Agilent Technologies, Inc. v. Synthego Corp.

United States Court of Appeals
for the Federal Circuit
______________________
AGILENT TECHNOLOGIES, INC.,
Appellant
v.
SYNTHEGO CORP.,
Appellee
______________________
2023-2186, 2023-2187
______________________
Appeals from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in Nos. IPR2022-
00402, IPR2022-00403.
______________________
Decided: June 11, 2025
______________________
MARK A. LEMLEY, Lex Lumina PLLC, Los Angeles, CA,
argued for appellant. Also represented by DENISE MARIE
DE MORY, AARON HAND, Bunsow De Mory LLP, Redwood
City, CA; R EBECCA EMILY WEIRES, Morrison & Foerster
LLP, Los Angeles, CA.
E DWARD R. R EINES, Jones Day, Palo Alto, CA, argued
for appellee. Also represented by DEREK C. WALTER , San
Francisco, CA.
______________________
Before P ROST, L INN, and REYNA , Circuit Judges.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 2
P ROST, Circuit Judge.
Agilent Technologies, Inc. (“Agilent”) appeals from two
final written decisions of the Patent Trial and Appeal
Board (“Board”) determining that all claims of U.S. Patent
Nos. 10,337,001 (“the ’001 patent”) and 10,900,034 (“the
’034 patent”) are unpatentable. Because the Board did not
commit legal error and substantial evidence supports its
factual findings, we affirm.
B ACKGROUND
I
The technology at issue relates to CRISPR-Cas1 sys-
tems for gene editing. At a high level, the CRISPR-Cas
system at issue here includes three components: (1) “non-
coding RNA species referred to as CRISPR RNA (‘crRNA’)”;
(2) “trans-acting RNA (‘tracrRNA’)”; and (3) the CRISPR-
associated (“Cas”) protein. ’001 patent col. 1 ll. 23–36. The
guide RNA, also known as “gRNA” or “double-molecule
gRNA,” is made up of two parts: a crRNA and a tracrRNA.
Id. at col. 1 ll. 33–36, 49–51. A single-molecule gRNA, also
known as a “sgRNA,” combines the crRNA and tracrRNA
on a single strand through a linker loop. Id. at col. 1 ll.
49–51; J.A. 473.
The CRISPR-Cas system permits one to selectively
cleave DNA at particular target sites. The gRNA and the
Cas protein bind to form a single complex. ’001 patent col.
1 ll. 36–37. The gRNA directs the gRNA-Cas complex to a
targeted DNA sequence, binds with the target DNA, and
then the Cas protein cleaves the DNA sequence at that lo-
cation. Id. at col. 1 ll. 36–43. For the CRISPR-Cas system
to work effectively, it needs to be able to bind to the target
1 “CRISPR” stands for “clusters of regularly inter-
spaced short palindromic repeats.” ’001 patent col. 1 ll.
18–19.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 3
polynucleotide sequence, the gRNA needs to remain stable
and resist degradation, and the gRNA needs to maintain
its functionality. Id. at col. 1 ll. 60–67.
The ’001 patent issued on July 2, 2019, claims priority
to a series of provisional applications, the earliest of which
was filed on December 3, 2014, and is assigned to Agilent.
The ’034 patent issued on January 26, 2021, claims priority
to a series of provisional applications, the earliest of which
was filed on December 3, 2014, and is assigned to Agilent.
The ’001 and ’034 patents are directed to chemically modi-
fied gRNAs and their use in the CRISPR-Cas system. Rep-
resentative claim 1 in each of the ’001 and ’034 patents is
reproduced below:
A synthetic CRISPR guide RNA having at least one
5′-end and at least one 3′-end, the synthetic guide
RNA comprising:
(a) one or more modified nucleotides within
five nucleotides from said 5′-end, or
(b) one or more modified nucleotides within
five nucleotides from said 3′-end, or
(c) both (a) and (b);
wherein said guide RNA comprises one or
more RNA molecules, and has gRNA func-
tionality comprising associating with a Cas
protein and targeting the gRNA:Cas protein
complex to a target polynucleotide, wherein
the modified nucleotide has a modification
to a phosphodiester linkage, a sugar, or
both.
’001 patent claim 1 (emphasis added).
A synthetic CRISPR guide RNA comprising:
(a) a crRNA segment comprising (i) a guide
sequence capable of hybridizing to a target
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 4
sequence in a polynucleotide, (ii) a stem se-
quence; and
(b) a tracrRNA segment comprising a nu-
cleotide sequence that is partially or com-
pletely complementary to the stem
sequence,
wherein the synthetic guide RNA has
gRNA functionality comprising associating
with a Cas protein and targeting the
gRNA:Cas protein complex to the target se-
quence, and comprises one or more modifi-
cations in the guide sequence, wherein the
one or more modifications comprises a 2′-O-
methyl.
’034 patent claim 1 (emphasis added). The dependent
claims narrow the modifications of the nucleotides to par-
ticular types of phosphodiester linkage or sugar modifica-
tions and combinations thereof. See, e.g., ’001 patent claim
8 (“The synthetic guide RNA of claim 1 wherein said guide
RNA comprises a modified internucleotide linkage or a
modified terminal phosphate group selected from a phos-
phonocarboxylate, a phosphonoacetate, and a phosphono-
thioacetate group.”); ’034 patent claim 6 (“The synthetic
guide RNA of claim 1, wherein said one or more modifica-
tions comprises a 2′-O-methyl nucleotide with a 3′-phos-
phonoacetate.”).
II
The key prior art relevant to the Board’s anticipation
determination is Pioneer Hi-Bred.2 Pioneer Hi-Bred was
filed on August 20, 2014, by Pioneer Hi-Bred International,
Inc. and is titled “Genome Modification Using Guide
2 Int’l Pub. No. WO 2015/026885 A1 (“Pioneer Hi-
Bred”), J.A. 2588–2736.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 5
Polynucleotide/Cas Endonuclease Systems and Methods of
Use.” Pioneer Hi-Bred Title (capitalization omitted). Pio-
neer Hi-Bred discloses “[c]ompositions and methods” for
“employing a guide polynucleotide/Cas endonuclease sys-
tem for genome modification of a target sequence in the ge-
nome of a cell or organism, for gene editing, and for
inserting a polynucleotide of interest into the genome of a
cell or organism.” Id. at 2 ll. 1–5.3 It also defines “guide
polynucleotide” to mean “a polynucleotide sequence that
can form a complex with a Cas endonuclease and enables
the Cas endonuclease to recognize and optionally cleave a
DNA target site.” Id. at 24 ll. 6–8. A “guide polynucleotide”
“can be a single molecule or a double molecule” and a “guide
polynucleotide that solely comprises ribonucleic acids is
also referred to as a ‘guide RNA.’” Id. at 24 ll. 8–9, 19–20.
In Example 4, Pioneer Hi-Bred discloses “modifying the nu-
cleotide base, phosphodiester bond linkage or molecular to-
pography of the guiding nucleic acid component(s) of the
guide polynucleotide/Cas endonuclease system” “for in-
creasing cleavage activity and specificity.” Id. at 104 l. 19–
105 l. 2. “To increase the effective lifespan or stability of
the nucleic acid component(s) of the guide polynucleo-
tide/Cas endonuclease system in vivo, nucleotide and/or
phosphodiester bond modifications may be introduced to
reduce unwanted degradation.” Id. at 106 ll. 14–17.
Relevant to this appeal, there are two additional prior-
art references that the Board relied on to determine certain
claims were unpatentable for obviousness: Threlfall4 and
3 The pages cited correspond to the page numbers of
Pioneer Hi-Bred itself.
4 Richard N. Threlfall et al., Synthesis and Biologi-
cal Activity of Phosphonoacetate- and Thiophosphonoace-
tate-modified 2′-O-methyl Oligoribonucleotides, 10 Org.
Biomol. Chem., 746–54 (2011) (“Threlfall”), J.A. 2773–81.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 6
Deleavey.5 Threlfall is a scientific article published on No-
vember 29, 2011. Threlfall describes “[c]himeric 2′-O-me-
thyl oligoribonucleotides (2′-OMe ORNs) containing
internucleotide linkages which were modified with phos-
phonoacetate (PACE) or thiophosphonoacetate (thio-
PACE).” J.A. 2773. Threlfall explains that
“[o]ligoribonucleotides with a 2′-O-methyl modification (2′-
OMe ORNs) are known to be nuclease resistant and in-
crease the stability of a duplex which is formed with com-
plementary RNA.” J.A. 2773 (footnote omitted). And
Threlfall notes that in “a previous study, [oligodeoxynucle-
otides] modified with PACE or thioPACE were shown to be
nuclease resistant.” J.A. 2773.
Deleavey is a scientific article published on August 24,
2012. According to Deleavey, there were several “obsta-
cles” with using chemically modified oligonucleotides, in-
cluding RNA molecules, for gene regulation purposes, such
as: “(1) their poor extracellular and intracellular stability,
(2) low efficiency of intracellular delivery to targets cells or
tissues, and (3) the potential for ‘off-target’ gene silencing,
immunostimulation, and other side effects.” J.A. 2737. To
overcome these “obstacles,” Deleavey discusses “a vast ar-
ray” of chemical modifications that have been developed,
J.A. 2737, including specific chemical modifications to in-
ternucleotide linkages, J.A. 2743 (Fig. 4), and to nucleotide
sugars, J.A. 2746 (Fig. 6).
III
Synthego Corp. (“Synthego”) filed two petitions for in-
ter partes review (“IPR”) of all claims of the ’001 and ’034
patents. J.A. 448, 9106. After instituting review on all
5 Glen F. Deleavey et al., Designing Chemically Mod-
ified Oligonucleotides for Targeted Gene Silencing, 19
Chem. & Bio. Review, 937–54 (2012) (“Deleavey”), J.A.
2737–54.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 7
claims, the Board found that every claim in both the ’001
and ’034 patents is unpatentable. J.A. 1–143.6 In particu-
lar, the Board found that Pioneer Hi-Bred anticipated
claims 1–7, 9–10, 12–15, 17–18, 20–25, and 27–30 of the
’001 patent and claims 1–5, 8–21, and 24–33 of the ’034 pa-
tent. The Board reasoned that Pioneer Hi-Bred both dis-
closes a functional gRNA and is enabling. The Board also
found Synthego had shown that claims 8, 11, 16, 19, and 26
of the ’001 patent and claims 6–7 and 22–23 of the ’034 pa-
tent would have been obvious in view of Pioneer Hi-Bred
and Threlfall or Deleavey. The Board relied on “Pioneer
Hi-Bred for the limitations of the independent claims and
Threlfall and Deleavey for their disclosure of ‘phosphono-
acetate’ and ‘phosphonothioacetate’ (i.e., PACE and thio-
PACE) modifications as recited in claims 8 and 16 and ‘2[′]-
O-methyl-3[′]-phosphonoacetate’ and ‘2[′]-O-methyl-3[′]-
phosphonothioacetate’ nucleotides as recited in claims 11,
19, and 26” of the ’001 patent. J.A. 58; see also J.A. 133
(similar for claims 6–7 and 22–23 of the ’034 patent).
Agilent timely appealed. We have jurisdiction under
28 U.S.C. § 1295(a)(4)(A).
DISCUSSION
“We review the Board’s legal determinations de novo
and its fact findings for substantial evidence.” Provisur
Techs., Inc. v. Weber, Inc., 50 F.4th 117, 124 (Fed. Cir.
2022). Because “[a]nticipation is a question of fact,” we re-
view “the Board’s determination of what is taught in the
prior art at issue” for substantial evidence. St. Jude Med.,
LLC v. Snyders Heart Valve LLC, 977 F.3d 1232, 1238
6 The two final written decisions at issue in this ap-
peal are substantially similar. In this opinion, we will cite
to the final written decision in IPR No. 2022-00402 (J.A. 1–
67), unless the record of IPR No. 2022-00403 (J.A. 68–143)
provides a relevant difference.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 8
(Fed. Cir. 2020); see also Oral Arg. at 5:14–40 (Agilent
agreeing substantial-evidence review applies to determine
whether Pioneer Hi-Bred expressly discloses the claimed
gRNA functionality).7 “Whether a prior[-]art reference is
enabling is a question of law based on underlying factual
findings.” In re Morsa, 803 F.3d 1374, 1376 (Fed. Cir.
2015). “For obviousness, the ultimate determination is a
legal one reviewed de novo, but underlying factual deter-
minations are reviewed for substantial-evidence support.”
St. Jude Med., 977 F.3d at 1238. Whether there is a rea-
sonable expectation of success is a question of fact. Teva
Pharms. USA v. Corcept Therapeutics, Inc., 18 F.4th 1377,
1380–81 (Fed. Cir. 2021). “Substantial[-]evidence review
asks whether a reasonable fact finder could have arrived at
the agency’s decision and requires examination of the rec-
ord as a whole, taking into account evidence that both jus-
tifies and detracts from an agency’s decision.” Intelligent
Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359,
1366 (Fed. Cir. 2016) (cleaned up). “Where two different
conclusions may be warranted based on the evidence of rec-
ord, the Board’s decision to favor one conclusion over the
other is the type of decision that must be sustained by this
court as supported by substantial evidence.” In re Chudik,
851 F.3d 1365, 1371 (Fed. Cir. 2017) (quoting In re Bayer
Aktiengesellschaft, 488 F.3d 960, 970 (Fed. Cir. 2007)).
Agilent raises three main issues on appeal. First, it
argues that substantial evidence does not support the
Board’s finding that Pioneer Hi-Bred expressly discloses
gRNA functionality. Second, it argues that, even if the
Board did not err in finding that Pioneer Hi-Bred discloses
gRNA functionality, Pioneer Hi-Bred is not enabling.
Third, it contends that substantial evidence does not sup-
port the Board’s finding that a skilled artisan would
7 No. 23-2186, https://oralarguments.cafc.uscourts.
gov/default.aspx?fl=23-2186_03072025.mp3.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 9
reasonably expect PACE and thioPACE modifications to
gRNA in a CRISPR-Cas system to be successful. We ad-
dress each argument in turn.
I
As to the first issue—whether Pioneer Hi-Bred ex-
pressly discloses the claimed functional gRNA—we con-
clude that substantial evidence supports the Board’s
finding.
The Board found that Pioneer Hi-Bred discloses the
claimed gRNA functionality, i.e., associating with a Cas
protein and targeting the gRNA:Cas protein complex to a
target polynucleotide. It explained that “Pioneer Hi-Bred
discloses that the guide polynucleotides described therein
can: (1) form a complex with a Cas endonuclease; and
(2) enable the endonuclease to recognize a DNA target site.
That disclosure reads on both the associating and targeting
aspects of the ‘gRNA functionality’ recited” in the chal-
lenged claims. J.A. 18. Specifically, the Board cited to the
modified sequences in Examples 4 and 5 of Pioneer Hi-
Bred. J.A. 18. Example 4 is titled “[m]odifying nucleic acid
component(s) of the guide polynucleotide/Cas endonuclease
system to increase cleavage activity and specificity,”
J.A. 2693, and Example 5 is titled “[e]xamining the effect
of nucleotide base and phosphodiester bond modifications
to the guide polynucleotide component of the guide polynu-
cleotide/Cas endonuclease system in maize,” J.A. 2697.
The Board found that “Pioneer Hi-Bred refers to the modi-
fied sequences in Examples 4 and 5 as ‘modified guide nu-
cleotides,’ indicating that those sequences have [the
claimed gRNA] functionality.” J.A. 18. The Board also
cited to several statements in Pioneer Hi-Bred further sup-
porting its findings. See, e.g., J.A. 18 (citing Pioneer Hi-
Bred at 107 ll. 14–24 (explaining that modified guide poly-
nucleotides may be delivered with the other components of
the “guide polynucleotide/Cas endonuclease system” to
“form a functional complex capable of binding and/or
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 10
cleaving a chromosomal DNA target site”); Pioneer Hi-Bred
at 107 l. 24–108 l. 2 (“Modified guide polynucleotides de-
scribed above may also be delivered simultaneously in mul-
tiplex to target multiple chromosomal DNA sequences for
cleavage or nicking.”)). The Board clarified that “[w]hile
the claimed ‘gRNA functionality’ does not require cleavage,
the fact that cleavage occurs at a target site indicates that
a gRNA is capable of associating with a Cas endonuclease
and targeting it to a particular site.” J.A. 18 n.9.
Agilent contends that Pioneer Hi-Bred does not ex-
pressly disclose the gRNA functionality, but only discusses
a research plan to test for functionality of modified guide
polynucleotides, such as Example 5, J.A. 2697, and falls
short of stating that any particular modified guide would
actually exhibit gRNA functionality. Agilent argues that
the statements in Pioneer Hi-Bred relied on by the Board
cannot be read as disclosures of functionality largely be-
cause Pioneer Hi-Bred does not differentiate functional
from non-functional guides. See, e.g., Appellant’s Br.
30–32; Reply Br. 1–12.
Agilent also argues that data in Pioneer Hi-Bred show-
ing no cleavage for a particular modified gRNA (and some
later testing of other modified guide polynucleotides dis-
closed in Pioneer Hi-Bred that did not show cleavage)
demonstrates that Pioneer Hi-Bred does not disclose gRNA
functionality. The Board rejected these arguments. It held
that cleavage “is not required for the ‘gRNA functionality’”
in the challenged claims and also cited Agilent’s own expert
admitting that “just because a gRNA in Table 4 [in Pioneer
Hi-Bred] lacks cleavage activity does not demonstrate that
it also lacks the ability to bind a Cas protein and target
that complex to target polynucleotide.” J.A. 25. The Board
found that “the data in Table 4 of [Pioneer Hi-Bred’s]
[s]pecification showing a lack of cleavage activity does not
demonstrate that the corresponding gRNA lacks the
claimed ‘gRNA functionality.’” J.A. 26. The disclosure of
some non-working examples in Pioneer Hi-Bred does not
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 11
undermine the disclosure of other examples that were dis-
closed as functional. Agilent has not demonstrated that
this finding lacks substantial evidence.
The Board also found Pioneer Hi-Bred’s statements as
express disclosures of functionality. See, e.g., J.A. 18 (cit-
ing Pioneer Hi-Bred at 107 l. 24–108 l. 2 (“Modified guide
polynucleotides described above may also be delivered sim-
ultaneously in multiplex to target multiple chromosomal
DNA sequences for cleavage or nicking.”)), J.A. 12 (citing
Pioneer Hi-Bred at 106 ll. 17–21 (“Examples of nuclease
resistant nucleotide and phosphodiester bond modifica-
tions are shown in Table 7 and may be introduced . . . at
the 5' and 3' ends of any one of the nucleic acid residues
comprising the VT or GER domains to inhibit exonuclease
cleavage activity.”)), J.A. 12–13 (“According to Pioneer Hi-
Bred, these modified guide polynucleotides may be used ‘in
any organism subject to genome modification with the
guide polynucleotide/Cas endonuclease system.’” (quoting
Pioneer Hi-Bred at 108 ll. 3–5)).
To the extent that Agilent argues that Pioneer Hi-Bred
does not disclose gRNA functionality because a person of
ordinary skill in the art would not know how to create a
functional modified guide from the disclosure because of
the number of non-working examples, we view this argu-
ment as one related to whether Pioneer Hi-Bred is an ena-
bling anticipatory reference rather than whether Pioneer
Hi-Bred expressly discloses the claimed gRNA functional-
ity. We address why Pioneer Hi-Bred is an enabling antic-
ipatory reference in Section II of this opinion’s Discussion.
For the foregoing reasons, substantial evidence sup-
ports the Board’s finding that Pioneer Hi-Bred expressly
discloses the claimed gRNA functionality, i.e., associating
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 12
with a Cas protein and targeting the gRNA:Cas protein
complex to a target polynucleotide.8
II
Turning to the Board’s enablement analysis, we see no
error in the Board’s conclusion that Pioneer Hi-Bred is en-
abling.
A finding of anticipation “does not require the actual
creation or reduction to practice of the prior art subject
matter; anticipation requires only an enabling disclosure.”
Schering Corp. v. Geneva Pharms., 339 F.3d 1373, 1380
(Fed. Cir. 2003). “[P]roof of efficacy is not required in order
8 Agilent also argues that the Board violated the re-
quirements of notice and an opportunity to respond found
in the Administrative Procedure Act (“APA”). Appellant’s
Br. 32–34; Reply Br. 12–14. Specifically, Agilent argues
that the final written decisions were “the first time either
Synthego or the Board explained that it read the mere use
of the term ‘modified guide polynucleotide’ as an express
disclosure of the claimed functionality.” Reply Br. 12. The
notice and opportunity-to-be-heard provisions of the APA
have been applied “to mean that ‘an agency may not change
theories in midstream without giving respondents reason-
able notice of the change’ and ‘the opportunity to present
argument under the new theory.’” Belden v. Berk–Tek
LLC, 805 F.3d 1064, 1080 (Fed. Cir. 2015) (quoting Rodale
Press, Inc. v. FTC, 407 F.2d 1252, 1256–57 (D.C. Cir.
1968)). Here, the Board did not “change theories in mid-
stream.” The Board based its decision on more than just
the definition of “guide polynucleotide” in Pioneer Hi-Bred.
See, e.g., J.A. 18, 20–21. And the question of whether the
modified guide polynucleotide met the gRNA functionality
limitation was central to the entire IPR proceedings. See,
e.g., J.A. 489–90 (petition), 698 (Board’s institution deci-
sion). We thus reject Agilent’s APA-based arguments.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 13
for a reference to be enabled for purposes of anticipation.”
Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318,
1326 (Fed. Cir. 2005). “Enablement of prior art requires
that the reference teach a skilled artisan—at the time of
filing—to make or carry out what it discloses in relation to
the claimed invention without undue experimentation.” In
re Morsa, 803 F.3d at 1377. “For a prior-art reference to be
enabling, it need not enable the [challenged] claim in its
entirety, but instead the reference need only enable a sin-
gle embodiment of the claim.” Id.; see also Schering,
339 F.3d at 1381 (“An anticipatory reference need only en-
able subject matter that falls within the scope of the claims
at issue, nothing more.”). Prior art disclosures are pre-
sumed enabling. Impax Labs., Inc. v. Aventis Pharms.,
Inc., 545 F.3d 1312, 1316 (Fed. Cir. 2008) (reaffirming that
an anticipating prior art patent is presumptively enabled);
In re Antor Media Corp., 689 F.3d 1282, 1288 (Fed. Cir.
2012) (extending the presumption to printed publications).
In assessing whether undue experimentation is re-
quired, the Board considered the Wands factors and found
that the “record demonstrates that a [person of ordinary
skill in the art], as of December 2014, could practice these
disclosures without undue experimentation.” J.A. 29; see
also J.A. 29 n.13 (citing In re Wands, 858 F.2d 731 (Fed.
Cir. 1988)). The Board rejected Agilent’s argument that it
would have been “extremely challenging for a [person of or-
dinary skill in the art] to chemically synthesize the claimed
chemically-modified gRNA.” J.A. 30 (cleaned up). It noted
that the ’001 and ’034 patents’ specifications “refer[] to the
use of click chemistry and TC chemistry techniques,” which
both parties’ experts agreed were techniques “known in the
prior art for synthesizing long oligonucleotides.” J.A. 29–
30. The Board also found that “while it appears that Ex-
amples 4 and 5 in Pioneer Hi-Bred are prophetic, as op-
posed to working[] examples, that fact alone does not
undermine the presumption that Pioneer Hi-Bred is ena-
bled.” J.A. 31. And it also rejected Agilent’s argument that
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 14
“the nascent state of the art demonstrates that undue ex-
perimentation would be required.” J.A. 32. It found that
“[i]t is undisputed that the use of gRNA in a CRISPR/Cas
system was a relatively new discovery first published in
mid-2012. That said, the record demonstrates that by De-
cember 2014 substantial research into such systems had
been published and would have been known to a [person of
ordinary skill in the art].” J.A. 32 (internal citations omit-
ted). The Board also found that:
[W]hile the art was somewhat unpredictable in De-
cember 2014, it was far from a blank slate with a
[person of ordinary skill in the art] understanding
how the different elements of a CRISPR/Cas sys-
tem are used and function together, including the
role of gRNA; the types of chemical modifications
that had been successfully used in other systems to
reduce RNA degradation, while preserving func-
tionality; and standard techniques for making
gRNAs with the modifications disclosed and exem-
plified in Pioneer Hi-Bred.
J.A. 32. Considering these findings, the Board concluded
that “undue experimentation would not have been required
to make and use a gRNA with the recited chemical modifi-
cations and functionality.” J.A. 33.
On appeal, Agilent argues that Impax is analogous to
the facts here. We disagree and conclude there are im-
portant distinctions between that case and this one. One
of the issues in Impax was whether a prior-art patent was
an enabling prior-art reference. We affirmed the district
court’s finding that the prior-art patent was not an ena-
bling prior-art reference. Impax, 545 F.3d at 1316. The
prior-art patent in Impax “disclose[d] hundreds or thou-
sands of compounds and several diseases,” as well as
“broad and general” dosage guidelines “without sufficient
direction or guidance to prescribe a treatment regimen.”
Id. at 1315. Unlike the prior-art reference at issue in
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 15
Impax, “Pioneer Hi-Bred exemplifies particular crRNA se-
quences having the recited chemical modifications at the
recited locations and teaches that gRNA comprising such
may be used as guide polynucleotides in a CRISPR Cas sys-
tem.” J.A. 33; see also Pioneer Hi-Bred at 107 (Table 7)
(disclosing five types of “[n]ucleotide base and phos-
phodiester bond modifications to decrease unwanted nucle-
ase degradation”); id. at 109–10 (Table 8) (disclosing
exemplary sequences of chemically modified crRNAs de-
scribed in Table 7). The Board found that “the particular
types of chemical modifications disclosed in Pioneer Hi-
Bred and recited in the challenged claims had been known
and used for decades to stabilize RNA against unwanted
degradation in other systems.” J.A. 32.
Agilent also likens this case to Amgen Inc. v. Sanofi,
598 U.S. 594 (2023).9 In Amgen, the asserted claims were
entirely functionally defined such that the patentee
“s[ought] to monopolize an entire class of things defined by
their function—every antibody that both binds to particu-
lar areas of the sweet spot of PCSK9 and blocks PCSK9
from binding to LDL receptors.” Id. at 613. The patentee
claimed the entire genus of antibodies that performed the
claimed functions. Id. at 602. As a result of the breadth of
the asserted claims, the Supreme Court concluded that a
person of ordinary skill in the art would have been “forced
to engage in painstaking experimentation to see what
works.” Id. at 614 (cleaned up). The Supreme Court qual-
ified its holding by stating that a specification does not “al-
ways” have to “describe with particularity how to make and
use every single embodiment within a claimed class.” Id.
at 610–11. “Nor is a specification necessarily inadequate
just because it leaves the skilled artist to engage in some
measure of adaptation or testing.” Id. at 611. Indeed, “[a]
9 Amgen issued after the Board’s final written deci-
sions issued.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 16
specification may call for a reasonable amount of experi-
mentation to make and use a patented invention,” and
“[w]hat is reasonable in any case will depend on the nature
of the invention and the underlying art.” Id. at 612.
This case is different in two meaningful ways. First,
the issue in Amgen was whether the asserted claims were
sufficiently enabling to be valid under 35 U.S.C. § 112, not
whether a prior-art reference was enabling and could thus
support anticipation. These are two separate inquiries.
See Novo Nordisk Pharms., Inc. v. Bio-Tech. Gen. Corp.,
424 F.3d 1347, 1355 (Fed. Cir. 2005). The reason for this
distinction “is that [§] 112 ‘provides that the specification
must enable one skilled in the art to “use” the invention
whereas [35 U.S.C. §] 102 makes no such requirement as
to an anticipatory disclosure.’” Rasmusson, 413 F.3d at
1325 (quoting In re Hafner, 410 F.2d 1403, 1405 (CCPA
1969)).10 Second, while the patent in Amgen required
“painstaking experimentation to see what works,” here the
Board found a person of ordinary skill in the art understood
“how the different elements of a CRISPR/Cas system are
used and function together, including the role of gRNA; the
types of chemical modifications that had been successfully
used in other systems to reduce RNA degradation, while
10 Indeed, in Amgen, the issue before the Supreme
Court was whether the patents’ specifications at issue “en-
able[d] the full scope of the invention as defined by its
claims.” Amgen, 598 U.S. at 610. In the § 112 context, en-
ablement ensures the patentee does not obtain a broader
monopoly than the specification teaches. Id. at 613 (“For if
our cases teach anything, it is that the more a party claims,
the broader the monopoly it demands, the more it must en-
able.”). That is not a concern in the enabling anticipatory
prior art context. Rather, an enabling anticipatory prior-
art reference “need only enable a single embodiment of the
claim.” In re Morsa, 803 F.3d at 1377.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 17
preserving functionality; and standard techniques for mak-
ing gRNAs with the modifications disclosed and exempli-
fied in Pioneer Hi-Bred.” J.A. 32.11 This finding is
supported by substantial evidence.
Agilent also argues that “Pioneer Hi-Bred discloses
many inoperable guides,” and “[a] skilled artisan reading
Pioneer Hi-Bred would have known this because the refer-
ence both discloses data that would lead them to doubt that
guide DNA works at all and acknowledges uncertainty
about which of the remaining modified guides in Examples
4 and 5 would work.” Appellant’s Br. 30. Agilent’s argu-
ment is unpersuasive because the testing data Agilent cites
is only applicable to synthetic DNA sequences, not to the
modified RNA sequences at issue in the challenged claims.
The Board also rejected Agilent’s argument and found:
Pioneer Hi-Bred discloses both DNA and RNA-
based embodiments. The Petition is premised on
the latter. Even if we accept [Agilent’s] argument
that the DNA-based examples lack gRNA function-
ality, that fact does not suggest that a [person of
ordinary skill in the art] would doubt that the
RNA-based embodiments, e.g., crRNAs comprising
sequences 64–69 in Table 8, lack such functional-
ity.
J.A. 22. Agilent has not demonstrated that this finding
lacks substantial evidence.
11 Agilent primarily argues that Pioneer Hi-Bred the-
oretically discloses “over a quadrillion quadrillion” possible
combinations. Appellant’s Br. 2. But Agilent’s framing of
the issue is not consistent with our case law. The relevant
question is whether, for a person of ordinary skill in the
art, undue experimentation is required to make and use a
gRNA with the claimed chemical modifications and func-
tionality given the relevant disclosures in Pioneer Hi-Bred.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 18
Agilent additionally argues that Pioneer Hi-Bred does
not enable “a single guide RNA” or “sgRNA” found in claim
2 of the ’001 patent and claim 4 of the ’034 patent. Appel-
lant’s Br. 59–60. In addition to all the reasons why the
Board found the relevant disclosures of Pioneer Hi-Bred
enabling, J.A. 27–33, the Board separately found that Pio-
neer Hi-Bred discloses a chemically-modified sgRNA, J.A.
34. The Board found that “Pioneer Hi-Bred specifically
states that the modifications in Table 8 can also be intro-
duced in a ‘long guide RNA,’ i.e., a sgRNA.” J.A. 34. The
Board concluded that “while sequences 64–69 are described
as part of a crRNA, a [person of ordinary skill in the art]
would have immediately envisioned that those sequences
could also be implemented in the corresponding domains of
a sgRNA.” J.A. 34. And as the Board explained, Agilent’s
challenged patents did not “disclose any new techniques for
synthesizing chemically-modified gRNAs.” J.A. 30. Hav-
ing affirmed the Board’s determination that Pioneer Hi-
Bred discloses and enables a modified guide polynucleo-
tide, the statement in Pioneer Hi-Bred that this can also be
accomplished on a sgRNA is also supported by substantial
evidence.
Agilent’s remaining arguments regarding whether Pi-
oneer Hi-Bred is enabling are unpersuasive. Substantial
evidence supports the Board’s findings that the anticipa-
tory disclosures of Pioneer Hi-Bred were enabling, and the
Board provided adequate explanation and reasoning for its
enablement finding. We also discern no legal error in the
Board’s determination of enablement of the relevant disclo-
sures in Pioneer Hi-Bred.
For the foregoing reasons, we affirm the Board’s deter-
mination that Pioneer Hi-Bred’s disclosure is enabling.
III
Next, Agilent argues that the Board erred in determin-
ing claims 8, 11, 16, 19, and 26 of the ’001 patent and claims
6–7 and 22–23 of the ’034 patent would have been obvious
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 19
in view of Pioneer Hi-Bred in combination with either
Threlfall or Deleavey. J.A. 58–61, 133–36. These depend-
ent claims recite a PACE or thioPACE modification with
the claimed functionality. The Board relied on Threlfall
and Deleavey for their disclosure of PACE and thioPACE
modifications. J.A. 58.
Agilent makes two main arguments: (1) Pioneer Hi-
Bred does not expressly disclose the functionality of the
claimed PACE- or thioPACE-modified guides; and (2) the
Board failed to explain its reasonable-expectation-of-suc-
cess finding. Neither of these arguments is persuasive.
As to Agilent’s first argument, it submits that
Synthego’s obviousness ground concerning Pioneer Hi-
Bred, Threlfall, and Deleavey fails because “Pioneer Hi-
Bred does not mention PACE or thioPACE modifications
with the claimed functionality and so cannot serve as a pro-
phetic hook for gRNA functionality in the alleged obvious-
ness combination.” Appellant’s Br. 40.12 We disagree with
Agilent. Relevant to this appeal, the Board analyzed
whether the challenged dependent claims would have been
obvious in view of Pioneer Hi-Bred and Threlfall or
Deleavey, not whether Pioneer Hi-Bred anticipated the
challenged dependent claims. Agilent’s argument assumes
that express disclosure of PACE and thioPACE modifica-
tions in Pioneer Hi-Bred is required, but the Board found
the dependent claims unpatentable as obvious, which does
not necessarily require all the claimed limitations to be ex-
pressly disclosed in Pioneer Hi-Bred. See, e.g., KSR Int’l
Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007) (“[T]he analy-
sis need not seek out precise teachings directed to the spe-
cific subject matter of the challenged claim, for a court can
12 Agilent also argues that “Pioneer Hi-Bred fails to
disclose the functionality of any particular guide,” Appel-
lant’s Br. 40, but as discussed in Section I of this opinion’s
Discussion, we reject that argument.
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 20
take account of the inferences and creative steps that a per-
son of ordinary skill in the art would employ.”). Indeed, the
Board provided a comprehensive analysis explaining why
a person of ordinary skill in the art would have been moti-
vated to combine Pioneer Hi-Bred with the teachings in
Threlfall and Deleavey. J.A. 60–61; see also J.A. 60 (“The
teachings in Threlfall and Deleavey support Dr. Fur-
neaux’s [Synthego’s expert] testimony regarding the bene-
fits, e.g., increased resistance to degradation and enhanced
cellular uptake, that would have motivated a [person of or-
dinary skill in the art] to use such modifications in Pioneer
Hi-Bred’s gRNA.” (cleaned up)); J.A. 44–51.
Contrary to Agilent’s second argument, the Board pro-
vided a thorough analysis as to why a person of ordinary
skill in the art would reasonably expect success in combin-
ing Pioneer Hi-Bred with either Threlfall or Deleavey. The
Board found that “a [person of ordinary skill in the art]
would reasonably expect PACE and thioPACE modifica-
tions to gRNA in a CRISPR/Cas system would be success-
ful.” J.A. 60. To support its obviousness analysis, the
Board cross-referenced its earlier discussion addressing
Agilent’s “global arguments” concerning motivation to com-
bine and reasonable expectation of success. J.A. 44 n.16;
see also J.A. 44–51. For example, the Board found that:
[B]y December 2014, several studies had shown
that the CRISPR/Cas system could successfully tol-
erate modifications. While these studies describe
different types of modifications than those in the
challenged claims, such evidence nevertheless sup-
ports Dr. Furneaux’s testimony that a [person of
ordinary skill in the art] would have expected that
chemical modifications could be made at the 5[′]
and 3[′]-ends of a gRNA while preserving the Cas
enzyme’s gene editing function.
The record further demonstrates that shortly after
the discovery of the CRISPR/Cas system for gene
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AGILENT TECHNOLOGIES , INC. v. SYNTHEGO CORP . 21
editing and prior to December 2014, there were al-
ready a number of researchers in addition to the
authors of the Pioneer Hi-Bred publication sug-
gesting the use of the claimed chemical modifica-
tions to improve the resistance of gRNA to
degradation. [Agilent’s] expert, Dr. Marshall, con-
ceded as much on cross-examination. The fact that
multiple groups of researchers independently sug-
gested the same types of gRNA modifications re-
cited in the challenged claims evidences that a
[person of ordinary skill in the art] would have had
a reasonable expectation those modifications could
be successfully employed in a CRISPR/Cas system.
Moreover, while [Synthego] points to multiple ref-
erences suggesting such modifications to gRNA,
neither [Agilent] nor Dr. Marshall identify any ref-
erence expressing doubt that such modifications
could be successfully implemented in a
CRISPR/Cas system. This contrast undermines
[Agilent’s] argument that a [person of ordinary
skill in the art] would not have reasonably expected
the prior art modifications to work in a
CRISPR/Cas system.
J.A. 49–50 (cleaned up). On this record, we conclude that
substantial evidence supports the Board’s finding of rea-
sonable expectation of success.
C ONCLUSION
We have considered Agilent’s remaining arguments
and find them unpersuasive. For the foregoing reasons, we
affirm the Board’s determination that all claims of the ’001
and ’034 patents are unpatentable.
AFFIRMED
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