`
`Filed on behalf of: ILLUMINA
`
`By: Robert A. Lawler
`rlawler@reinhartlaw.com
`(608) 229-2217
`____________________________
`
`James G. Morrow
`jmorrow@reinhartlaw.com
`(414) 298-8136
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`ILLUMINA, INC.
`
`Petitioner,
`
`v.
`
`Patent of THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF
`
`NEW YORK
`
`Patent Owner.
`
`_____________________
`
`Case No. IPR2012-00007
`U.S. Patent No. 7,790,869
`
`_____________________
`
`PETITIONER ILLUMINA'S REPLY TO
`PATENT OWNER COLUMBIA'S RESPONSE TO PETITION
`
`Columbia Ex. 2039
`Illumina, Inc. v. The Trustees
`of Columbia University
`in the City of New York
`IPR2020-01177
`
`
`
`
`
`
`
`I.
`
`II.
`
`TABLE OF CONTENTS
`
`COLUMBIA'S “STARTING POINT” ANALYSIS IS IRRELEVANT
`AND IMPROPER ............................................................................................ 1
`
`CLAIMS 34-54 DO NOT REQUIRE INCORPORATION BY A
`POLYMERASE ............................................................................................... 2
`
`III. CLAIMS 34-54 ARE OBVIOUS OVER TSIEN AND PROBER I ............... 3
`
`A. Motivations Existed to Make the Single Change to Tsien (in
`view of Prober I) to Meet All Limitations of the Challenged
`Claims .................................................................................................... 3
`
`1.
`
`1.
`
`Tsien Expressly Teaches to Use Prober I’s 7-Deazapurine ........ 4
`
`The Emergence of 7-Deazapurines as the Preferred Label
`Site Elevated Motivation to Combine Tsien with Prober I......... 6
`
`B. One Would Reasonably Expect Success in Modifying Tsien’s
`Nucleotides to Attach a Label at C7 of a Deazapurine ......................... 8
`
`C. One Would Have Reasonably Expected Successful Polymerase
`Incorporation of Modified Nucleotides ............................................... 10
`
`IV. CLAIMS 34-54 ARE OBVIOUS OVER STEMPLE AND
`ANAZAWA ................................................................................................... 11
`
`A.
`
`B.
`
`C.
`
`Stemple III Discloses Every Element Except Attachment of a
`Label to a Deazapurine Base of a Nucleotide Analogue .................... 11
`
`Stemple III Expressly Teaches Use the Deazapurine Bases ............... 11
`
`Reasonable basis for expectation of success ....................................... 12
`
`V.
`
`SECONDARY CONSIDERATIONS DO NOT DEMONSTRATE
`NON-OBVIOUSNESS, BUT RATHER, OBVIOUSNESS ......................... 13
`
`VI. CONCLUSION .............................................................................................. 15
`
`
`
`
`
`i
`
`
`
`
`
`Columbia does not defend the validity of the original claims, essentially
`
`admitting unpatentability of the original challenged claims. Proposed claims 34-54
`
`are unpatentable for the reasons in Illumina’s Petition, and for the reasons below.
`
`I.
`
`COLUMBIA'S “STARTING POINT” ANALYSIS IS IRRELEVANT
`AND IMPROPER
`
`Instead of addressing Illumina’s invalidity analysis, Columbia
`
`inappropriately tries to shoehorn the proposed claims into a pharmaceutical “lead
`
`compound” analysis for rebuttal. However, unlike the “starting point” case
`
`Columbia cited, the claims here are directed to sequencing methods, not
`
`pharmaceutical compounds. Columbia’s “starting point” analysis is thus
`
`inapplicable to the claims at issue. Moreover, Illumina has not asserted a
`
`“structural similarity” obviousness-type analysis, so the lead compound cases
`
`would not be relevant even if the Columbia claims were considered to be
`
`pharmaceutical compounds. Finally, even if a “starting point” analysis were
`
`appropriate, Columbia’s emphasis on a single starting point (3’-OH labeled
`
`dNTPs) is not. USPTO guidelines at 75 F.R. 53643, at 53652, col. 3 (“[i]t should
`
`be noted that the lead compound cases do not stand for the proposition that
`
`identification of a single lead compound is necessary in every obviousness
`
`rejection of a chemical compound.”) Instead, a “starting point” is any compound
`
`that would be “a natural choice for further development efforts.” Otsuka Pharm.
`
`Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012). Tsien’s base-
`
`1
`
`
`
`
`
`labeled dNTPs are a natural choice for further development efforts in view of
`
`Tsien’s teachings about label positioning and enzymatic competence, and Dr.
`
`Trainor himself agreed that a labeled base was a preferred embodiment of
`
`Tsien. Ex. 2094 at 237:19-239:9; Ex. 1002 at 27:35-30:36.
`
`Nor are the straw man changes proposed by Dr. Trainor realistic. For
`
`example, Dr. Trainor posits that one of skill in the art would need to convert a
`
`ddNTP to a dNTP. See, e.g., Ex. 2033 ¶ 65, 80. Not only is this wrong (both Tsien
`
`and Prober I/Hobbs disclose dNTPs), but no one of skill in the art would “convert”
`
`a ddNTP to a corresponding dNTP. Ex. 1053 ¶ 73. Rather, they would synthesize
`
`the dNTP from an appropriate starting material. Id. Also, contrary to Dr. Trainor's
`
`declaration (see, e.g., Ex. 2033.¶¶ 61-63), the prior art as of 1999 provided express
`
`reasons to adopt the base-labeled approach for 3’-blocked nucleotides. Ex. 1045 at
`
`956; Ex. 2094 at 349:20-350:21, 352:11-25; Ex. 1053 ¶¶ 60 & 98-109.
`
`Thus, a lead compound analysis is not appropriate to analyze these claims,
`
`and, even if it were, Tsien’s base labeled nucleotides would be a proper starting
`
`point. Tsien and other prior art expressly teach that base labeled nucleotides were
`
`a natural choice for further development at the time the ’869 patent was filed.
`
`II. CLAIMS 34-54 DO NOT REQUIRE INCORPORATION BY A
`POLYMERASE
`
`Dr. Trainor's opinions are based on the incorrect premise that the claims
`
`require that the nucleotide analogue can be incorporated by a polymerase. See, e.g.,
`
`
`
`2
`
`
`
`
`
`Ex. 2033, ¶¶ 33, 39, 68(8), 108(4). No such requirement exists in claim 34, and no
`
`separate argument is present with respect to any dependent claim. Ex. 1053 ¶ 85.
`
`Claim 43 requires that the nucleotide is “incorporated onto a primer,” but does not
`
`specify that incorporation is performed by a polymerase. Id. Claim 49 requires
`
`only that the “cleavable chemical group does not interfere with the recognition of
`
`the nucleotide by a polymerase.” Id. Dr. Trainor admitted that this property is met
`
`by any 3' blocking group that allows incorporation by a polymerase. Ex. 2094 at
`
`154:10-156:22. For example, Tsien discloses an allyl 3' blocking group, which
`
`would not interfere. Ex. 1002 at 24:29-30; Ex. 2094 at 106:14-108:21.
`
`III. CLAIMS 34-54 ARE OBVIOUS OVER TSIEN AND PROBER I
`
`Illumina’s Petition demonstrated that Tsien in view of Prober I disclosed all
`
`limitations of Claims 35-54. Petition at 21-29. Columbia does not dispute this,
`
`instead raising motivation to combine, expectation of success, and secondary
`
`considerations.
`
`A. Motivations Existed to Make the Single Change to Tsien (in view
`of Prober I) to Meet All Limitations of the Challenged Claims
`
`Columbia asserts that a skilled artisan would have had to make "7 [sic]
`
`changes” to the “starting point” in Tsien to arrive at the proposed claims. Paper 78
`
`at 18; Ex. 2033 at ¶ 92. But Dr. Trainor admitted that all but two (#1 & #2) of the
`
`8 “changes” are not changes at all – they are expressly disclosed in Tsien.
`
`Specifically, Dr. Trainor agreed that Tsien teaches: (#3-5) chemically
`
`
`
`3
`
`
`
`
`
`cleavable linkers for nucleobases (Ex. 1002 at 28:1-4 & 28:19-36; Ex. 2094 at
`
`113:19-115:14; 220:4-221:6 & 227:2-228:4); (#6-#7) a chemically removable 3-
`
`OH capping group (Ex. 1002 at 27:35-28:10; Ex. 2094 at 105:20-106:13, 217:11-
`
`218:10, & 219:14-220:3); and (#8) incorporation by polymerase (Ex. 1002 at
`
`28:10-18; Ex. 2094 at 449:3-20 & 213:8-217:10). Dr. Trainor agreed that Tsien
`
`described its base-labeled approach as a preferred way to carry out its Fig. 2
`
`process, and that features #3-8 were either required by or preferred in that Fig. 2
`
`process. Ex. 1002 at 10:4-15, 12:14-18, & 14:22-26; Ex. 2094 at 213:8-217:10,
`
`228:5-230:15, & 238:21-24; see also Ex. 1053 at ¶¶ 31-40. Also, “changes” #1
`
`and #8 are not limitations of claim 34. Thus, none of Dr. Trainor’s changes #1 and
`
`#3-8 are actually changes to Tsien.
`
`“Change” #2 is using a deazapurine, which is the only type of purine taught
`
`by Prober I. Ex. 1003 at 337, Fig. 2A. Thus, the issue of invalidity is the same one
`
`identified by the Board – whether a person of skill in the art would use deaza-
`
`purines as in Prober I in the sequencing method of Tsien. Paper 38 at 25-27. A
`
`skilled artisan would have been motivated to make this “change” based on the
`
`express suggestion in Tsien to use the analogues in Prober I. Accordingly, claims
`
`34-54 would have been obvious in view of Tsien and Prober I.
`
`1.
`
`Tsien Expressly Teaches to Use Prober I’s 7-Deazapurine
`
`Tsien cites to Prober I for guidance on the creation of nucleotide analogues
`
`
`
`4
`
`
`
`
`
`for use in SBS methods (Ex. 1002, at 28:5-18 & 29:3-16; see also Ex. 1021 ¶¶ 45-
`
`49, 53, 57, & 63-67), thus suggesting to modify the nucleotide analogues of Tsien
`
`using Prober I. Paper 38 at 25-27. Prober I only discloses labeling purines at the 7
`
`position, and Dr. Trainor agrees that attaching labels there requires the use of 7-
`
`deazapurines. Petition at 27; Ex. 1021 at ¶ 49; Ex. 2094 at 309:16-19).
`
`Columbia asserts that a skilled artisan could not have combined Tsien and
`
`Prober I to arrive at the proposed claims. Paper 78 at 19-21. But Tsien expressly
`
`teaches to combine Prober I’s 7-deazapurines with the nucleotide analogues of
`
`Tsien. Ex. 1002 at 28:5-18 & 29:3-16; see also Ex. 1021 at 45-49, 53, 57, & 63-
`
`67; Paper 38 at 25-27. Indeed, 7-deazapurines are the only label option disclosed
`
`by Prober I for purine analogues. Ex. 1003; Ex. 1053 at ¶¶ 41-48.
`
`Columbia wrongly asserts that Prober I’s ddNTPs would have deterred a
`
`skilled artisan from combining the 7-deazapurine feature of Prober I with the
`
`dNTPs of Tsien. Paper 78 at 19-20. But Tsien itself expressly relied on Prober I
`
`for how to make and use dNTPs in SBS reactions. Ex. 1002 at 29:12-16; Ex. 2094
`
`at 261:2-20; see also Ex. 1011 at 5:38-43 & Fig. 3 (showing similar reliance); Ex.
`
`2033 at ¶ 32. The same is true of Columbia’s argument regarding Prober I’s
`
`synthesis disclosure (Ex. 2033 ¶ 72); Hobbs disclosed the method of making
`
`Prober I’s nucleotides. Ex. 1021 at ¶ 46; Ex. 2094 at 239:20-240:10 & 264:19-
`
`265:9; Ex. 1050 at 2473-2474; see also Ex. 1053 at ¶ 55. Even the ’869 patent
`
`
`
`5
`
`
`
`
`
`relied on Prober I’s “well-established procedures” to make 7-deazapurine dNTPs.
`
`Ex. 1001 at 26: 32-34. The Board thus correctly determined that Tsien’s express
`
`citation to Prober I constitutes a suggestion to use the teachings of Prober I to
`
`modify Tsien’s nucleotide analogues for SBS methods.1 Paper 38 at 25-27.
`
`The Emergence of 7-Deazapurines as the Preferred Label
`1.
`Site Elevated Motivation to Combine Tsien with Prober I
`
`Columbia asserts that C8-labeled bases were “ideal” such that a skilled
`
`artisan would not have used C7-labeled bases. Paper 78 at 19. However, this
`
`argument ignored the emergence of C7-labeled 7-deazapurines as the dominant,
`
`preferred location for label attachment between Tsien’s 1991 publication and 1999.
`
`Ex. 1053 ¶ 54. Applied Biosystems, the near-monopoly producer of reagents for
`
`Sanger sequencing (i.e., “first generation” sequencing) used 7-deazapurines.
`
`Petition at 14; Ex. 1021 at ¶¶ 37, 43, & 59 (point 3); Ex. 1034 at 338:6-18 &
`
`347:15-348:1; Ex. 2094 178:16-179:6 & 262:25-264:18; Ex. 1030; Ex. 1053 ¶ 44.
`
`The literature recognized that the 7-deaza position was preferred over the
`
`C-8 position because 7-deazanucleotides were more readily incorporated by
`
`
`1 Another panel found that Tsien incorporated Prober I’s deazapurines. IPR2013-
`
`00128, Paper 23, at 9-11. Incorporation by reference is a legal question. Advanced
`
`Display Sys., Inc. v. Kent State Univ., 212 F.3d 1272, 1283 (Fed. Cir. 2000). The
`
`same facts support Illumina, that there is an express reason to combine here.
`
`
`
`6
`
`
`
`
`
`polymerase, and C-8 substitutions destabilize the double helix. Petition at 57-58;
`
`Ex. 1021 at ¶ 47; Ex. 2094 at 267:21-268:16, 276:22-333:21 (discussing Exs.
`
`1041-1044), 333:22-334:7, 335:2-336:25, & 339:3-25; Ex. 1034 at 350:20-351:23;
`
`Ex. 1032 at 6:48-55 & 7:54-65; Ex. 1053 at ¶¶ 48, 50 & 51; see also, e.g., Ex. 1043
`
`at 1087; Ex. 1044 at 965. While Dr. Trainor argued that a person of skill in the art
`
`would not be concerned with more efficient incorporation (Ex. 2094 at 292:16-
`
`293:2), the prior art clearly contradicts him. Ex. 1002 at 19:30-32 & 26:6-12; Ex.
`
`1013 at 8:41-60; Ex. 1001 at 2:43-49; Ex. 1053 at ¶ 51. Dr. Trainor further asserts
`
`that stabilization of the double helix would not matter because only a single
`
`nucleotide is required to be incorporated. Ex. 2094 at 297:11-298:5. But Tsien is
`
`not limited to a single incorporation, so a person of skill in the art seeking to
`
`implement the SBS method of Tsien would have been motivated to use the 7-
`
`deazapurines taught by Prober I and the subsequent literature because of their
`
`stabilizing effect on the double helix during sequencing. Ex. 1002 at 6:34-7:14,
`
`11:5-12, 13:28-35, & 17:33-18:2; Ex. 1053 at ¶ 49-51. It is undisputed that this
`
`combination would meet the claims of the ’869 patent.
`
`Dr. Trainor asserted in his deposition that he had not heard of anyone
`
`applying the teachings of Prober I to SBS. Ex. 2094 at 311:14-312:13. However,
`
`his own testimony and declaration contradict this assertion. Ex. 2094 at 566:14-
`
`567:25; Ex. 2033 at ¶ 33 (citing Anazawa’s discussion of using Prober I’s
`
`
`
`7
`
`
`
`
`
`teachings to create base-labeled deaza dNTPs). Neither Columbia, nor Dr. Trainor
`
`addressed the fact that deazapurines were a known, interchangeable analogue of
`
`purines in next generation sequencing. Petition at 14-16; Ex. 1021 at ¶ 66; Ex.
`
`1053 at 163:4-164:10. See also, e.g., Takeda Chemical Industries, Ltd. v.
`
`Alphapharm Pty., Ltd., 492 F.3d 1350, 1356 (Fed. Cir. 2007).
`
`In sum, combining Prober I’s deazapurines with Tsien’s nucleotide
`
`analogues would have been obvious to one of ordinary skill in the art because
`
`deazapurines were widely used and preferred. Thus, developments in the art
`
`between Tsien and the ’869 patent, which Columbia failed to consider, elevated the
`
`desirability of combining Tsien with the 7-labeled deazapurines of Prober I.
`
`B. One Would Reasonably Expect Success in Modifying Tsien’s
`Nucleotides to Attach a Label at C7 of a Deazapurine
`
`In addition to being motivated, one skilled in the art would have had a
`
`reasonable expectation of successfully attaching Tsien’s label to the 7-position of a
`
`7-deaza deoxypurine. The nucleotides of Tsien could have been modified by
`
`knowledge of the methods taught by Prober I, with only routine adaptations – use
`
`of a dNTP instead of a ddNTP, and use of a cleavable linker in place of (or in
`
`addition to) a non-cleavable linker. Ex. 1053 at ¶ ; Ex. 2033 at ¶ 104; Ex. 2094 at
`
`170:7-171:5; 191:23-192:5. Prober I taught this method was highly general, and,
`
`as such, one would have expected to successfully incorporate these routine
`
`changes. Ex. 1003 at 337, col. 1; Ex. 1053 at ¶¶ 64-70.
`
`
`
`8
`
`
`
`
`
`Indeed, the ’869 specification takes this modification as so well accepted
`
`that it does not even explain how 7-labeled 7-deazapurine nucleotides are made.
`
`Instead, citing to Prober I and Hobbs, it provides just two sentences stating that the
`
`synthesis begins with 7-deaza-substituted intermediates prepared according to
`
`“well-established procedures.” Ex. 1001 at 24:64-67 and Fig. 8 (showing 7-deaza
`
`dGTP); Ex. 2094 at 174:17-176:23; 179:7-23; Ex. 1053 at ¶ 78-79. See
`
`Pharmastem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 1362 (Fed. Cir.
`
`2007) (“Admissions in the specification regarding the prior art are binding on the
`
`patentee for purposes of a later inquiry into obviousness.”).
`
`Dr. Trainor suggested in his declaration that it would have been difficult to
`
`make 7-deaza dATP and 7-deaza dGTP based on the disclosure of ddNTPs in
`
`Prober I. Ex. 2033 at ¶ 80. As just noted, this is inconsistent with the ’869 patent
`
`itself. Further, Dr. Trainor admitted at his deposition that his own patent (Hobbs)
`
`taught that 7-deaza dATP with C7 attached linkers could be readily made and
`
`incorporated. Ex. 2094 at 241:22-244:2 & 264:10-267:7 (discussing Ex. 1013 at
`
`28:62-67 and 27:39-59); see also Ex. 1053 at ¶ 65. He also admitted that a skilled
`
`artisan would have reasonably expected to successfully make 7-deaza dGTP. Ex.
`
`2094 at 179:7-23, 247:10-249:4, & 258:18-259:23; Ex. 1053 at ¶ 75. In addition,
`
`others had published precursors and methods that could be used to make 7-labeled
`
`7-deaza dATPs and dGTPs usable in Tsien’s method. Ex. 1044, at 963; Ex. 1043,
`
`
`
`9
`
`
`
`
`
`at 1084-85 and “Scheme”; Ex. 1042 at 1811; Ex. 1053 ¶ 45.
`
`Regarding the use of a cleavable linker, Tsien describes Prober I’s synthetic
`
`route as having “great flexibility in that the linker can be varied with respect to
`
`length or functionality.” Ex. 1002 at 29:12-19 (emphasis added); Ex. 2094 449:3-
`
`450:9. Dr. Trainor did not disagree with Tsien; he addressed the linker used in
`
`Prober I, but he never suggested that a cleavable linker would not be expected to
`
`be usable in its place. Ex. 2033 ¶ 111. Then, at his deposition, he admitted that
`
`attaching a 7-deaza dNTP intermediate to a cleavable linker/label would be “a
`
`trivial reaction” (Ex. 2094 at 189:7-190:2), whether the nucleotide was a ddNTP or
`
`a dNTP. Id. at 190:3-193:2; see also Ex. 1053 at ¶ 72.
`
`Accordingly, a person of ordinary skill would reasonably expect that the
`
`nucleotide analogues used in the ’869 claims could have been readily produced.
`
`C. One Would Have Reasonably Expected Successful Polymerase
`Incorporation of Modified Nucleotides
`
`In a single paragraph, but without explanation, Dr. Trainor asserted that a
`
`nucleotide with a 3’-OH block and a label attached to the base would not be
`
`expected to be incorporated by a polymerase. Ex. 2033 at ¶ 113. This unsupported
`
`opinion contradicts the teachings in the prior art and the ’869 patent. Tsien stated
`
`that a 3’-OH blocked, base-labeled nucleotide would be incorporated. Ex. 1002 at
`
`26:1-12 & 28:5-12; Ex. 1053 at ¶ 87. The ’869 patent also states that base-labeled
`
`nucleotides and 3’-OH blocked nucleotides were known to be recognized by
`
`
`
`10
`
`
`
`
`
`polymerases. Ex. 1001 at 2:44-55, 3:12-16. The knowledge that C7-labeled
`
`deazapurines promote stable incorporation would have enhanced the expectation of
`
`successful incorporation. Ex. 1032 at 6:48-55 & 7:54-65; Ex. 2094 at 291:24-
`
`292:17; Ex. 1053 at ¶ 90.
`
`IV. CLAIMS 34-54 ARE OBVIOUS OVER STEMPLE AND ANAZAWA
`
`Columbia's minimal discussion in its Response (p. 21-25) does not set forth
`
`any argument related to features not present in Stemple in view of Anazawa.
`
`A.
`
`Stemple III Discloses Every Element Except Attachment of a
`Label to a Deazapurine Base of a Nucleotide Analogue
`
`Columbia asserts that a skilled artisan would have had to make four
`
`“changes” to the “starting point” in Stemple III to arrive at the proposed claims.
`
`Paper 68 at 23-24; Ex. 2033 at ¶ 108. Three of the four “changes” asserted by Dr.
`
`Trainor with respect to Fig. 1B are taught by Stemple III. Ex. 1053 at ¶ 116. Dr.
`
`Stemple III expressly teaches that “[i]n another preferred embodiment, the labeling
`
`group is attached to the base of each nucleotide with a detachable linker rather than
`
`to the detachable 3' blocking group. The labeling group and the 3' blocking group
`
`can be removed enzymatically, chemically, or photolytically.” Ex. 1008, at 3:31-
`
`35. Dr. Trainor's opinion that Stemple III discloses only photocleavable
`
`nucleotides (see Ex. 2033, ¶¶ 110-112) is without basis. Ex. 1053 at ¶ 119.
`
`B.
`
`Stemple III Expressly Teaches Use the Deazapurine Bases
`
`Stemple III expressly teaches use of Anazawa's attachment methods where
`
`
`
`11
`
`
`
`
`
`the label and linker are “attached directly to the base of the nucleotide.” Ex. 1053
`
`at ¶ 127. A person of ordinary skill in the art would look to the linkage chemistry
`
`and methods for attachment, including position on the nucleotide bases where the
`
`linker is attached. Ex. 1053 at ¶¶ 128-130. A person of skill in the art would apply
`
`the teachings of Anazawa to analogues of all four nucleotides. Importantly, the
`
`only purine analogues shown in Anazawa having a label attached to the base are 7-
`
`deazapurines with the linker attached to the 7 position. Ex. 1011 at Figs. 7, 16
`
`&18; Ex. 1053 at ¶ 129. Thus, the disclosure of Stemple III directs a person of
`
`skill in the art to use attachment methods, including attachment to the 7-position of
`
`a 7-deazapurine for the purine analogues, as shown in Fig. 7 of Anazawa. Ex.
`
`1053 at ¶ 130. Anazawa further directs the reader to Prober I. Ex. 1053 at ¶ 45.
`
`C. Reasonable basis for expectation of success
`
`For the same reasons set forth with respect to Tsien above, a person of skill
`
`in the art would reasonably expect to be able to synthesize nucleotide analogues of
`
`Stemple III having a chemically cleavable 3' blocking group and chemically
`
`cleavable label on a deazapurine base, based on the “well established” procedures
`
`set forth in Hobbs and Prober I. See Ex. 1053 at ¶¶ 138-140. Similarly, because
`
`Stemple III discloses SBS and deazapurine nucleotides were widely known to be
`
`incorporated by polymerases, a person of skill in the art would reasonably expect
`
`such nucleotides to be incorporated by a polymerase. Ex. 1053 at ¶¶ 142-145.
`
`
`
`12
`
`
`
`
`
`V.
`
`SECONDARY CONSIDERATIONS DO NOT DEMONSTRATE NON-
`OBVIOUSNESS, BUT RATHER, OBVIOUSNESS
`
`Columbia did not show a nexus between anything novel in its claims and
`
`any secondary considerations. “Where the offered secondary consideration
`
`actually results from something other than what is both claimed and novel in the
`
`claim, there is no nexus.” In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011).
`
`Where he identifies claim limitations, Dr. Trainor points to three supposedly
`
`novel features: “[1] a cleavable chemical group capping the 3′-OH position of the
`
`sugar and [2] a label attached to the nucleotide base via a cleavable linker … [that
`
`are] [3] incorporated into a primer extension strand by a polymerase.” Ex. 2033 at
`
`¶ 198; see also ¶¶ 222, 225-227, 231 & 237; Ex. 2094 at 430:10-16. But, as Dr.
`
`Trainor admitted, each feature is disclosed in Tsien (and is not novel). Ex. 2094
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`105:15-106:13 & 245:16-246:11. Also, feature [3] is not an element of claim 34,
`
`and Dr. Trainor’s opinion does not reflect a nexus with the claims.
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`None of Columbia’s generalized evidence about supposed praise for Dr. Ju’s
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`work (e.g. his 2006 paper, Ex. 2034), or the Seo article (Ex. 2043) is tied to any
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`novel, claimed aspect. See Ex. 2033, ¶¶ 211-220 (praise) and 244-251 (Seo). In
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`fact, Dr. Ju's 2006 paper has multiple features not in the patent (Ex. 2094 at 80:14-
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`83:6, 85:17-86:5, & 397:12-404:11), and the Seo article lacks several features of
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`the amended claims. Id. at 69:14-70:12; 71:7-72:7. Columbia identifies two
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`specific items in support of “skepticism”: a potential need for different 3' blocking
`
`
`
`13
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`
`
`
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`groups, and a potential need for more than one polymerase. (Ex. 2033 at ¶¶ 262 &
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`263-264.) In addition to being unsupported by the evidence (Ex. 2094 at 75:12-
`
`77:25), neither feature is claimed in the ’869 Patent (Ex. 2094 at 73:3-75:11).
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`With regard to commercial success, infringement is a matter the Board “does
`
`not determine” in inter partes review proceedings. IPR2012-00001, Paper 26, at
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`11-12, 35 U.S.C. §311(b) (Scope). No court has determined that Illumina infringes
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`the ’869 patent; thus, Columbia's argument based on the commercial success of
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`Illumina's accused SBS products (ex. 2033, ¶¶ 221-251) should be disregarded.
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`In any event, Columbia has not presented any evidence supporting its
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`commercial success argument. Both Mr. Sims and Dr. Trainor admitted they had
`
`no knowledge of the SBS market (Ex. 2094 at 422:13-424:16; Ex. 2095 at 51:6-55-
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`14), so their opinions about reasons for Illumina’s commercial success are sheer
`
`speculation. Mr. Sims relies on Dr. Trainor for a nexus (Ex. 2095 at 7:7-22 &
`
`68:3-69:19), and Dr. Trainor admits he does not know if Illumina would have been
`
`equally successful using a non-claimed technology. Ex. 2094 at 423:2-425:12. In
`
`fact, despite hearing Dr. Weinstock, a major sequencing user, state that cost-benefit
`
`was a key factor (Ex. 1034 at 328:1-330:22), neither Dr. Trainor nor Mr. Sims
`
`even knew how Illumina’s sequencing cost compared to competitors. Ex. 2094 at
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`425:13-22; Ex. 2095 22:7-22; 30:13-35:2. Columbia has not established a nexus.
`
`Finally, the “strong inference of copying” advanced by Columbia is based
`
`
`
`14
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`
`
`
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`on misleadingly incomplete evidence. In truth, Solexa independently (and nearly
`
`simultaneously) had the same claimed ideas. Ex. 1037, 7:17-22, 8:13-9:23, 10:1-
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`23, and Figs. 1 & 2; Ex. 2094 20:16-33:24; 43:16-50:16, & 416:18-422:10; Ex.
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`1038, p. 132998; Ex. 1053 at ¶¶ 105-113. Columbia knew of Solexa’s application,
`
`as it is part of the co-pending litigation with the ’869 patent, but inexplicably did
`
`not provide it to Dr. Trainor. Ex. 2094 42:16-25; 386:2-16. Dr. Trainor was also
`
`unaware, despite Amersham's work being cited in the IPR of Solexa's patents, that
`
`Amersham also arrived at the same “invention” before Dr. Ju (filing prior to Dr. Ju,
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`but in the UK). Ex. 1048, 3:14-16, 4:25-5:2, 5:30-31, 6:16-20, 7:12-30, 8:12-17,
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`9:9-32, 11:3-5, & Figs. 1 & 2; Ex. 2094 413:2-6; 430:17-443:14; Ex. 1053 at ¶
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`109. The contemporaneous, independent invention by others is evidence of
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`obviousness, not non-obviousness. Geo M. Martin Co. v. Alliance Machine
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`Systems Intern, LLC, 618 F.3d 1294, 1305-1306 (Fed. Cir. 2010).
`
`VI. CONCLUSION
`
`For the foregoing reasons, Illumina respectfully submits that each of the
`
`challenged claims of the ’869 Patent (both in their original form, and as proposed
`
`for amendment by Patent Owner) are invalid.
`
`Dated: September 27, 2013
`
`Reinhart Boerner Van Deuren s.c.
`P.O. Box 2965
`Milwaukee, WI 53201-2965
`Telephone: 414-298-1000
`
`Respectfully submitted,
` /Robert A. Lawler/
`Lead Counsel for Petitioner
`Robert A. Lawler (Reg. No. 62,075)
`rlawler@reinhartlaw.com
`
`
`
`
`15
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`
`
`Atty. Dkt. No. 048522-0027-869
`Proceeding No.: IPR2012-00007
`Re. Patent No.: 7,790,869
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re U.S. Patent of:
`
`Jingyue Ju et al.
`
`Title:
`
`Patent No.:
`
`Issue Date:
`
`MASSIVE PARALLEL METHOD FOR DECODING
`DNA AND RNA
`
`7,790,869
`
`September 7, 2010
`
`IPR Proceeding No.:
`
`IPR2012-00007
`
`IPR Proceeding Filing
`Date
`
`September 16, 2012
`
`Attorney Docket No.:
`
`048522-0027-869
`
`Customer No.:
`
`22922
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`CERTIFICATE OF SERVICE
`
`Copies of the following were served electronically this 27th day of
`
`September 2013 to Columbia at jwhite@cooperdunham.com,
`
`ColumbiaIPR@fchs.com and dthibode@nsf.gov:
`
`1.
`
`Petitioner Illumina's Reply to Patent Owner Columbia's Response to
`
`Petition.
`
`10339873
`
`1
`
`
`
`Dated this 27th day of September 2013.
`
`Atty. Dkt. No. 048522-0027-869
`Proceeding No.: IPR2012-00007
`Re. Patent No.: 7,790,869
`
`Nicole A. Wilson
`nwilson@reinhartlaw.com
`
`BY: /Nicole A. Wilson/
`Reg. No. 66,672
`
`Reinhart Boerner Van Deuren s.c.
`1000 North Water Street
`Suite 1700
`Milwaukee, WI 53202
`Telephone: 414-298-1000
`Facsimile: 414-298-8097
`
`Mailing Address:
`P.O. Box 2965
`Milwaukee, WI 53201-2965
`
`
`
`10339873
`
`2
`
`