Trials@uspto.gov
`572-272-7822
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`Paper 128
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ILLUMINA, INC.
`Petitioner
`
`v.
`
`THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF
`NEW YORK
`Patent Owner
`___________
`
`Case IPR2012-00006
`Patent 7,713,698 B2
`___________
`
`
`
`Before SALLY G. LANE, RICHARD M. LEBOVITZ, and
`DEBORAH KATZ, Administrative Patent Judges.
`
`LEBOVITZ, Administrative Patent Judge.
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
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`572-272-7822
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`Paper 128
` Mailed: March 6, 2014
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ILLUMINA, INC.
`Petitioner
`
`v.
`
`THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF
`NEW YORK
`Patent Owner
`___________
`
`Case IPR2012-00006
`Patent 7,713,698 B2
`___________
`
`
`
`Before SALLY G. LANE, RICHARD M. LEBOVITZ, and
`DEBORAH KATZ, Administrative Patent Judges.
`
`LEBOVITZ, Administrative Patent Judge.
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`
`Case IPR2012-00006
`Patent 7,713,698
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`I. BACKGROUND
`
`A. Introduction
`Petitioner, Illumina, Inc. (“Illumina”), filed a petition on
`September 16, 2012 (“Pet.), for inter partes review of claims 1-7, 11, 12, 14,
`15, and 17 of U.S. Patent 7,713,698 B2 (“the ’698 Patent”) pursuant to 35
`U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1 to 42.123. On March 12, 2013,
`the Board instituted inter partes review of claims 1-7, 11, 12, 14, 15, and 17
`on three grounds of unpatentability (Paper 28, Decision on Petition (“Dec.
`Pet.”)). Illumina requested rehearing on two of the grounds of
`unpatentability (Paper 30), which had been denied in the Decision on
`Petition. Upon reconsideration, the Board instituted inter partes review of
`one of these grounds of unpatentability as to claims 1-7, 11, 12, 14, 15, and
`17 (Paper 43, Decision on Rehearing (“Dec. Reh’g”)).
`After institution of the inter partes review, Patent Owner, The
`
`Trustees of Columbia University in the City of New York (“Columbia”),
`filed a response under 37 C.F.R. § 42.120 to the decision instituting inter
`partes review (Paper 69, “PO Resp.”). Columbia also filed a Motion to
`Amend Claims (Paper 70) and a Motion to Exclude Evidence (Paper 93).
`Illumina filed a reply to Columbia’s response under 37 C.F.R. § 42.120
`(Paper 76, “Pet’r Reply”) and a Motion to Exclude Evidence (Paper 90
`(redacted); Paper 107 (unredacted)). An oral hearing was held on December
`17, 2013, with both parties in attendance. (Record of Oral Hearing, Paper
`124.)
`Among the evidence cited in this proceeding are declarations by
`
`George L. Trainor, Ph.D. (Ex. 2033, Trainor Decl.), on behalf of Columbia,
`and by George Weinstock, Ph.D. (Ex. 1021, Weinstock Decl.), on behalf of
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`Illumina. Dr. Trainor has a Ph.D. in Organic Chemistry and experience in
`DNA sequencing (Exhibit 2033, Trainor Decl. ¶¶ 3 and 6-8), qualifying him
`to testify on the issues discussed in his declaration. Dr. Weinstock has a
`Ph.D. in Microbiology and experience in DNA sequencing, including as a
`director of large-scale genome centers (Ex. 1021, Weinstock Decl. ¶¶ 4, 6, 8,
`and 9), qualifying him to testify on the issues discussed in his declaration.
`The Board has jurisdiction under 35 U.S.C. § 6(c). This final written
`decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`Illumina has shown, by a preponderance of the evidence, that claims 1-7, 11,
`12, 14, 15, and 17 are unpatentable.
`
`B. The ’698 Patent
`The ’698 Patent issued May 11, 2010. The named inventors are
`Jingyue Ju, Zengmin Li, John Robert Edwards, and Yasuhiro Itagaki. The
`invention of the ’698 Patent involves sequencing DNA by incorporating a
`base-labeled nucleotide analogue into a primer DNA strand, and then
`determining the identity of the incorporated analogue by detecting the label
`attached to the base of the nucleotide. A polymerase is used to incorporate
`the nucleotide analogue into the strand of DNA (’698 Patent, col. 2, ll. 24-
`28). The method is generally referred to as “sequencing DNA by synthesis,”
`or “SBS,” because the sequence of the DNA is determined by identifying the
`successive additions of labeled nucleotides to a strand of DNA as it is
`synthesized, using a complimentary DNA strand as a template (id. at col. 2,
`ll. 6-11).
`Columbia does not argue the novelty of the steps utilized in the
`claimed method of “determining the identity of a nucleotide analogue
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`incorporated into a nucleic acid primer extension strand… (’698 Patent,
`cl. 1),” but rather focuses its arguments on the novelty and non-obviousness
`of the nucleotide analogue utilized in the sequencing method. Nucleotides,
`which are the building blocks of DNA, comprise a sugar (ribose or
`deoxyribose), a phosphate attached to the 5’-position of the sugar, and a
`nitrogen base on the 1’-position of the sugar. During DNA synthesis, the 5’-
`position in the sugar of a new incoming nucleotide is linked by DNA
`polymerase to the 3’-OH group in the sugar of a preexisting nucleotide in the
`strand under synthesis. In order to identify the newly incorporated
`nucleotide, one approach described in the prior art is to attach a detectable
`label to the nucleotide at its 3’-OH group (’698 Patent, col. 2, ll. 33-37). For
`reference, the 3’-OH corresponds to 3’-position of the deoxyribose sugar of
`the nucleotide, and serves as the site where a new nucleotide is added during
`DNA synthesis.
`The approach described in the ‘698 Patent is to make nucleotide
`analogues by linking a unique label, such as fluorescent dye, through a
`cleavable linker to the nucleotide base or to an analogue of the nucleotide
`base and to use a small removable chemical moiety to cap the 3’-OH group
`of the deoxyribose to make it reversibly nonreactive (’698 Patent, col. 2, ll.
`57-65). The reason the 3’-OH group is made reversibly nonreactive is to
`allow the sequencing reaction to be terminated after each nucleotide is added
`in order to determine its identity (id. at col. 2, l. 64 to col. 3, l. 2). According
`to the ’698 Patent, the prior art teaches attaching the label to the 3’-OH
`group. The ’698 Patent, in contrast, puts the label on the nucleotide base and
`the removable chemical moiety on the 3’-OH group. These latter features
`are at the center of the patentability challenges.
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`All the claims at issue in this inter partes review involve a nucleotide
`analogue which comprises 1) a base labeled with a unique label, 2) a
`removable chemical moiety capping the 3'-OH group, and 3) a base which is
`deaza-substituted. A deaza-substituted nucleotide is a nucleotide analogue
`which includes a deazabase as the nitrogen base (’698 Patent, col. 7, ll. 44-
`63). A deazabase is a nitrogen base in which one of the natural nitrogen
`atoms in the base ring is substituted with a carbon atom (id.). For example,
`in a 7-deazapurine, the natural 7-position nitrogen in the base ring is
`replaced with a carbon atom (id.).
`In summarizing the state of the art in Columbia’s Patent Owner
`Response, Columbia states that, “[d]uring the 1990s, despite some interest in
`base-labeled nucleotide analogues, efforts focused on including a label on
`the 3’OH group on the sugar in a nucleotide analogue and on the design and
`synthesis of new nucleotide analogues that could be incorporated by a
`polymerase into a primer extension strand.” (Paper 69, PO Resp. 8.)
`Columbia cites paragraphs 30-35 of Dr. Trainor’s declaration as evidence
`that “[r]esults were mixed and it was recognized that new nucleotide
`analogues were needed [for use in] BASS [sequencing by synthesis; also
`known as SBS] sequencing.” (Id.)
`As discussed in more detail below, Columbia’s characterization of the
`prior art as having “some interest in base-labeled nucleotide analogues”
`understates the interest level shown in the prior art. Tsien1 and Dower,2
`
`
`1 Roger Tsien et al., WO 91/06678 (May 16, 1991), Exhibit 1002 (“Tsien”).
`2 William Dower et al., U.S. Pat. No. 5,547,839 (August 20, 1996), Exhibit
`1005 (“Dower”).
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`cited in this inter partes review, and Stemple III,3 cited in related
`proceedings, describe SBS methods, which disclose base-labeled nucleotides
`and nucleotides containing a removable chemical moiety at the 3’-OH
`position (Ex. 2033, Trainor Decl. ¶¶ 24 and 26-29). Columbia
`acknowledges that base-labeled nucleotides were described in the prior art
`(id. at 28). We understand it to be Columbia’s position that because there is
`no single working example in the cited prior art of a nucleotide with the
`base-label and removable 3’-OH blocking group being used in a DNA
`sequencing reaction, the disclosure of such a nucleotide is somehow
`diminished and amounts only to “some interest.” Columbia, however, has
`not identified where in the prior art a nucleotide with a label on the base and
`removable 3’-OH chemical moiety was so disparaged that a person of
`ordinary skill in the art would have been dissuaded from using it in SBS
`methods. To the contrary, the disclosure in several publications of
`nucleotides with a label on the nucleotide base with a removable 3’-OH
`group group (e.g., Tsien, Dower, and Stemple III) shows a recognition
`within the prior art that such nucleotides were useful and effective in SBS
`methods.
`
`C. Related Proceedings
`The ’698 Patent is the subject of The Trustees of Columbia University
`in the City of New York v. Illumina, Inc., 1:12-cv-00376-UNA, currently
`pending in the United States District Court for the District of Delaware
`
`
`3 Derek L. Stemple et al., U.S. Pat. No. 7,270,951 B1 (September 18, 2007),
`Exhibit 1008 (“Stemple III”).
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`(Petition 3-4). According to Illumina, Columbia alleges in that proceeding
`that Illumina has infringed, and continues to infringe, the ’698 Patent (id.).
`There are two pending inter partes trials related to this trial:
`A petition for inter partes review was filed on September 16, 2012,
`for U.S. Pat. No. 7,790,869 B2 (“the ’869 Patent”).4 The ’869 Patent is
`assigned to Columbia, has claims directed to related subject matter of the
`’698 patent, and has the same lineage as the ’698 Patent. We instituted inter
`partes review on March 12, 2013.
`A petition for inter partes review was filed on October 3, 2012, for
`U.S. Pat. No. 8,088,575 B2 (“the ’575 Patent”)5 which is based on a
`continuation application of the ’869 Patent. The ’575 patent is assigned to
`Columbia and has claims directed to related subject matter of the ’698
`patent. We instituted inter partes review on March 12, 2013.
`
`D. The Alleged Grounds of Unpatentability
`We instituted inter partes review on the following four grounds of
`
`unpatentability:
`I. Claims 1-7, 11, 12, 14, 15, and 17 under 35 U.S.C. § 103(a) as
`obvious in view of Tsien and Prober I6 (Petition 27).
`II. Claims 5 and 12 under 35 U.S.C. § 103(a) as obvious in view of
`Tsien, Prober I, and Rabani7 (Petition 52).
`
`
`4 IPR2012-00007.
`5 IPR2013-00011.
`6 James M. Prober et al., A System for Rapid DNA Sequencing with
`Fluorescent Chain-Terminating Dideoxynucleotides, 238 SCIENCE 336-341
`(1987), Exhibit 1003 (“Prober I”).
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`III. Claims 1-7, 11, 12, 14, 15, and 17 under 35 U.S.C. § 103(a) as
`obvious in view of Tsien and Seela I8 (Petition 56).
`IV. Claims 1-7, 11, 12, 14, 15, and 17 under 35 U.S.C. § 102(b) as
`anticipated by Dower (Petition 30).
`
`E. Claims
`
`Claims 1 and 11 are the only independent claims under review.
`Claims 2-7, 14, 15, and 17 depend from claim 1. Claim 12 depends from
`claim 11.
`Claims 1 and 11 are reproduced below:
`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 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,
`
`
`7 Ely Rabani et al., WO 96/27025 (September 6, 1996), Exhibit 1006
`(“Rabani”).
`8 Frank Seela, U.S. Pat. No. 4,804,748 (February 14, 1989), Exhibit 1014
`(“Seela I”).
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`so as to thereby determine the identity of the nucleotide
`analogue incorporated into the nucleic acid primer extension
`strand.
`
`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 of the nucleotide analogue.
`
`
`
`PATENTABILITY CHALLENGES
`II. TSIEN AND PROBER I
`We instituted inter partes review of claims 1-7, 11, 12, 14, 15, and 17
`
`on the grounds that the claims would have been obvious under 35 U.S.C.
`§ 103 in view of Tsien and Prober I. We first turn to the description in Tsien
`and Prober I of key elements of the claims, and then to the reason for
`combining Tsien and Prober I to have arrived at the claimed invention.
`
`
`A. Claim 1 and others
`
`Claim 1 is drawn to nucleic acid sequencing involving steps of: a)
`contacting a nucleic acid template with a primer; b) contacting the template
`hybridized with a polymerase and four nucleotide analogues, where each
`base has a unique label and a removable chemical moiety capping the 3’-OH
`group of the nucleotide sugar; and c) detecting the unique label of the
`nucleotide analogue which is incorporated into the primer as the primer is
`extended. At least one of the four nucleotide analogues is deaza-substituted.
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`A nucleotide analogue of claim 1 has the following structures or
`features: 1) a unique label attached to a base; 2) a removable chemical
`moiety capping the 3’-OH group of the nucleotide sugar; and 3) a deaza-
`substituted base.
`
`Tsien
`
`Tsien describes a DNA sequencing by synthesis method (Tsien, p. 6-
`7). The method uses nucleotides labeled with reporter groups to identify
`when they are incorporated into the newly synthesized strand (id. at p. 7,
`ll. 3-14).
`The following evidence from Tsien supports Illumina’s contention
`that features 1) and 2) are described in Tsien (see also Pet. 19-25).
`
`1) Unique label attached to a base
`Tsien has the following teachings:
`When they [deoxynucleotide triphosphates or dNTPs] are each
`tagged or labeled with different reporter groups, such as
`different fluorescent groups, they are represented as dA'TP,
`dC''TP, dG'''TP and dT''''TP. As will be explained in more
`detail below, the fact that the indication of labeling appears
`associated with the "nucleoside base part" of these
`abbreviations does not imply that this is the sole place where
`labeling can occur. Labeling could occur as well in other parts
`of the molecule.
`(Tsien, page 10, ll. 7-15 and Fig. 2.)
`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.
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`(Id. at 27, l. 33 to p. 28, l. 2.)
`One method involves the use of a fluorescent tag attached
`to the base moiety. . . . This method is included because a
`number of base moiety derivatized dNTP analogues have been
`reported to exhibit enzymatic competence.
`(Id. at 28, ll. 5-6, 10-12.)
`2) Removable 3’-OH chemical moiety (capping group)
`During DNA synthesis, nucleotides are sequentially added to the 3’-
`OH group of the nucleotide sugar. The 3’-OH group contains a removable
`blocking group in Tsien’s sequencing method so the labeled nucleotides can
`be added one at a time. After each addition, the label is detected and the 3’-
`OH group is deblocked and new nucleotide is added (Tsien, p. 13).
`Specifically, Tsien teaches:
`A deblocking solution is added via line 28 [Fig. 2] to remove
`the 3' hydroxyl labeled blocking group. This then generates an
`active 3' hydroxyl position on the first nucleotide present in the
`complementary chain and makes it available for coupling to the
`5' position of the second nucleotide.
`(Tsien, p. 13, ll. 17-22.)
`The coupling reaction generally employs 3' hydroxyl
`blocked dNTPs to prevent inadvertent extra additions [of
`nucleotides to the 3’-OH end].
`(Tsien, p. 20, ll. 25-27.)
`Structures 1) and 2) combined
`Figure 2 of Tsien, reproduced below, shows nucleotides used in a
`
`sequencing reaction, each with a unique label and a blocked 3’-OH group
`(18a, 18b, 18c, and 18d) (Tsien, p. 12, ll. 14-18; p. 9, l. 35 to p. 10, 15):
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` portion of Tsien’s Figure 2,reproduced above, shows nucleotides
`each with a unique label attached to the nucleotide and a blocked 3’-OH
`group. The figure indicates that the labeling is on the base, but “these
`abbreviations [do] not imply that this is the sole place where labeling can
`occur.” (Tsien, p. 10, ll. 7-15 and Fig. 2.)
`
`3) A deaza-substituted base
`
`Tsien does not disclose a deaza-substituted base, but references Prober
`
`I, which does. Specifically, Tsien teaches:
`One method involves the use of a fluorescent tag attached
`to the base moiety. . . . This method is included because a
`number of base moiety derivatized dNTP analogues have been
`reported to exhibit enzymatic competence. [citing Sarfati et al.
`(1987)] . . . . [Prober I] show enzymatic incorporation of
`fluorescent ddNTPs by reverse transcriptase and Sequenase™.
`(Tsien, p. 28, ll. 5-18.)
`Prober I discloses the “set of four fluorescence-tagged chain-
`terminating reagents we have designed and synthesized is shown in Fig. 2A.
`These are ddNTP’s to which succinylfluorescein has been attached via a
`linker to the heterocyclic base. . . . The linker is attached . . . to the 7 position
`in the 7-deazapurines. (Prober I, p. 337.) In sum, Prober I describes a
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`nucleotide comprising a deazapurine base to which a label has been
`attached.
`
`Reason to combine
`In making an obviousness determination, “it can be important to
`identify a reason that would have prompted a person of ordinary skill in the
`relevant field to combine the elements in the way the claimed new invention
`does.” KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 418 (2007). Illumina
`contends that Tsien’s reference to Prober I’s fluorescent nucleotides would
`have provided one of ordinary skill in the art with a reason to have used
`Prober I’s labeling technique in Tsien’s method
`because the nucleotide analogues disclosed in Prober I, wherein
`“a linker is attached to the 5 position in the pyrimidines and to
`the 7 position in the 7-deazapurines,” is shown to be an
`effective way to attach a fluorescent label to a nucleic acid base
`while maintaining the ability of the Sequenase™ polymerase
`used by Tsien to incorporate the associated dNTP into the
`primer extension strand.
`(Petition 29.) Even absent disclosure of Prober I in Tsien, Dr. Weinstock
`testified that it would have been obvious to have used Prober I’s teachings in
`Tsien.
`Prober I specifically teaches that nucleotide analogues
`incorporating 7-deazapurines may be used in sequencing
`reactions. Thus, the combination of Tsien and Prober I is the
`use of the known techniques of Prober I to improve similar
`Tsien systems and methods in the same way that the known
`features improve the methods and reagents of Prober I.
`Furthermore, use of the features taught by Prober I for their
`intended purpose, as disclosed by Prober I, would enhance the
`capability of the Tsien systems and methods in the same way
`they enhance the capability of the Prober I methods and
`reagents.
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`(Ex. 1021, Weinstock Decl. ¶ 66.)
`
`Discussion
`Columbia did not respond substantively to the patentability challenge
`of claim 1 based on Tsien and Prober I under 35 U.S.C. § 103 in either the
`Preliminary Response (Paper 21) or Patent Owner Response (Paper 69).
`However, in arguing for the patentability of a claim with narrower scope
`than claim 1 (i.e., proposed claim 18), Columbia contends that Tsien’s base
`label nucleotide would not have been the “starting point” to make novel
`nucleotide analogues because of a preference for nucleotides with the label
`attached to the 3’-OH group (Paper 69, PO Resp. 18). We do not find this
`argument persuasive because there is an explicit description of base-labeled
`nucleotides in Tsien, and no specific disclosure has been identified in Tsien
`by Columbia which disparages these alternative nucleotide analogues, or
`which would have led one of ordinary skill in the art to conclude that they
`were unsuitable for the SBS purpose described by Tsien.
`
`B. Claim 15
`
`Claim 15 depends on claim 1 and further adds the limitation that
`“each of said unique labels is attached to the nucleotide analogue via a
`cleavable linker.”
`Although Illumina identified where in Tsien the “cleavable linker”
`limitation in claim 15 was described, Columbia did not separately address
`claim 15 in their Patent Owner Response. However, in the Motion to
`Amend the Claims, proposed new claim 18, which incorporates all the
`limitations of claim 15 into claim 1 (Paper 70, p. 4), was submitted by
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`Columbia along with arguments for its patentability over the cited art (Paper
`69, PO Resp.). We consider these arguments below.
`
`Tsien
`
`Illumina cites the following passage in Tsien for a description of “a
`cleavable linker,” as recited in claim 15 (Petition 26):
`In another type of remote labeling the fluorescent moiety
`or other innocuous label can be attached to the dNTP through a
`spacer or tether. The tether can be cleavable if desired to release
`the fluorophore or other label on demand. There are several
`cleavable tethers that permit removing the fluorescent group
`before the next successive nucleotide is added--for example,
`silyl ethers are suitable tethers which are cleavable by base or
`fluoride, allyl ethers are cleavable by Hg(II), or 2,4-
`dinitrophenylsulfenyls are cleavable by thiols or thiosulfate.
`(Tsien, p. 28, ll. 19-29.)
`
`Tsien, in this passage, thus describes a “space or tether” – the “linker”
`in claim 15 – which can attach the label to the nucleotide analogue (“dNTP”
`in Tsien). The tether is expressly taught by Tsien to “be cleavable if desired
`to release the fluorophore or other label on demand” and, therefore, is a
`“cleavable linker,” as recited in the claim. This passage does not describe
`the label attached via a linker to the base of the nucleotide as required by
`claim 15, and claim 1 from which it depends. However, Illumina cited Tsien
`for its teaching “of a fluorescent tag attached to the base moiety” (Tsien, p.
`28, ll. 5-6) to meet this limitation of the claim (Petition 21). A person of
`ordinary skill in the art reading Tsien would have recognized that its
`teaching of a cleavable tether to release the label would have been useful
`when the label is attached to the base moiety.
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`Columbia contends that the patentability challenge based on Tsien and
`
`Prober I is insufficient because “no starting point is identified and no
`rationale for the obviousness of the novel nucleotide analogue is provided.”
`(Paper 69, PO Resp. 17.)
`Columbia’s argument is not persuasive. In the petition, Illumina cited
`Tsien’s reference to Prober I for teaching labeled nucleotides and expressly
`stated that “Tsien thus provides an express teaching, suggestion, and
`motivation to combine Tsien with the disclosures of Prober I with respect to
`‘base moiety derivatized’ nucleotide analogues.” (Petition 28.)
`Furthermore, Illumina stated that Tsien teaches that “the synthesis scheme
`for ddNTPs used in Prober I should be used in Tsien to produce ‘fluorescent
`dNTPs.’ Tsien, p. 29, ll. 10-19.” (Id.) Columbia’s “starting point” argument
`is, therefore, unsubstantiated. A rationale to combine the publications was
`also described above in Section A based on testimony by Dr. Weinstock.
`
`Columbia argues that if one of skill in the art would have used the
`base-labeled nucleotide analogues of Tsien as a “starting point,” several
`differences between those nucleotide analogues and the claimed nucleotide
`analogues would “have had to be addressed.” (Paper 69, PO Resp. 21.)
`Relying on Dr. Trainor’s testimony, Columbia asserts that one of skill in the
`art would have had to make the following changes (Ex. 2033, Trainor Decl.
`¶ 92):
`
`1. remove the identical (non-unique) labels from the C-8
`positions of the two purines despite the C-8 position being
`described by Tsien as the “ideal” position for the attachment of
`the labels to purines;
`2. change the purine bases of the purines to deazapurines;
`3. change the identical labels on the pyrimidines to unique
`labels;
`
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`Case IPR2012-00006
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`4. replace the uncleavable, acetylenic linker (described in
`Prober I) on the pyrimidines with a cleavable linker;
`5. replace the uncleavable alkylamino linker on the purines with
`a cleavable linker);
`6. include removable 3’-OH capping groups on the uncapped
`3’-OH groups of the nucleotide analogues; and
`7. incorporate such a novel nucleotide analogue into the end of
`a primer extension strand.
`(Ex. 2033, Trainor Decl. ¶ 92.)
`We address each of these differences, below.
`
`Deaza-substituted nucleotide (Nos. 1 and 2 in Ex. 2033, Trainor Decl.
`¶ 92)
`Citing the Trainor Declaration, Columbia argues “there was no reason
`
`to use a deaza-purine labeled at the 7-positiResn given Tsien’s specific
`guidance to the contrary that a label on the 8-position of a non-deaza purine
`was ‘ideal.’ (Exhibit 2033, Trainor Decl., ¶§95-98 []).” (Paper 69, PO Resp.
`22.) Columbia further argues that there would have been no reason “to
`change the uncleavable linkers on the 8-position of the purine labeled
`nucleotide analogues of Tsien to a cleavable linker, particularly since the
`linker in Prober I is uncleavable (Exhibit 2033, Trainor Decl., ¶98 [])” (id.).
`
`Dr. Trainor cites Tsien’s statement that the “C-8 position of the purine
`structure presents an ideal position for attachment of a label.” (Tsien, p. 29,
`ll. 3-4.) Dr. Trainor acknowledges that Tsien cites Prober I in the same
`paragraph in which purine labeling is described and that Prober I describes
`producing labeled deazapurines (Ex. 2033, Trainor Decl. ¶ 96). However,
`Dr. Trainor states that Tsien ignored Prober I’s teaching because Tsien
`“refers to Prober I for teaching an approach to producing fluorescently
`
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`Case IPR2012-00006
`Patent 7,713,698
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`labeled derivatives of pyrimidines.” (Id.) The mentioned teaching in Prober
`I is reproduced below:
`A number of approaches are possible to produce fluorescent
`derivatives of thymidine and deoxycytidine. One quite versatile
`scheme is based on an approach used by Prober et al. (1987) to
`prepare ddNTPs with fluorescent tags.
`(Tsien, p. 29, ll. 10-14.)
`
`Columbia’s argument is not persuasive or consistent with the full
`labeling disclosure in Tsien. Beginning at page 26, Tsien describes reporter
`groups on dNTPs and how they can be incorporated into a dNTP. Tsien
`states that one “approach employs fluorescent labels. These can be attached
`to the dNTP's via the 3'OH blocking groups or attached in other positions.”
`(Tsien, p. 26, ll. 17-19.) After describing approaches to label the 3’-OH
`blocking group, Tsien goes on to state that “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.” (Id. at
`p. 27, l. 33 to p. 28, l. 4.) In the following paragraph, Tsien describes
`attaching a label to the base, and states:
`One method involves the use of a fluorescent tag attached
`to the base moiety. . . . This method is included because a
`number of base moiety derivatized dNTP analogues have been
`reported to exhibit enzymatic competence. Sarfati et al, (1987)
`demonstrates the incorporation of biotinylated dATP in nick
`translations, and other biotinylated derivatives such as 5-biotin
`(19)-dUTP (Calbiochem) are incorporated by polymerases and
`reverse transcriptase. Prober et al. (1987) [Prober I] show
`enzymatic incorporation of fluorescent ddNTPs by reverse
`transcriptase and Sequenase™.
`
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`Case IPR2012-00006
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`(Id. at p. 28, ll. 5-18.)
`This passage, cited by Illumina on page 28 of the Petition, expressly
`mentions Prober I’s method in its discussion of base labeling, reasonably
`suggesting that Tsien considered it suitable for Tsien’s sequencing method.
`While Tsien discloses that the C-8 position of the nucleotide base is “ideal”
`for labeling a purine, that disclosure would not have dissuaded one of
`ordinary in the art from labeling at other positions in the base. “[J]ust
`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). “A reference may be said to teach away
`when a person of ordinary skill, upon reading the reference, would be
`discouraged from following the path set out in the reference, or would be led
`in a direction divergent from the path that was taken by the applicant.” In re
`Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). For a reference to “teach away”
`from using a particular approach, it must be shown that “the line of
`development flowing from the reference’s disclosure is unlikely to be
`productive of the result sought by the applicant.” Id. Dr. Trainor, himself,
`admitted that fluorescently labeled deazapurines had been used in the prior
`art (Ex. 2033, Trainor Decl. ¶¶ 20-21).
`
`In this case, as mentioned above, there is generic disclosure in Tsien
`of labeling the base moiety, including a specific reference to Prober I, the
`latter describing C-7 deaza-labeled purine bases. Thus, even if labeling at
`the C-8 position is superior, Prober I’s method is still reasonably suggested
`by Tsien, which characterizes Prober I as showing “enzymatic incorporation
`of fluorescent ddNTPs by reverse transcriptase and Sequenase™” (Tsien, p.
`2, ll. 6-9; p. 19, ll. 9-18). Thus, those of skill in the art would have found the
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`Case IPR2012-00006
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`use of Prober’s analogues to be useful and effective, even if nucleotide
`analogues with a label on the 8-position of a non-deaza purine might have
`been better.
`
`
`Unique labels (No. 3 in Ex. 2033, Trainor Decl. ¶ 92)
`In his declaration, Dr. Trainor testifies that to have arrived at the
`
`claimed nucleotides from Tsien, a person of ordinary skill would have had to
`change the identical labels on the pyrimidines to unique labels. As
`explained by Illumina and in the section above on claim 1, Tsien has an
`express disclosure of using different reporter groups of each dNTP (see
`Section A). See also the following passage of Tsien:
`The detected florescence is then correlated to the fluorescence
`properties of the four different labels present on the four
`different deoxynucleotide triphosphates to identify exactly
`which one of the four materials was incorporated at the first
`position of the complementary chain. This identity is then
`noted.
`
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