In widely watched biotech case, skepticism by others in the art and other factors give rise to a lack of a reasonable expectation of success, and thus a lack of interference-in-fact
| December 17, 2018
Regents of the University of California et al. v. Broad Institute, Inc., et al.
September 21, 2018
Before Prost, Schall and Moore. Opinion by Moore.
Summary
The CAFC upheld the PTAB’s decision of the lack of an interference-in-fact between UC’s claims generically directed to the CRISPR-Cas9 gene editing system in any context and Broad’s claims directed to the CRISPR-Cas9 system in eukaryotes specifically. The CAFC affirmed the PTAB’s weighing of substantial evidence with respect to the likelihood of success of one skilled in the art based on UC’s claims, in view of statements by the inventors and experts, as well as the details of other gene editing system. The CAFC dismissed UC’s arguments regarding an alleged “specific instructions” test and evidence of simultaneous invention.
Details
I. Background
This case relates to the CRISPR-Cas9 gene editing system, which is widely considered to be the most revolutionary discovery in molecular biology since PCR (Polymerase Chain Reaction) was developed in the 1980s. Briefly, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) system is a highly specific find-and-replace system that essentially allows the substitution of an undesirable DNA sequence with a revised version of the DNA sequence. CRISPR-Cas9 is naturally found in prokaryotes (simple organisms, usually bacteria), but is not naturally found in eukaryotes, such as plants and animals. It may potentially be used to eliminate genetic diseases, create genetically modified foods, and give rise to ethically-questionable practices such as “designer babies.”
In August 2012, researchers at the University of California published a paper demonstrating use of the CRISPR-Cas9 system in an in vitro, non-cellular environment. In February 2013, researchers at the Broad Institute (affiliated with MIT and Harvard) published a paper describing the use of the CRISPR-Cas9 system in a human cell line. Both filed patent applications, with UC filing first by approximately 6 months. UC’s non-provisional application contains the following representative claim:
165. A method of cleaving a nucleic acid comprising contacting a target DNA molecule having a target sequence with an engineered and/or non-naturally-occurring Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)—CRISPR associated (Cas) (CRISPR-Cas) system comprising
a) a Cas9 protein; and
b) a single molecule DNA-targeting RNA comprising
i) a targeter-RNA that hybridizes with the target sequence, and
ii) an activator-RNA that hybridizes with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment,
wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides,
wherein the single molecule DNA-targeting RNA forms a complex with the Cas9 protein,
whereby the single molecule DNA-targeting RNA targets the target sequence, and the Cas9 protein cleaves the target DNA molecule.
Broad’s later-filed application was eventually issued as U.S. Patent No. 8,697,359, including the following representative claim:
1. A method of altering expression of at least one gene product comprising introducing into a eukaryotic cell containing and expressing a DNA molecule having a target sequence and encoding the gene product an engineered, non-naturally occurring Clustered Regularly Interspaced ShortPalindromic Repeats (CRISPR)—CRISPR associated (Cas) (CRISPR-Cas) system comprising one or more vectors comprising:
a) a first regulatory element operable in a eukaryotic cell operably linked to at least one nucleotide sequence encoding a CRISPR-Cas system guide RNA that hybridizes with the target sequence, and
b) a second regulatory element operable in a eukaryotic cell operably linked to a nucleotide sequence encoding a Type-II Cas9 protein,
wherein components (a) and (b) are located on same or different vectors of the system, whereby the guide RNA targets the target sequence and the Cas9 protein cleaves the DNA molecule, whereby expression of the at least one gene product is altered; and, wherein the Cas9 protein and the guide RNA do not naturally occur together.
An interference was instituted by the PTAB. Broad moved to halt the interference on the basis that its claims are patentably distinct from UC’s claims. Broad argued that one skilled in the art would not have had a reasonable expectation of success of the CRISPR-Cas9 system in a eukaryotic environment. The PTAB agreed, and held that there was no interference-in-fact.
II. The Federal Circuit Decision
The question in an interference is whether the claims recite patentably indistinct subject matter, and if so, who invented first. Whether claims are patentably distinct or not turns on a two-way test of whether the claimed subject matter of a first party would anticipate or obviate the second party’s claims, and vice versa. In this case, the outcome depends on whether UC’s claims render Broad’s claims obvious, and thus the analysis is similar to a typical obviousness analysis.
As noted above, the PTAB held that in view of the substantial evidence, one having ordinary skill in the art would not have had a reasonable expectation of success in applying the CRISPR-Cas9 system to eukaryotic cells. The CAFC agreed for multiple reasons.
First, Broad’s expert, Dr. Simons, explained that protein folding is one of many differences between prokaryotes and eukaryotes, and that folding of the Cas9 protein is an important part of the CRISPR-Cas9 system. Additionally, Dr. Simons explained other distinctions between prokaryotes and eukaryotes, such as intracellular temperature, pH, etc. Dr. Simons also explained that the CRISPR-Cas9 system includes two singled-stranded RNA components, and that eukaryotes include ribonucleases, which destroy single-stranded RNA molecules. Dr. Simons also explained that eukaryotic cells also include systems that destroy double-stranded RNA, and that the CRISPR-Cas9 system includes double stranded RNA.
UC’s expert witness, Dr. Carroll, wrote an article in September 2012 identifying some of these issues in eukaryotic systems, saying that “there is no guarantee that Cas9 will work effectively on the chromatin target or that the required DNA-RNA hybrid can be stabilized in that context.” Dr. Carroll also stated that the effectiveness of CRISPR-Cas9 in eukaryotes “remains to be seen” and “only attempts to apply the system in eukaryotes will resolve these concerns.”
UC’s own inventors also made statements questioning the effectiveness of CRISPR-Cas9 in eukaryotes, saying that “our 2012 paper was a big success, but there was a problem. We weren’t sure if CRISPR/Cas9 would work in eukaryotes.” An inventor referred to “many frustrations” and that use of CRISPR-Cas9 in eukaryotes would be a “profound discovery.” One of the UC inventors informed another of Broad’s success by saying “I hope you’re sitting down…”
Furthermore, other genetic editing systems, such as TALEN and zinc finger nuclease were considered not to be analogous to CRISPR-Cas9, and thus any transferability from prokaryotes to eukaryotes for these systems was not relevant. Additionally, Broad showed evidence of other gene editing systems derived from prokaryotes that had either lower efficacy or required a specific strategy when applying to eukaryotes.
Although the CAFC acknowledged some evidence that supported UC’s position, the court indicated that as an appellate body they do not “reweigh” evidence. Instead, the CAFC based the holding on whether the evidence supports the findings that were made.
Additionally, UC argued that the PTAB applied a pre-KSR type of “specific instructions” test. However, the CAFC dismissed this argument, holding that the PTAB’s conclusions were based on the lack of specific instructions in the art to apply CRISPR-Cas9 to eukaryotes, as well as examples of success or failure of similar systems and other facts. Thus, UC’s argument on this point was unfounded.
Finally, the CAFC disagreed with UC’s argument regarding simultaneous invention. Shortly after publication of UC’s 2012 paper, six other research groups were successful in applying CRISPR-Cas9 to eukaryotes. UC argued that if these groups did not have a reasonable expectation of success, they would not have pursued the application of CRISPR-Cas9 in eukaryotes. However, the CAFC concluded that this does not mean that one having ordinary skill in the art necessarily would have expected success. The PTAB declined to apply a bright line test that simply because a group attempted an approach and was successful that this corresponds to a reasonable expectation of success. Rather, the PTAB weighed this fact and held that a reasonable expectation of success was not established given the “specific context of the art at the time.” Thus, the CAFC held that UC’s arguments on this point were misplaced.
Therefore, in view of all the evidence of record, the CAFC held that there was not a reasonable expectation of success when applying CRISPR-Cas9 to eukaryotes. Thus, Broad’s claims are patentably distinct from UC’s claims, and there is no interference-in-fact.
However, the CAFC explicitly stated that its decision is limited to a determination of no interference-in-fact, and should not be interpreted as a comment on the validity of the claims of Broad’s patent or UC’s application. Certainly, one can see some potential problems for UC ahead, such as an argument that claims generic to eukaryotes and prokaryotes may fail to comply with the written description and/or enablement requirements.
Takeaway
Although the holdings of this case are very specific to the facts of the case, some of the reasoning could be applied generally to arguments of obviousness. Thus, if available, evidence such as skepticism by others in the art and surprise at success can be helpful to demonstrate the non-obviousness of a follow-up invention in a similar, but demonstrably different, environment.
