Opinion ID: 2818127
Heading Depth: 3
Heading Rank: 1

Heading: A method of determining the identity of a

Text: nucleotide analogue incorporated into a nucleic acid primer extension strand, comprising: a) contacting a nucleic acid template attached to a solid surface with a nucleic acid primer which hybridizes to the template; b) simultaneously contacting the product of step a) with a polymerase and four nucleotide analogues which are either (i) aA, aC, aG, and aT, or (ii) aA, aC, aG, and aU, so as to incorporate one of the nucleotide analogues onto the nucleic acid primer and form a nucleic acid primer extension strand, wherein each nucleotide analogue within (i) or (ii) comprises a base labeled with a unique label and contains a removable chemical moiety capping the 3’-OH group of the sugar of the nucleotide analogue, and wherein at least one of the four nucleotide analogues within (i) or (ii) is deaza- substituted; and c) detecting the unique label of the incorporated nucleotide analogue, so as to thereby determine the identity of the nucleotide analogue 18 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. incorporated into the nucleic acid primer extension strand. ’698 patent col. 35 ll. 2–23 (emphases added). 11. A plurality of nucleic acid templates immobilized on a solid surface, wherein a nucleic acid primer is hybridized to such nucleic acid templates each such nucleic acid primer comprising a labeled incorporated nucleotide analogue, at least one of which is deaza- substituted, wherein each labeled nucleotide analogue comprises a base labeled with a unique label and contains a removable chemical moiety capping the 3’-OH group of the sugar of the nucleotide analogue. Id. col. 36 ll. 24–31 (emphases added). The only challenged independent claim of the ’869 patent is claim 12, which recites: 12. A nucleotide having a base that is attached to a detectable label through a cleavable linker, wherein the nucleotide has a deoxyribose comprising a cleavable chemical group capping the 3’ OH group, wherein the cleavable linker is cleaved by a means selected from the group consisting of one or more of a physical means, a chemical means, a physical chemical means, heat, and light, and wherein the cleavable chemical group capping the 3’ OH group is cleaved by a means selected from the group consisting of one or more of a physical means, a chemical means, a physical chemical means, heat, and light. ’869 patent col. 33 ll. 40–50 (emphases added). In addition, claim 15 of the ’869 patent recites: “15. The nucleotide of claim 12, wherein the base is a deazapurine.” Id. col. 33 ll. 10–11 (emphasis added). TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 19 The only challenged independent claim of the ’575 patent is claim 1, which recites: 1. A method of determining the identity of a nucleotide analogue incorporated into a nucleic acid primer extension strand, comprising: a) contacting a nucleic acid template attached to a solid surface with a nucleic acid primer which hybridizes to the template; b) simultaneously contacting the product of step a) with a polymerase and four nucleotide analogues which are either (i) aA, aC, aG, and aT, or (ii) aA, aC, aG, and aU, so as to incorporate one of the nucleotide analogues onto the nucleic acid primer and form a nucleic acid primer extension strand, wherein each nucleotide analogue within (i) or (ii) comprises a base labeled with a unique label and contains a small removable chemical moiety capping the 3’-OH group of the sugar of the nucleotide analogue, wherein said small cleavable chemical group does not interfere with the recognition of the nucleotide analogue by polymerase as a substrate; and c) detecting the unique label of the incorporated nucleotide analogue, so as to thereby determine the identity of the nucleotide analogue incorporated into the nucleic acid primer extension strand. ’575 patent col. 33 ll. 30–45 (emphases added). In addition, claim 6 of the ’575 patent recites: “6. The method of claim 1, wherein said base of at least one of said nucleotide analogues is a deazapurine.” Id. col. 34 ll. 42– 43 (emphasis added). Inter partes review of independent claims 1 and 11 of the ’698 patent was instituted on grounds of anticipation by Dower, and obviousness over Tsien, Prober, and Seela. Inter partes review of claim 12 of the ’869 patent was instituted on grounds of anticipation by Tsien and 20 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. Stemple, and claim 15 on grounds of obviousness over Tsien, Prober, Stemple, and Anazawa. Inter partes review of claim 1 of the ’575 patent was instituted on grounds of anticipation by Dower and Tsien, and of claim 6 on grounds of obviousness over Tsien, Prober, and Seela. The PTAB evaluated the content of the prior art, finding Tsien disclosed an SBS method that used “a fluorescent tag attached to the base moiety,” and a removable 3’-OH blocking group. J.A. 10–11. The PTAB noted “Tsien does not disclose a deaza-substituted base, but references Prober I, which does.” J.A. 12. Columbia University argues Tsien’s citation to Prober does not render obvious its invention because “Tsien does not cite Prober for labeling purines,” but only for labeling pyrimidines. Appellant’s Br. 43. However, Tsien explicitly invites the PHOSITA to consider Prober in a paragraph discussing both purines and pyrimidines. Although Tsien asserts “[t]he C-8 position of the purine structure presents an ideal position for the attachment of a label,” J.A. 3030, it also states: While the above-described approaches to labeling focus on incorporating the label into the 3’-hydroxyl blocking group, there are a number of alternatives—particularly the formation of a 3’-blocked dNTP analogue containing a label such as a fluorescent group coupled to a remote position such as the base. This dNTP can be incorporated and the fluorescence measured and removed according to the methods described below. . . . One method involves the use of a fluorescent tag attached to the base moiety. The tag may be chemically cleaved. . . . This method is included because a number of base moiety derivatized dNTP analogues have been reported to exhibit enzymatic competence. . . . Prober et al. (1987) show enzymatic incorporation of fluorescent TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 21 ddNTPs by reverse transcriptase and Sequenase . TM J.A. 3028–29 (emphases added). Tsien thus invites use of the “method[] described [in Prober]” in combination with a “3’-blocked dNTP analogue” and a fluorescent label “coupled to a remote position such as the base.” Id. Prober’s method includes the use of a fluorescent dye “attached . . . to the 7 position in the 7-deazapurines” and explains “the 7-deazapurines were used to facilitate stable linker attachment at that site.” J.A. 3063. A PHOSITA may find reason to combine references to achieve a claimed invention even absent an explicit mention in one reference of the other. See KSR, 550 U.S. at 417 (“[I]f a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill.”). Here, the express invitation to incorporate a 3’-blocked dNTP having a fluorescent base label using the method disclosed in Prober provides a motivation to combine Tsien with the 7-deazapurine of Prober. Seela, issued in 1989, also helps to provide a motivation by teaching, according to the PTAB, that deazapurine nucleotides “can advantageously be used . . . in polymerase-based sequencing methods,” such as SBS. J.A. 80. In addition, Dr. Weinstock testified that a PHOSITA would be motivated to use the 7-deazapurines of Prober “to improve similar Tsien systems and methods.” J.A. 3181. When asked whether “[t]he use of ddNTP that . . . had fluorescent labels attached to the 7-deazapurine position . . . was common by the year 2000 [for Sanger sequencing],” Columbia University’s witness, Dr. Trainer, conceded that it was. J.A. 4250. Taken together, the testimony and references provide substantial evidence to support the PTAB’s finding that a 22 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. PHOSITA would combine the two references to achieve the claimed invention. Columbia University argues the PTAB “never identified any affirmative motivation that would have led a skilled artisan to abandon the ‘ideal,’ natural C-8 position taught by Tsien.” Appellant’s Br. (-1550) 44. However, Tsien itself specifically references Prober as “show[ing] enzymatic incorporation of fluorescent ddNTP’s by reverse transcriptase and SequenaseTM,” J.A. 3029, and Prober discloses attaching a fluorescent label via a linker only at the 7-deaza position, J.A. 4335 (Question: “[Attaching a label to the 7-deaza position is] the only way that you [Trainer] disclose in this particular article [i.e., Prober]?” Answer: “Yes.”); see also J.A. 3063. Although Tsien described the C-8 position as “ideal,” J.A. 3030, this court has previously explained that “just because better alternatives exist in the prior art does not mean that an inferior combination is inapt for obviousness purposes,” In re Mouttet, 686 F.3d 1322, 1334 (Fed. Cir. 2012); see also In re Mills, 470 F.2d 649, 651 (CCPA 1972) (“We find no merit in appellants’ contention that the disclosure of propylene is so submerged in Cooper, and the teaching of the use of ethylene so predominant, that Cooper cannot be said to place foams composed of the claimed ingredients in the possession of the public. All the disclosures in a reference must be evaluated . . . .”). Columbia University further argues there was no motivation for a PHOSITA to use deazapurines with SBS because “the need for ‘stable’ linkers was unique to Sanger sequencing, with its harsh conditions” associated with electrophoresis. Appellant’s Br. (-1550) 44. However, although Prober was concerned only with Sanger sequencing, Tsien’s explicit reference to Prober combined with the wide use of deazapurines with prior art sequencing techniques, see J.A. 4335 (use of deazapurines was part of a “preferred embodiment” in Prober that was TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 23 “commercialized by Applied Bio-Systems”), 3401 (deazapurines were “wide[ly] availab[le]” and “widely used”), provides substantial evidence supporting the PTAB’s finding of motivation to combine, see J.A. (-1550) 21–24. D. Reasonable Expectation of Success To render a claim obvious, a PHOSITA must have had not only a “reason to combine the teaching of the prior art references to achieve the claimed invention,” but also “a reasonable expectation of success from doing so.” In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1069 (Fed. Cir. 2012) (internal quotation marks and citation omitted). Columbia University challenges the PTAB’s finding that a PHOSITA “would have had a reasonable expectation of success in combining Tsien with Prober or with Seela to synthesize a 3’-OH-capped nucleotide with a label attached to a deazapurine base (via a cleavable linker, for claim 15).” Appellant’s Br. 45. Specifically, it cites Dr. Trainor’s testimony that the chemistry for creating a nucleotide analogue with the claimed features was complex, and a PHOSITA could not have reasonably expected to be successful in devising an appropriate chemical procedure. Id. at 45–46; see also J.A. 3827. Illumina responds “that every step of the synthetic process would have been understood to be within the level of ordinary skill [in the art],” and that Dr. Trainer conceded this to be the case. Appellee’s Br. 39. It cites the testimony of Dr. Trainer in which he admits to be within the PHOSITA’s skill level: the use of “a starting deazaguanine with a 7-iodide for linker attachment;” “attaching a cleavable alkynylamino linker to the 7-iodo position;” and “attaching a fluorescent label to the alkynylamino linker.” Id. at 39–40. Tsien references Prober as disclosing a method that would be applicable to the synthesis of both ddNTPs and dNTPs. J.A. 3029–30. 24 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. Most significantly, the ’869 patent explains a “7 deazaalkynylamino-dGTP[6] is prepared using well-established procedures,” and does not provide additional guidance with respect to chemical procedures. ’869 patent col. 23 ll. 37–38 (emphasis added). Taken together, these disclosures constitute substantial evidence supporting the PTAB’s finding that a PHOSITA would have had a reasonable expectation of success in achieving the claimed invention. III. Secondary Considerations Do Not Weigh Strongly in Favor of Nonobviousness Both parties present arguments with respect to secondary considerations. Illumina argues simultaneous invention supports its position that the claimed invention was obvious. Columbia University asserts copying, attempted licensing, commercial success, and unexpected results support the nonobviousness of the claimed invention. A. Simultaneous Invention Weighs Modestly in Favor of Obviousness “Independently made, simultaneous inventions, made within a comparatively short space of time, are persuasive evidence that the claimed apparatus was the product only of ordinary mechanical or engineering skill.” George M. Martin Co. v. Alliance Mach. Sys. Int’l LLC, 618 F.3d 1294, 1305 (Fed. Cir. 2010) (internal quotation marks and citation omitted). Illumina asserts two entities, Solexa and Amersham, each separately conceived of an SBS approach as early as December 2001, i.e., before Dr. Ju’s patent applications were published, containing the novel features of Dr. Ju’s patent claims.” Appellee’s Br. 47. 6 The notation “dGTP” refers to a deoxyribonucleoside triphosphate in which guanine is the base. TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 25 Columbia University first responds that the activities of Solexa and Amersham “are not prior art.” Reply Br. 6. This response reflects confusion over the difference between simultaneous invention on the one hand and anticipation and obviousness on the other. If simultaneous invention were only relevant where the object of the simultaneous invention constituted prior art, it would be analyzed under 35 U.S.C. § 102 and as part of the second Graham factor (i.e., as part of a determination of the “differences between the prior art and the claims at issue”) under 35 U.S.C. § 103. Graham, 383 U.S. at 17. As a secondary consideration, however—which falls under the fourth Graham factor—simultaneous invention is relevant when it occurs within a short space of time from the date of invention, and “is strong evidence of what constitutes the level of ordinary skill in the art.” Ecolochem v. S. Cal. Edison Co., 227 F.3d 1361, 1379 (Fed. Cir. 2000). Unlike the ultimate determination of obviousness, which requires courts to answer the hypothetical question of whether an invention “would have been obvious,” 35 U.S.C. § 103, simultaneous invention demonstrates what others in the field actually accomplished. The tendency of simultaneous invention to weigh in favor of obviousness would, of course, be negated if the purported simultaneous invention was not made independently of the claimed invention. Perhaps with this in mind, Columbia University asserts the Solexa patent was filed “months after features of Dr. Ju’s SBS method were disclosed in a public National Science Foundation Grant Announcement.” Reply Br. 6–7. However, Columbia University asserts that at the time of Solexa’s disclosure, “Solexa . . . thought that a nucleotide with the requisite combination of features was patentable.” Id. It makes a similar assertion with respect to Amersham. Id. In so asserting, Columbia University undermines its own argument: If Solexa and Amersham 26 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. had copied their purported simultaneous inventions from the grant announcement, they would have had no basis to believe their simultaneous inventions were patentable. Columbia University also argues Amersham’s activities did not constitute simultaneous invention because the chemical configuration it described was “useless as a chain terminator.” Reply Br. 7. It points out that Illumina did not present its simultaneous invention argument to the PTAB. Because the record is not fully developed, the evidence of simultaneous invention as a whole weighs only modestly in favor of obviousness. B. Copying Does Not Favor Nonobviousness Columbia University asserts “Manteia, a company whose intellectual property was later acquired by Illumina’s predecessor-in-interest Solexa, copied Dr. Ju’s invention” as reflected in a 2003 presentation. Appellant’s Br. 12. The 2003 presentation cites Dr. Ju’s publication. See J.A. 3894. Illumina responds that the asserted copying is irrelevant because the only elements shown to be copied were disclosed in Tsien, Dower, and Stemple, and that the presentation does not disclose a deazapurine and therefore does not reflect copying of the claimed invention. Appellee’s Br. 57. Illumina further responds that Solexa did not copy Dr. Ju’s invention, citing a December 2001 patent application filed by Solexa that discloses “a base that is linked to a detectable label via a cleavable linker,” and a removable “protecting group” at the 3’ position that “is intended to prevent nucleotide incorporation.” J.A. 3750, 3755; see also Appellee’s Br. 11–14, 58. The PTAB considered Columbia University’s evidence of copying and did not find it persuasive. J.A. 29. Because the record is inconclusive as to whether any party in fact copied Dr. Ju’s invention, because the PTAB did not make an explicit factual finding in this regard, and because it is unclear whether the asserted actions represent copying or TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 27 independent invention, the asserted copying does not weigh in favor of nonobviousness. C. Attempted Licensing Weighs Modestly in Favor of Nonobviousness Columbia University cites several emails from Illumina showing an interest in “collaborating with Dr. Ju from Columbia University on his reversible terminators,” and stating “Professor Jingyue Ju purportedly has solved the reversible terminator cleavable dye label issue.” J.A. 3993–95. Although these emails demonstrate an interest in Dr. Ju’s work, none of the emails mentions the ’698, ’575, or ’869 patents or clearly indicates the subject matter sought to be licensed fell within the claims of those patents. In re GPAC, 57 F.3d 1573, 1580 (Fed. Cir. 1995) (“Because, in affidavits reciting the licensing history of the ’111 patent, GPAC did not establish which claim(s) of the patent the licensing program incorporates, GPAC has not shown that licensing . . . arose out of recognition and acceptance of the subject matter claimed in the ’111 patent.”). This factor therefore provides only modest evidence of nonobviousness. D. Commercial Success Does Not Favor Nonobviousness Commercial success of a product embodying an invention tends to show nonobviousness when “the commercial success . . . results from the claimed invention” and is “due to the merits of the claimed invention beyond what was readily available in the prior art.” J.T. Eaton & Co. v. Atl. Paste & Glue Co., 106 F.3d 1563, 1571 (Fed. Cir. 1997). “When a patentee can demonstrate commercial success, usually shown by significant sales in a relevant market, and that the successful product is the invention disclosed and claimed in the patent, it is presumed that the commercial success is due to the patented invention.” Id. 28 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. Columbia University asserts Illumina’s sales were significant and embody the claims of the ’698, ’869, and ’575 patents. Appellant’s Br. 59 (citing J.A. 3879–85); Appellant’s Br. (-1548) 57; Appellant’s Br. (-1550) 57. Illumina responds that “the very features proclaimed by Columbia [University] to be the reason for Illumina’s commercial success (attachment of the label to the base via a cleavable linker) were already known in Tsien, Dower, and Stemple,” and that Columbia University did not assert the deazapurine contributed to commercial success. Appellee’s Br. 54. Commercial success does not favor nonobviousness. “[I]f the feature that creates the commercial success was known in the prior art, the success is not pertinent.” Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299, 1312 (Fed. Cir. 2006). Here, each of the features claimed to be responsible for the commercial success of the invention was disclosed in a single prior art reference, Tsien. In addition, Columbia University does not itself sell its patented invention. Although reliance on a defendant’s or third party’s sale of a patented invention to demonstrate commercial success may be probative of nonobviousness in some cases, it is not particularly helpful in the present matter because it is unclear whether any success was attributable to developments in the field that led to simultaneous invention (which would tend to show the invention was obvious) or to copying (which would tend to show the invention was nonobvious). E. Unexpected Results Do Not Favor Nonobviousness Evidence of “some superior property or advantage that a person of ordinary skill in the relevant art would have found surprising or unexpected” tends to indicate nonobviousness. In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). Columbia University asserts, as evidence of unexpected results, Dr. Trainor’s testimony that the claimed nucleotides are unexpectedly better than TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 29 pyrosequencing. Appellant’s Br. 53; see also J.A. 30. According to the ’698 patent, pyrosequencing is a “widely used” process that “employs four natural nucleotides . . . for sequencing DNA by synthesis” and “is based on the pyrophosphate (PPi) released during the DNA polymerase reaction, the quantitative conversion of pyrophosphate to adenosine triphosphate (ATP) by sulfurylase, and the subsequent production of visible light by firefly luciferase.” ’698 patent col. 2 ll. 19–28. Unexpected results “‘must be shown to be unexpected compared with the closest prior art.’” Kao Corp. v. Unilever U.S., Inc., 441 F.3d 963, 970 (Fed. Cir. 2006) (quoting In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991)). The PTAB found pyrosequencing was not the closest prior art. Columbia University argues pyrosequencing was the closest prior art because it was “the only commercial embodiment of SBS at the time of Dr. Ju’s invention.” Appellant’s Br. 63. However, there is no requirement that the closest prior art be commercialized. See In re Merchant, 575 F.2d 865, 869 (CCPA 1978) (“In In re Wright . . . , failure of a particular reference to constitute the commercial standard did not diminish its position as the closest prior art.”) (internal quotation marks and citation omitted); see also In re Chupp, 816 F.2d 643, 644 (Fed. Cir. 1987) (“To rebut the prima facie case of obviousness, Chupp submitted a declaration discussing the results of tests comparing the herbicidal activity of the claimed compound with that of the closest prior art compounds and with two commercial herbicides . . . . It is undisputed that the claimed compound gave superior results . . . .”) (emphases added). Evidence of unexpected results in comparison to pyrosequencing is therefore not probative of nonobviousness. 30 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.