Patent Battle Casts Cloud Over Ownership of Gene-Editing Tool

September 8, 2015Articles New Jersey Law Journal

Who will win the CRISPR fight?

A patent battle between the University of California and the Massachusetts Institute of Technology (MIT) has cast a cloud over the ownership of the CRISPR gene-editing technology potentially worth billions of dollars. Bio-pharma companies, investors and researchers should use caution when navigating the complex intellectual property landscape.

CRISPR, an acronym for "clustered regularly interspaced short palindromic repeats" relies on an enzyme called Cas9 that uses a guide RNA molecule to home in on its target DNA, then it edits the DNA to disrupt genes or insert desired sequences. Just like PCR was in the 1980s, CRISPR is a game changer in molecular biology. It is faster, cheaper and easier to use than any other gene-editing technology.

Scientists in the 1980s noticed that bacteria had small blocks of palindromic DNA repeats with nonrepeat spacers of DNA interspersed between them. This pattern is an immune system known by the acronym CRISPR. The spacers match pieces of DNA from viruses that bacteria had been infected with before. When necessary, the DNA contained in the spacer is converted to RNA. The Cas9 and a second piece of RNA bind, forming a complex that will bind to strands of DNA that match the spacer's sequence.

When a matching strand of DNA is found, the Cas9 protein opens the double helix and cuts both sides, breaking the strand and disabling the viral DNA. If a bacterium survives an attack by an unfamiliar virus, it will make and store a new spacer, which can be inherited by future generations.

Scientists realized that this CRISPR cellular defense system might be used to edit genomes, not just kill viruses. A specific sequence of guide RNA could be made to attach to a spot anywhere on the genome, and the Cas9 protein would cleave the DNA at that spot. Then pieces of the DNA could be deleted or added, just as a film editor might cut a film and splice in new frames.

Researchers are learning how to use synthetic RNA sequences to control the cutting of any piece of DNA they choose. The cell will repair the cut, but an imperfect repair may disable the gene. Or a snippet of different DNA can be inserted to fill the gap, effectively editing the DNA sequence.

Using the CRISPR technology, researchers have already reversed mutations that cause blindness, stopped cancer cells from multiplying and made cells impervious to the HIV virus. Plant molecular biologists have rendered wheat invulnerable to killer fungi like powdery mildew, hinting at engineered staple crops that can feed the population of the world. Scientists have used CRISPR to alter the DNA of yeast so that it consumes plant matter and excretes ethanol, as a new energy source. Early stage life sciences companies focused on CRISPR have emerged.

The CRISPR gene-editing technology has created intense excitement in the community of bio-pharma and the venture capital industry. It is believed that this technology will transform our ability to edit the genomes of all living organisms, including humans. "CRISPR is absolutely huge. It's incredibly powerful and it has many applications, from agriculture to potential gene therapy in humans," said Craig Mello of the University of Massachusetts, who shared the 2006 Nobel Prize for medicine for discovery of RNA interference. See Andrew Pollack, Profiles in Science, The New York Times, May 11, 2015. Last year, bioengineer Daniel Anderson of MIT and his colleagues used CRISPR in mice to correct a mutation associated with a human metabolic disease called tyrosinaemia. It was the first use of CRISPR to fix a disease-causing mutation in an adult animal—and an important step toward using the technology for gene therapy in humans. The idea that CRISPR could accelerate the gene-therapy field is a major source of excitement in scientific and biotechnology circles.

Two of the most powerful universities in the U.S. are engaged in a war over the basic patent. While venture capital funds and biotech-pharmaceutical companies are pouring money into companies developing CRISPR technology (see, e.g., FierceBiotech, April 28, 2015), the University of California and MIT are entering into a fight for control of what could be hugely lucrative intellectual property rights to the technology. On April 15, the U.S. Patent and Trademark Office (USPTO) awarded the first CRISPR-related patent (US 8697359) to a group led by Dr. Feng Zhang at the Broad Institute of MIT and Harvard University. Since then a group of inventors led by Dr. Jennifer Doudna at the University of California, Berkeley, who also filed their own patent applications, have submitted thousands of pages of documents to the USPTO challenging the patent. If the USPTO accepts the U.C. Berkeley group's challenge, a so-called "interference" proceeding will be initiated to prove which group invented the claimed technology first.

Had either of the two groups filed their patent application after March 16, 2013, there would be no such fight, because after that date, the U.S. patent system changed to a "first-to-file" system. Before that date, however, the U.S. patent system was a "first-to-invent" system and, under that system, whoever invented a claimed technology first is entitled to the patent right. In this CRISPR fight, the U.C. Berkeley group actually filed their patent application about seven months earlier than the MIT group. Yet, the latter group secured a patent first as they took advantage of a so-called "fast track" practice, which allowed them to jump the queue at the USPTO. Despite the timing differences, both groups' applications are assessed under the old system and the "interference" proceeding can be used to decide who invented what first. The scientists have formed competing companies with rights to their patents and pending patents. Dr. Doudna co-founded Caribou Biosciences to work on research uses of Crispr-Cas9, and more recently, Intellia Therapeutics to work on disease treatments. Dr. George Church and Dr. Zhang are co-founders of Editas Medicine, which Dr. Doudna also helped start but then withdrew from.

Going forward, this legal battle could take several years to settle and either party may end up with significantly limited patent protection, or even walk away empty-handed. Meanwhile, more and more patent applications have been filed in the field. As of August 6, there are about 963 published PCT international patent applications (including some filed by Fox Rothschild for its clients) that are related to CRISPR. As more funds are pouring in, companies, investors and researchers should use caution in their licensing, investing, collaboration and R&D activities in connection with the technology and related intellectual property landscape.

This patent battle of the CRISPR technology is not the only famous one in the patent history of molecular biology. As a matter of fact, it is like déjà vu for people who are familiar with another famous patent battle, which involved another seminal technology and several industry giants.

KaryMullis received a Nobel Prize in chemistry in 1993 for his invention of the polymerase chain reaction(PCR),while he was a scientist at Cetus in 1983. Following the discovery of PCR, there were a few patent lawsuits. In 1986, Kodak entered into an agreement with Cetus to develop in-vitroPCR diagnostics. In 1989, Dupont unsuccessfully sued Cetus, claiming that the PCR patents were not novel. Cetus licensed the rights to diagnostic uses of PCR to Hoffmann-La Roche in 1991. Kodak sued Cetus in 1991 seeking an injunction to stop the transfer of the PCR rights from Cetus to Roche. The court denied Kodak's motion for an injunction. Although Roche has successfully asserted the PCR patents against other entities, over the years Roche formed a subsidiary to handle the manufacturing of reagents and licensing of PCR rights to other companies. Over time, PCR has generated a few billion dollars in licensing revenue. Yet, in spite of the robust PCR patent estate and licensing program, there has been widespread patent infringement by research scientists. This is because there is a reluctance on the part of large multinational corporations to sue researchers for patent infringement. The PCR story provides a good lesson for CRISPR: Solve the patent issues, ethically treat human diseases and cure world hunger as we enter this brave new world.

Reprinted with permission from the September 8, 2015, edition of the New Jersey Law Journal © 2015 ALM Media Properties, LLC. All rights reserved. Further duplication without permission is prohibited. For information, contact 877.257.3382 -[email protected] or visit www.almreprints.com