by Lee McGuire
Chief Communications Officer, Broad Institute of MIT and Harvard
Updated April 20, 2018
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Update on patent process in the United States
On February 15, 2017, the United States Patent Trial and Appeal Board (PTAB) ruled that the claims of patents granted by USPTO to Broad Institute, MIT, and Harvard concerning CRISPR editing in eukaryotic cells do not interfere with patent claims filed by UC Berkeley and the University of Vienna. UCB then appealed the PTAB’s judgment to the United States Court of Appeals for the Federal Circuit, based in Washington DC. (Broad Institute is managing the CRISPR patent portfolio on behalf of Broad, MIT, and Harvard.)
The Federal Circuit will hear oral arguments in this appeal on Monday, April 30.
Summary of appeal
UCB has asked the Federal Court to re-weigh the factual evidence from scratch and reach a different conclusion than the PTAB.
This is not, however, the question before the Court.
In an appeal from a PTAB decision, the Court does not re-weigh the factual evidence. Rather, the Court decides whether the PTAB had sufficient evidence to reach its decision, and whether it correctly applied any applicable legal standards.
The PTAB decision was clearly supported by sufficient evidence and clearly followed applicable legal standards.
There are thus no grounds for overturning the PTAB decision.
The Broad Institute's response to the UCB appeal
On October 25, 2017, Broad Institute filed its brief in the United States Court of Appeals for the Federal Circuit in Washington, DC, which outlines the arguments to be made in the hearing on April 30, 2018. This brief concerns UCB’s appeal of the judgment by the PTAB that there is no interference-in-fact between the Broad Institute, MIT, and Harvard claims concerning the use of the CRISPR-Cas9 system in eukaryotic cells and claims of the patent application of UCB, because the claims are patentably distinct.
The UCB argument hinges on its belief that, although UCB’s work in Jinek 2012 focused on biochemical characterization of purified components in a test tube, it rendered obvious that genome editing with the CRISPR-Cas9 system worked in living mammalian cells.
To be successful, UCB must persuade the Federal Circuit (which hears patent appeals) on at least one of these arguments:
- UCB must convince the Court that the PTAB did not have “substantial evidence” — defined legally as “more than a mere scintilla of evidence” — to support its findings. For such cases, the standard of review was established by the Supreme Court in Consol. Edison Co. v. Nat'l Labor Relations Bd., 305 U.S. 197, 229-30 (1938).
- UCB must convince the Court that the PTAB made a material legal error, or
- UCB must convince the Court that the PTAB failed to consider certain evidence.
Broad’s brief makes clear that neither of UCB’s arguments are accurate.
I. The PTAB’s ruling was supported by substantial factual evidence.
The PTAB ruled that, in 2012, a person of ordinary skill in the art would not have had a reasonable expectation of success that the CRISPR-Cas9 systems, which occur only in prokaryotic (bacterial) cells, could be made to function in the radically different setting of eukaryotic (mammalian) cells, such as in animals and plants.
Under the well-established standard for review, the Federal Circuit should affirm the PTAB’s judgment unless it finds that the PTAB had no substantial evidence whatsoever to support its ruling.
To the contrary, as detailed in the Broad brief, the PTAB relied on five separate categories of supporting evidence — each of which individually provides substantial evidence to support the PTAB’s judgment. Together, they provide overwhelming evidence:
Category 1: Contemporaneous statements by the UCB Inventors themselves expressing frustrations and doubts about the ability to make CRISPR-Cas9 systems function in eukaryotic cells (PTAB decision, pages 14-17).
Category 2: Contemporaneous statements by skilled artisans, including a scientific article in a peer-reviewed journal written by one of UCB’s own experts (Dr. Dana Carroll) in the Interference, that stated clear concerns and identified multiple reasons why CRISPR-Cas9 systems might not function in eukaryotic cells (PTAB decision, pages 17-19).
Category 3: Contemporaneous statements and actions by other researchers who sought to engineer CRISPR systems to work in eukaryotic cells demonstrating that, while they were motivated to try, they had no reasonable expectation of success (PTAB decision, pages 23-25).
Category 4: Extensive scientific evidence of the fundamental differences between prokaryotic and eukaryotic cells that would weigh heavily against an expectation that a prokaryotic system could be adapted to function in eukaryotic cells (PTAB decision, pages 29-35).
Category 5: Extensive evidence of obstacles and failures encountered in prior-art attempts to adapt other prokaryotic systems to eukaryotes (PTAB decision, pages 35-38).
To prevail on this appeal, UCB would need to establish that the PTAB was not entitled to accord any weight whatsoever to each of these five independent categories of evidence. As noted in the Broad brief, there is substantial evidence to support the PTAB’s judgement on the facts.
II. Broad’s brief makes clear that the PTAB’s decision was fully consistent with the law.
Because it cannot overcome the extensive factual record, UCB claims the PTAB ruling made legal errors by misapplying certain legal standards. As detailed in the brief, these arguments lack merit because the PTAB correctly applied these legal standards.
In short, the PTAB’s judgment was supported by substantial evidence and in full conformity with the law.
We are confident the Federal Circuit will affirm the PTAB’s judgment and recognize the contribution of the Broad, MIT and Harvard in developing this transformative technology.
III. Broad’s brief makes clear that the PTAB considered evidence presented.
UCB argues that the PTAB failed to consider evidence related to simultaneous invention and certain prior art. As detailed in the brief, these arguments lack merit because UCB failed to make such arguments at the PTAB, and even if UCB had, the arguments would have had no impact on the PTAB’s decision.
Update on patent process in Europe
January 17, 2018
In a decision that is unrelated to the substantive merits of the CRISPR patent, an initial review panel of the European Patent Office (EPO) denied the Broad Institute’s reliance on its U.S. priority provisional application in Europe based on a technical formality.
This technicality concerns the current interpretation of rules that dictate what happens when the names of inventors differ across international applications. This interpretation affects many other European patents that rely on U.S. provisional patent applications, and is inconsistent with treaties designed to harmonize the international patent process, including that of the United States and Europe.
In today’s ruling, the EPO’s Opposition Division was restricted by a formal technical requirement that it must follow these procedures despite the inconsistency with international treaties. The decision does not involve the actual scientific merits of the CRISPR patent application.
The Broad Institute will appeal the decision to EPO’s Technical Board of Appeal, which is expected to use this case as an opportunity to review and resolve this international inconsistency, not just for CRISPR patents, but for a wider range of European patents and applications that originated as U.S. provisional applications.
The Broad Institute is confident that the EPO will, on appeal, harmonize the EPO procedures to be consistent with international treaties and compatible with the fundamental principles of the Paris Convention -- and that it will recognize the same priority dates for the inventions as those the USPTO has repeatedly affirmed for the Broad’s U.S. applications.
Many experts support the Broad Institute’s position, including Lord Hoffmann, retired UK Law Lord; Tobias Bremi, Second Ordinary Judge of the Federal Patent Court of Switzerland; The Honorable Paul R. Michel, retired Chief Judge of the United States Court of Appeals for the Federal Circuit; James Pooley, former Deputy Director General, responsible for operation of the international patent system at the World Intellectual Property Organization, which administers international patent-related treaties; Professor Dr. Dres. h.c. Joseph Straus, Director Emeritus, Max Planck Institute for Innovation and Competition; Professor John Thomas, Professor of Law, Georgetown University and Professor Paul Torremans, Professor of Intellectual Property Law, School of Law, University of Nottingham and Advisor to the WIPO Academy.
Status of patent process by jurisdiction
October 25, 2017
United States: Broad Institute, MIT, and Harvard have been granted 13 patents in the United States for CRISPR-Cas9, as well as one CRISPR-Cpf1 patent. The USPTO It is still considering whether to issue a patent directed to CRISPR-Cas9 to UC Berkeley (UCB), University of Vienna and Emmanuelle Charpentier.
Europe: Broad Institute, MIT, and Harvard have been issued 10 fundamental CRISPR patents in Europe since 2015. UCB was issued a CRISPR patent in 2017. The European patent-review process differs from the US process and may involve adjusting patent claims after a patent has been issued, in response to oppositions filed within nine months after issuance. Once oppositions are filed, the EPO carries out review proceedings, which typically take more than a year, after which the EPO may maintain, revoke or allow amendment to the patent. It is widely expected that many parties will file oppositions and that adjustments may be required in this case.
China: The State Intellectual Property Office has issued a notice that UCB will receive a patent (2017). It is currently considering patent applications of Broad Institute, MIT, and Harvard, which we expect will issue. In China, patents are subject to invalidation proceedings after they are issued.
Broad Institute and collaborators have been issued three CRISPR patents in Australia and one in Japan. Other applications are in process. Clearly, the patent landscape continues to unfold.
Questions and answers about CRISPR patents
Q: How many CRISPR patents are there?
A: CRISPR research is a large field that involves contributions from many talented scientists around the world. The US Patent and Trademark Office has issued more than 60 patents with claims to CRISPR and/or Cas9 to approximately 100 inventors from 18 applicant organizations. The European Patent Office (EPO) has issued more than 20 such patents to approximately 30 inventors from about ten applicant institutions.
The Broad Institute, MIT, and Harvard hold 23 key CRISPR-Cas9 patents in the United States and Europe.
The claims of these patents are directed to eukaryotic genome editing methods and other distinct inventions by Broad Institute core member Feng Zhang and the Zhang lab for optimizing the CRISPR-Cas9 components and system for delivery and function in such cells and organisms. The USPTO has issued additional CRISPR patents to Harvard University relating to inventions of Broad Senior Associate member George Church and the Church lab and also of Broad Institute core member David Liu and the Liu lab; three CRISPR patents to DuPont; one to Agilent Technologies; one to University of Georgia Research Foundation; one to Institut Pasteur; one to Caribou Biosciences; and one to Vilnius University.
Over the next several years, there will be many more patents issued in the CRISPR field, to many inventors from many institutions, in recognition of each individual's contribution to advancing CRISPR technology.
Q: What is the key issue with respect to the CRISPR-Cas9 patents?
The patent applications filed by Broad were not the first applications related to CRISPR, but they were the first that described the complete invention of mammalian genome editing — that is, actual experimental data constituting a reduction to practice.
Various patent applications with speculation about the potential utility of CRISPR for genome editing have been filed over the years. This includes applications by:
- Northwestern University in September 2008 (Erik Sontheimer and Luciano Marraffini, US Patent Application No. 61/099,317);
- Vilnius University in March 2012 (Virginijus Siksnys and others, US Patent Application No. 61/613,373);
- UC Berkeley in May 2012 (Jennifer Doudna and others, US Patent Application No. 61/652,086); and
- ToolGen in October 2012 (Jin Soo Kim and others, US Patent Application No. 61/717,324).
The status, elements, and outcomes of these applications have varied:
- The USPTO rejected the Sontheimer application as to failing to describe invention; the Sontheimer application was abandoned.
- The applications filed in 2012 by the Vilnius team and the Berkeley team each showed only that purified Cas9 protein and a certain purified RNA could cut a short piece of DNA in a solution in a test tube. In both cases, the applications in 2012 contained no disclosure of work in cells, no genomes, and no editing.
- The USPTO granted method claims to use of CRISPR-Cas9 systems assembled in vitro in one of the Vilnius applications, which issued as US Patent No. 9,637,739 on May 2, 2017.
- The USPTO continues to consider the Berkeley application, which describes similar results in 2012 as the Vilnius application.
- The USPTO has rejected the ToolGen application as failing to describe invention.
In April, 2014, the USPTO granted US Patent No. 8,697,359 to Broad Institute, MIT and Dr. Feng Zhang. This Patent (which draws priority from a provisional patent application filed in December 2012) contained successful experiments. It was based on original work that began at the Broad Institute and MIT in early 2011, was further reflected in a January 2012 federal grant application to the National Institutes of Health and culminated in the manuscript submitted on October 5, 2012 that was published in Science on January 3, 2013 as Cong et al. It marked the world's first engineering of CRISPR-Cas9 to be delivered and used to achieve mammalian genome editing. Zhang was the first to file a patent application, on December 12, 2012, that described and enabled such a method. These components and methods have since become the leading standard for genome editing worldwide.
In awarding this patent to Broad, MIT and Dr. Zhang, the USPTO was fully aware of and fully considered the claims and specifications of the other patent applications. (While the application was considered under "accelerated examination", this does not change the standard for review. The USPTO still compares the patent application to all other relevant applications.)
Q: Why did the PTAB decide in favor of the Broad Institute?
On February 15, 2017, the Patent Trial and Appeal Board declared that the patents granted by USPTO to the Broad Institute, MIT and Harvard concerning CRISPR editing of eukaryotic genomes do not interfere with patent claims filed by UCB and the University of Vienna.
The decision confirmed that the patents and applications of Broad Institute and UCB are about different subjects and do not interfere with each other.
Broad’s issued patents were for genome editing in eukaryotic (including animal, human, and plant) cells, while the claims in UCB’s application in the Interference were based on studies in cell-free systems and not directed to genome editing in eukaryotic cells.
"Broad has persuaded us that the parties claim patentably distinct subject matter, rebutting the presumption created by declaration of this interference. Broad provided sufficient evidence to show that its claims, which are all limited to CRISPR-Cas9 systems in a eukaryotic environment, are not drawn to the same invention as UC's claims, which are all directed to CRISPR-Cas9 systems not restricted to any environment. Specifically, the evidence shows that the invention of such systems in eukaryotic cells would not have been obvious over the invention of CRISPR-Cas9 systems in any environment, including in prokaryotic cells or in vitro, because one of ordinary skill in the art would not have reasonably expected a CRISPR-Cas9 system to be successful in an eukaryotic environment. This evidence shows that the parties' claims do not interfere. Accordingly, we terminate the interference."
Exhibitions (slides) presented at the December 6, 2016 oral hearing:
A summary of the key motions in the PTAB proceedings is available here.
Q: Do patents limit the ability to share CRISPR widely?
A: This depends on the choices made by the institution or company that is licensing an invention. At the Broad Institute, we believe CRISPR should be available to the global scientific community to advance our understanding of the biology and treatment of human disease, and to help lay the groundwork for a new generation of therapies.
Consistent with our founding principle to propel the understanding and treatment of disease, Broad Institute and our partner organizations will continue to work to disseminate and share CRISPR genome editing tools to maximize public benefit, especially by continuing to make this transformative technology freely available to the worldwide academic community and for commercial and human therapeutic research through our inclusive innovation model.
Q: What happens if the Broad Institute wins the patent fight in the United States, but UCB wins in Europe and China?
A: It is inaccurate to claim that there is a “winner” and a “loser” in each jurisdiction. Not only does the landscape continue to unfold, but there are already dozens of different CRISPR patents issued to many different institutions and companies. Ultimately, many institutions will hold many patents in many countries.
Q: With so many players holding CRISPR patents, how will researchers know who to license from?
A: Broad Institute, Harvard, MIT, and our collaborators already make CRISPR tools freely available to the academic and nonprofit communities. To streamline the landscape for commercial research, we have offered to join a worldwide patent pool. However, to be effective, other license holders would need to join as well.
Q: Can CRISPR be patented?
No. CRISPR itself cannot be patented. Cas9 is a naturally occurring protein and part of a naturally-occurring bacterial process, but this process, on its own, does not work in mammalian cells. What Broad has patented are methods, engineered components and compositions specifically altered from their naturally-occurring form to be useful for editing the genomes of living mammalian cells.
Q: What is a patent interference?
Until recently, the US had a "first to invent" patent system. When two patent applicants claimed overlapping inventions, a key question was: Which patent applicant was the "first to invent" by "reducing the concept to practice". (The US moved to a "first to file" system on March 16, 2013, but the relevant applications for CRISPR-Cas9 fall under the previous "first to invent" system.)
Applicants for a patent may request that the US Patent and Trademark Office (USPTO) hold a process, called an "interference" whereby USPTO considers and compares historical (that is, contemporaneous) documentary evidence from applicants concerning invention dates. The decision to allow an interference involves no presumption about inventorship or previously-granted patents. Broad Institute, which manages the patent portfolio on behalf of Broad, MIT, and Harvard, is responding to an interference process at the Patent Trial and Appeal Board initiated by UCB. The costs are reimbursed by Editas as part of the existing Cas9 licensing agreement.
Q: Did the USPTO examine Broad's application under its accelerated examination procedure?
Yes, this is a standard option on the patent form for which Broad simply paid a $70 fee.
Q: Does the accelerated examination procedure mean that the USPTO used a different level of scrutiny in reviewing Broad's patent application — for example, that the application was not compared to claims by others?
A: No. Accelerated examination simply means that the USPTO agrees to consider the application more quickly and the Broad agrees to respond more quickly to questions raised by the USPTO.
It does not change the level of scrutiny applied to the application — the same process of comparing the application to all other potentially-related patents takes place.
The USPTO's decision is the same as it would have been had the process not been accelerated. In this case, Broad's applications were considered against those from UC Berkeley and other institutions, as they would have been regardless of whether the patent had been examined via the accelerated review process or otherwise.
Q: What is a re-examination?
A: An ex parte re-examination is a process by which third parties can request that the USPTO consider prior patent applications or printed publications. The third party can be anonymous. In May 2016 the USPTO granted an ex parte request by an attorney in California for re-examination regarding Broad/MIT US Patent No. 8,771,945. The third party argues that an October 2012 patent application by Toolgen and a December 2012 application by Sigma-Aldrich Corporation did not receive sufficient consideration relative to the '945 patent award. The party asked the USPTO to re-examine the decision. This process is separate from the interference declared in January 2016.
On May 12, 2016, Judge Katz issued an order suspending the reexamination until the conclusion of the current interference process.
Front page image by Ian Slaymaker