The Patent Trial and Appeal Board (PTAB) of the U.S. Patent and Trademark Office (USPTO) today ruled that the inventions claimed in the pending U.S. patent application filed by the Doudna/Charpentier research group and the patents and applications filed by the Broad Institute are separately patentable from one another, thereby moving the Doudna/Charpentier group’s application closer to issuance as a U.S. patent.
More particularly, the PTAB ruled that the use of CRISPR-Cas9 systems in eukaryotic cells, such as human cells, as claimed in the patents and applications filed by the Broad Institute of MIT and Harvard, is a separate invention from the general use of CRISPR-Cas9 gene-editing technology in any type of cell, as claimed in the pending U.S. patent application filed by Jennifer Doudna, Emmanuelle Charpentier and their research teams at UC Berkeley and the University of Vienna.
In its ruling, the PTAB justified its finding of “no interference in fact” by stating: “Broad has persuaded us that the parties claim patentably distinct subject matter.” As such, the patent board ultimately determined that they will “enter judgment of no interference-in-fact, which neither cancels nor finally refuses either parties’ claims” (emphasis added).
In light of this decision, the Doudna/Charpentier patent application will be returned to the Patent Examiner, who previously determined it to be allowable, thus moving the Doudna/Charpentier group’s application closer to issuance as a patent covering the use of CRISPR-Cas9 in all types of cells and organisms, including bacteria, plants, animals and humans.
“The team led by UC’s Jennifer Doudna and Emmanuelle Charpentier, now at the Max Planck Institute for Infection Biology, invented the CRISPR-Cas9 gene-editing technology that has been rightfully hailed as the scientific breakthrough of the century,” said UC President Janet Napolitano. “We are pleased that today’s ruling affirms the spectacular accomplishments of these two scientists and their research teams and highlights the incomparable value of basic research at our public research universities and scientific institutions.”
The PTAB decision does, however, leave in place patents previously issued to the Broad Institute for use of CRISPR-Cas9 in human and other “eukaryotic” cells. The University of California and its co-owners maintain that using the CRISPR-Cas9 system in eukaryotic cells is not separately patentable from using the system in other cell types, and for that reason disagrees with the PTAB’s decision. As such, the university and its co-owners will be considering all possible options for moving forward in the current legal dispute, including other legal challenges to the Broad Institute’s patents and the possibility of appealing the PTAB’s decision.
“UC respects today’s ‘no-interference-in-fact’ decision by the PTAB and is pleased that its patent application covering the use of CRISPR-Cas9 gene editing technology for all cell types can now move closer to issuance,” said Paul Alivisatos, UC Berkeley vice chancellor for research and professor of chemistry. “Nevertheless, the university continues to believe that the use of the CRISPR-Cas9 system in eukaryotic cells is not separately patentable from the general application of the CRISPR-Cas9 system in any cell type, as invented and claimed by the Doudna/Charpentier group. As such, we will be carefully considering all possible legal options at this juncture. As always, UC will proceed based on our assessment of what best serves and supports the public interest and the greater good.”
“As the legal dispute moves forward, my team will continue to focus on using CRISPR-Cas9 to deliver advances and solutions that can help solve our greatest challenges across human health, agriculture and the environment,” said Doudna, a professor of molecular and cell biology and of chemistry and a Howard Hughes Medical Institute investigator at UC Berkeley.
The ultimate genesis of this legal dispute came when the Doudna/Charpentier team re-engineered a DNA-cutting system from bacteria to create the CRISPR-Cas9 technology, which was capable of editing DNA at any desired location within any cell type. In addition, the Doudna/Charpentier research group took the engineering a step further by combining two separate RNA molecules from the natural system into a single molecule, referred to as a “single-guide RNA,” thereby greatly simplifying the system and making it much easier to use.
In May 2012, the Doudna/Charpentier group filed a patent application covering the use of CRISPR-Cas9 gene-editing technology in all cells, including prokaryotes and eukaryotes; and, in June 2012, the Doudna/Charpentier team published the results of their studies in the journal Science. Since then, the technology has been used in thousands of laboratories around the world to target and cut desired sequences of DNA, analogous to cutting and pasting letters or words with a word processor. This technology has already revolutionized the study of genetic diseases, and has spawned promising new therapies for blood diseases, AIDS and cancer.
Once the Doudna/Charpentier team described how to engineer and use the CRISPR-Cas9 system for cutting any desired DNA target in their June 2012 publication, a “person of ordinary skill” could adapt it to cut DNA in any type of cell. As an illustration that no “secret sauce” was needed to edit DNA in eukaryotic cells following that initial June 2012 publication by the Doudna/Charpentier team, by January 2013, a mere six months later, six separate teams of researchers — including Doudna’s own team, a group in Korea, two groups at Harvard University and the team at the Broad Institute — had successfully edited DNA in human cells and even a complex organism (fish) using CRISPR-Cas9.
Following that initial publication by the Doudna/Charpentier research team, a team of researchers from the Broad Institute filed their first patent application directed toward the use of the CRISPR-Cas9 system for cutting DNA in eukaryotic cells in December 2012, and that was subsequently followed by many more patent application filings by the same team at the Broad Institute directed toward that same subject matter. The USPTO issued patents to the Broad Institute for use of the CRISPR-Cas9 gene-editing technology in eukaryotic cells — cells of higher organisms such as plants, animals, and fungi — despite the fact that the Doudna/Charpentier group had filed for a patent on CRISPR-Cas9 gene-editing technology in May 2012, seven months before the Broad Institute filed its patent application. The Broad Institute’s patent applications moved rapidly through the patent system because the Broad Institute paid an extra fee for expedited examination of their applications.
The University of California contested the issuance of Broad’s patents, claiming that the Broad patents interfered with, i.e., are directed toward substantially the same invention as, the Doudna/Charpentier team’s earlier-filed patent application, and the PTAB heard oral arguments from both sides in the dispute on December 6, 2016. In the interference proceeding, UC and its co-owners argued, and continue to believe, that the key invention was taking a system evolved for a completely different purpose, bacterial adaptive immunity, and engineering it to make genome editing easy, cheap and efficient in any type of cell.
“The Doudna/Charpentier publication in Science in 2012 brought a new level of understanding of genome editing to the entire scientific community because it showed exactly which three bacterial protein and RNA elements, including a guide RNA the paper taught how to engineer to cut in any target gene from any organism, are necessary for genome editing in a test tube or any organism,” said Gary Ruvkun, a molecular biologist at Massachusetts General Hospital and a professor of genetics at Harvard Medical School in Boston.
“This breakthrough is enabling many technologies and marked the birth of CRISPR-Cas9 gene editing,” Ruvkun added. “The Doudna/Charpentier discoveries in 2011 and 2012 grew out of pioneering genetic discoveries by other scientists, especially by Barrangou, Horvath and Siksnys, about the molecular functions of CRISPR in bacterial immunity and how it constitutes a programmable scalpel that bacteria evolved for protecting their genomes. But the 2012 Doudna/Charpentier Science paper was the true launch of re-programming CRISPR for the editing of any genome. The expression of the CRISPR RNA and protein components identified in 2012 by Charpentier and Doudna in mammalian cells by the Zhang group in 2013 at the Broad Institute was one example among thousands of the expression of gene activities from other organisms in mammalian cells to modify the features of those cells. After the 2012 Doudna and Charpentier paper, there were parallel CRISPR expression experiments in dozens of organisms by dozens of lab groups; this was obvious to those who know the art. The seminal nature of the Doudna/Charpentier Science paper has been recognized by scores of scientific prize committees; a small subset of these prizes have also anointed Zhang, Barrangou, Siksnys and Horvath but never without Doudna and Charpentier, reinforcing the view that the 2012 Doudna/Charpentier paper was key.”
Stephen Elledge, a professor of genetics at Harvard Medical School, said that the 2012 paper by Doudna, Charpentier and their team “brought a new level of understanding of genome editing to the entire scientific community. This breakthrough and the previous discoveries from bacterial geneticists were the key findings that enabled the use of CRISPER-Cas9 for gene editing.”
As part of their commitment to furthering basic and applied research that is in the public interest, the University of California and University of Vienna have reserved the right to allow educational and other non-profit institutions to use the CRISPR-Cas9-related intellectual property for educational and research purposes, and the technology continues to be used worldwide to address important questions in biology. Through a UC Berkeley-UCSF partnership, the Innovative Genomics Institute, Doudna and her colleagues are working to advance the use of CRISPR-Cas9 gene editing to treat diseases such as sickle cell disease and other genetic disorders, and to develop new disease-resistant crops.
“I am convinced that this technology will solve important problems in clinical medicine, drug discovery and agriculture,” said Doudna.