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`Case: 15-1123 Document: 27 Page: 1 Filed: 03/10/2015
`
`No. 2015-1123
`
`IN THE
`United States Court of Appeals
`FOR THE FEDERAL CIRCUIT
`
`
`
`
`
`
`
`
`
`ILLUMINA CAMBRIDGE LTD.,
`Appellant,
`
`
`
`
`
`
`
`v.
`
`INTELLIGENT BIO-SYSTEMS, INC.,
`Appellee.
`
`APPEAL FROM THE UNITED STATES PATENT AND TRADEMARK OFFICE
`PATENT TRIAL AND APPEAL BOARD IN NO. IPR2013-00128
`
`BRIEF OF PATENT OWNER-APPELLANT
`ILLUMINA CAMBRIDGE LTD.
`
`BRENTON R. BABCOCK
`KNOBBE, MARTENS, OLSON
`
`& BEAR, LLP
`2040 Main Street, 14th Fl.
`Irvine, CA 92614
` (949) 760-0404
`
`KERRY S. TAYLOR, PH.D.
`NATHANAEL R. LUMAN, PH.D.
`KNOBBE, MARTENS, OLSON
`
`& BEAR, LLP
`12790 El Camino Real
`San Diego, CA 92130
`(858) 707-4000
`
`March 10, 2015
`
`WILLIAM R. ZIMMERMAN
` Counsel of Record
`JONATHAN E. BACHAND
`KNOBBE, MARTENS, OLSON
`
`& BEAR, LLP
`1717 Pennsylvania Avenue N.W.
`Suite 900
`Washington, DC 20006
`(202) 640-6400
`
`Attorneys for Appellant
`
`
`
`
`
`Columbia Ex. 2023
`Illumina, Inc. v. The Trustees
`of Columbia University
`in the City of New York
`IPR2020-01177
`
`
`
`Case: 15-1123 Document: 27 Page: 2 Filed: 03/10/2015
`
`CERTIFICATE OF INTEREST
`
`Counsel for Appellant certifies the following:
`
`The full name of every party or amicus represented by me is:
`
`The name of the real party in interest represented by me is:
`
`1.
`
`Illumina Cambridge Ltd.
`
`2.
`
`Illumina Cambridge Ltd.
`
`3.
`All parent corporations and any publicly held companies that own
`10 percent or more of the stock of the party or amicus curie represented by me
`are:
`
`
`Illumina Cambridge Ltd. is a wholly owned subsidiary of Illumina, Inc.,
`a Delaware corporation with its principal place of business in San Diego,
`CA.
`
`4.
`The names of all law firms and the partners or associates that
`appeared for the party or amicus now represented by me in the trial court or
`agency or are expected to appear in this court are:
`
`Knobbe, Martens, Olson & Bear, LLP: Brenton R. Babcock, William R.
`Zimmerman, Jonathan E. Bachand, Kerry S. Taylor, Nathanael R.
`Luman, Andrew E. Morrell; Reinhart Boerner Van Dueren s.c.: James G.
`Morrow, James D. Borchardt.
`
`
`Dated: March 10, 2015
`
`
`
`By: /s/ William R. Zimmerman
`William R. Zimmerman
`Brenton R. Babcock
`Jonathan E. Bachand
`Kerry S. Taylor
`Nathanael R. Luman
`Attorneys for Patent Owner-Appellant
`Illumina Cambridge Ltd.
`
`
`i
`
`
`
`Case: 15-1123 Document: 27 Page: 3 Filed: 03/10/2015
`
`TABLE OF CONTENTS
`
`Page No.
`
`STATEMENT OF RELATED CASES ........................................................... viii
`
`JURISDICTIONAL STATEMENT ................................................................... 1
`
`I.
`
`II.
`
`STATEMENT OF THE ISSUE ............................................................... 1
`
`STATEMENT OF THE CASE ................................................................ 1
`
`III. STATEMENT OF THE FACTS .............................................................. 2
`
`A.
`
`Technological Background ............................................................ 2
`
`1.
`
`2.
`
`3.
`
`Sequencing by synthesis ...................................................... 2
`
`Illumina’s ’026 patent ........................................................ 10
`
`The prior art ....................................................................... 12
`
`a.
`
`b.
`
`c.
`
`The prior art did not teach nucleotides that
`combine a 3’-protecting group and a
`disulfide linkage attaching a label to the
`base .......................................................................... 12
`
`The prior art recognized the importance of
`deblocking the 3’-protecting group in SBS ............. 15
`
`The prior art taught that disulfide linkage
`cleavage conditions yielded inefficient and
`variable results ......................................................... 16
`
`B.
`
`The Inter Partes Review Proceedings .......................................... 19
`
`1.
`
`2.
`
`3.
`
`IBS’s petition and the Board’s institution decision ........... 19
`
`Illumina’s Motion to Amend ............................................. 21
`
`The Board’s Final Written Decision .................................. 23
`
`ii
`
`
`
`Case: 15-1123 Document: 27 Page: 4 Filed: 03/10/2015
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`IV. SUMMARY OF THE ARGUMENT ..................................................... 27
`
`V. ARGUMENT .......................................................................................... 31
`
`A.
`
`B.
`
`Standard Of Review ..................................................................... 31
`
`The Board Erred In Determining That Substitute Claims
`9-12 Would Have Been Obvious ................................................. 32
`
`1.
`
`2.
`
`The Board improperly focused on the added
`disulfide linkage limitation rather than
`combination of amended claim limitations ........................ 33
`
`The Board failed to provide a motivation for, or a
`reasonable expectation of success in, combining
`the prior art to achieve Illumina’s claimed
`invention ............................................................................. 35
`
`a.
`
`b.
`
`c.
`
`d.
`
`The uncontroverted evidence showed that
`SBS requires efficient removal of the 3’
`protecting group ....................................................... 38
`
`The Board misapprehended Illumina’s
`argument regarding cleavage efficiency .................. 42
`
`One skilled in the art would not have been
`motivated to use disulfide linkage cleavage
`conditions because they result in inefficient
`and variable cleavage ............................................... 46
`
`The Board’s conclusion that the disulfide
`linkage cleavage efficiency of the prior art
`could have been increased with an
`expectation of success was clearly
`erroneous .................................................................. 50
`
`iii
`
`
`
`Case: 15-1123 Document: 27 Page: 5 Filed: 03/10/2015
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`i.
`
`ii.
`
`The Board imposed an improperly
`heightened standard of
`nonobviousness ............................................. 50
`
`There is no evidence to support the
`Board’s conclusion that a nucleotide
`having a disulfide linkage would
`provide sufficient cleavage efficiency
`of the 3’-protecting group ............................. 51
`
`3.
`
`4.
`
`The Board did not identify any 3’-protecting group
`and disulfide linkage that are cleavable under
`identical conditions ............................................................ 55
`
`The Board improperly discounted Illumina’s
`evidence of unexpected results .......................................... 58
`
`a.
`
`b.
`
`c.
`
`Illumina presented testing demonstrating
`unexpected results using the claimed
`nucleotides ............................................................... 58
`
`Illumina properly compared its claims to
`the closest prior art................................................... 61
`
`Illumina demonstrated that the unexpected
`results are not a latent property of the
`disulfide linkage....................................................... 63
`
`5.
`
`Illumina demonstrated the patentability of the
`substitute claims ................................................................. 64
`
`VI. CONCLUSION ....................................................................................... 65
`
`ADDENDUM
`
`
`
`iv
`
`
`
`Case: 15-1123 Document: 27 Page: 6 Filed: 03/10/2015
`
`TABLE OF AUTHORITIES
`
`Page No(s).
`
`In re Baxter Travenol Labs,
`952 F.2d 388 (Fed. Cir. 1991) ...................................................................... 63
`
`In re Blondel,
`499 F.2d 1311 (C.C.P.A. 1974) .................................................................... 63
`
`CFMT, Inc. v. Yieldup Int’l. Corp.,
`349 F.3d 1333 (Fed. Cir. 2003) .................................................................... 55
`
`Consolidated Edison Co. v. NLRB,
`305 U.S. 197 (1938) ...................................................................................... 32
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ........................................................ 37, 45, 49
`
`Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) .................................................................... 32
`
`Envtl. Designs, Ltd. v. Union Oil Co.,
`713 F.2d 693 (Fed. Cir. 1983) ...................................................................... 33
`
`In re Fouche,
`439 F.2d 1237 (C.C.P.A. 1971) .................................................................... 63
`
`In re Gartside,
`203 F.3d 1305 (Fed. Cir. 2000) .................................................................... 32
`
`Geo M. Martin Co. v. Alliance Mach. Sys. Int’l, LLC,
`618 F.3d 1294 (Fed. Cir. 2010) .................................................................... 49
`
`Heidelberger Druckmaschinen AG v. Hantscho
`Commercial Prods., Inc.,
`
`21 F.3d 1068 (Fed. Cir. 1994) ...................................................................... 57
`
`Hybritech, Inc. v. Monoclonal Antibodies, Inc.,
`802 F.2d 1367 (Fed. Cir. 1986) .................................................................... 58
`
`v
`
`
`
`Case: 15-1123 Document: 27 Page: 7 Filed: 03/10/2015
`
`TABLE OF AUTHORITIES
`(cont’d)
`
`Page No(s).
`
`In re ICON Health & Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007) .................................................................... 46
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ................................................................ 49, 57
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .................................................................... 54
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ........................................................ 33, 35, 36, 49, 50, 57
`
`Lucent Techs., Inc. v. Gateway, Inc.,
`580 F.3d 1301 (Fed. Cir. 2009) .................................................................... 57
`
`In re Merchant,
`575 F.2d 865 (C.C.P.A. 1978) ................................................................ 61, 62
`
`In re Mills,
`916 F.2d 680 (Fed. Cir. 1990) ...................................................................... 64
`
`In re Ochiai,
`71 F.3d 1565 (Fed. Cir. 1995) ...................................................................... 55
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 35
`
`Procter & Gamble Co. v. Teva Pharms. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ................................................................ 35, 51
`
`Rambus Inc. v. Rea,
`731 F.3d 1248 (Fed. Cir. 2013) .................................................................... 31
`
`In re Royka,
`490 F.2d 981 (C.C.P.A. 1974) ...................................................................... 55
`
`vi
`
`
`
`Case: 15-1123 Document: 27 Page: 8 Filed: 03/10/2015
`
`TABLE OF AUTHORITIES
`(cont’d)
`
`Page No(s).
`
`Ruiz v. A.B. Chance Co.,
`357 F.3d 1270 (Fed. Cir. 2004) ........................................................ 33, 35, 50
`
`Schenck v. Nortron Corp.,
`713 F.2d 782 (Fed. Cir. 1983) ...................................................................... 34
`
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995) ........................................................................ 64
`
`In re Sullivan,
`498 F.3d 1345 (Fed. Cir. 2007) .................................................................... 63
`
`United States v. Adams,
`383 U.S. 39 (1966) .................................................................................. 38, 49
`
`Vizio, Inc. v. U.S. Int’l Trade Comm’n,
`605 F.3d 1330 (Fed. Cir. 2010) .................................................................... 58
`
`In re Zeidler,
`682 F.2d 961 (C.C.P.A. 1982) ...................................................................... 54
`
`OTHER AUTHORITIES
`
`28 U.S.C. § 1295 .................................................................................................. 1
`
`35 U.S.C. § 141 .................................................................................................... 1
`
`35 U.S.C. § 142 .............................................................................................. 1, 27
`
`35 U.S.C. § 316 .............................................................................................. 2, 64
`
`37 C.F.R. § 42.65 ............................................................................................... 53
`
`37 C.F.R. § 42.121 ............................................................................. 2, 22, 64, 65
`
`37 C.F.R. § 90.3 ............................................................................................. 1, 27
`
`
`
`vii
`
`
`
`Case: 15-1123 Document: 27 Page: 9 Filed: 03/10/2015
`
`
`
`STATEMENT OF RELATED CASES
`
`Pursuant to Federal Circuit Rule 47.5, Appellant provides the following
`
`statement of related cases:
`
`(a) This is an appeal of the Final Written Decision from the United
`
`States Patent and Trademark Office Patent Trial and Appeal Board (“Board”) in
`
`inter partes review (“IPR”) 2013-00128 regarding U.S. Patent No. 7,057,026
`
`(“the ’026 patent”), owned by Appellant Illumina Cambridge Ltd. (“Illumina”).
`
`No other appeal in or from the proceeding below was previously before this or
`
`any other appellate court.
`
`(b) Pending before this Court is appeal No. 2015-1243, an appeal of the
`
`Final Written Decision from the Board in IPR2013-00266 regarding U.S. Patent
`
`No. 8,158,346 (“the ’346 patent”), also owned by Illumina. The ’346 patent
`
`claims priority to the ’026 patent, and the specifications of the two patents
`
`largely overlap. On December 5, 2014, Illumina filed an unopposed motion
`
`requesting coordination of appeal Nos. 2015-1123 and 2015-1243. The Court
`
`granted Illumina’s motion by Order dated December 31, 2014.
`
`Additionally, Illumina has alleged infringement of, inter alia, the ’026
`
`and ’346 patents in counterclaims against Appellee Intelligent Bio-Systems,
`
`Inc. (“IBS”) before the District of Delaware in Trustees of Columbia Univ. v.
`
`Illumina, Inc., No. 12-cv-376 (D. Del.). The district court litigation is presently
`
`viii
`
`
`
`Case: 15-1123 Document: 27 Page: 10 Filed: 03/10/2015
`
`
`
`stayed, except for limited fact discovery, pending the outcome of this appeal
`
`and appeal No. 2015-1243, as well as the outcome of three coordinated appeals
`
`and an additional inter partes review:
`
` Federal Circuit Appeal No. 2014-1547 (appeal of IPR2012-00006
`
`regarding U.S. Patent No. 7,713,698 (“the ’698 patent”), where the
`
`Trustees of Columbia University (“Columbia”) is the Appellant-patent
`
`owner and Illumina is the Appellee-petitioner). IBS is the exclusive
`
`licensee of ’698 patent;
`
` Federal Circuit Appeal No. 2014-1548 (appeal of IPR2012-00007
`
`regarding U.S. Patent No. 7,790,869 (“the ’869 patent”), where
`
`Columbia is the Appellant-patent owner and Illumina is the Appellee-
`
`petitioner). IBS is the exclusive licensee of ’869 patent;
`
` Federal Circuit Appeal No. 2014-1550 (appeal of IPR2013-00011
`
`regarding U.S. Patent No. 8,088,575 (“the ’575 patent”), where
`
`Columbia is the Appellant-patent owner and Illumina is the Appellee-
`
`petitioner). IBS is the exclusive licensee of the ’575 patent; and
`
` IPR2013-00517 regarding U.S. Patent No. 7,566,537, where Illumina
`
`is the patent owner and IBS is the petitioner. On February 11, 2015,
`
`the Board issued a Final Written Decision upholding the patentability
`
`of the challenged claims of the ’537 patent.
`
`ix
`
`
`
`Case: 15-1123 Document: 27 Page: 11 Filed: 03/10/2015
`
`
`
`
`
`JURISDICTIONAL STATEMENT
`
`On July 25, 2014, the Board issued its Final Written Decision in
`
`IPR2013-00128. JA26-57. Illumina timely filed its notice of appeal on
`
`September 24, 2014. See 35 U.S.C. § 142; 37 C.F.R. § 90.3(a). This Court has
`
`jurisdiction pursuant to 35 U.S.C. § 141(c) and 28 U.S.C. § 1295(a)(4)(A).
`
`I. STATEMENT OF THE ISSUE
`Did the Board err in denying Illumina’s Motion to Amend to add
`
`substitute Claims 9-12 to U.S. Patent No. 7,057,026 (“the ’026 patent”) by:
`
`(1) improperly focusing on a single limitation added by amendment, the
`
`disulfide linkage limitation, rather than the combination of amended limitations,
`
`specifically a disulfide linkage connecting a label to the base and a
`
`3’-protecting group that are cleavable under identical conditions;
`
`(2) failing to provide any motivation for, or reasonable expectation of
`
`success in, combining the prior art to achieve the combination of amended
`
`limitations; and
`
`(3) improperly discounting Illumina’s evidence of unexpected results.
`
`II. STATEMENT OF THE CASE
`In IPR2013-00128, IBS challenged Claims 1-8 of Illumina’s ’026 patent
`
`as being either anticipated by or obvious in view of the prior art. JA27-29;
`
`JA197. The Board instituted review of all claims on July 29, 2013. JA27-29;
`
`JA332-33; JA349.
`
`1
`
`
`
`Case: 15-1123 Document: 27 Page: 12 Filed: 03/10/2015
`
`
`
`On February 19, 2014, Illumina filed a Substitute Motion to Amend
`
`seeking to cancel Claims 1-8 and replace them with substitute Claims 9-12.
`
`JA27-30; JA496-518; 35 U.S.C. § 316(d); 37 C.F.R. § 42.121. Following oral
`
`hearing, the Board issued a Final Written Decision cancelling Claims 1-8, but
`
`denying Illumina’s request to enter substitute Claims 9-12. JA26-57. Illumina
`
`appeals the Board’s refusal to enter substitute Claims 9-12.
`
`III. STATEMENT OF THE FACTS
`A. Technological Background
`This appeal relates to innovative, non-natural nucleotide triphosphate
`
`molecules used in deoxyribonucleic acid (“DNA”) sequence determination
`
`methods known as sequencing by synthesis (“SBS”). As relevant to the
`
`amended claims,
`
`Illumina’s
`
`innovative nucleotides contain a unique
`
`combination of: (1) a disulfide linkage attaching a label to the base; (2) a
`
`protecting group attached to the 3’-oxygen atom of the sugar moiety
`
`(“3’-protecting group”); and (3) the disulfide linkage and the 3’-protecting
`
`group are cleavable under identical conditions. JA501-03.
`
`Sequencing by synthesis
`
`1.
`The ’026 patent is directed to non-natural, labeled nucleotides used in
`
`SBS. JA37; JA66-67 at 1:12-14, 2:65-3:11. SBS is a term that includes
`
`methods of DNA sequencing in which labeled nucleotides are incorporated one-
`
`by-one by an enzyme to synthesize a DNA strand. JA70 at 9:15-24; JA1490 at
`
`2
`
`
`
`Case: 15-1123 Document: 27 Page: 13 Filed: 03/10/2015
`
`
`
`l.34-JA1491 at l.14. As each nucleotide is sequentially added to the growing
`
`DNA strand, the nucleotide is identified according to its label, allowing the
`
`sequence of the DNA to be determined. JA70 at 9:15-24; JA1490 at l.34-
`
`JA1491 at l.14.
`
`DNA is a linear strand of linked nucleotides whose sequence determines
`
`traits about an organism. Determining the sequence of the DNA opens
`
`important avenues to diagnose, prevent, and treat numerous diseases and
`
`conditions. JA850; JA1485 at ll.18-23.
`
`A nucleotide consists of a nitrogen-containing base, a ribose or
`
`deoxyribose sugar moiety, and one or more phosphate groups. JA67 at 4:59-61.
`
`In a naturally occurring nucleotide from DNA, the base can be one of four
`
`types: adenine (“A”), cytosine (“C”), guanine (“G”), or thymine (“T”). JA67 at
`
`4:63-66; JA1588-89 ¶30. The sugar portion of a nucleotide contains five
`
`carbon atoms, which are conventionally numbered 1’-5’, as shown below in
`
`connection with a G nucleotide:
`
`ester bond
`
`- fl 1 ¥
`o-i-0- - H
`••
`
`s·
`
`pb04phate
`
`ba.se
`
`0 (;c(_,
`
`'
`H
`1~
`g lycoaidic
`bond
`
`HO
`ribOae
`
`3
`
`
`
`
`
`Case: 15-1123 Document: 27 Page: 14 Filed: 03/10/2015
`
`
`
`JA1587-88 ¶28. In their isolated state, nucleotides contain a hydroxyl group
`
`(“-OH”) at the 3’-position of the sugar, referred to as a “3’-OH.” Id.
`
`As illustrated below, each DNA strand consists of nucleotides in which
`
`the phosphate group of one nucleotide binds with the 3’-OH of the previous
`
`nucleotide:
`
`T
`
`
`
`JA5113. DNA within a cell is double-stranded, and the two separate strands
`
`bind
`
`to one another
`
`through hydrogen bonds between
`
`the bases of
`
`complementary nucleotides in each strand. In this complementary base pairing,
`
`A nucleotides in one strand bind to T nucleotides in the other strand, and C
`
`nucleotides in one strand bind to G nucleotides in the other strand.
`
`SBS is a process used to determine the nucleotide sequence in a single
`
`strand of DNA complementary to a sample single strand of DNA (referred to as
`
`4
`
`
`
`Case: 15-1123 Document: 27 Page: 15 Filed: 03/10/2015
`
`
`
`the “template” DNA strand). JA70 at 9:15-24; JA1490 at ll.34-36. This
`
`sequence determination occurs by synthesizing
`
`the strand of DNA
`
`complementary to the template DNA strand, one labeled nucleotide at a time,
`
`and identifying each nucleotide that is added to the complementary DNA
`
`strand. JA70 at 9:15-34; JA1490 at l.36-JA1491 at l.14. In some SBS methods,
`
`the non-natural nucleotides used to synthesize the complementary DNA strand
`
`contain a label attached, directly or indirectly (via a linker), to the nucleotide.
`
`See, e.g., JA60-62 at Figs. 1-3. These labels are used to identify which
`
`nucleotide was added into the complementary DNA strand. JA66 at 2:65-JA67
`
`at 3:11; JA1490 at l.36-JA1491 at l.14.
`
`To facilitate clear identification of each added nucleotide, the addition
`
`step is limited to a single nucleotide. This is accomplished by adding a
`
`“protecting group” to the nucleotide, which prevents polymerase from
`
`incorporating more than one nucleotide. JA69 at 8:11-14. After one identifies
`
`the nucleotide added to the complementary DNA strand, the protecting group is
`
`removed (also referred to as “deblocked”) to regenerate or expose a 3’-OH
`
`moiety that allows incorporation of the next nucleotide. JA67 at 3:6-9; JA69 at
`
`8:31-33. Through this sequential process (adding one nucleotide, identifying
`
`the added nucleotide, and then deblocking the nucleotide to allow the next
`
`nucleotide to be added), the sequence of the template DNA strand can be
`
`5
`
`
`
`Case: 15-1123 Document: 27 Page: 16 Filed: 03/10/2015
`
`
`
`determined in a stepwise fashion. JA66 at 2:65-JA67 at 3:11. A generic
`
`illustration of a nucleotide having a protecting group at the 3’-position of the
`
`sugar and a label attached to the base via a linker is shown below:
`
`Tripbosphate X
`
`A ' Base
`
`3'-0H pos1
`
`
`
`JA32.
`
`Ideally, this process of incorporation, identification, and deblocking is
`
`repeated for each and every nucleotide in the template DNA strand. Due to the
`
`complexity of DNA sequencing methods, an SBS process should be able to
`
`determine the sequence of at least 20 consecutive nucleotides in the template
`
`DNA strand to be effective. JA4983 at ll.9-12; JA2866 at l.21-JA2867 at l.25;
`
`JA2899 at l.14-JA2900 at l.6. The prior art taught SBS methods that achieved
`
`much greater sequence lengths. For example, WO 91/06678 (“Tsien”)
`
`describes in detail SBS methods that allow sequencing of “25 to 300, or more”
`
`consecutive nucleotides in the template DNA strand. JA1501 at ll.33-36. Since
`
`6
`
`
`
`Case: 15-1123 Document: 27 Page: 17 Filed: 03/10/2015
`
`
`
`each subsequent nucleotide identification relies on the fidelity of the preceding
`
`incorporation, identification, and deblocking steps, each of these steps must be
`
`performed with very high efficiency to achieve 20 cycles and thereby be useful
`
`in SBS. JA1504 at l.24-JA1505 at l.3; JA3958 at 2:22-27; JA2896 at ll.3-8, 14-
`
`20.
`
`In SBS processes, the systems often contain numerous identical copies of
`
`the same template DNA strand so that several complementary DNA strands are
`
`sequenced simultaneously. JA1490 at l.34-JA1491 at l.3; JA1563 at 2:66-
`
`JA1564 at 3:2; JA4029 at l.30-JA4030 at l.15. This allows for a more accurate
`
`signal measurement by detection equipment and resultant determination of the
`
`sequence of the template DNA strand, even if errors are introduced during
`
`sequencing in any particular complementary DNA strand.
`
`If the protecting group is not removed efficiently during the SBS process,
`
`the protecting group will remain intact in some of the complementary DNA
`
`strands, while being removed from others. For those complementary DNA
`
`strands with intact protecting groups, the protecting group will continue to
`
`block the 3’-OH group, preventing a nucleotide from being added in the next
`
`incorporation step. For the other complementary DNA strands in which the
`
`protecting groups were removed, the next incorporation step will properly add a
`
`nucleotide. When this occurs, all of the complementary DNA strands that did
`
`7
`
`
`
`Case: 15-1123 Document: 27 Page: 18 Filed: 03/10/2015
`
`
`
`not properly incorporate the next nucleotide are a round behind (“out of phase”)
`
`with those that did properly incorporate the next nucleotide. Such out of phase
`
`complementary DNA strands produce signal measurements for the wrong
`
`nucleotide, which hinders the ability of the SBS method to accurately determine
`
`the sequence of the template DNA strand. JA3699-701 ¶50. These errors are
`
`multiplicative, in that the strand(s) that go out of phase each round rarely catch
`
`up to the proper phase.
`
`Accordingly, nearly 100% efficiency in removing the protecting group is
`
`required to prevent complementary DNA strands from becoming out of phase
`
`and hindering the usefulness of the method. JA1504 at l.24-JA1505 at l.3;
`
`JA3958 at 2:22-27; JA2896 at ll.3-8, 14-20. For example, if a protecting group
`
`can be cleaved with only 85% efficiency, 85% of the complementary DNA
`
`strands will contain the correct sequence of nucleotides and 15% will not. After
`
`just 8 cycles, there would be only (0.85)8, or just 27%, of the complementary
`
`DNA strands that contain the correct sequence of nucleotides. JA3699-701 ¶50.
`
`The remaining 73% of the complementary DNA strands would be out of phase
`
`by one or more rounds because they failed to incorporate a nucleotide during a
`
`previous iteration. Id. With only 27% of the complementary DNA strands
`
`providing the correct signal, and the other strands providing inaccurate signals,
`
`accurate identification of the next incorporated nucleotide is not possible. Id.
`
`8
`
`
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`Case: 15-1123 Document: 27 Page: 19 Filed: 03/10/2015
`
`
`
`While nearly 100% cleavage efficiency in removing the protecting group
`
`is required for SBS, the cleavage efficiency for the linkage connecting a label to
`
`the base need not be as high. JA3013 ¶27 (90% cleavage efficiency for the
`
`3’-protecting group is ineffective, but “it is not necessary to cleave the linker
`
`with such high efficiency.”). In contrast to the cleavage efficiency required for
`
`the protecting group, as discussed above, if the linkage connecting the label to
`
`the base is not removed in any particular cycle, the next nucleotide will still be
`
`properly
`
`incorporated
`
`into
`
`the complementary DNA strand.
`
` That
`
`complementary DNA strand, however, would contain two labels. Thus, the
`
`complementary DNA strand will still be in phase with other complementary
`
`DNA strands, even if it provides some ambiguous or incorrect signal from
`
`having multiple labels.
`
`Moreover, that strand with two linkers/labels will most likely catch up in
`
`subsequent rounds. This means that the label that was not removed during the
`
`previous cycle is likely to be removed during the following cycle, and the SBS
`
`process will proceed without accumulated error. Accordingly, SBS can proceed
`
`with good accuracy even if the cleavage efficiency of the linkage connecting a
`
`label to the base does not reach the nearly 100% efficiency required for
`
`removing the protecting group.
`
`9
`
`
`
`Case: 15-1123 Document: 27 Page: 20 Filed: 03/10/2015
`
`
`
`As a consequence of strands with linkers/labels that are not properly
`
`cleaved catching up in subsequent rounds, but strands with uncleaved protecting
`
`groups not catching up, skilled artisans tested linkers with lower cleavage
`
`efficiency, but had much stricter requirements for protecting group cleavage
`
`efficiency.
`
`Illumina’s ’026 patent
`
`2.
`SBS is currently the leading method for sequencing DNA, and Illumina is
`
`the market leader in this field. JA3795 at ll.8-16; JA820 at l.21-JA821 at l.1
`
`(IBS’s counsel referring to Illumina as “the foremost research in, you know,
`
`sequencing company in the world.”). Illumina’s specialized nucleotides were
`
`developed through years of scientific research and development efforts.1
`
`Illumina filed the ’026 patent on August 23, 2002, and it issued on June
`
`6, 2006. JA58. The ’026 patent discloses and claims Illumina’s nucleotides
`
`and corresponding kits containing such nucleotides. JA75. As issued, the ’026
`
`patent contained eight claims. Id. Independent Claim 1 recites:
`
`1. A nucleotide or nucleoside molecule, having a base that
`is linked to a detectable label via a cleavable linker, wherein the
`molecule has a ribose or deoxyribose sugar moiety comprising a
`protecting group attached via the 2’ or 3’ oxygen atom and the
`cleavable linker and the protecting group are cleavable under
`identical conditions. Id.
`
`
`1
`The inventors of the ’026 patent were employed at Solexa Ltd.
`when the ’026 patent was filed. Illumina acquired Solexa in 2006. JA201 n.1.
`
`10
`
`
`
`Case: 15-1123 Document: 27 Page: 21 Filed: 03/10/2015
`
`
`
`Claim 6 specified that the linker was “acid labile, photolabile or contains a
`
`disulphide linkage.” Id.
`
`When Illumina filed the ’026 patent, numerous research groups were
`
`searching for improved methods of performing SBS. See, e.g., JA58-75;
`
`JA848-97; JA977-1041; JA1277-1304; JA1305-55; JA1483-1544; JA1551-77;
`
`JA3945-69; JA4025-84; JA4167-75; JA4176-80; JA5040-87. Illumina’s
`
`innovative SBS technologies emerged from this crowded field to become the
`
`industry-leader for efficient and cost-effective DNA sequencing. JA820 at l.21-
`
`JA821 at l.1.
`
`This appeal focuses on the patentability of four claims directed to a
`
`narrow class of Illumina’s specialized nucleotides and kits containing such
`
`nucleotides. Illumina submitted these four claims as substitute Claims 9-12 in
`
`its Motion to Amend. JA501-03. Claim 9, which replaces Claim 1, recites:
`
`11
`
`
`
`
`
`
`
`Case: 15-1123 Document: 27 Page: 22 Filed: 03/10/2015
`
`9. A nucleotide triphosphate 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 3’ oxygen atom, and the
`disulfide linkage of the cleavable linker and the protecting
`group are cleavable under identical conditions. JA3684 ¶22
`(emphases added); see also JA30; JA501.
`
`The prior art
`
`3.
`The prior art contains numerous non-natural nucleotides, but none with
`
`the unique combination of limitations added to Illumina’s substitute claims—a
`
`disulfide linkage attaching a label to the base and a 3’-protecting group
`
`cleavable under identical conditions as the disulfide linkage.
`
`a.
`
`The prior art did not teach nucleotides that combine a
`3’-protecting group and a disulfide linkage attaching a
`label to the base
`
`WO 00/53805 (“Stemple”) discloses SBS methods, including methods
`
`that utilize a broad genus of nucleotides having a 3’-protecting group that is
`
`photolabile (i.e., cleaved by certain forms of light), as well as a label that is
`
`attached to the nucleotide base via a photolabile linker. JA852-53; JA887 at
`
`Fig. 1. Stemple also discloses 3’-protecting groups and cleavable linkers
`
`attaching a label to the base, both of which can be removed enzymatically,
`
`chemically, or photolytically. JA853. Stemple, however, does not disclose a
`
`12
`
`
`
`Case: 15-1123 Document: 27 Page: 23 Filed: 03/10/2015
`
`
`
`label attached to the base via a disulfide linkage or a disulfide linkage and a
`
`3’-protecting group that are cleavable under identical conditions. JA508.
`
`Similarly, WO 91/06678 (“Tsien”) discloses SBS methods, including
`
`methods that use a broad genus of nucleotides having a 3’-protecting group and
`
`a label attached to the base via a cleavable linkage. JA1490 at l.28-JA149
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