Case: 15-1693 Document: 55-1 Page: 1 Filed: 05/09/2016
`UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT
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`FOR THE COURT
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`/s/ Peter R. Marksteiner
`Peter R. Marksteiner
`Clerk of Court
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`
`15-1693 - Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd.
`United States Patent and Trademark Office, Case No. IPR2013-00517
`
`Illumina Ex. 1069
`IPR Petition - USP 10,435,742
`
`

`

`Case: 15-1693 Document: 55-2 Page: 1 Filed: 05/09/2016
`
`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, Philadel-
`
`phia, 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.
`
`______________________
`
`
`

`

`Case: 15-1693 Document: 55-2 Page: 2 Filed: 05/09/2016
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` INTELLIGENT BIO-SYSTEMS, INC. v.
` ILLUMINA CAMBRIDGE LTD.
`
`Before O’MALLEY, WALLACH, and HUGHES, Circuit Judges.
`O’MALLEY, Circuit Judge.
`Illumina Cambridge Ltd. (“Illumina”) owns U.S. Pa-
`tent 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 demonstrat-
`ing the obviousness of the challenged claims by a prepon-
`derance 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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`INTELLIGENT BIO-SYSTEMS, INC. v.
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`
`3
`
`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 modi-
`fied 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 stop-
`ping 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 un-
`known nucleotides and adds complementary nucleotides
`one-by-one to form the complete, double-helix structure.
`“The protecting group allows the polymerase to incorpo-
`rate 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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` INTELLIGENT BIO-SYSTEMS, INC. v.
` ILLUMINA CAMBRIDGE LTD.
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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 com-
`prises 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 re-
`quirements 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 nu-
`cleic acid molecule a nucleotide or nucleoside mol-
`ecule, 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 at-
`tached via the 2′ or 3′ oxygen atom, and said pro-
`tecting 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 teach-
`es 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
`tri-
`phenylphosphine 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 com-
`bination of Tsien and Zavgorodny with James M. Prober
`et al., A System for Rapid DNA Sequencing with Fluores-
`cent Chain-Terminating Dideoxynucleotides, 238 SCIENCE
`336 (1987), but IBS does not appeal the Board’s conclu-
`sion 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 “fundamen-
`tal 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 nucleo-
`tide.” 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 robust-
`ness 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 az-
`idomethyl 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 az-
`idomethyl 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 Zavgo-
`rodny 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 inven-
`tion. J.A. 144–47.
`Illumina disagreed with IBS, and argued that an or-
`dinary 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 remov-
`al” 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, “demon-
`strates 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 az-
`idomethyl 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 prepon-
`derance of the evidence, that an ordinary artisan would
`have considered it obvious to use Zavgorodny’s azidome-
`thyl 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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` INTELLIGENT BIO-SYSTEMS, INC. v.
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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 reasona-
`ble 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 ordi-
`nary skill and common sense. In that in-
`stance the fact that a combination was
`obvious to try might show that it was ob-
`vious 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 expecta-
`tion that prior art elements are capable of being
`physically combined, but also that the combina-
`tion would have worked for its intended purpose.”
`Depuy Spine, Inc v. Medtronic Sofamor Danek,
`Inc., 567 F.3d 1314, 1326 (Fed. Cir. 2009) (cita-
`tions omitted).
`Id. at *6. The Board further described Tsien and Zavgo-
`rodny, 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 re-
`moval 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 require-
`ment under conditions suitable for use in Tsien’s sequenc-
`ing 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 develop-
`ing the claimed invention, or (3) both. The Board’s opin-
`ion 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 pro-
`vides that a “reply may only respond to arguments raised
`in the corresponding opposition or patent owner re-
`sponse,” 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 Zavgo-
`rodny’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 declara-
`tion “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 documen-
`tary 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
`§ 1295(a)(4)(A).
`
`to 28 U.S.C.
`
`DISCUSSION
`Obviousness is a mixed question of fact and law. Alt-
`hough 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 pro-
`cedures 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 viola-
`tion 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 “obvi-
`ous 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 suc-
`cess 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 re-
`fers 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 expecta-
`tion of success . . . constitutes a legal error that [is] re-
`view[ed] without deference.” Allergan, 754 F.3d at 966
`(emphasis added). Under the Board’s uncontested con-
`struction, “claim 1 does not require removal of the protect-
`ing 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 oper-
`ate 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 expecta-
`tion 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 expecta-
`tion of success”).
`Yet this court “sit[s] to review judgments, not opin-
`ions.” 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 suc-
`cess 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 refer-
`ences 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) (quot-
`ing 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 az-
`idomethyl group taught by Zavgorodny.” J.A. 145 (em-
`phasis 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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` 14
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` INTELLIGENT BIO-SYSTEMS, INC. v.
` ILLUMINA CAMBRIDGE LTD.
`
`The Board, therefore, was justified in finding that,
`“despite having acknowledged the quantitative deblocking
`requirement in Tsien (Pet. 37), the Petition did not pro-
`vide 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 suc-
`cess 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 combina-
`tion, a person of ordinary skill would have had a reasona-
`ble 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 acknowl-
`edged 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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`Case: 15-1693 Document: 55-2 Page: 15 Filed: 05/09/2016
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`INTELLIGENT BIO-SYSTEMS, INC. v.
`ILLUMINA CAMBRIDGE LTD.
`
`15
`
`removal of an azidomethyl methyl group from the 3′
`hydroxyl position of a deoxyribonucleotide moiety is likely
`to proceed with even lower efficiency. Intelligent Bio-
`Sys., 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 Zavgo-
`rodny 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 moti-
`vated 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 refer-
`ences 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 wheth-
`er 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 declara-
`tion.
`
`

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` INTELLIGENT BIO-SYSTEMS, INC. v.
` ILLUMINA CAMBRIDGE LTD.
`
`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 argum