PTAB Decides CRISPR Interference in Favor of Broad Institute -- Their Reasoning

By Kevin E. Noonan --

Yesterday, the Patent Trial and Appeal Board (PTAB) of the U.S. Patent and Trademark Office rendered judgment that there was no interference-in-fact between the claims in interference between the Regents of the University of California/Berkeley and the Broad Institute.  Shortly after this judgment appeared, the Board issued its "Decision on Motions" (Paper No. 893) explaining its reasoning.

Although both parties had received the Board's permission to file a number of briefs in the preliminary part of the interference, the Board rendered its decision on Broad Motion No. 2, that there was no interference in fact.  The basis of the requirement for an interference-in-fact can be found in the Rules governing interferences:

An interference exists if the subject matter of a claim of one party would, if prior art, have anticipated or rendered obvious the subject matter of a claim of the opposing party and vice versa.

37 C.F.R. 17 § 41.203(a).  In this case, the Board set out these requirements with respect to these parties:

In this proceeding, to prevail on its argument that there is no interference, Broad must show that the parties' claims do not meet at least one of the following two conditions:

1) that, if considered to be prior art to UC's claims, Broad's involved claims would not anticipate or render obvious UC's involved claims, or

2) that, if considered to be prior art to Broad's claims, UC's involved claims would not anticipate or render obvious Broad's claims.

Broad will prevail and a determination of no interference-in-fact will be made if a preponderance of the evidence indicates one of these conditions is not met.

Here, it was undisputed that UC's claims would not anticipate the Broad's claims-in-interference because all of Broad's claims contained the affirmative limitation that the CRISPR technology be operative in eukaryotic cells, and the UC's claims were devoid of any limitation regarding the context in which CRISPR was applied.

Thus, the question before the Board was whether the evidence presented by the parties established that the UC claims, if prior art, would have rendered the Broad's claims obvious.  The Board concluded that they would not, and hence there was no interference-in-fact between the parties' claims in the interference.

In considering the evidence before it, the PTAB gave greater weight to contemporaneous, cautious statements in the art in view of Doudna's disclosure of in vitro CRISPR activity regarding whether the system would work in eukaryotic cells.  Specifically these statements convinced the Board that while the results "suggested the 'exciting possibility'" that CRISPR-Cas9 could be operative in eukaryotic cells, "it was not known whether such a bacterial system would function in eukaryotic cells."  And, "[i]n another report, Doudna was quoted as stating that she had experienced 'many frustrations' getting CRISPR to work in human cells and that she knew that if she succeeded, CRISPR would be 'a profound discovery.'"  UC's assertion of other statements by their inventors that could be interpreted more positively did not convince the Board that there was a reasonable expectation of success in the art for getting the CRISPR-Cas9 system to work in eukaryotic cells, the Board stating that:

Although the statements express an eagerness to learn the results of experiments in eukaryotic cells and the importance of such results, none of them express an expectation that such results would be successful.

The Board swept aside UC's argument that this reasoning was flawed because the standard is not the inventor's expectations but those of the worker of ordinary skill by stating that "if the inventors themselves were uncertain, it seems that ordinarily skilled artisans would have been even more uncertain."  Even UC's own expert voiced (contemporaneous) skepticism regarding whether the skilled worker would have had an expectation of success that the invention would be operative in eukaryotic cells in view of Inventor Doudna's success in vitro.  In particular, the Board quoted UC's expert as having said (contemporaneously with Inventor Doudna's report of in vitro CRISPR activity):

There is no guarantee that Cas9 will work effectively on a chromatin target or that the required DNA-RNA hybrid can be stabilized in that context.

The Board concluded that "[w]e fail to see how 'no  guarantee' indicates an expectation of success."

All the other contemporaneous references cited by UC suffered the same fate, wherein scientists' characteristic caution in predicting how a developing technology will actually develop was interpreted by the Board as not supporting UC's argument that the skilled worker had a reasonable expectation of success in having the CRISPR-Cas9 system be operative in eukaryotic cells.

Nor was the Board convinced based on the history of the development of CRISPR technology, which showed that many laboratories independent of the Doudna group quickly applied the new technology to manipulate eukaryotic cell genomic DNA:

Regardless of how many groups achieved success in eukaryotic cells, we are not persuaded that such success indicates there was an expectation of success before the results from these experiments were known.  The unpublished results of research groups are not necessarily an indication of whether ordinarily skilled artisans would have expected the results achieved.  Instead of viewing such work as evidence of an expectation of success, we consider the number of groups who attempted to use CRISPR-Cas9 in eukaryotic cells to be evidence of the motivation to do so, an issue that is not in dispute.  We agree with Broad's argument that a large reward might motivate persons to try an experiment even if the likelihood of success is very low.

The Board supported its determination with a survey of case law where the evidence showed there was, or was not, a reasonable expectation of success in obviousness determinations.  On balance, the Board found that this evidence further supported their decision that there was insufficient evidence of a reasonable expectation of success to support UC's allegation that their earlier work and publications would have rendered the Broad's invention obvious.  In this case, this evidence was that "differences in gene expression, protein folding, cellular compartmentalization, chromatin structure, cellular nucleases, intracellular temperature, intracellular ion concentrations, intracellular pH, and the types of molecules in prokaryotic versus eukaryotic cells, would contribute to this unpredictability [regarding whether the CRISPR-Cas9 system would be operative in eukaryotic cells]."  In response to UC's allegations that these considerations turned out not to be an impediment to CRISPR's activity in eukaryotic cells, the Board said "[t]he relevant question before us is whether those of skill in the art would have expected there to be problems before the experiments were done," not whether it turned out that the experiments were successful once they were tried.

Finally, the Board rejected UC's citation of other prokaryotic genetic modification systems found to work in eukaryotes, generally on the grounds that there was no "commonality" in these methods that would have refuted the Broad's evidence that the skilled worker would not have had any reasonable expectation of success.

In conclusion, the Board stated that "[w]e note that '[i]t is well-settled that a narrow species can be non-obvious and patent eligible despite a patent on its genus,'" citing AbbVie Inc. v. Mathilda & Terence Kennedy Inst. of Rheumatology Trust, 764 F.3d 8 1366, 1379 (Fed. Cir. 2014), and that "[a]n 'earlier disclosure of a genus does not necessarily prevent patenting a species member of the genus,'" citing Eli Lilly & Co. v. Bd. of Regents of Univ. of Wash., 334 F.3d 1264, 1270 (Fed. Cir. 2003).

UC/Berkeley has suggested in public statements that it may appeal the Board's decision.  It is well to recognize in this regard that the question of whether there is a reasonable expectation of success in an obviousness determination is a question of fact (see, e.g.,  Par Pharm., Inc. v. TWi Pharm., Inc., 773 F.3d 1186, 1196 (Fed. Cir. 2014)), and that the Federal Circuit must defer to the  PTAB's factual determinations under the substantial evidence standard of review.  Dickenson v. Zurko.  Accordingly, while appeal of this decision remains a possibility the manner in which the Board rendered its decision and its reasoning suggest that prevailing in such an appeal may be quite difficult.

Comments

[Cardinal Intellectual Property]

If the expectation of success of CRISPR/CAS9 in eukaryotes is the deciding factor, the following reference published 29 January 2013 might help UCB's case, if not used already. In this reference HEK 293T and HeLa cells were used. HEK 293T cells are human kidney cells (eukaryotic)(https://www.atcc.org/Products/All/CRL-11268.aspx), HeLa cells are Henrietta Lacks' cervical cancer cells (also eukaryotic)(http://www.the-scientist.com/?articles.view/articleNo/48492/title/Henrietta-Lacks-s-Family-Seeks-Compensation/):

Abstract: "the CRISPR-Cas system of Streptococcus pyogenes as programmable RNA-guided endonucleases (RGENs) to cleave DNA in a targeted manner for genome editing in human cells. We show that complexes of the Cas9 protein and artificial chimeric RNAs efficiently cleave two genomic sites and induce indels with frequencies of up to 33%."
Cho et al., Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease, Nature Biotechnology 31, 230–232 (2013), Published online 29 January 2013.

Supporting Information: Targeted genome engineering in human cells with RNA-guided endonucleases (http://www.nature.com/nbt/journal/v31/n3/extref/nbt.2507-S1.pdf).

"HEK 293T cells were co-transfected with Cas9-encoding plasmid (0.8 μg) and the RFP-GFP reporter plasmid (0.2 μg) in a 24-well plate using Lipofectamine 2000 (Invitrogen). At 12h post-transfection, sgRNA (1 μg) prepared by in vitro transcription was transfected using Lipofectamine 2000. At 3 d post-transfection, transfected cells were subjected to flow cytometry and cells expressing both RFP and GFP were counted.

HeLa cells transfected with the C4BPB-specific RGEN (160 μg sgRNA) were fixed on glass slides and incubated first with anti-TP53BP1 rabbit polyclonal antibodies (Bethyl Laboratories) and then with Alexa Fluor 488-conjugated secondary antibodies (InvitrogenMolecular Probes). Cells were mounted in the presence of DAPI (Sigma) and examined under an immunofluorescence microscope (Zeiss). DAPI (blue) and TP53BP1 (green)
images were merged. Etoposide (1 μM) was used as a positive control. The average number of foci per cell and the standard error of the mean are shown at the bottom of each picture.

[Kevin E. Noonan]

Dear CIP: I think the priority date in question was in 2012, so this (like many of the references cited by UC/Berkeley) was post-filing. The question is whether the skilled worker would have had a reasonable expectation of success at that time, so the Board was correct in not crediting this evidence as showing or supporting such an expectation.

Thanks for the comment.

[Cardinal Intellectual Property]

"Involved Applications and Patents" (see "Decision on Motions" pg 51 http://patentdocs.typepad.com/files/decision-on-motions.pdf)

UC
Application Number Filing Date
13/842,859, 15 March 2013 (61/652,086 provisional priority date May 25, 2012).

61/652,086 [00127] Non-limiting examples of suitable eukaryotic promoters (promoters functional in a eukaryotic cell) include those from cytomegalovirus (CMV) immediate early, herpes simplex virus (HSV) thymidine kinase, early and late SV40, long terminal repeats (LTRs) from retrovirus, and mouse metallothionein-1. Selection of the appropriate vector and promoter is well within the level of ordinary skill in the art. The expression vector may also contain a ribosome binding site for translation initiation and a transcription terminator. The expression vector may also include appropriate sequences for amplifying expression. The expression vector may also include nucleotide sequences encoding protein tags (e.g., 6xHis tag, hemagglutinin tag, green fluorescent protein, etc.) that are fused to the site-directed modifying polypeptide, thus resulting in a chimeric polypeptide.
[00152], [00165],[00175], [00198], [00202], [00216],[00218],
claim 69. The method of Claim 68, wherein the cell is a human cell. claims 99-109.

[Kevin E Noonan]

Yes, the provisional priority date was May 25, 2012. This is related to the Jinik reference discussed in the opinion. By the time they filed their March 15, 2013 application they had included the eukaryotic disclosure but UC did not have that disclosure in their original filing.

Moreover there were no claims directed to eukaryotic embodiments. That was the basis for the decision as I understand it.

Thanks for following up.

[Cardinal Intellectual Property]

Thanks, Kevin.
Based on what you indicated, is it fair to conclude that the listed claims and paragraphs from the provisional 61/652,086 [00127], [00152], [00165],[00175], [00198], [00202], [00216],[00218], claims 68- 69 and 99-109 etc. that I cited in my comment for support do not provide support and were invalid/unpatentable for lack of enabling disclosure (section 112?), i.e., the cited paragraphs are not enough to get a claim for Eukaryotes?

Jinek et al., A Programmable Dual-RNA–Guided
DNA Endonuclease in Adaptive Bacterial Immunity, 2012 publication was focussed on prokaryote, without any mention of the above paragraphs from the provisional app.

http://genetics.wustl.edu/bio5491/files/2013/03/Jinek-et.-al.-2012.pdf

I thought that the Patent Trial and Appeal Board declared "No interference" because the patent granted by USPTO to the Broad Institute, MIT and Harvard concerning CRISPR editing of eukaryotic genomes did not interfere with patent claims filed by UC Berkeley and the University of Vienna, clearing the way for UC Berkeley to receive patent on CRISPR-Cas9 gene editing; indicating species/genus relationship to Broad/UC claims (citing Abbvie); setting a stage for mutual licensing (both having claims to Eukaryotes, but different for interference purpose).
https://www.linkedin.com/post/edit/6238102651297427456.

[Kevin E Noonan]

The Board indicated that there was no dispute that UC/Berkeley did not have sufficient support to claim the eukaryotic embodiments at their earliest priority date and that this is the reason why there was no interference-in-fact.

I'm sure UC/Berkeley will challenge this conclusion as part of the appeal.