The next war of bio-patents has already begun and has to CRISPR protagonist – Hypertext

Jennifer Doudna / UC Berkeley

The system CRISPR-Cas9 , baptized by Jennifer Doudna as the “molecular scalpel” to edit the genome, it has completely revolutionized research. These tools allow you to modify the DNA more precisely and effectively. Their discovery was a milestone in biology, by their own -the discoverers Doudna and Emmanuelle Charpentier -. Were awarded the Princess of Asturias Award for Technical and Scientific Research last year

The importance of CRISPR is of such magnitude that the technique was even sound for the Nobel Prize. Although he failed, this genetic technology has already shown its effectiveness in curbing a rare disease in animal models. But these peculiar “molecular scissors” are not without controversy. CRISPR now live immersed in a real patent war , which overshadows its potential and, above all, delayed its hypothetical applications. This is the chronicle of a legal and scientific battle between the University of California and the Massachusetts Institute of Technology (MIT). A legal fight that is at stake estimated at over 46,000 billion market

The origin:. Gold mine biotechnology

The year was 1974. A group of US scientists led by Paul Berg , requested a moratorium to implement technology to revolutionize the world. The recombinant DNA technology , which subsequently led to the promotion of genetic engineering and biotechnology, presented important bioethical implications, the researchers said. The recombinant DNA technology led a considerable ethical and social debate, but also demonstrated the profitability of biotechnology

Three scientific articles published between October 1972 and November 1973 the controversy had exploded. First, David A. Jackson, Robert H. Symons and Paul Berg had succeeded in introducing new pieces of DNA into the genome of the SV40 virus. Later, Annie Chang Stanley Cohen and had gotten a piece of bacterial DNA recombinant Escherichia coli “autofotocopiara” itself. The latest work, Stanley Cohen, Annie Chang, Herbert Boyer and Robert Helling allowed to build bacterial plasmids in vitro . The result? The scientific community was able for the first time to “cut and paste” DNA, a possibility that anticipated the GM of living organisms.

Following the publication of these three items, the debate on the ethical and social implications shot. Were the scientists themselves, led by Paul Berg, who proposed the organization of Asilomar conference , a meeting in which the applications of recombinant DNA technology were analyzed. But there was an important underlying economic impact to that discussion.

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Patent on recombinant DNA technology, requested by Herbert Boyer (University of California) and Stanley Cohen (Stanford University), guaranteed the “exclusive exploitation” for twenty years of genetic modification tools. The patent was granted only in the United States, since the industrial property system of this country contemplates called grace period . Thus, US law gives inventors the option of having spread its invention twelve months prior to the patent application. In Europe, however, this possibility does not exist. Those who disclose their invention of preform-through scientific papers or conference papers, for example can not patent it. For this reason, recombinant DNA technology was patented in the USA and not in Europe. The royalties from the exploitation of the patent of California and Stanford totaled $ 255 million

With this patent on the tools to “cut and paste” DNA, the biotechnology industry began to grow exponentially. From the seventies to 1997, which expired protection, recombinant DNA technology graduated 468 companies. The Royalty who received the mentioned universities, according to some estimates, reached $ 255 million . Biotechnology showed well be a real gold mine, with an associated technique for genetic modification of 35,000 billion market. In countries like Spain, protection of inventions as virus phi29 polymerase, the CSIC reported revenues of 4 million euros, almost 50% of the Royalty obtained by the Superior Council for Scientific Research. Modify the genome not only was a real scientific, social and bioethics revolution. The exploitation of the patent US 4,237,224 on recombinant DNA technology also proved profitable.

The advent of genomics edition

Forty years after the birth of genetic engineering, Jennifer Doudna (University of California) and Emmanuelle Charpentier (Max Planck Institute) published in the journal Science a job in demonstrating the potential of the CRISPR-Cas9 system. But the discovery of the CRISPR repeat sequences actually corresponded to a Spanish researcher, Francis Mojica . The scientist discovered a new system of adaptive immunity in archaea, as published in the journal Molecular Microbiology in 1993. Two decades before the “bombing” of Doudna and Charpentier, today professor at the University of Alicante realized that those tools could be applied in biotechnology. Even as he admits to Hypertext , “was unclear serve to edit the genome, especially in the case of human cells.” The Spanish microbiologist Francis Mojica discovered CRISPR-Cas9 system in 1993

The Spanish discovered by microbiologist system was employed by Doudna and Charpentier to edit the genome of prokaryotic organisms, living beings more “simple” in the world. Less than a year later, the group Feng Zhang expanded the potential of CRISPR-Cas9. As published in the journal Science , the “molecular scalpel” was able to edit the genome in eukaryotes, ie agencies more “complex” that have their DNA “locked” in the nucleus of cells. The possibilities of genetic modification that opened, as happened with the technology of recombinant DNA, were endless. But also the bioethical debate generated hypothetical and profitability of the invention.

Emmanuelle Charpentier and Jennifer Doudna, one of the events organized by the Princess of Asturias Foundation on the occasion of the award. Credit: FPA

Jennifer Doudna explained in this interview in Hypertext your caution to the ethical implications that could have the new “molecular scalpel” genomic editing. Reasons not lacked. In April 2015, Chinese scientists at the Sun Yat-sen University in Guangzhou They genetically modified human embryos by CRISPR-Cas9 technology. As it happened with the recombinant DNA technology, the bioethical debate on genomics issue again revived. For this reason, Doudna and other researchers urged holding a conference in Washington last December, similar to what happened with the Asilomar conference in the seventies. In 2012, Jennifer Doudna and Emmanuelle Charpentier showed that CRISPR-Cas9 could be used to edit the genome

The ethical discussion generated recovering some of the Asilomar approaches: maintaining the precautionary principle and promote the development of technology described as “revolutionary”. A few weeks later, three independent studies published in Science demonstrated the usefulness of CRISPR-Cas9 to curb the Duchenne Muscular Dystrophy in mice. The group Feng Zhang and George M. Church, the Broad Institute of MIT, participated in two of these investigations. The same entity which, incidentally, remains open patent war with the University of California. And that is when the success of CRISPR-Cas9 seems closer than ever, economic interest also hit the technology. An interest that keeps immersed two of the largest in the world in a legal controversy that seems endless academic institutions. At least for now.

The patent war by CRISPR

On March 15, 2013, the University of California (Berkeley) and the University of Vienna conducted the application 13 / 842.859 patent for CRISPR-Cas9 method. The original document, which contained 152 claims covering the protection of “non-human cells,” presented as the priority date May 25, 2012. The data are particularly relevant to understanding the legal conflict unleashed with MIT. For in the latter case, the Broad Institute asked a second patent with application 14 / 054.414 on 15 October 2013. On the other hand, the priority date the document that consists Feng Zhang as inventor is 12 December 2012. In other words, the MIT patent application is after the University of California. Two patent applications commercially exploit this molecular “scalpel” has caused a war between two of the most prestigious academic institutions in the world

What happened then? The document presented by the team of Doudna and Charpentier was too complex technically and did not cover all possible claims of the CRISPR-Cas9 technology. Furthermore, the request was processed by the normal route of the United States Patent and Trademark Office (USPTO). These issues were used by the MIT team of lawyers who decided to seek the second patent-covering human cells and, therefore, potential clinical- applications using a faster procedure, technically known as Accelerated Examination Request .

“He’s played all or nothing,” admits the Dr. Lluís Montoliu , the National Center for Biotechnology. And this process only supports three claims to a single invention. The decision to take the USPTO could not be appealed by the MIT. But while Doudna Patent and Charpentier languished in legal bureaucracy, the card played by Zhang won the game: It was accepted on April 15, 2014 . The Broad Institute of MIT, once the patent was granted, began to issue licenses for the use of CRISPR-Cas9 system.

Feng Zhang in his laboratory at the Broad Institute of MIT. Source: MIT Tech TV

During 2014, the legal team of the University of California sought to amend the mistakes of the first application, a complex task as they were also involved various European institutions . On January 8, 2015, finally, the initial 152 claims were replaced by 9 claims , which covered the use of CRISPR-Cas9 as genomics editing tool also in eucariotas- cells. Throughout this period, a mysterious third party has tried to overthrow in court the patent application Doudna and Charpentier. A document would be modified afterwards in April 2015, to extend the patent claims. At that time, California’s lawyers decided to go for it: apply for a “interference procedure” , published here by Technology Review , in relation to the invention protected by Zhang . It seems that researchers themselves have fully entered a debate so far remained only among law firms

The war between the two parties was already a reality. The scientific community is still pending today that this conflict between industrial property rights is resolved. But in this debate several key questions arise. Was Zhang inventing entirely new? Does your application of state of the art broadcast by Doudna and Charpentier is not derived? “We must tread lightly in this debate, as if paralyzed months leading patent is for something,” says Montoliu to Hypertext . The latest controversy in this battle has emerged over an article in the journal Cell written by Eric Lander , then director of the Broad Institute of MIT. In it contributions “CRISPR heroes” are reviewed, including Mojica own. The researcher says Hypertext that is “very happy” because “is great to be recognized, and if it does someone like Lander”. The microbiologist at the University of Alicante prefer not to enter into the discussion between Berkeley and MIT, although he admits that whoever wins will finally have “a huge impact”.

However, some people accused of using Lander this review to “underestimate” the work of Doudna and Charpentier in this patent war between the two institutions. Scientific own, in fact, criticized the publication in PubMed with these comments. “We can not believe the article is immaculate Lander,” admits Dr. Lluís Montoliu, who stands out as positive recognition to Dr. Francis Mojica of the University of Alicante. Anyway, it seems that researchers themselves have fully entered a debate so far remained only among law firms . It could not be understood otherwise Lander both work in Cell as the angry reactions Doudna and Jennifer Charpentier Emanuelle. A discussion that even goes beyond academic authorship of inventions. Several companies founded by Zhang, Church, Doudna and Charpentier, such as Editas Medicine, Biosciences Caribou, or CRISPR Intellia Therapeutics Therapeutics, also fighting for exclusive marketing rights in such revolutionary technology as according to all analysis-billionaire. But what will happen from now?

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According Montoliu, the solution is to figure out what the operating entity will be awarded exclusively CRISPR-Cas9. Will the University of California to win the race? Or how the strategy will work against MIT, why they are presenting laboratory notebooks to show investigating the “molecular scalpel” while Doudna and Charpentier? The new war is the bio-patents were causing an “absolute delay” in applications CRISPR to reach agreement both entities, as with the University of Stanford and California in the case of recombinant DNA technology, so shared royalties equally ? The legal and scientific battle, far from being solved, is causing an “absolute delay” in implementing CRISPR-Cas9 , in the words of the researcher at the National Center for Biotechnology.

this impact academic level is “less” as Montoliu argues, it is possible to obtain reagents through established legal procedures the signature of the “material transfer agreement” (MTA, for its acronym in English). The big problem lies in the biotechnology industry because, according to sources consulted by this means, many companies refuse to license the rights to the Broad Institute while not clarify who owns the patent. “Some companies, directly, have chosen not to use the technology in their development CRISPR while the patent ownership is unclear. Which is a risk too,” confirmed. These words show the total war that hangs over the issue genomics and could have a very negative impact on their multiple and hypothetical applications that go beyond medicine. According to Mojica says Hypertext , the use of CRISPR-Cas9 also could allow us to create or microbial resistant virus to produce foods that are not affected by virus attacks factories plants. Its use also generate less social controversy, as in the words of Alicante microbiologist, “genomics issue leaves no traces”. The great future that you might expect to CRISPR, however, is overshadowed by a new war of bio-patents, as was the case with patents BRCA1 and BRCA2 . The solution to this conflict is not simple, but at stake is the scientific and innovative progress that promised the “molecular scalpel” CRISPR-Cas9.