Biotech DNA

A futuristic gene-editing technology holds almost fantastical promise to turn biologists' wildest dreams into reality. The technology called CRISPR could one day be used to delete the HIV virus from patients' cells, create a limitless supply of organs for transplant and produce better crops. Already, it's being used in laboratories across the world.

This week, the fierce battle over who invented it officially kicked off, with hundreds of millions of dollars on the line.

A patent judge rang the opening bell Monday, pitching two heavyweight research institutions perched on opposite coasts against each other: the University of California Berkeley vs. the MIT- and Harvard-affiliated Broad Institute in Cambridge. The judge's declaration of "interference," a technical term meaning that a conflict exists between a patent application and another patent or application, draws CRISPR, one of the hottest discoveries in biology, into a drawn-out, arcane trial process that will determine who invented it. CRISPR's bedfellows in interference include the telephone, the integrated circuit and the lockstitch technology used in the Singer sewing machine.

"These types of actions typically arise only in the context of very successful, very valuable patents," said Adam Mossoff, a patent specialist at George Mason University School of Law. "This patent, in particular, is ... a significantly huge advance in gene-editing technology, and this type of technology is the core of what has made the biotech revolution."

Whether CRISPR will transform health as everyone hopes is currently uncertain, without even a single clinical trial started. But the tool is already so crucial to how science is done that it straddles an unusual cultural divide: named breakthrough of 2015 by Science magazine and also nominated for word of the year.

CRISPR, short for the tongue-tying "clustered regularly interspaced short palindromic repeats," is a clever hack of the way bacteria defend themselves against infections. In 2012, Jennifer Doudna and Emmanuelle Charpentier reported that they could reprogram this mechanism; instead of snipping invading viruses, they could use CRISPR to cut DNA very precisely, opening the doorway to genome editing. In 2013, Feng Zhang at the Broad Institute and George Church at Harvard Medical School led teams that showed it was possible to use the technology to edit the genomes of human and mouse cells. Although genome editing had been tried before, previous techniques tended to be far more painstaking and limited. CRISPR was versatile and simple to use; it allowed for easy and efficient genome editing -- and it worked in all kinds of cells.

"I think genetics is going to be the source of lot of big decisions that are made by stock analysts, politicians, and so forth, and it’s about time we got excited about genetics," said Church, who holds CRISPR patents that have not been challenged. "If there weren’t a race to sequence the human genome, the human genome would have gotten less attention. If CRISPR didn’t have a race for the technology, there would have been less attention."

At the center of the race are superstars of science and a dozen key patents that outline the use of CRISPR to edit DNA in cells. Feng Zhang, a scientist at the Broad Institute in Cambridge, was granted those patents in 2014 and 2015. This week, they were found to interfere with a patent application filed by Doudna, a scientist at Berkeley and Emmanuelle Charpentier, who now directs the Max Planck Institute for Infection Biology in Berlin.

The institutions on both sides of the dispute have made the technology freely available to academic researchers who are using it for basic research, which is precisely what has allowed for a laboratory technique first described in 2012 to become ubiquitous practically overnight. The Broad said it does not plan to change that access to the tool, and Doudna said she did not, either. Companies that plan to commercialize the technology, however, will need to license patents from whichever institution wins the battle.

At the end of 2015, three groups of scientists used CRISPR to treat mice with an errant gene that causes Duchenne muscular dystrophy, a fatal disease --- raising hopes for a therapy that could be tested in people one day. Laboratory experiments that were once tedious and time-consuming, such as figuring out which genes are important in disease, or creating animal versions of disease, are suddenly relatively trivial because CRISPR now allows scientists to introduce multiple genetic changes in one step.

"It speeds up the pace of everything we’ve been able to do in the past, to the point where experiments become routine to do that we couldn’t imagine attempting" before, Doudna said in an interview.

As evidence of that promise, a handful of companies set up by different camps in the patent war have already raised hundreds of millions from investors, based on the hope -- likely still years away -- of CRISPR drugs and treatments.

Business has been booming for CRISPR companies. Editas Medicine, a Cambridge-based company that previously raised $163 million, announced last week that it planned a $100 million initial public offering and hoped to begin clinical trials in 2017 for a rare genetic disease that causes blindness. CRISPR Therapeutics has raised $89 million and recently announced major partnerships with two drug companies, Bayer and Vertex Pharmaceuticals. Another company, Intellia, has raised $85 million and is working with Novartis. Caribou Biosciences has partnered with DuPont and raised $11 million last April.

If the patent contest ends with a winner-takes-all sweep, it will mean several things: a significant revenue stream for the victorious institution, and in the interim a bit more uncertainty for the many companies trying to push the technology forward into the clinic. The companies are not directly a party to the current patent dispute, but each has entered into different licensing agreements. Caribou, for example, licenses intellectual property from Berkeley and the University of Vienna; Intellia licenses its technology from Caribou. Editas has licensed the Broad's technology. CRISPR Therapeutics says on its website it has licensed its technology from Charpentier.

"It may chill investment in the competing companies," said Jacob Sherkow, a law professor at New York Law School who has been closely following the issue. If "you don't know what the patent situation is going to be, why plunk down $100 million... [if] you don't know who is going to be the last man standing?"

But people aren't just considering traditional drugs and therapies. Church is spinning a company out of his laboratory called eGenesis that will use CRISPR to make genetic changes that would humanize pig organs and make them safe for transplant -- potentially creating a large supply of organs for transplant.

In fact, due to the ease of deploying the technology to alter the human genome, scientists have widely called for restraint, too, before it is used to make genetic tweaks in people that are permanent and can be inherited by the next generation, such as by altering human embryos.

While the science rushes forward, the issue of who gets credit continues along its slow, legalistic path. The U.S. has moved to a system in which patents are awarded based on who files the application first. But because Doudna filed her patent before that change, this case is still subject to the older rules -- in which the patent goes to the first inventor.

"I really want to see this move towards clarity in the space," Doudna said. "Even though I don’t see the field held back by this, I think there will be benefits in having clarity in the foundational intellectual property in this field."

Zhang said in an e-mail that he hoped the issue would be resolved quickly, since he worries it will become a distraction from science. In his own laboratory, he said CRISPR is being used to do research on cancer, mental illness, Alzheimer's disease, muscular dystrophy, malaria, and rare genetic diseases.

"I would much rather be focusing on science and new research that will benefit human health," Zhang said in an email.

The Broad Institute released a statement explaining it expected the original patents to be upheld.

"Given that the underlying facts have not changed, we are confident the U.S. Patent and Trademark Office will reach the same conclusion it did initially when it awarded the patent and will continue to recognize the Broad and MIT roles in developing this transformative technology," Lee McGuire, a Broad spokesman, said in a statement.

Bob Sanders, a spokesman for the University of California Berkeley, said that its lawyers declined to comment on the case.