercial side of products as well.

On owning the microscope and therefore leukaemia, Sherkow said CRISPR is both the research tool and the platform. Neuman said CRISPR is “very unique,” and involves a system that can be used as both the microscope and a drug. And for the pool, they want to include the patents that are so broad they cover the microscope as well as the drug, to make those broadly available. She thinks they’re going to see companies getting patents that are like small molecule patents, specific, targeted and narrow but still very valuable.

What is Fair?

And finally the speakers were asked what is fair in CRISPR licensing. Sherkow said a law school answer is, “fair to whom?” but perhaps it would be whatever gets the most therapies out there so that people stop of dying of diseases when they don’t have to, and people who need it have some way to afford the treatments, and people taking all the risks have some way of getting paid.

Contreras said no one knows what is fair pricing, and it’s different in each industry and in each licensing contract. For him, the fair price is the one that maximises social utility, results in the most cures.

Rozen said, “What you want to do is to maximise public interest with the funding” from NIH. The Broad Institute has hundreds of patents and thinks carefully about them, but it knew CRISPR was “very special” and took over a year to come up with its strategy of a mix of exclusive and non-exclusive licensing and a safety valve. “Whether our solution is the best? We think so, that’s why we spent a year thinking about it,” he said. But they welcome experts making suggestions on how it can be even better next time. And Broad seeks to be in line with NIH guidelines, and NIH itself is on record saying therapeutics should be licensed exclusively, he said.

 

Image Credits: KEI