We answer some of the most commonly asked questions about the CRISPR-Cas9 intellectual property situation globally.
We answer some of the most commonly asked questions about the CRISPR-Cas9 intellectual property situation globally.
The USPTO has not yet examined who was first to invent CRISPR-Cas9 gene editing in eukaryotic cells. What we do know is that the Broad was the fourth team to file a patent application for use of CRISPR-Cas9 gene editing in eukaryotic cells:
We also know that in addition to the Broad, four other teams published articles describing experiments in eukaryotic cells in January 2013:
George Church’s lab at Harvard University reported experiments in eukaryotic cells at the same time and in the same issue of Science where the Broad’s paper appeared on January 3, 2013
Jennifer Doudna’s lab at University of California Berkeley followed up its initial discovery with a paper in eLife describing its use of CRISPR-Cas9 to edit genes in human cells on January 29, 2013
Jin-Soo Kim and his team at Seoul National University in South Korea published their report in Nature Biotechnology on January 29, 2013
The appearance of all these publications within weeks of each other reflects the importance of the Jinek 2012 paper — published nearly seven months earlier by the Doudna-Charpentier team — and the incredible ease of applying this technology in multiple contexts. Within seven months, each research team was able to plan experiments, order materials, complete and replicate multiple experiments, draft its manuscript, undergo peer-review, revise its manuscript and publish.
No, it was not difficult. No additional special instructions or inventions were needed beyond what was presented in the Jinek 2012 paper and known already by scientists in the field. Many different types of routine techniques were easily and quickly used by numerous groups to apply the CRISPR-Cas9 system to many different types of eukaryotic cells.
All of the techniques used to transfer the CRISPR-Cas9 system to eukaryotic cells had already been used and known for decades. The USPTO acknowledged this, stating: “We credit Drs. Greider’s and Carroll’s testimony regarding some of the strategies that were known in the art, including direct injection, codon optimization, and targeting of proteins and RNA to the cell nucleus. According to their testimony, these techniques were routine and known to be useful in achieving activity of prokaryotic proteins in eukaryotic cells.” (PTAB decision, page 35, lines 3-7.)
Within a year after the Jinek 2012 paper, at least ten different groups were able to plan experiments, order materials, complete and replicate multiple experiments, draft manuscripts, undergo peer-review, revise their manuscripts and publish. These groups used a variety of different common techniques – some injected the CRISPR-Cas9 complex directly into eukaryotic cells, some introduced the RNA guides directly and produced the Cas9 through expression vectors, and some produced both the RNA guides and the Cas9 through expression vectors. Some groups added extra features to increase targeting to the cell nucleus, but some did not. All achieved success, enabled by the information in the Jinek 2012 paper.
There are always hypothetical reasons why a scientific experiment might not work, but none of the successful teams reported that they needed to take special steps to account for potential obstacles.
It was apparent from the quick, simultaneous implementation that there were no substantial technical challenges or obstacles; the promise of the CRISPR-Cas9 system was immediately recognized and immediately applied by many groups at the same time.
Under U.S. patent law, an invention must be new, useful and nonobvious. As such, a scientist is not entitled to a patent simply because he or she performed an experiment that has not yet been done by someone else. A claimed invention must be a concept that is not an obvious variation or use of techniques or components already known to the public.
After publication of the Jinek 2012 paper, no inventive steps were needed to use the CRISPR-Cas9 system in eukaryotic cells. No additional special instructions were needed beyond what was presented in the Jinek 2012 paper. Many different types of routine techniques were easily and quickly used by numerous groups to apply the CRISPR-Cas9 system to many different types of eukaryotic cells. Thus, using the CRISPR-Cas9 system in eukaryotic cells was not a separately patentable invention when compared to the Doudna-Charpentier team’s work.
This rapid success of so many different groups using so many different well-known techniques illustrates how easy and obvious it was to apply the CRISPR-Cas9 system in eukaryotic cells.
Five research teams filed patent applications in the United States within a period of seven months for certain applications of CRISPR-Cas9 gene-editing technology in eukaryotic cells. Of these teams, the Broad was the fourth to file its patent application. Although it was the fourth filer, the Broad paid a fee to the USPTO for expedited review of its patent application, which allowed it to be the first to present arguments to the patent office; because of this, the Broad received the first patent granted on CRISPR-Cas9 gene editing.
The USPTO has in fact not determined who was first to invent the use of the CRISPR-Cas9 system in eukaryotic cells. There has been no USPTO decision that the Broad is the first inventor of CRISPR-Cas9. Although the Doudna-Charpentier team asked the USPTO Patent Trial and Appeal Board (PTAB) to declare an interference to decide who first invented CRISPR-Cas9 gene editing, the Broad asked the PTAB to terminate the interference without deciding the question of who invented first. The PTAB granted the Broad’s request.
Before March 16, 2013, the U.S. patent system operated on a “first to invent” basis, which awards patents to the first person to invent the invention. Effective March 16, 2013, the U.S. adopted a “first to file” system, which awards patents to the first person to file a patent application on an invention.
Under the “first to invent” system, an interference is a USPTO proceeding designed to determine who was first to invent an invention. A three-judge panel of administrative patent judges receives arguments and evidence regarding what is overlapping subject matter and the relative invention dates of the involved parties; the panel decides who was first to invent the overlapping subject matter. There are two stages to an interference: a motions phase and a priority phase.
The Doudna-Charpentier team requested an interference, which was granted in January 2016.
The Broad filed a request (a motion) with the PTAB asking it to terminate the interference without deciding the question of who invented first. The PTAB granted the Broad’s motion and terminated the interference after the motions phase. Thus, the priority phase did not occur, and the PTAB did not decide who was first to invent gene editing using CRISPR-Cas9.
In legal terms, the PTAB decided that “the parties’ claims do not interfere” because they are of different scope; the Doudna-Charpentier team’s claims are not restricted to any environment, while the Broad’s claims are all limited to use of CRISPR-Cas9 systems in a eukaryotic cell environment. Thus, the PTAB’s decision said that the PTAB would “terminate the proceeding without entering judgment against either party’s claims.”
No. The PTAB terminated the interference without deciding who was the first to invent. The Doudna-Charpentier team had requested that the PTAB proceed to review the parties’ laboratory notebooks and other evidence to determine which party actually invented first. The Broad, however, asked the PTAB to end the proceeding without reviewing any evidence or making a decision regarding dates of invention. Because the Doudna-Charpentier team’s patent application claims cover the CRISPR-Cas9 gene editing system and its use in any cellular or non-cellular setting, the Broad argued that using the system specifically in eukaryotic cells was sufficiently different so that the PTAB should not proceed with a determination of who was first to invent. The PTAB concluded that, even though the Doudna-Charpentier team’s claims were broader than the Broad’s, there was still enough of a difference that the interference should not proceed. Accordingly, the PTAB refused to use this particular set of claims from the Doudna-Charpentier team to determine which party was the first to invent the application of CRISPR/Cas9 to eukaryotic cells.
The Doudna-Charpentier team appealed to the Federal Circuit to reverse the February 2017 decision of the PTAB finding no interference in fact between issued patents of the Broad Institute on CRISPR-Cas9 genome editing in eukaryotes and a patent application filed earlier by the Doudna-Charpentier team for gene editing in all environments, both cellular and non-cellular. The arguments on appeal focus on the fact that the PTAB used incorrect standards in assessing whether CRISPR-Cas9 genome editing in eukaryotes was an obvious extension of its core invention and the Jinek 2012 paper describing it. Specifically, it argues that previous court decisions, including by the U.S. Supreme Court, establish that the correct standard is whether, given the teaching of the Doudna-Charpentier patent claims, the Jinek 2012 paper and standard laboratory techniques known and available to those skilled in the art, researchers would have had a “reasonable expectation of success” in achieving CRISPR-Cas9 genome editing in eukaryotes. Instead, the PTAB concluded that the existence and availability of conventional techniques for applying CRISPR-Cas9 gene-editing systems in eukaryotic cells did not “guarantee” success; and in doing so, discounted evidence that six different labs had quickly achieved eukaryotic editing using the information provided in the Jinek 2012 paper, including the Doudna-Charpentier team itself, in work conducted before the Broad Institute filed for its patent.
The PTAB’s decision terminated the interference without deciding who was first to invent. There are three possible outcomes from the Federal Circuit appeal: (1) the PTAB decision is upheld, (2) the PTAB decision is reversed, or (3) the Federal Circuit voids (vacates) the PTAB decision and instructs the PTAB to re-evaluate its decision using the proper legal framework.
If the PTAB decision is upheld, the interference remains terminated. A second interference to the use of CRISPR-Cas9 systems in eukaryotic cells could be initiated to determine who was first to invent the use of CRISPR-Cas9 systems in eukaryotic cells.
In addition, if the PTAB decision is upheld, it is likely that the USPTO will issue a patent to the Doudna-Charpentier team for the use of CRISPR-Cas9 gene editing in any environment, which would overlap with the Broad patents claiming use in eukaryotic cells. The USPTO has stated that the patent application involved in the interference, which has claims covering use of the single-guide RNA format of the CRISPR-Cas9 system in any environment, is allowable. In addition, the USPTO has allowed a separate Doudna-Charpentier patent application covering methods of using this CRISPR-Cas9 system in any cell type, which was suspended in view of the appeal and could then be granted.
If the PTAB decision is reversed, then the case will be returned to the PTAB to continue the interference. A number of pending motions filed by the parties will need to be decided, and then the priority phase will be entered where the parties will submit evidence regarding who invented first.
If the PTAB decision is vacated, then the case will be returned to the PTAB with instructions to re-evaluate its decision using the proper legal framework. Upon such re-evaluation, the PTAB can decide that use of CRISPR-Cas9 gene editing in eukaryotic cells is not separately patentable and the interference should continue, or it can come to the same conclusion as it did before (see (1) above for the outcomes in this instance).
The Doudna-Charpentier team has a number of allowable patent applications in the U.S., which the USPTO put on hold because of the Federal Circuit appeal of the interference decision by the PTAB, and an allowable patent application that has not been put on hold.
Although the Doudna-Charpentier team filed its patent application first, in May 2012 before the Jinek 2012 paper, it did not apply for expedited review of its patent applications. Under the first-to-invent system in effect prior to March 2013, when different research groups have overlapping patent claims, the USPTO typically does not issue a second patent on the same invention but rather requires the groups to go through an interference proceeding to determine who was really first to invent. After this proceeding finishes, the first person (group) to invent is entitled to receive the patent.
When the same research team successfully argues for a patent on a specific technology, the USPTO often will allow a second or subsequent patent to the same research team for overlapping or related aspects of the technology. Having multiple patents does not make it more likely that you were first to invent. Whether you have one patent or many, any number of patents can be brought into a single interference, at which time the PTAB will decide which group was first to invent. An example of this is the current interference on appeal, in which the PTAB included 12 issued Broad patents and one pending allowed Broad application.
We expect an opinion approximately two to six months after the April 30 hearing. However, the CAFC does not have a specific deadline for issuing an opinion.