The U.S. Court of Appeals for the Federal Circuit has affirmed Patent Trial and Appeal Board (PTAB) decisions invalidating Agilent Technologies' patents covering chemically modified CRISPR guide RNAs, marking a significant victory for Synthego Corp. and potentially clearing obstacles for CRISPR therapeutic development.
In a precedential decision issued on June 11, 2025, the Federal Circuit upheld PTAB's inter partes review (IPR) rulings that invalidated U.S. Patent Nos. 10,337,001 and 10,900,034. The patents claimed chemically modified synthetic CRISPR guide RNAs featuring modifications like 2'-O-methyl and phosphonoacetate near their ends, alterations purported to enhance stability and functionality in genome-editing applications.
Patent Challenge and PTAB Findings
Synthego Corp. challenged the validity of these patents through IPR proceedings, asserting that the claims were either anticipated by or rendered obvious in view of a 2014 scientific publication known as Pioneer Hi-Bred, combined with additional prior art literature. The PTAB's original decision, dated May 17, 2023, invalidated all claims of the Agilent patents, which were directed to guide RNAs having at least one 2'-O-methyl modification and guide RNAs having certain modifications within 5 nucleotides of their 5' and/or 3' end, as well as methods of using such modified guide RNAs for CRISPR gene editing.
Federal Circuit's Key Rulings
The Federal Circuit addressed three primary arguments from Agilent on appeal. First, regarding gRNA functionality, Agilent argued Pioneer Hi-Bred did not explicitly disclose the required ability of modified guide RNAs to associate with Cas proteins and accurately target DNA sequences. The court rejected this argument, affirming that substantial evidence demonstrated Pioneer Hi-Bred expressly disclosed chemically modified guide RNAs capable of binding Cas proteins and targeting DNA sequences.
On enablement, Agilent challenged whether the publication sufficiently guided skilled artisans to practice the claimed invention without undue experimentation. The court reiterated the longstanding presumption that printed publications used as anticipatory references under Section 102 are presumed to be enabled, drawing a clear distinction between the enablement standard required for anticipation and the broader full-scope enablement standard applicable under Section 112, as recently articulated by the Supreme Court in Amgen v. Sanofi.
"The Federal Circuit clarified that for anticipation under § 102, enablement requires only one operable embodiment, not the full scope of claims mandated under § 112," the court stated, emphasizing that enablement need only show that one embodiment within the prior art reference is operable without undue experimentation.
Obviousness and Chemical Modifications
Regarding obviousness, Agilent argued against determinations concerning specific chemical modifications, specifically PACE and thioPACE, contending there was no reasonable expectation these modifications would maintain necessary functionality of guide RNAs. The Federal Circuit disagreed, affirming PTAB's conclusion by pointing to contemporaneous literature suggesting these chemical modifications would likely enhance RNA stability without impairing intended functionality.
The court also rejected Agilent's procedural objections under the Administrative Procedure Act, finding no merit in allegations of inadequate notice from PTAB regarding its interpretation of "gRNA functionality."
Industry Impact and Future Implications
"This critical decision, affirming that Agilent's claims on chemically modified gRNAs are unpatentable, keeps the path clear for broader innovation and advancement in the CRISPR therapeutics market," said Craig Christianson, CEO of Synthego. "Synthego will continue our focus on supporting our clients' efforts to enhance human health with curative cell and gene therapies."
The ruling underscores the considerable evidentiary burden patentees face when attempting to rebut the presumption of enablement for anticipatory prior art. The court's clarification highlights the narrower requirement for anticipation, contrasting sharply with the broader full-scope enablement required for patent claims, and underscores the Federal Circuit's deferential substantial evidence review standard for factual findings by the PTAB.
Synthego continues to support innovation in CRISPR-enabled research and therapeutics, with this affirmation enabling researchers and therapeutic developers to continue driving successful patient outcomes through streamlined licensing models and technical expertise in CRISPR cell and gene therapies.
