Document ID: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-ca13-15-01693/USCOURTS-ca13-15-01693-0/pdf.json

Parties Involved:
Illumina Cambridge Ltd.
Appellee
Intelligent Bio-Systems, Inc.
Appellant

Document Text:

United States Court of Appeals 

for the Federal Circuit ______________________ 

INTELLIGENT BIO-SYSTEMS, INC.,

Appellant

v.

ILLUMINA CAMBRIDGE LTD.,

Appellee

______________________ 

2015-1693

______________________ 

Appeal from the United States Patent and Trademark 

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

00517.

______________________ 

Decided: May 9, 2016

______________________ 

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

S. SEGAL; SCOTT DAVID MARTY, Atlanta, GA. 

 WILLIAM R. ZIMMERMAN, Knobbe, Martens, Olson & 

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

represented by JONATHAN EDWARD BACHAND; BRENTON R.

BABCOCK, JOSEPH S. CIANFRANI, SHEILA N. SWAROOP, 

Irvine, CA; NATHANAEL LUMAN, KERRY S. TAYLOR, San 

Diego, CA.

______________________ 

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Before O’MALLEY, WALLACH, and HUGHES, Circuit Judges.

O’MALLEY, Circuit Judge. 

Illumina Cambridge Ltd. (“Illumina”) owns U.S. Patent No. 7,566,537 (“the ’537 patent”), which is directed to 

a method of labeling nucleotides in a deoxyribonucleic 

acid (“DNA”) strand. Intelligent Bio-Systems, Inc. (“IBS”)

filed a revised petition to the Patent Trial and Appeal 

Board (“Board”) requesting inter partes review of claims 

1–6 and 8 of the ’537 patent on August 30, 2013. The 

Board instituted review of the challenged claims on the 

basis that they were invalid as obvious under 35 U.S.C. 

§ 103 in view of certain prior art references. In its Final 

Written Decision, issued February 11, 2015, the Board 

found that IBS failed to satisfy its burden of demonstrating the obviousness of the challenged claims by a preponderance of the evidence. IBS appeals. Because we find 

that the Board’s judgment was supported by substantial 

evidence, we affirm.

BACKGROUND

A. Technology

By way of background, DNA is comprised of two 

strands of nucleotides, which bind to each other to form a 

double helix structure. “A nucleotide is made up of a 

sugar molecule, a phosphate, and a ‘base.’ It is the 

‘base’—adenine (A), cytosine (C), guanine (G), or thymine 

(T)—that provides the code for the genetic information in 

DNA.” Appellant Br. 4. The bases of two nucleotide 

strands pair predictably: A with T, and G with C. In this 

way, if one knows the identity of a nucleotide in one 

strand, the identity of the corresponding nucleotide in the 

other strand is easily inferred. Identification of the 

sequence of nucleotides in DNA is important, as “the 

sequence of nucleotides in DNA determines the traits of 

living organisms.” Id.

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The invention of the ’537 patent “relates to labelled 

nucleotides.” ’537 patent, col. 1 l. 14. The labels, used to 

identify the nucleotides, are removable and are intended 

for “use in polynucleotide sequencing methods.” Id. at col. 

1 ll. 14–16. The polynucleotide sequencing method at 

issue is the so-called sequencing by synthesis (“SBS”) 

method. SBS “is a process used to identify the sequence 

of nucleotides in DNA by synthesizing a single strand of 

DNA using nucleotides that are complementary to the 

nucleotides in a sample single strand of DNA.” Appellee 

Br. 3.

The claimed method in the ’537 patent is directed to

labelling nucleotide bases to determine their identity. 

The 3′-OH (“three prime hydroxyl”) position of the sugar

components of the labeled nucleotides are further modified with a blocking group (also referred to as a protecting 

group). The blocking group (or protecting group) attached 

to the sugar molecule “prevent[s] the natural linking 

process between nucleotides.” Appellant Br. 4. By stopping the linking process, one can detect the label on the 

nucleotide base and determine its identity (A, C, G, or T). 

The blocking group is cleavable, which allows the linking 

process to continue after the label is detected. 

The SBS method starts with a single strand of unknown nucleotides and adds complementary nucleotides 

one-by-one to form the complete, double-helix structure. 

“The protecting group allows the polymerase to incorporate only one nucleotide at a time into the complementary 

strand.” Intelligent Bio-Sys., Inc. v. Illumina Cambridge 

Ltd., IPR2013-00517, 2015 WL 996355, at *3 (PTAB Feb. 

11, 2015) (Final Written Decision of the Board). “By 

incorporating such modified nucleotides one-by-one into a 

growing DNA chain, researchers are able to first detect 

the label to determine the base of each nucleotide, before 

another nucleotide (with its own label attached to its own 

base) is added.” Appellant Br. 4–5. The identity of the

attached label is determined “by any suitable method, 

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including fluorescence spectroscopy or by other optical 

means.” ’537 patent, col. 5 ll. 21–23. 

The claims require that “the protecting group comprises an azido group.” Id. at col. 19 ll. 58–59 (claim 1). 

According to Illumina, “the inventors of the ’537 patent 

were the first to identify the azidomethyl group (CH2N3) 

as a protecting group that would meet the rigorous requirements of SBS.” Appellee Br. 9.

Claim 1, the only independent claim under review, is 

reproduced below:

1. A method of labeling a nucleic acid molecule, 

the method comprising incorporating into the nucleic acid molecule a nucleotide or nucleoside molecule, wherein the nucleotide or nucleoside 

molecule has a base that is linked to a detectable 

label via a cleavable linker and the nucleotide or 

nucleoside molecule has a ribose or deoxyribose 

sugar moiety, wherein the ribose or deoxyribose 

sugar moiety comprises a protecting group attached via the 2′ or 3′ oxygen atom, and said protecting group can be modified or removed to expose 

a 3′ OH group and the protecting group comprises 

an azido group. 

Id. at col. 19 ll. 49–59 (emphases added). 

B. Prior Art

There are three articles of prior art at issue in this 

appeal: (1) Roger Tsien et al., WO 91/06678 (May 16, 

1991) (“Tsien”); (2) Jingyue Ju et al., U.S. Patent No. 

6,664,079 (Dec. 16, 2003) (“Ju”); and (3) Zavgorodny et al., 

1-Alkylthioalkylation of Nucleoside Hydroxyl Functions 

and Its Synthetic Applications: A New Versatile Method in 

Nucleoside Chemistry, 32 TETRAHEDRON LETTERS 7593 

(1991) (“Zavgorodny”). IBS argued to the Board that Ju 

in combination with Zavgorodny or Tsien in combination 

with Zavgorodny render the patent invalid as obvious 

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pursuant to 35 U.S.C. § 103.1 IBS relied on Tsien and Ju 

for similar purposes. 

In its Decision to Institute, the Board determined that 

both Ju and Tsien “describe[] a process of labeling, and 

ultimately sequencing, a nucleic acid molecule” by a 

polymerase. J.A. 166, 169. Both Ju and Tsien disclose a 

method of sequencing unknown DNA involving the SBS 

method, including the labeling of nucleotides for detection 

and the use of a protecting group at the 3′-OH position of 

the nucleotide. Neither Ju nor Tsien disclose a protecting 

group that comprises an azido group, however.

Regarding Zavgorodny, the Board found that it teaches that an “azidomethyl moiety is a suitable protecting 

group for the 3′ OH position of nucleosides, precisely the 

position requiring protecting in Ju’s [or Tsien’s] process, 

as well as the fact that the azidomethyl group is cleavable 

from the nucleoside under specific and mild conditions.” 

J.A. 167, 172. As Zavgorodny notes, the “[a]zidomethyl 

group is of special interest, since it can be removed under 

very specific and mild conditions, viz. with triphenylphosphine in aqueous pyridine at 20 °C.” J.A. 861. 

Of particular importance to this appeal, Tsien teaches 

that one of “[t]he criteria for the successful use of 3′-

 

1 The Board also instituted proceedings on the combination of Tsien and Zavgorodny with James M. Prober 

et al., A System for Rapid DNA Sequencing with Fluorescent Chain-Terminating Dideoxynucleotides, 238 SCIENCE

336 (1987), but IBS does not appeal the Board’s conclusion that it failed to show “by a preponderance of the 

evidence that claim 3 of the ’537 patent would have been 

obvious over the combination of Tsien, Zavgorodny, and 

Prober.” Intelligent Bio-Sys., Inc., 2015 WL 996355, at 

*13. 

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blocking groups” is “the availability of mild conditions for 

rapid and quantitative deblocking.” J.A. 1010 (emphasis 

added). In order for the deblocking (i.e., the removal of 

the protecting group) to be quantitative, it must take 

place at 100% or near-100% efficiency. Appellant Br. 26 

n.10; Appellee Br. 6. Ju similarly notes as a “fundamental requirement” that “the tag and the [protecting] group 

capping the 3′-OH need to be removed with high yield to 

allow the incorporation and detection of the next nucleotide.” J.A. 742, col. 21 ll. 3–16 (emphasis added). 

C. The Board’s Decision

In its Final Written Decision, the Board construed 

claim 1 to “encompass[] the use of any protecting group 

attached via the 2′ or 3′ oxygen atom of a [sugar] moiety, 

in which the protecting group can be modified or removed 

to expose a 3′ OH group.” Intelligent Bio-Sys., Inc., 2015 

WL 996355, at *4. It also noted that its construction of 

“claim 1 does not require removal of the protecting group 

to allow subsequent nucleotide incorporation.” Id. The 

parties did not dispute that construction below and do not 

dispute it here.

The Board then considered whether the combination 

of Tsien and Zavgorodny rendered claims 1–6 and 8 of the 

’537 patent invalid as obvious. Based on the teachings of 

Tsien and Zavgorodny, IBS argued “that an ordinary 

artisan, ‘to improve the efficiency, reliability, and robustness of the sequencing by synthesis method taught in 

Tsien, would have been motivated to use other protecting 

groups that meet the criteria of Tsien, such as the azidomethyl group taught by Zavgorodny.’” Id. (citation

omitted). In addition to contending that an ordinary 

artisan would be motivated to combine these references, 

IBS separately asserted that an ordinary artisan would 

have a reasonable expectation of success in meeting the 

limitations of the claimed invention by combining Tsien 

and Zavgorodny. See id. at *5 (“[B]ecause an ordinary 

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artisan would have recognized that Zavgorodny’s azidomethyl group met Tsien’s criteria for a suitable 3′ OH 

protecting group, the artisan ‘would have expected to

succeed in combining the teachings of Tsien and Zavgorodny to carry out’” the claimed invention.) (quoting IBS’s 

Petition, J.A. 146). In its Petition, IBS first addressed 

whether there was a motivation to combine Tsien or Ju 

with Zavgorodny and then separately addressed whether 

an ordinary artisan would have a reasonable expectation 

of success in meeting the limitations of the claimed invention. J.A. 144–47.

Illumina disagreed with IBS, and argued that an ordinary artisan would not expect the azidomethyl group of 

Zavgorodny to meet the specific criteria of Tsien or Ju. In 

particular, Tsien requires “quantitative and rapid removal” of the protecting group, which it understands “to mean 

essentially 100% removal.” Intelligent Bio-Sys., Inc., 2015 

WL 996355, at *5. Prior art of record, however, “demonstrates that an ordinary artisan would have expected 

Zavgorodny’s azidomethyl group to be removed at a much 

lower efficiency than required by Tsien’s methods.” Id. 

That prior art reference is known as Loubinoux. See J.A. 

971–87 (Bernard Loubinoux et al., Protection of Phenols 

by the Azidomethylene Group Application to the Synthesis 

of Unstable Phenols, 44 TETRAHEDRON 6055 (1988)). 

Loubinoux reports a 60–80% removal efficiency for azidomethyl groups from phenols using triphenylphosphine. 

Intelligent Bio-Sys., Inc., 2015 WL 996355, at *7, *10, *12;

J.A. 974–75. 60–80% removal is not quantitative removal 

within the meaning of Tsien or Ju.

Ultimately, the Board credited Illumina’s argument 

that, given Loubinoux, IBS “has not shown, by a preponderance of the evidence, that an ordinary artisan would 

have considered it obvious to use Zavgorodny’s azidomethyl group as the 3′ hydroxyl protecting group in Tsien’s 

processes.” Id. at *5. See also id. at *12 (finding similarly 

that IBS failed to establish “that an ordinary artisan 

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would have considered it obvious to use Zavgorodny’s 

azidomethyl protecting group in the processes described

in Ju”). 

In discussing the legal requirements of obviousness, 

the Board particularly pointed out the requirement for a 

reasonable expectation of success:

[A] conclusion of obviousness requires a reasonable expectation of success:

When there is a design need or market 

pressure to solve a problem and there are 

a finite number of identified, predictable

solutions, a person of ordinary skill has 

good reason to pursue the known options 

within his or her technical grasp. If this 

leads to the anticipated success, it is likely 

the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was 

obvious to try might show that it was obvious under § 103.

[KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421

(2007)] (emphases added).

As the Court of Appeals for the Federal Circuit 

has explained, “[a]lthough predictability is a 

touchstone of obviousness, the ‘predictable result’ 

discussed in KSR refers not only to the expectation that prior art elements are capable of being 

physically combined, but also that the combination would have worked for its intended purpose.” 

Depuy Spine, Inc v. Medtronic Sofamor Danek, 

Inc., 567 F.3d 1314, 1326 (Fed. Cir. 2009) (citations omitted).

Id. at *6. The Board further described Tsien and Zavgorodny, stressing that “the Petition does not point to any 

specific evidence explaining why an ordinary artisan 

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would have expected Zavgorodny’s azidomethyl protecting 

group to meet” the quantitative deblocking requirement of 

Tsien. Id. at *7. And as Loubinoux “discloses that removal of an azidomethyl protecting group from a phenolic 

hydroxyl . . . resulted in deprotected phenols ‘as pure 

products at a yield between 60 and 80%,’” id. (citing 

Loubinoux, J.A. 975), IBS’s “Petition did not provide a 

specific or credible explanation why an ordinary artisan 

would have expected Zavgorodny’s azidomethyl protecting 

group to meet Tsien’s quantitative deblocking requirement under conditions suitable for use in Tsien’s sequencing methods,” id. at *8.2

Although the Board’s precise legal underpinnings are 

difficult to discern, it appears to have relied on IBS’s 

failure to demonstrate (1) a motivation to combine the 

relevant references, (2) that a person of ordinary skill 

would have a reasonable expectation of success of developing the claimed invention, or (3) both. The Board’s opinion conflates these legal issues but its ultimate conclusion 

is clear. IBS failed to demonstrate that the challenged 

claims were obvious under the prior art at issue.

In reaching its decision, the Board refused to consider 

IBS’s reply brief and accompanying expert declaration 

because it found that IBS’s reply was improper under two 

regulations: first under 37 C.F.R. § 42.23(b), which provides that a “reply may only respond to arguments raised 

in the corresponding opposition or patent owner response,” and then under 37 C.F.R. § 42.6(a)(3), which 

states that “[a]rguments must not be incorporated by 

 

2 The Board similarly found that IBS failed to show 

by a preponderance of the evidence that the claims of the 

’537 patent were obvious over Ju in combination with 

Zavgorodny under the same reasoning. Id. at *10–12.

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reference from one document into another document.” See 

Intelligent Bio-Sys., Inc., 2015 WL 996355, at *8–9.

According to the Board, IBS ran afoul of § 42.23(b) by 

presenting a new argument for the first time in its reply 

brief. “[T]he Reply presents new issues by changing the 

unpatentability rationale from express reliance on Zavgorodny’s deprotecting conditions, to asserting that those 

conditions would have been obvious to modify, as well as 

presenting new evidence to support the new rationale and 

explain the modifications to Zavgorodny.” Id. at *9. 

The reply, moreover, was accompanied by an expert 

declaration. According to the Board, the expert declaration “expands on the assertions in the Reply by presenting 

a number of additional new arguments explaining why 

quantitative deblocking would have been expected, and 

cites a number of non-patent literature references which 

were not relied upon to support unpatentability in the

Petition.” Id. That expert declaration, the Board found, 

contains “in-depth explanations and supporting documentary evidence” not contained in the reply itself. Id. In 

this way, the Board found, IBS ran afoul of § 42.6(a)(3) by 

improperly incorporating by reference arguments and 

evidence from the expert declaration into the reply brief.

IBS now challenges the Board’s conclusion that IBS 

failed to demonstrate the challenged claims were obvious 

by a preponderance of the evidence. IBS also argues the 

Board abused its discretion to the extent it found IBS’s 

reply brief improper.

We have jurisdiction pursuant to 28 U.S.C. 

§ 1295(a)(4)(A).

DISCUSSION

Obviousness is a mixed question of fact and law. Although the Board’s ultimate conclusion that the claims are 

not obvious is a legal determination subject to de novo 

review, the subsidiary factual findings are reviewed for 

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substantial evidence. In re Gartside, 203 F.3d 1305, 1312, 

1316 (Fed. Cir. 2000). “Substantial evidence is more than 

a mere scintilla.” Consol. Edison Co. v. N.L.R.B., 305 U.S. 

197, 229 (1938). Substantial evidence review asks 

“whether a reasonable fact finder could have arrived at 

the agency’s decision” and requires examination of the 

“record as a whole, taking into account evidence that both 

justifies and detracts from an agency’s decision.” In re

Gartside, 203 F.3d at 1312.

“The presence or absence of a motivation to combine 

references in an obviousness determination is a pure 

question of fact.” Par Pharm., Inc. v. TWI Pharm., Inc., 

773 F.3d 1186, 1196 (Fed. Cir. 2014) (citations omitted). 

“The presence or absence of a reasonable expectation of 

success is also a question of fact.” Id. Accordingly, the 

substantial evidence standard of review applies to the 

Board’s resolution of these factual determinations. The 

Court can review de novo, however, whether the Board 

“fail[ed] to consider the appropriate scope of 

the . . . patent’s claimed invention in evaluating the

reasonable expectation of success.” Allergan, Inc. v. 

Apotex Inc., 754 F.3d 952, 966 (Fed. Cir. 2014). 

Decisions related to compliance with the Board’s procedures are reviewed for an abuse of discretion. Bilstad v. 

Wakalopulos, 386 F.3d 1116, 1121 (Fed. Cir. 2004). “An 

abuse of discretion is found if the decision: (1) is clearly 

unreasonable, arbitrary, or fanciful; (2) is based on an 

erroneous conclusion of law; (3) rests on clearly erroneous 

fact finding; or (4) involves a record that contains no 

evidence on which the Board could rationally base its 

decision.” Id. Accordingly, the Board’s determinations 

that IBS exceeded the scope of a proper reply in violation 

of 37 C.F.R. § 42.23(b) and improperly incorporated 

arguments by reference from another document in violation of 37 C.F.R. § 42.6(a)(3) are reviewed for an abuse of

discretion.

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A. Motivation to Combine/Reasonable 

Expectation of Success

The Board found that Zavgorodny would not be “obvious to use” with Tsien or Ju because its azidomethyl 

group would not be removed quantitatively (at or near 

100%). Intelligent Bio-Sys., Inc., 2015 WL 996355, at *5, 

*12. IBS argues that, “[b]ecause the claims do not require 

quantitative cleavage, the Board erred by imposing such a 

requirement through the reasonable expectation of success analysis.” Appellant Br. 38. To the extent the 

Board’s decision is based on the “reasonable expectation of 

success” requirement, we agree.

The reasonable expectation of success requirement refers to the likelihood of success in combining references to 

meet the limitations of the claimed invention. “[F]ailure 

to consider the appropriate scope of the . . . patent’s 

claimed invention in evaluating the reasonable expectation of success . . . constitutes a legal error that [is] review[ed] without deference.” Allergan, 754 F.3d at 966 

(emphasis added). Under the Board’s uncontested construction, “claim 1 does not require removal of the protecting group to allow subsequent nucleotide incorporation,” 

let alone quantitative removal. Intelligent Bio-Sys., Inc., 

2015 WL 996355, at *4. Accordingly, it is of no moment 

that Zavgorodny’s protecting group would not be removed 

quantitatively in Tsien or Ju’s sequencing method—

removal is simply not required by the claim of the ’537 

patent. The Board seemed to believe that the “reasonable 

expectation of success” inquiry looked to whether one 

would reasonably expect the prior art references to operate as those references intended once combined. That is 

not the correct inquiry—one must have a motivation to 

combine accompanied by a reasonable expectation of 

achieving what is claimed in the patent-at-issue. The 

Board’s reliance on the absence of a reasonable expectation of success was, thus, improper. See id. at *5–6 (citing 

KSR, 550 U.S. at 421 to support the proposition “that a 

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conclusion of obviousness requires a reasonable expectation of success”).

Yet this court “sit[s] to review judgments, not opinions.” Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 

1540 (Fed. Cir. 1983). And while the Board conflated two 

different legal concepts—reasonable expectation of success and motivation to combine—it nevertheless made

sufficient factual findings to support its judgment that the 

claims at issue are not invalid. It was IBS’s burden to 

demonstrate both “that a skilled artisan would have been

motivated to combine the teachings of the prior art references to achieve the claimed invention, and that the 

skilled artisan would have had a reasonable expectation 

of success in doing so.” Kinetic Concepts, Inc. v. Smith & 

Nephew, Inc. 688 F.3d 1342, 1360 (Fed. Cir. 2012) (quoting Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 

F.3d 989, 994 (Fed. Cir. 2009) (internal quotation marks 

omitted)); In re Cyclobenzaprine Hydrochloride Extended–

Release Capsule Patent Litig., 676 F.3d 1063, 1068–69 

(Fed. Cir. 2012). Despite the loose language employed by 

the Board, its factual findings support its conclusion that 

the claims are not invalid.

IBS argued in its revised initial petition to the Board 

that the combination of Tsien or Ju with Zavgorodny was 

based entirely on a shared purpose: SBS. IBS argued that 

an ordinary artisan would have a motivation to combine 

Tsien or Ju with Zavgorodny: “[O]ne of ordinary skill in 

the art, in order to improve the efficiency, reliability, and 

robustness of the sequencing by synthesis method taught in 

Tsien, would have been motivated to use other protecting 

groups that meet the criteria of Tsien, such as the azidomethyl group taught by Zavgorodny.” J.A. 145 (emphasis added). This argument follows immediately after 

IBS lists the “criteria for the successful use of 3′-blocking 

groups,” which includes “quantitative deblocking.” J.A. 

144. 

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The Board, therefore, was justified in finding that, 

“despite having acknowledged the quantitative deblocking 

requirement in Tsien (Pet. 37), the Petition did not provide a specific or credible explanation why an ordinary 

artisan would have expected Zavgorodny’s azidomethyl 

protecting group to meet Tsien’s quantitative deblocking 

requirement under conditions suitable for use in Tsien’s 

sequencing methods.” Intelligent Bio-Sys., Inc., 2015 WL 

996355, at *8. While this shortcoming is irrelevant to a 

finding that there was no reasonable expectation of success in meeting the claims of the ’537 patent, which do not 

require quantitative deblocking at all, it is central to a 

finding of no motivation to combine. This is because the 

petitioner’s sole argument for why one of skill in the art 

would be motivated to combine Zavgorodny’s azidomethyl 

group with Tsien’s SBS method was because it would 

meet Tsien’s quantitative deblocking requirement. “When 

an obviousness determination relies on the combination of 

two or more references, there must be some suggestion or 

motivation to combine the references.” WMS Gaming, 

Inc. v. Int’l Game Tech., 184 F.3d 1339, 1355 (Fed. Cir. 

1999); see also Dome Patent L.P. v. Lee, 799 F.3d 1372, 

1380 (Fed. Cir. 2015) (“If all elements of a claim are found 

in the prior art, as is the case here, the factfinder must 

further consider the factual questions of whether a person 

of ordinary skill in the art would be motivated to combine 

those references, and whether in making that combination, a person of ordinary skill would have had a reasonable expectation of success.”).

There is, moreover, substantial evidence to support a 

finding that a person of ordinary skill would not have had 

reason to combine Tsien or Ju with Zavgorodny to achieve 

the claimed invention. In its decision the Board acknowledged two background references presented by Illumina: 

Loubinoux, which teaches that azidomethyl methyl 

groups are removed from phenols with modest efficiency 

(60-80% yield), and Greene & Wuts, which teaches that 

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removal of an azidomethyl methyl group from the 3′ 

hydroxyl position of a deoxyribonucleotide moiety is likely 

to proceed with even lower efficiency. Intelligent BioSys., Inc., 2015 WL 996355, at *7–8 (citing Loubinoux 

(J.A. 974–75) and Theodora W. Greene & Peter G.M. 

Wuts, Protective Groups in Organic Synthesis 246–92 (3d 

ed. 1999) (J.A. 863–970)). These references support a 

conclusion that the claimed efficiency that allegedly 

motivated the combination would not be achieved and 

that a person of ordinary skill in this field would not have 

been motivated to use the azidomethyl group of Zavgorodny as a “protecting group [that] can be modified or 

removed to expose a 3′ [hydroxyl] group” of a nucleic acid 

molecule, as the claim requires. This is so because the 

azidomethyl group would have been expected to perform 

inefficiently in that role.

IBS submitted an initial petition that articulated a set 

of rationales for why the challenged claims were invalid, 

including why a person of ordinary skill would be motivated to combine the prior art references at issue. IBS 

made a clear argument as to why a person of ordinary 

skill would be motivated to combine the prior art references at issue and Illumina demonstrated the error in 

that argument, which the Board credited. This factual 

finding by the Board is supported by substantial evidence. 

The Board did not err in finding that the grounds of 

invalidity described in IBS’s petition were not established.

B. IBS’s Improper Reply Brief

IBS also argues that “the Board must consider whether it is within the skill of the ordinary artisan to modify 

the cleavage conditions to satisfy the alleged cleavage 

requirements.” Appellant Br. 44. The Board did not 

consider this argument, however, because it was raised 

for the first time in IBS’s reply brief and expert declaration. 

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It is of the utmost importance that petitioners in the 

IPR proceedings adhere to the requirement that the 

initial petition identify “with particularity” the “evidence 

that supports the grounds for the challenge to each 

claim.” 35 U.S.C. § 312(a)(3). “All arguments for the 

relief requested in a motion must be made in the motion. 

A reply may only respond to arguments raised in the 

corresponding opposition or patent owner response.” 37 

C.F.R. § 42.23(b). Once the Board identifies new issues 

presented for the first time in reply, neither this court nor 

the Board must parse the reply brief to determine which, 

if any, parts of that brief are responsive and which are 

improper. As the Board noted, “it will not attempt to sort 

proper from improper portions of the reply.” Office Patent 

Trial Practice Guide, 77 Fed. Reg. 48,756, 48,767 (Aug. 

14, 2012).

IBS argued in its petition that “Zavgorodny teaches 

the desired property [in Tsien] that the azidomethyl group 

‘can be removed under very specific and mild conditions.’” 

J.A. 145–46 (quoting Zavgorodny, J.A. 861). Illumina 

presented evidence in its response that, “an ordinary 

artisan would not have considered Zavgorodny’s conditions suitably mild for Tsien’s sequencing purposes.” Id. 

IBS’s reply then argued, for the first time, “that an ordinary artisan would have considered it obvious to use 

deprotecting conditions other than those described in 

Zavgorodny.” Id. But IBS chose which grounds of invalidity to assert in its petition and it chose not to assert 

this new one. Unlike district court litigation—where 

parties have greater freedom to revise and develop their 

arguments over time and in response to newly discovered 

material—the expedited nature of IPRs bring with it an 

obligation for petitioners to make their case in their 

petition to institute. While the Board’s requirements are 

strict ones, they are requirements of which petitioners are 

aware when they seek to institute an IPR.

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IBS supported its new theory of invalidity by reference to new evidence, citing “a number of non-patent 

literature references which were not relied upon to support unpatentability in the Petition.” Id. at *9. See Office 

Patent Trial Practice Guide, 77 Fed. Reg. at 48,767 (“Examples of indications that a new issue has been raised in 

a reply include new evidence necessary to make out a 

prima facie case for the . . . unpatentability of an original . . . claim, and new evidence that could have been 

presented in a prior filing.”). In these circumstances, we 

find that the Board did not err in refusing the reply brief 

as improper under 37 C.F.R. § 42.23(b) because IBS relied 

on an entirely new rationale to explain why one of skill in 

the art would have been motivated to combine Tsien or Ju 

with a modification of Zavgorodny.

Because we conclude that the reply brief and accompanying declaration exceeded the scope of the reply under 

§ 42.23(b), and, therefore, that the Board did not abuse its 

discretion in excluding those documents, we need not 

resolve whether the reply brief complied with 37 C.F.R. 

§ 42.6(a)(3), which states that “[a]rguments must not be 

incorporated by reference from one document into another 

document.” See Intelligent Bio-Sys., Inc., 2015 WL 

996355, at *9. Nor do we review the Board’s conclusion 

that, even if proper, the arguments contained in the reply 

brief are unpersuasive for the same reason it found the 

arguments in the petition unpersuasive. Id. at *10. 

CONCLUSION

We find the Board’s conclusion that IBS failed to 

demonstrate by a preponderance of the evidence that the 

challenged claims of the ’537 patent are invalid as obvious 

over the combination of Tsien and Zavgorodny or Ju and 

Zavgorodny is supported by substantial evidence. Because the Board correctly determined that IBS failed to 

carry its burden to establish obviousness of the challenged 

claims, and because the Board did not abuse its discretion 

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in finding that IBS’s reply brief and accompanying declaration were improper, we need not address IBS’s other 

arguments. Accordingly, we affirm the Board. 

AFFIRMED

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