Right now, behind the walls of the USPTO, there is a fiery interference battle occurring between two scientific teams over who created a groundbreaking, DNA altering technique first. In addition to the patent rights associated with core CRISPR technology, the victor stands to receive incredible gains. At stake is being named in history books as the inventor, a place in the National Inventors Hall of Fame and, perhaps, winning a Nobel Prize.
In one corner is a team of scientists from UC Berkeley headed by biologist Jennifer Doudna from the University of California, Berkeley and microbiologist Emmanuelle Charpentier from Umeå University in Sweden and the Max Planck Institute for Infection Biology in Berlin. In the other, a group led by synthetic biologist Feng Zhang of the Broad Institute of the Massachusetts Institute of Technology and Harvard in Cambridge, Massachusetts.
CRISPR (aka “CRISPR–Cas9”) stands for “clusters regularly interspaced palindromic repeats” and are found naturally in some bacteria. Bacteria use it as a “gene editing” technique to defend against invaders, such as a virus. By cutting out portions of the viral DNA while leaving some behind, the bacteria are able to later recognize and defend against the virus the next time it invades.
Scientists have been able to harness this method to cut out, replace, or add parts to a DNA sequence, making the technique the most versatile, precise and simplest form of genetic manipulation. Furthermore, it can be used in a wide range of organisms with numerous applications such as editing genes in human embryos, curing disease, discovering famine-proof and climate-proof food crops, making drugs or even bringing back the woolly mammoth!
The technique involves two molecules, Cas9 and guide RNA, that make the change in the DNA. Cas9 is an enzyme that acts as “molecular scissors” to cut the two strands of DNA at a specific location of the genome, allowing for other pieces of DNA to be introduced or taken out. The guide RNA, or gRNA, contains a particular sequence and will only attach to the portion of DNA with its complement base pair in that same particular sequence. (If we recall from high school biology, a base will only pair with its complement base forming the “rungs” of the DNA “ladder.”) The relationship between the two molecules is that the gRNA guides the Cas9 scissors to the specific spot on the DNA and cuts it. The cell containing the DNA determines that the DNA has been damaged and then aims to repair itself. During this reparation process, there are frequently base pairs “casualties” which make a permanent mutation in the genome. Mutations, even minor ones, in the DNA can lead to the gene not working properly or at all. These mutations are what the scientists seek to create and study when they use CRISPR. Additionally, DNA can repair itself using a template. If the scientist provides the template, the genome can be edited to create almost any sequence at almost any location they choose. These repair techniques can afford the researcher the ability to turn genes on and off as they please.
Before CRISPR, geneticists would use chemicals or radiation to create modifications, or mutations, but those methods are unpredictable and uncontrollable. More recently there was transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs). However, these methods are expensive, time consuming and not as reliable for editing genes. TALENS and ZFN locate target sequences using proteins which are expensive and difficult to produce. Since CRISPR uses RNA, it is easier to design and more cost effective.
A day before the first-to file rule took effect on March 15, 2013, Doudna and Charpentier of Berkeley filed their patent application while Zhang of Broad Institute filed in October 15, 2013. The Doudna/Berkeley application had a priority date of May 25, 2012. Nevertheless, Zhang/Broad filed the patent under an expedited review program where Broad had to respond faster to questions asked by the USPTO, called “accelerated examination”. Patent No. 8,697,359 was granted to Broad in April 2014. Claimed in the Broad patent is not CRISPR itself, since it is a naturally occurring process in bacteria, but rather a specific engineered method for editing genes of living mammalian cells which is different from the naturally occurring form. (CRISPR in its natural form is incompatible with mammalian cells). The patent claimed priority to a provisional application filed in December 2012, based on work begun at the Broad Institute and MIT in 2011.
A key difference between the Zhang/Broad and the Doudna/Berkeley patent applications is that the former claimed the technology was adapted for eukaryotic cell applications and the latter did not. Between 2014 and 2105, Doudna ultimately revised and cancelled previous claims to cover the broadest applications of CRISPR as a gene editing tool directed to “a desired cell type” as a way to encompass both prokaryotic and eukaryotic cells. Doudna/Berkeley also filed a Suggestion of Interference claiming that ten of Zhang/Broad’s patents with later priority dates interfered with their patent application.
Interestingly, this is not the first CRISPR patent issued by the USPTO. As of December 2015, there have been 23 patents, thirteen of which were granted to the Broad Institute, MIT and other affiliated groups from Dr. Zhang. Doudna has none.
What Is At Stake?
Patent protection grants the inventor the right to exclude others from making, using, selling, offering to sell, and importing the invention. Whoever wins the patent, either Broad or Berkeley, will have the exclusive rights and will be able to ask large licensing fees of other companies that wish to use the technology.
This bitter fight over a patent between universities is uncharacteristic because academic institutions typically reach an agreement to share the rights to the invention. However, universities and major research institutions are placing increasing importance on licensing revenue and in this case it means millions of dollars. And the winning University will have the power to decide how the technology is used, which could cause ethical concerns. Both University have indicated their commitment to public interest, namely licensing widely and cheaply to other nonprofit institutions.
If the USPTO decides that Broad does not own the core CRISPR technology, Zhang and his team may be stripped of the other CRISPR patents. This decision would cause major problems for the companies that have invested hundreds of millions of dollars in Broad (like Editas which filed a $100 million IPO) allowing companies that have licenses for the Berkeley technology to benefit.
It is unlikely, though, that the victor would sue other academics using the technology for basic research. Since they are not selling a product, infringement damages and royalties from the marketed product are improbable and not worth the time and money of a lawsuit.
Also at stake is being named in history books as the inventor and, perhaps, winning a Nobel Prize.
What Is Interference?
Although the AIA changed the patent system from “first to invent” to “first to file”, the issue before the USPTO’s Patent Trial and Appeals Board (PTAB) is who created CRISPR first? Since key patents were filed by both parties before the March 16, 2013 transition date, they are argued under the old “first to invent” system. If there is a dispute as to which party invented first, it is resolved through a procedure called an interference. Generally, the first party to conceive and reduce to practice without abandoning, suppressing or concealing the invention, wins the patent rights.
In this administrative proceeding before a panel of three administrative patent judges at the PTAB, both parties present documentary evidence of their invention date -like published articles, lab notebooks and affidavits- which is considered by the USPTO. The panel determines which applicant is entitled to the patent where both parties claimed the same invention. During the interference, applicants are referred to as either “senior” or “junior” parties, where the “senior” is the first to file and the “junior” is not. Being the “senior” party does not grant any legal protection but the “junior” party is responsible for proving that he or she is the first inventor.
On January 11, 2016 the USPTO declared Interference No. 106,048 with Zhang/Broad as the junior party and Doudna/Berkeley as senior party. The USPTO first had to establish one or more “counts” that indicates the interfering subject matter, which it did on March 18, 2016. Here, there was only one count:
“A method, in a eukaryotic cell, of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded thereon, the method comprising:
contacting, in a eukaryotic cell, a target DNA molecule having a target sequence with an engineered and/or non-naturally-occurring Type II Clustered Regularly lnterspaced Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) system comprising:
a) a DNA-targeting RNA comprising
i) a targeter-RNA or guide sequence that hybridizes with the target sequence, and
ii) an activator-RNA or tracr sequence that hybridizes with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment, and
b) a Cas9 protein,
wherein the DNA-targeting RNA forms a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule, whereby said target DNA molecule is cleaved or edited or transcription of at least one gene encoded by the target DNA molecule is modulated.”
Then, the interference follows a two stage process. In the first (motions phase), the PTAB sets a motions calendar for when the parties present initial briefs. The three-judge panel also considers motions that modify the count, claiming certain claims are outside the scope of the count, or asking for a finding that the claims are invalid. Both parties are limited in discovery to mostly documents containing priority dates, inventor depositions and cross-examinations. If the motions do not disqualify one or both parties, then the interference goes to the second stage.
In the second stage (priority phase), the PTAB determines which party invented first. The junior party with the burden of proof, shows its evidence of conception and reduction to practice in substantive briefs while the senior party may contest the evidence. The senior party would only present evidence that it had conceived earlier than its earliest filing date, if the junior party provides evidence of even earlier conception.
A full timeline of the interference may be referenced on the Broad Institute’s website.
The parties also have the option to settle the interference privately. The losing party would file a Concession of Priority and the winner typically grants a license to the loser.
We will have to wait for a final decision from the PTAB over the coming months (interferences are designed to conclude within two years). It can award the patent to one, or neither of the parties. If it is awarded to one of them, the losing party could, and with everything at stake most likely would, appeal to the U.S. Court of Appeals for the Federal Circuit. Something tells me this won’t be over for quite a while!