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For journalists: Statement and background on the CRISPR patent interference process

by Lee McGuire
Chief Communications Officer, Broad Institute of MIT and Harvard
Updated February 15, 2017

Media inquiries: communications@broadinstitute.org

 

February 15, 2017: PTAB issues decision declaring ‘no interference-in-fact’

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 UC Berkeley and the University of Vienna.

Broad Institute statement regarding PTAB decision

We agree with the decision by the patent office, which confirms that the patents and applications of Broad Institute and UC Berkeley are about different subjects and do not interfere with each other.

Broad Institute and collaborators were issued patents for methods for genome editing in eukaryotic (including human) cells, while UC Berkeley and collaborators applied for patents concerning CRISPR methods based on studies in cell-free systems that did not involve genome editing in eukaryotic cells.

CRISPR research is a very large field that involves contributions from talented scientists around the world. We have deep respect for all of these scientific contributions, including the work from Emmanuelle Charpentier, Jennifer Doudna, and their teams, as well as all of those who continue to advance the field and educate the public about this important technology.

Over the next few years there will be many patents issued in the CRISPR field to many institutions. As of February, 2017 the USPTO has issued 50 patents with claims to CRISPR and/or Cas9, including a robust portfolio of 13 CRISPR patents to the Broad Institute, MIT and affiliated groups for inventions from Dr. Feng Zhang and the Zhang lab.

We believe CRISPR should continue to 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.

Read the judgment and decision on motions, which include this summary:

“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.”

 

About the December 6, 2016 oral hearing (updated December 6, 2:36 p.m.):

This hearing reinforced the fact that the Broad Institute, MIT and Harvard were first to invent the subject matter in patent applications with regard to CRISPR genome editing in eukaryotic cells. The underlying facts have not changed and we are confident the patent office will continue to recognize the leadership of the Broad, MIT and Harvard in developing this transformative technology.

This hearing came at the request of both parties, and offered an opportunity for the respective legal teams to argue why particular motions should be granted. A summary of the key motions in the proceedings since January is available here.

Exhibitions (slides) presented at the oral hearing:

Discussion focused on:

  • No interference in fact: Broad has argued that the claims of its involved patents do not interfere with the involved claims of the UCB application, and thus that this interference process should not continue.
  • The count: In any patent interference the judges set "the count," which is the definition of what the invention in question is. In this case, the judges have set the count as the use of CRISPR in a method in an eukaryotic cell. UCB is arguing that this decision should be revisited.

The judges have not set a timeline for a decision on these matters, although a decision is likely within a month or two after the hearing. These decisions will set the stage for the next phase of the interference process, which would likely extend through 2017 and potentially beyond.

What CRISPR-Cas9 patents have been issued to Broad Institute and MIT?

As of November 2016 the USPTO has issued 42 patents with claims to CRISPR and/or Cas9, including a robust portfolio of 13 CRISPR patents to the Broad Institute, MIT and affiliated groups for inventions from Dr. Feng Zhang and the Zhang lab. The claims of these patents are directed to mammalian genome editing methods and other distinct inventions optimizing the CRISPR-Cas9 components and system for delivery and function in such cells and organisms.

The USPTO has further issued ten 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 and one to Institut Pasteur, and one to Caribou Biosciences.

Zhang is a core member of the Broad Institute and an investigator at the McGovern Institute for Brain Research at MIT and an associate professor at MIT with a joint appointment in the Departments of Brain and Cognitive Sciences and Biological Engineering. As such, his CRISPR patents are assigned jointly to Broad Institute and MIT. For convenience they are often referred to as the "Broad patents," but Broad Institute is acting on behalf of both institutions in managing this IP portfolio.

In addition the European Patent Office (EPO) has granted six of Broad's patent applications as of February 2016.

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 engineered components and compositions specifically altered from their naturally-occurring form to be useful in methods for editing the genomes of living mammalian cells.

What is the key issue with respect to the CRISPR-Cas9 patents?

The patent applications filed by Broad and MIT were not the first applications related to CRISPR, but they were the first that described complete invention of mammalian genome editing -- that is, actual experimental data constituting a reduction to practice.

Various patent applications speculating about the potential utility of CRISPR for genome editing have been filed over the years. They include applications by:

  • Northwestern University in September 2008 (Erik Sontheimer and Luciano Marraffini, 61/099,317);
  • Vilnius University in March 2012 (Virginijus Siksnys and others, 61/613,373);
  • UC Berkeley in May 2012 (Jennifer Doudna and others, 61/652,086); and
  • ToolGen in October 2012 (Jin Soo Kim and others, 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 eventually 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 cells, no genomes, and no editing.
  • The USPTO rejected the Vilnius application as not having significantly more than a study of the natural system and failing to describe invention.
  • 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 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 materials in 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.)

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.

What is the latest update with the patent proceeding?

January 6, 2017: On December 22, UCB requested a conference call seeking authorization to file additional evidence in the interference proceeding. PTAB denied UCB's request. This order is available as document 891 on the PTAB interference website.

A full timeline of events related to this ongoing proceeding is available here.  

What is a re-examination?

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 patent 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.

The Broad Institute is confident the USPTO will reach the same conclusion it did initially when it awarded this patent and will continue to recognize Broad, MIT and Harvard roles in developing this transformative technology.

On May 12, 2016, Judge Katz issued an order suspending the reexamination until the conclusion of the current interference process.

Does the fact that the Broad's patent application was reviewed under the USPTO's accelerated review process mean that the level of scrutiny was lower -- or that the application was not compared to claims by others?

No. Expediting a consideration of patent application via the "fast track" process (called "accelerated examination") simply means that the application was considered more quickly and that the Broad had to agree 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 fast-tracked. 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.

What does Senior or Junior party status mean?

When an interference is first declared, the parties are temporarily designated as "Senior" or "Junior" parties according to the date of a particular filing date designated by the Patent Office (in this case, March, 2013 for UC Berkeley and December, 2013 for Broad/MIT). The initial designations were based on dates for completed applications as published rather than the underlying provisional applications that were filed in 2012 and through March 15, 2013.

Each party then has an opportunity to request that its priority date be pushed back to the first patent filing that is pertinent to the question before the administrative law judge--in this case, the use of CRISPR in a eukaryotic cell. After the parties present evidence as to whether their earlier patent filing demonstrated the use of CRISPR to achieve genome editing in a eukaryotic cell, a final determination will be made as to who is the "Senior" and "Junior" party. The Judge will be asked to review the priority applications of the Broad/MIT December 2012 application (61/736,527, available here) and likely also the UC Berkeley May 2012 application (61/652,086, available here) to identify the first actual description of evidence of methods using CRISPR-Cas9 in eukaryotic cells to cleave or edit target DNA or modulate transcription of a gene prior to the January 3, 2013 Science papers.

In this case, Broad/MIT's first filing demonstrating the use of CRISPR to achieve genome editing in a eukaryotic cell considerably predates the Berkeley filing.

What is Broad Institute's position with respect to sharing of CRISPR-Cas9 with researchers around the world?

Broad Institute is an academic non-profit research organization. Our faculty develop innovative techniques, create analytical tools, and make groundbreaking discoveries that we share with the global scientific community to benefit human health.

Broad Institute, MIT, and Harvard partners have made CRISPR-Cas9 technology broadly available to the research community. Broad Institute is working with Addgene, a non-profit plasmid repository, to offer Zhang lab CRISPR plasmids and reagents to accelerate academic research. Since February 2013, Addgene has shared more than 37,000 plasmids and reagents with more than 2,000 institutions across 59 countries. In addition we have non-exclusively licensed many industry partners for development of research tools and reagents and will continue to do so.

Additional resources

 

Front page image by Ian Slaymaker