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Federal Circuit Affirms Patent Trial And Appeal Board Decision, Finding Claims Of Patents Covering CRISPR Guide RNA Technology As Anticipated And Obvious
06/16/2025On June 11, 2025, the United States Court of Appeals for the Federal Circuit affirmed the Patent Trial and Appeal Board (PTAB) decision invalidating two patents owned by Agilent Technologies. The patents at issue, U.S. Patent Nos. 10,337,001 and 10,900,034, claim synthetic CRISPR guide RNAs with specific chemical modifications intended to improve stability and functionality. This CRISPR-Cas system enables targeted DNA cleavage, with the gRNA (composed of crRNA and tracrRNA, or as a single-molecule sgRNA) directing the Cas protein to specific DNA sequences.
The case came before the PTAB after Synthego Corp. filed two petitions for inter partes review (IPR) challenging all claims of the '001 and '034 patents. The key prior art references considered were Pioneer Hi-Bred (2015), which discloses methods and compositions for genome modification using guide polynucleotide/Cas endonuclease systems, including chemically modified guide RNAs, Threlfall (2011) which describes oligoribonucleotides with phosphonoacetate (PACE) or thiophosphonoacetate (thioPACE) modifications known to increase nuclease resistance, and Deleavey (2012) which reviews chemical modifications to oligonucleotides for gene regulation, including modifications to inter-nucleotide linkages and nucleotide sugars.
The PTAB found that all claims of both patents were unpatentable as anticipated and obvious. For anticipation, the PTAB determined that Pioneer Hi-Bred anticipated the majority of the claims by expressly disclosing the claimed gRNA functionality (association with Cas protein and DNA targeting) and the relevant chemical modifications. The PTAB found Pioneer Hi-Bred to be enabling, meaning a skilled artisan could make and use the claimed invention without undue experimentation. Additionally, the PTAB found the remaining dependent claims reciting specific modifications (e.g., PACE, thioPACE) as obvious in view of Pioneer Hi-Bred combined with Threlfall or Deleavey. The PTAB concluded that a skilled artisan would have been motivated to combine these references and would have had a reasonable expectation of success.
Agilent appealed, arguing that: (i) substantial evidence did not support the Board’s finding that Pioneer Hi-Bred expressly discloses the claimed gRNA functionality; (ii) even if Pioneer Hi-Bred discloses the functionality, it was not enabling as an anticipatory reference; and (iii) the PTAB’s finding of a reasonable expectation of success in combining Pioneer Hi-Bred with Threlfall or Deleavey (for obviousness) was not supported by substantial evidence.
The Federal Circuit affirmed the PTAB decision, finding the claims anticipated and obvious. Regarding the express disclosure of gRNA Functionality in Pioneer Hi-Bred, the Court found that substantial evidence supported the PTAB’s finding that Pioneer Hi-Bred expressly discloses the claimed gRNA functionality—namely, the ability of the guide RNA to associate with a Cas protein and target the gRNA:Cas protein complex to a specific polynucleotide sequence. The Court reasoned that the PTAB had sufficiently cited specific examples and statements in Pioneer Hi-Bred, including definitions and examples showing that the guide polynucleotide can form a complex with a Cas endonuclease and enable recognition and cleavage of a DNA target site, descriptions of chemically modified guide RNAs and their use in CRISPR-Cas systems, including modifications to nucleotide bases and phosphodiester linkages to increase stability and reduce degradation, and statements that modified guide polynucleotides may be delivered with other system components to form a functional complex capable of binding and/or cleaving chromosomal DNA.
The Court also found that Pioneer Hi-Bred, as an anticipatory reference, was enabled. The Court highlighted that anticipation requires only an enabling disclosure, not actual reduction to practice or proof of efficacy. Following the Wands factors, a person of ordinary skill in the art, as of December 2014, could have practiced the disclosed inventions without undue experimentation because the techniques for synthesizing long, chemically modified oligonucleotides were known in the art, including click chemistry and TC chemistry. The state of the art, while relatively new, was not a blank slate. Substantial research had been published, and the types of chemical modifications claimed had been used for decades to stabilize RNA in other systems. Further, Pioneer Hi-Bred provides specific examples of modified crRNA sequences and teaches that these could be used in CRISPR-Cas systems.
The Court further affirmed as obvious the remaining dependent claims requiring specific modifications (e.g., PACE, thioPACE), as obvious in view of Pioneer Hi-Bred combined with Threlfall or Deleavey because the PTAB had provided adequate reasoning. The PTAB conducted comprehensive analysis of why a skilled artisan would have been motivated to combine the references, including the known benefits of the modifications (increased resistance to degradation, enhanced cellular uptake). The PTAB found that, by December 2014, several studies had shown that the CRISPR/Cas system could tolerate various chemical modifications, and multiple groups had independently suggested the same types of modifications to improve gRNA stability. Further, there was no evidence in the record suggesting that the claimed modifications would not work in CRISPR systems, and Agilent’s own expert conceded that the modifications were suggested in the art. The Court found that the PTAB’s analysis of reasonable expectation of success was thorough and supported by substantial evidence, including the state of the art and the lack of contrary evidence.
This decision highlights that the prior art enablement standard in the context of anticipation is less demanding than in the context of Section 112 patent validity. Further, it shows that, when reviewing factual findings by the PTAB, the substantial evidence standard is very deferential. If the record supports two possible conclusions, the Board’s choice of one of the two will be upheld. Last, the decision clarified that a prior art reference does not need to provide experimental proof or working examples of every embodiment to anticipate a claim. Here, the Pioneer Hi-Bred reference was found to expressly disclose the claimed gRNA functionality (association with Cas protein and targeting), even though some examples were prophetic or non-working. The presence of some non-functional examples does not negate the disclosure of functional ones.
