N OTE : This disposition is nonprecedential. 

# United States **Court of Appeals**  **for the Federal Circuit**

______________________
ILLUMINA CAMBRIDGE L TD., 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 L TD., Appellant

v.

INTELLIGENT BIO

- SYSTEMS, INC., Appellee

______________________

2015 -1 243

______________________ILLUMINA CAMBRIDGE L TD

. v. INTELLIGENT BIO

- SYSTEMS 2

Appeal from the United States Patent and Trademark Office, Patent Trial and Appeal Board in No. IPR2013

- 00266.

______________________
Decided: January 29, 2016

______________________

W ILLIAM R. Z IMMERMAN , Knobbe, Martens, Olson & Bear, LLP, Washington, DC, argued for appellant. Also represented by J ONATHAN E DWARD B ACHAND ; B RENTON R. B ABCOCK , Irvin e, CA; N ATHANAEL L UMAN , K ERRY S. T AYLOR , San Diego, CA

.

R OBERT R. B ARON , J R

. , Ballard Spahr LLP, Philade lphia, PA

, argued for appellee. Also represented by M ARC S. S EGAL ; J OHN L. C UDDIHY , Washington, DC; S COTT D AVID M ARTY , Atlanta, GA.

______________________
Before L OURIE , B RYSON , and S TOLL , Circuit Judges.

L OURIE , 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 Bio

Systems, 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 f ailed to show that the prop osed substi tute claims a re patentable over the prior art of record

, and thus did not err in den ying in part the motion s to amend, we affirm

.ILLUMINA CAMBRIDGE L TD

. v. INTELLIGENT BIO

- SYSTEMS 3

B ACKGROUND 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 synthesiz ing new copies of the DNA. Briefly, the synthesis process involves splitting the double helix of a target DNA molecule into two strands and then incorp orating complementary labeled nucleotides on to each strand to create two double helices. Non- natural nucle otides 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 ex e mplary non

- natural nucleotide of the two p atents , 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 link age )

. According to the ’026 and ’346 patents, t he linker and the protecting group for the claimed non

natural nucleotide s ar e cleavable under identical cond itions.ILLUMINA CAMBRIDGE L TD

. 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

c orrected, in subsequent cycles. In 2012, a third party filed suit against Illumina, a sserting several DNA sequencing patents for which Intell igent Bio

- Systems, Inc. (“ Intelligent Bio

- Systems ”) is the exclusive licensee. In its answer, Illumina counte rclai med 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 ’34 6 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 ob viousness

. 2015

- 1123 Joint App. (“1123

- J.A.”) 332 –3 50; 2015

- 1243 Joint App. (“1243

- J.A.”) 208

– 221

. Instead of s ubmitting responses to the institution decisions, Illumina filed motions to amend, requesting cancellation of all cha llenged claims of both patents , and entry of sub stitute 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 bei ng 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:ILLUMINA CAMBRIDGE L TD

. v. INTELLIGENT BIO

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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 moie ty comprising a protec ting 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 f ound only one new limitation that is diff erent from the original claims : that the cleav able linker “ contains a disulfide linkage. ” 1123

- J.A. 30. Starting with the premise that the obviousness of u sing a disulfide linkage was the main issue to be decided, the Board found that all of the claim lim itations we re de scribed in the prior art. 1123

- J.A. 37

– 39. T he Board also found that the prior art provided a reason to use a disulfide linkage to attach a label to a base of a nucle otide, including for DNA sequencing

, and with a reason able 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 effici ency 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 exper imentation. 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 disu lfide linkage is cleavable with less than 90% efficiency and theILLUMINA CAMBRIDGE L TD

. v. INTELLIGENT BIO

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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 disu lfide 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 no ted that s uch 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 substi tute claims for the ’346 patent, which recite met hods 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 sing le set of chemical cleavage conditions. 12 43

- J.A. 23

– 24. The Board again f

ound 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 enter ing the proposed subst itute claims. Illumina timely appealed from the Board’s final written decisions . We have juris diction pursuant to 28 U.S.C. § 1295(a)(4 ).ILLUMINA CAMBRIDGE L TD

. v. INTELLIGENT BIO

- SYSTEMS 8

D ISCUSSION 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, 131 5 (Fed. Cir. 2000). “Substantial evidence . . . means such relevant evidence as a reasonable mind might accept

a s adequate to support a conclusion.” Consol. Edison Co. v. NLRB , 305 U.S. 197, 217 (1938).

Obviousness is a que stion 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 d uring an inter partes review proceeding , the patentee bears the burden of show ing that its proposed sub stitute claims are patent able over the prior art of record

. Microsoft Corp. v. Proxyconn, Inc.

, 789 F.3d 1292, 130 6– 08 (Fed. Cir. 2015); Prolitec, Inc. v. ScentAir Techs., Inc.

, 807 F.3d 1353
, 1363

– 64 ( Fed. Cir. 2015).
Illumina argues that t he Board improperly limited its analysis to the disulfide linkage limitation, rather than also considering the combination of the additional limit ations. Illumina contends that t he ’026

- substitut e claims added limitations of both (i) the linker containing a disu lfide linkage and (ii) th e disulfide linkage being cleavable under identical condi tions as the protecting group . S imilarly, the ’346

- substitute claims added limitation s of both (i) the linker containing a disulfide linkage and (ii) the disulfide link age 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 t he Board only found a motivation to u se a linker with a disulfide link age in SBSILLUMINA CAMBRIDGE L TD

. v. INTELLIGENT BIO

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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 be en motivated to combine the prior art for SBS methods

. Worse yet , Illumina argues , t he Board improperly imp osed 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 clea vage efficiency yields for disulfide linkages . I llumina also
asserts that t he 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 -Sy stems responds that Illumina failed to carry its burden of showing that the proposed subst itute 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 a ll of the limitations in the or iginal claims , Intelligent Bio

- Systems contends

, the only additional limitation in the proposed claims was the disulfide linker, and thus the Board only needed to a ddress the prior a rt relating to the successful use of disu lfide linkers in DNA sequencing. Intelligent Bio

- Systems characterizes Illumina ’s arguments as using the variable cleavage efficiency of a disulfide link age as a proxy for the greater than 90% cleavage efficiency of a protecting group required by the prior art ; h owever, Intelligent Bio

Systems notes, the Board found that the claims do not require that they cleave at the same efficiency. Intell igent Bio

- Systems also asserts that the Board did not err in finding that Illumina ’s evidence of unexpected results was insufficient to meet its b urden of showing nonobv ious ness

.ILLUMINA CAMBRIDGE L TD

. v. INTELLIGENT BIO

- SYSTEMS 10

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 bor e 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 hist ory

. See Prolitec v. ScentAir Techs.

, 807 F.3d at 1363

– 64

. B ecause none of the original claims comprised the limit ation 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
t he 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 expect ed to succeed in using a linker with a disulfide linkage as claimed. The prior art taught the use of linkers contai ning disulfide linkages for attac hing a label to a nucleotide, as well as the desirability of simultaneously removing labels and protecting groups, in DNA sequencing met hods. One of skill in the art would have been motivated to use a commercially available linker to attach a label to a

n ucleotide that also could be removed when removing the protecting group, and thus would have be en 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

. Ill umina 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 aILLUMINA CAMBRIDGE L TD

. v. INTELLIGENT BIO

- SYSTEMS 11

protecting group, would not have been obvious in view of the prior art

. Importantly

, Illumina’s argument s rel y 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 —bec ause disulfide linkage s did not appear to have sufficiently high cleavage efficiency to match the supposed minimum cleavage e fficiency of protecting groups for SBS . T he proposed substitute claims do not require that the linke r and the protecting
group be cleave d at the same efficiency rates, however, only that they are cleav abl e 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 nono bviousness might have been supported by evidence that one of skill in the art would not have expect ed there to be

a ny 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
stat ing that the prior art did not provide a n expectation that disulfide cleavage conditions would cleave a protec ting group with greater than 90% efficiency , t he 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 argu ment that one of skill in the art would not have been motivated to us e a disulfide linkage as claimed

, because the prior art does not expressly disclose greater than 90% cleavage efficiency of disulfide linkages

.ILLUMINA CAMBRIDGE L TD

. v. INTELLIGENT BIO

- SYSTEMS 12

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 reaso nably have expect ed to increase the cleavage efficiency of disulfide linkages by simple experimentation. Moreover, a s the Board noted, it was not critical for the prior art to achieve higher cleavage efficiency of disulfide bonds

. The lack of prior art disclosure s of actually achie ving 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 ref erence must be considered for everything it teaches by way of technol ogy and is not limited to the particular invention it is describing and attempting to protect. ” ). Expert testimony in the record also sup port s the Board’s finding that one of skill in th e art would have reasonably expected to achieve increased efficiency for a disulfide linkage. S ubstantial evidence thus supports the Board’s findings that several prior art references taught the additional limitations of the proposed substitute claim s 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 unexpect ed results relative to the prior art was insufficient

. Illumina failed to show that the une xpected results obtained w ere due to the claimed nucle otide rather than differences from the prior art, e.g. , the cleavage reagent used or other experimental conditions, or a latent property of the dis ulfide linkage. The Board therefore did not err in finding that Illumina had not met its burden to prove that the substitute claims were p atentable over the prior art.ILLUMINA CAMBRIDGE L TD

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C ONCLUSION We have considered the remaining arguments and conclude that they are withou t merit. Because substa ntial 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