NOTE: This disposition is nonprecedential.

United States Court of Appeals 

for the Federal Circuit ______________________ 

ILLUMINA CAMBRIDGE LTD.,

Appellant

v.

INTELLIGENT BIO-SYSTEMS, INC.,

Appellee

______________________ 

2015-1123

______________________ 

Appeal from the United States Patent and Trademark 

Office, Patent Trial and Appeal Board in No. IPR2013-

00128. 

 ------------------------------------------------------------------

ILLUMINA CAMBRIDGE LTD.,

Appellant

v.

INTELLIGENT BIO-SYSTEMS, INC.,

Appellee

______________________ 

2015-1243

______________________ 
2 ILLUMINA CAMBRIDGE LTD. v. INTELLIGENT BIO-SYSTEMS 

Appeal from the United States Patent and Trademark 

Office, Patent Trial and Appeal Board in No. IPR2013-

00266.

______________________ 

Decided: January 29, 2016

______________________ 

WILLIAM R. ZIMMERMAN, Knobbe, Martens, Olson & 

Bear, LLP, Washington, DC, argued for appellant. Also 

represented by JONATHAN EDWARD BACHAND; BRENTON R.

BABCOCK, Irvine, CA; NATHANAEL LUMAN, KERRY S.

TAYLOR, San Diego, CA. 

ROBERT R. BARON, JR., Ballard Spahr LLP, Philadelphia, PA, argued for appellee. Also represented by MARC 

S. SEGAL; JOHN L. CUDDIHY, Washington, DC; SCOTT 

DAVID MARTY, Atlanta, GA.

______________________ 

Before LOURIE, BRYSON, and STOLL, Circuit Judges.

LOURIE, Circuit Judge. 

Illumina Cambridge Ltd. (“Illumina”) appeals from 

the final written decisions of the United States Patent 

and Trademark Office, Patent Trial and Appeal Board 

(“the Board”) cancelling all challenged claims of its

U.S. Patents 7,057,026 (“the ’026 patent”) and 8,158,346

(“the ’346 patent”) and denying entry of substitute claims

in two inter partes review proceedings. Intelligent BioSystems, Inc. v. Illumina Cambridge Ltd., IPR2013-

00128, Paper No. 92 (P.T.A.B. July 25, 2014); Intelligent 

Bio-Systems, Inc. v. Illumina Cambridge Ltd., IPR2013-

00266, Paper No. 73 (P.T.A.B. Oct. 28, 2014). Because the 

Board did not err in determining that Illumina failed to 

show that the proposed substitute claims are patentable 

over the prior art of record, and thus did not err in denying in part the motions to amend, we affirm. 
ILLUMINA CAMBRIDGE LTD. v. INTELLIGENT BIO-SYSTEMS 3

BACKGROUND

Illumina owns the ’026 and ’346 patents, which are 

both directed to DNA sequencing by synthesis (“SBS”) 

with non-natural nucleotides. As the name implies, SBS 

allows one to determine the composition of a target DNA 

sequence by synthesizing new copies of the DNA. Briefly, 

the synthesis process involves splitting the double helix of 

a target DNA molecule into two strands and then incorporating complementary labeled nucleotides onto each 

strand to create two double helices. Non-natural nucleotides contain a non-natural base, i.e., a modified purine or 

pyrimidine base.

The ’026 patent is directed to nucleotide compositions 

of matter, while the ’346 patent relates to methods of 

using such nucleotides. As the issues relating to the 

patentability of the claims of both of these patents are 

essentially the same, we evaluate both of them here in 

one opinion and decision.

An exemplary non-natural nucleotide of the two patents, pictured below, has a deoxyribose ring, with a 

protecting group attached at the 3′-OH position and a 

label connected to the non-natural base (here, 

deazapurine) by a linker (here, containing a disulfide 

linkage). According to the ’026 and ’346 patents, the 

linker and the protecting group for the claimed nonnatural nucleotides are cleavable under identical conditions.

ILLUMINA CAMBRIDGE LTD. v. INTELLIGENT BIO-SYSTEMS 5

phase” with the other strands, i.e., its sequence will no

longer match the others in any future steps. In contrast, 

if a linker for a label fails to be cleaved, the strand will 

still be in phase despite its incorrect or mixed signals; 

moreover, the linker will likely be cleaved, and the signal 

corrected, in subsequent cycles.

In 2012, a third party filed suit against Illumina, asserting several DNA sequencing patents for which Intelligent Bio-Systems, Inc. (“Intelligent Bio-Systems”) is the 

exclusive licensee. In its answer, Illumina counterclaimed that Intelligent Bio-Systems infringed Illumina’s

’026 and ’346 patents. Intelligent Bio-Systems then filed 

petitions for inter partes review at the Board, challenging 

claims 1–8 of the ’026 patent and claims 1, 2, 4, 11, 12, 17, 

18, and 19 of the ’346 patent. The district court case was

stayed pending resolution of these and several other

related inter partes review proceedings.

The Board instituted review of both the ’026 and ’346

patents on the grounds of anticipation and obviousness. 

2015-1123 Joint App. (“1123-J.A.”) 332–350; 2015-1243 

Joint App. (“1243-J.A.”) 208–221. Instead of submitting

responses to the institution decisions, Illumina filed 

motions to amend, requesting cancellation of all challenged claims of both patents, and entry of substitute 

claims 9–12 for the ’026 patent (“’026-substitute claims”), 

1123-J.A. 501–503, and claims 20–26 for the ’346 patent

(“’346-substitute claims”), 1243-J.A. 278–279. Noting that 

the cancellation requests were not contingent on the 

original claims being found unpatentable, the Board 

granted Illumina’s motions in part, cancelling all of the 

challenged claims of both patents. 1123-J.A. 29–30; 1243-

J.A. 23.

The Board then examined the proposed substitute 

claims for the ’026 patent. Representative proposed 

substitute claim 9 for the ’026 patent reads as follows, 

with Illumina’s annotations for replacing claim 1:
6 ILLUMINA CAMBRIDGE LTD. v. INTELLIGENT BIO-SYSTEMS 

9. A nucleotide triphosphate or nucleoside molecule, having a 7-deazapurine base that is linked to 

a detectable label via a cleavable linker, wherein 

the cleavable linker is attached to the 7-position of 

the 7-deazapurine base and wherein the cleavable 

linker contains a disulfide linkage, and wherein 

the nucleotide triphosphate molecule has a ribose 

or deoxyribose sugar moiety comprising a protecting group attached via the 2′ or 3′ oxygen atom, 

and the disulfide linkage of the cleavable linker 

and the protecting group are cleavable under 

identical conditions.

1123-J.A. 30. The Board found only one new limitation 

that is different from the original claims: that the cleavable linker “contains a disulfide linkage.” 1123-J.A. 30.

Starting with the premise that the obviousness of using a disulfide linkage was the main issue to be decided, 

the Board found that all of the claim limitations were 

described in the prior art. 1123-J.A. 37–39. The Board 

also found that the prior art provided a reason to use a 

disulfide linkage to attach a label to a base of a nucleotide, including for DNA sequencing, and with a reasonable expectation of success. 1123-J.A. 40–42. Because the 

proposed substitute claims do not require a disulfide 

linkage between the protecting group and the 3′-OH, the 

Board rejected Illumina’s argument that the prior art’s 

requirement of greater than 90% cleavage efficiency for a 

protecting group also applied to the claimed disulfide 

linkage. 1123-J.A. 42–44. Even so, the Board also found 

that one of skill in the art would have expected to achieve

more than 90% cleavage efficiency of the disulfide bond by 

routine experimentation. 1123-J.A. 44–50. The Board 

determined that Illumina had not met its burden of 

showing that one of skill in the art would not have had a 

reasonable expectation of success, viz., that identical 

conditions could not be selected in which the disulfide 

linkage is cleavable with less than 90% efficiency and the 
ILLUMINA CAMBRIDGE LTD. v. INTELLIGENT BIO-SYSTEMS 7

protecting group is cleavable with greater than 90% 

efficiency.

The Board also rejected Illumina’s proffered evidence 

of unexpected results of high cleavage efficiency of disulfide linkages. The Board found that Illumina did not 

provide a proper comparison to the closest prior art, and 

failed to provide evidence that the results were due to the 

claimed subject matter, not the experimental conditions 

or the latent properties of the bond. 1123-J.A. 52–54. 

The Board thus concluded that Illumina had not met its 

burden of showing that the proposed ’026-substitute 

claims are patentable over the prior art of record. 1123-

J.A. 54. The Board noted that such a showing is required 

in order to establish that the patent owner is entitled to 

the relief requested, i.e., to amend the patent with the 

proposed substitute claims. 1123-J.A. 29, 31 (citing 35 

U.S.C. § 316; 37 C.F.R. § 42.20(c)).

The Board separately also examined the proposed 

substitute claims for the ’346 patent, which recite methods comprising providing, similarly, a nucleotide with a 

linker containing a disulfide linkage for attaching a label 

to the base, and removing the label and the protecting 

group from the nucleotide under a single set of chemical 

cleavage conditions. 1243-J.A. 23–24. The Board again 

found only one new limitation as compared to the original 

claims: that the cleavable linker “contains a disulfide 

linkage.” 1243-J.A. 24. For virtually the same reasons as 

for the ’026-substitute claims, the Board concluded that 

Illumina had not met its burden of showing that the 

proposed ’346-substitute claims are patentable. 1243-J.A. 

26–48.

The Board therefore denied in part Illumina’s motions 

to amend both patents by entering the proposed substitute claims. Illumina timely appealed from the Board’s 

final written decisions. We have jurisdiction pursuant to

28 U.S.C. § 1295(a)(4).
8 ILLUMINA CAMBRIDGE LTD. v. INTELLIGENT BIO-SYSTEMS 

DISCUSSION

We review the Board’s legal conclusions de novo, In re 

Elsner, 381 F.3d 1125, 1127 (Fed. Cir. 2004), and the 

Board’s factual findings underlying those determinations 

for substantial evidence, In re Gartside, 203 F.3d 1305, 

1315 (Fed. Cir. 2000). “Substantial evidence . . . means 

such relevant evidence as a reasonable mind might accept 

as adequate to support a conclusion.” Consol. Edison Co. 

v. NLRB, 305 U.S. 197, 217 (1938).

Obviousness is a question of law based on underlying 

factual findings, including what a reference teaches and 

whether there would have been sufficient motivation to 

combine the prior art. In re Baxter Int’l, Inc., 678 F.3d 

1357, 1361 (Fed. Cir. 2012); Rapoport v. Dement, 254 F.3d 

1053, 1060–61 (Fed. Cir. 2001); In re Gartside, 203 F.3d at

1316. For a motion to amend during an inter partes

review proceeding, the patentee bears the burden of 

showing that its proposed substitute claims are patentable over the prior art of record. Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1306–08 (Fed. Cir. 2015); 

Prolitec, Inc. v. ScentAir Techs., Inc., 807 F.3d 1353, 

1363–64 (Fed. Cir. 2015).

Illumina argues that the Board improperly limited its 

analysis to the disulfide linkage limitation, rather than

also considering the combination of the additional limitations. Illumina contends that the ’026-substitute claims 

added limitations of both (i) the linker containing a disulfide linkage and (ii) the disulfide linkage being cleavable 

under identical conditions as the protecting group. Similarly, the ’346-substitute claims added limitations of both 

(i) the linker containing a disulfide linkage and (ii) the 

disulfide linkage and the protecting group being removed 

under a single set of chemical conditions. Although each 

limitation may have been independently disclosed in the 

prior art, Illumina asserts that the Board only found a 

motivation to use a linker with a disulfide linkage in SBS
ILLUMINA CAMBRIDGE LTD. v. INTELLIGENT BIO-SYSTEMS 9

methods, which was insufficient to find the full scope of 

the claimed subject matter obvious. Illumina reasons 

that because the prior art teaches both that SBS requires 

greater than 90% deblocking efficiency, and that cleaving 

disulfide linkages was variable and inefficient, one of skill 

in the art would not have been motivated to combine the 

prior art for SBS methods. Worse yet, Illumina argues, 

the Board improperly imposed a heightened standard of 

nonobviousness by requiring proof that it would have 

been impossible to combine the prior art to arrive at the 

substitute claims, e.g., impossible to achieve higher cleavage efficiency yields for disulfide linkages. Illumina also 

asserts that the Board improperly discounted its evidence 

of unexpected results, which showed not simply high 

cleavage efficiency of the disulfide linkage, but superior 

SBS results using the claimed nucleotides. 

Intelligent Bio-Systems responds that Illumina failed 

to carry its burden of showing that the proposed substitute claims were patentable over the prior art of record. 

Because the Board had already decided in its Decisions to 

Institute that the prior art taught all of the limitations in 

the original claims, Intelligent Bio-Systems contends, the 

only additional limitation in the proposed claims was the 

disulfide linker, and thus the Board only needed to address the prior art relating to the successful use of disulfide linkers in DNA sequencing. Intelligent Bio-Systems 

characterizes Illumina’s arguments as using the variable 

cleavage efficiency of a disulfide linkage as a proxy for the 

greater than 90% cleavage efficiency of a protecting group 

required by the prior art; however, Intelligent BioSystems notes, the Board found that the claims do not 

require that they cleave at the same efficiency. Intelligent Bio-Systems also asserts that the Board did not err 

in finding that Illumina’s evidence of unexpected results 

was insufficient to meet its burden of showing nonobviousness. 
10 ILLUMINA CAMBRIDGE LTD. v. INTELLIGENT BIO-SYSTEMS 

We agree with Intelligent Bio-Systems that the Board 

did not err in focusing on the prior art regarding disulfide 

linkages. For the proposed substitute claims in the 

context of inter partes review proceedings, Illumina bore 

the burden of proving patentability over the prior art of 

record; here, specifically, Illumina had to show that the 

substitute claims would not have been obvious in view of, 

inter alia, prior art raised during the review proceedings 

and prior art from the patent’s original prosecution history. See Prolitec v. ScentAir Techs., 807 F.3d at 1363–64. 

Because none of the original claims comprised the limitation of the linker containing a disulfide linkage, the Board 

chose to primarily address prior art relevant to that 

limitation to determine whether Illumina had proven that 

the addition rendered the claims as a whole nonobvious.

The Board did not analyze the obviousness of using a 

disulfide linkage in SBS in isolation, however; the original

claims provided a backdrop for the Board to find that one 

of skill in the art would have reasonably expected to 

succeed in using a linker with a disulfide linkage as 

claimed. The prior art taught the use of linkers containing disulfide linkages for attaching a label to a nucleotide, 

as well as the desirability of simultaneously removing 

labels and protecting groups, in DNA sequencing methods. One of skill in the art would have been motivated to 

use a commercially available linker to attach a label to a 

nucleotide that also could be removed when removing the 

protecting group, and thus would have been motivated to 

modify SBS prior art with a disulfide linkage as claimed. 

The heightened standard that Illumina decries is instead 

properly Illumina’s burden to show nonobviousness, proof 

that one of skill in the art would not have a reasonable 

expectation of success in using a disulfide linkage. Illumina simply failed to sufficiently elucidate grounds upon 

which the use of a disulfide linkage for SBS, particularly 

such a linkage cleavable under the same conditions as a 
ILLUMINA CAMBRIDGE LTD. v. INTELLIGENT BIO-SYSTEMS 11

protecting group, would not have been obvious in view of 

the prior art. 

Importantly, Illumina’s arguments rely on the idea 

that one of skill in the art would not have used a linker 

with a disulfide linkage—for a desired combination in 

which the label and protecting group would be cleaved in 

identical conditions—because disulfide linkages did not 

appear to have sufficiently high cleavage efficiency to 

match the supposed minimum cleavage efficiency of 

protecting groups for SBS. The proposed substitute 

claims do not require that the linker and the protecting 

group be cleaved at the same efficiency rates, however, 

only that they are cleavable under the same conditions. 

The Board alluded to this by finding that Illumina had 

not met its burden to show that identical conditions could 

not have been selected; the implication being that nonobviousness might have been supported by evidence that 

one of skill in the art would not have expected there to be 

any set of conditions in which a disulfide linkage has 

lower cleavage efficiency than a protecting group and is 

still suitable for SBS.

Although Illumina provided an expert declaration 

stating that the prior art did not provide an expectation 

that disulfide cleavage conditions would cleave a protecting group with greater than 90% efficiency, the claims 

also do not require that the protecting group be cleaved at 

greater than 90% efficiency, much less that the linker also

be cleaved at such efficiency. Nor do the claims limit the 

protecting group to one also involving a disulfide bond, 

which would inherently link its efficiency rate to the 

cleavage efficiency of the linker. We are not persuaded by 

Illumina’s argument that one of skill in the art would not 

have been motivated to use a disulfide linkage as claimed, 

because the prior art does not expressly disclose greater 

than 90% cleavage efficiency of disulfide linkages. 
12 ILLUMINA CAMBRIDGE LTD. v. INTELLIGENT BIO-SYSTEMS 

Regardless, the Board found that even if that cleavage 

efficiency were required of the linker, Illumina had not 

met its burden to show that one of skill in the art would 

not have reasonably expected to achieve greater than 90%

efficiency. The prior art taught that one of skill in the art 

could reasonably have expected to increase the cleavage 

efficiency of disulfide linkages by simple experimentation. 

Moreover, as the Board noted, it was not critical for the 

prior art to achieve higher cleavage efficiency of disulfide 

bonds. The lack of prior art disclosures of actually achieving higher efficiency yields does not render the teachings

about increasing efficiency irrelevant; obviousness is not a 

question of novelty. See EWP Corp. v. Reliance Universal 

Inc., 755 F.2d 898, 907 (Fed. Cir. 1985) (“A reference must 

be considered for everything it teaches by way of technology and is not limited to the particular invention it is 

describing and attempting to protect.”). Expert testimony

in the record also supports the Board’s finding that one of 

skill in the art would have reasonably expected to achieve 

increased efficiency for a disulfide linkage. Substantial 

evidence thus supports the Board’s findings that several 

prior art references taught the additional limitations of 

the proposed substitute claims and that one of skill in the 

art would have had a reasonable expectation of success in 

combining the prior art to obtain the claimed invention.

The Board also did not err in finding that Illumina’s

evidence of unexpected results relative to the prior art 

was insufficient. Illumina failed to show that the unexpected results obtained were due to the claimed nucleotide rather than differences from the prior art, e.g., the 

cleavage reagent used or other experimental conditions, 

or a latent property of the disulfide linkage. The Board 

therefore did not err in finding that Illumina had not met 

its burden to prove that the substitute claims were patentable over the prior art.
ILLUMINA CAMBRIDGE LTD. v. INTELLIGENT BIO-SYSTEMS 13

CONCLUSION

We have considered the remaining arguments and 

conclude that they are without merit. Because substantial evidence supports the Board’s determination that 

Illumina failed to meet its burden in showing that the 

proposed substitute claims in both patents are patentable 

over the prior art of record, we affirm.

AFFIRMED