Trials@uspto.gov
`572-272-7822
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` Paper 130
` 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 IPR2013-00011
`Patent 8,088,575 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
`
`
`
`
`572-272-7822
`
`
`
`
`
` Paper 130
` Mailed: March 6, 2014
`
`
`
`
`
`
`
`
`
`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 IPR2013-00011
`Patent 8,088,575 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 IPR2013-00011
`Patent 8,088,575
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`
`I. BACKGROUND
`
`A. Introduction
`Petitioner, Illumina, Inc. (“Illumina”), filed a petition on October 3,
`2012, for inter partes review of claims 1-3 and 6 of U.S. Patent 8,088,575
`B2 (“the ’575 Patent”) pursuant to 35 U.S.C. §§ 311-319 and 37 C.F.R. §§
`42.1 - 42.123. On March 12, 2013, the Board instituted inter partes review
`of claims 1-3 and 6 on four grounds of unpatentability (Paper 26, Decision
`on Petition (“Dec. Pet.”)). Illumina requested rehearing on two of the
`grounds of unpatentability (Paper 29), 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 claim 6 (Paper 44,
`Decision on Rehearing (“Dec. Reh’g”)). This corresponded to one of the
`same grounds of unpatentability authorized for claims 1-3.
`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 70, “PO Resp.”). Columbia also filed a Motion to
`Amend Claims (Paper 56) 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). An
`oral hearing was held on December 17, 2013 with both parties in attendance.
`(Record of Oral Hearing, Paper 126.)
`
`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
`Illumina. Dr. Trainor has a Ph.D in Organic Chemistry and experience in
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`DNA sequencing (Exhibit 2033, Trainor Decl. ¶¶ 3 and 6-8), qualifying him
`to testify on the prior art 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 prior art 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 1-3 and
`6 are unpatentable.
`
`B. The ‘575 Patent
`The ‘575 Patent issued January 3, 2012. The named inventors are
`Jingyue Ju, Zengmin Li, John Robert Edwards, and Yasuhiro Itagaki. The
`invention of the ‘575 Patent involves sequencing DNA by incorporating a
`base-labeled nucleotide analogue into primer DNA strand, and then
`determining the identity of the incorporated analogue by detecting a label
`attached to the base of the nucleotide. A polymerase is used to incorporate
`the nucleotide analogue into the strand of DNA (‘575 Patent, col. 3, ll. 2-3).
`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. 9-13).
`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,” but rather focuses
`its arguments on the novelty and unobviousness of the nucleotide utilized in
`the sequencing method. Nucleotides, which are the building blocks of DNA,
`comprise a sugar (ribose or deoxyribose), phosphates 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 (‘575 Patent,
`col. 2, ll. 35-39). 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 ‘575 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 (id. at col. 2, ll. 59-65).
`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. 3, ll. 1-4). According to the ‘575 Patent,
`the prior art teaches attaching the label to the 3’-OH group. The ‘575 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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`Claims 1-3 in this inter partes review involve a nucleotide analogue
`that comprises: 1) a base labeled with a unique label; and 2) a removable
`chemical moiety capping the 3’-OH group. Claim 6 further requires a base
`that is deaza-substituted. A deaza-substituted nucleotide is a nucleotide
`analogue that includes a deazabase as the nitrogen base (id. at col. 7, ll. 46-
`65). 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 70, 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., US 5,547,839 (August 20, 1996), Exhibit 1005
`(“Dower”).
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`cited in this inter partes review, and Stemple III,3 which is cited in related
`proceedings, describe SBS methods that use base-label nucleotides and
`nucleotides containing a removable chemical moiety at the 3’-OH position
`(Ex. 2033, Trainor Decl. ¶¶ 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
`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 and a removable 3’-OH group (e.g., Tsien, Dower, and
`Stemple III) shows a recognition within the prior art that such nucleotide
`analogues were useful and effective in SBS methods.
`
`C. Related Proceedings
`The ’575 Patent is the subject of the litigation, 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 (Petition 3-4). According to Illumina, Columbia
`
`
`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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`alleges in that proceedings that Illumina has infringed, and continues to
`infringe, the ’575 Patent (id.).
`There are two pending inter partes trials which are related to this trial:
`A petition for inter partes review was filed on September 16, 2012 for
`U.S. Pat. No. 7,713,698 B2 (“the ’698 patent”).4 The ’698 patent is assigned
`to Columbia, has claims directed to related subject matter, and has a similar
`lineage as the ’575 Patent. We instituted inter partes review on March 12,
`2013.
`
`A petition for inter partes review was filed on September 16, 2012 for
`U.S. Pat. No. 7,790,869 B2 (“the ‘869 patent”).5 The ’869 patent is assigned
`to Columbia and has claims directed to related subject matter. The ’575
`Patent is a continuation of the ‘869 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 1-3, and 6 under 35 U.S.C. § 102(b) as anticipated by
`Dower;
`II. Claims 1-3, under 35 U.S.C. § 102(b) as anticipated by Tsien;
`III. Claim 6 under 35 U.S.C. § 103(a) as obvious in view of Tsien and
`Prober I;6 and
`
`
`4 IPR2012-00006.
`5 IPR2012-00007.
`6 James M. Prober et al., A System for Rapid DNA Sequencing with
`Flourescent Chain-Terminating Dideoxynucleotides, 238 SCI. 336 (1987),
`Exhibit 1003 (“Prober I”).
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`IV. Claim 6 under 35 U.S.C. § 103(a) as obvious in view of Tsien
`and Seela I.7
`
`E. The Claims
`The ’575 Patent was granted with claims 1-6. Illumina challenges the
`patentability of independent claim 1 and claims 2, 3, and 6, which depend
`from claim 1. Claims 1 and 6 read as follows (bracketed numerals added to
`emphasize certain claim limitations):
`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 [1] a base labeled with a unique
`label and contains [2] 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.
`
`6. The method of claim 1, wherein said base of at least one of
`said nucleotide analogues is a deazapurine.
`
`
`
`
`7 Frank Seela, US 4,804,748 (February 14, 1989), Exhibit 1014 (“Seela I”.
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`PATENTABILITY CHALLENGES
`II. CLAIM INTERPRETATION
`Claim 6 recites that the base of at least one of the nucleotide
`
`analogues is a “deazapurine.” One of ordinary skill in the art would
`understand that a “deazapurine” is a nitrogen base in which one of the
`natural nitrogen atoms in the base ring is substituted with a carbon atom.
`(’575 Patent, col. 7, ll. 39-65.) For example, in a 7-deazapurine, the natural
`7-position nitrogen in the base ring is replaced with a carbon atom. Id.
`
`
`ANTICIPATION
`Independent claim 1 is directed to a method of “determining the
`
`identity of a nucleotide analogue incorporated into a nucleic acid primer
`extension strand,” comprising three recited steps using a nucleotide analogue
`with “a base labeled with a unique label” and “small removable chemical
`moiety capping the 3’-OH group of the sugar of the nucleotide analogue.”
`Claim 6 further recites that the base is a deazapurine. Columbia does not
`dispute that the claimed methods steps were known in the art, but rather
`argues that the claimed nucleotide analogue was not.
`
`
`III. DOWER
`
`Claims 1-3
`We instituted inter partes review of claims 1-3 based on Dower as an
`anticipatory publication. Dower describes methods for sequencing DNA
`(Dower, col. 6, ll. 19-20). In one embodiment, a primer is elongated, one
`nucleotide at a time, using labeled nucleotide analogues in a polymerase-
`catalyzed enzymatic reaction (id. at col. 14, ll. 37-59; col. 15, l. 56 to col. 16,
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`l. 21). As explained in more detail below, Dower describes nucleotides with
`a label attached to the base and a small removable chemical moiety capping
`the 3’-OH group of the sugar of the nucleotide analogue, the two structural
`features of the nucleotide utilized in the claimed method of “determining the
`identity of a nucleotide analogue incorporated into a nucleic acid primer
`extension strand” (’575 Patent, claim 1). We address each of these features
`below.
`
`A. “a base labeled with a unique label”
`The phrase “unique label” is not defined in the ’575 patent. We adopt
`the ordinary meaning of “unique” as “being the only one of its kind.”8
`Therefore, the phrase “unique label” would be understood to mean that each
`of the recited four nucleotides has a different label (see ’575 patent, col. 21,
`ll. 31-35). Dower has express disclosure of each nucleotide bearing its own
`distinct label (Dower, col. 23, ll. 22-24 (“This is done in a one-step process
`where each of the four dNTP analogs is identified by a distinct dye, such as
`described in Prober et al. Science 238:336-341 . . .”)).
`Illumina also points to disclosure in Dower, which is said to describe
`a label attached to a base of a nucleotide (Petition 20).
`FIG. 9 schematically illustrates the synthesis of a generic
`protected nucleotide. A suitable nucleotide is labeled with the
`FMOC fluorescently detectable label by reaction under the
`conditions described, e.g., in Ser. No. 624,114 filed Dec 6,
`1990, FMOC-Cl, and H2O. A protection moiety will be added
`using conditions also described there.
`(Dower, col. 18, l. 64-col. 19, l. 2.)
`Figure 9 is reproduced below:
`
`8 http://www.thefreedictionary.com/unique. Accessed February 9, 2013.
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`35-37), annd thus, haas
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`Figure 99 shows a ffluorescentt label, FMMOC, attachhed to the bbase of a
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`eoside. Doower statess that “the FMOC maay be attacched to adeenine,
`nucl
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`
`
`cystoosine [sic, cytosine], or guaninee” (Dowerr, col. 5, ll.
`
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`exprress disclossure of a unnique labell attached tto the basee of a nucleeotide as
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`requuired by claaim 1.
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`B. ““small removable cheemical moiiety cappinng the 3’-OOH of the ssugar”
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`Illuminaa provided factual suppport for itts contentioon that Doower
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`desccribes a small removaable chemical moietyy at the 3’-OOH of the
`sugar
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`(Petiition 21). TThis evideence includdes the folloowing discclosures:
`
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`Foor a nucleic acid, a unnit for adddition woulld typicallyy be
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`a single nucleotidee. . . . To pprevent eloongation byy a unit lenngth
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`greater tthan one mmonomer, thhe nucleotiide shouldd be blockeed at
`e
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`the posittion of 3’ eelongation.. Usually, tthe nucleo
`tide will b
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`blocked at the 3’ hhydroxyl grroup wheree successivve nucleotiides
`would b
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`e attached..
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`(Dowwer, col. 15, ll. 25, 333-37.)
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`agent theereby allowwing for deeblocking
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`and subseqquent
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`elongation.
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`(Id. aat col. 15,
`ll. 38-40.)
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`AAppropriatee blocking agents incllude, amonng others, llight
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`sensitivee groups suuch as 6-niitoveratrylooxycarbonnyl (NVOCC), 2-
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`nitobenzzyloxycarbbonyl (NBOOC), α,α-ddimethyl-
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`. . . typiccally the bllocking agent will bee a reversibble blockinng
`
`dimethoxybenzylooxycarbonyyl (DDZ), 55-bromo-77-
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`nitroindolinyl, o-hydroxy-2-methyl cinnamoyl, 2-oxymethylene
`anthraquinone, and t-butyl oxycarbonyl (TBOC).
`(Id. at col. 18, ll. 52-77.)
`
`C. Discussion
`
`In its preliminary comments, Columbia argued, unsuccessfully, that
`Dower is not anticipatory because there is no single example of a nucleotide
`with both structural features [1] and [2]. However, a single example is not
`required to establish anticipation. In re Petering, 301 F.2d 676, 681 (CCPA
`1962); WM. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356,
`1361-62 (Fed. Cir. 2012). For a prior art reference to anticipate a claim, it
`must disclose all of the limitations of the claim, “arranged or combined in
`the same way as in the claim.” Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d
`1359, 1370 (Fed. Cir. 2008).
`With respect to limitation [2], Dower expressly describes blocking the
`3’-OH group of the sugar molecule in order to halt polymerase catalyzed
`elongation of the primer strand (Dower, col. 15, ll. 35-37 (reproduced
`above)). The blocking group is, thus, necessary for Dower’s one-step
`process (id. at Fig. 8; col. 23, ll. 26-30). The nucleotide must also be
`detectably labeled in order to determine whether it was added to the primer
`end. Thus, the reversibly blocked nucleotide must be labeled as recited in
`limitation [1] of claim 1. Dower expressly teaches a nucleotide detectably
`labeled on a base, for example, as shown in Figure 9 (id. at col. 5, ll. 35-37;
`col. 18, l. 64-col. 19, l. 2; Figure 9). While Figure 9 does not depict the
`nucleotide with a blocked 3’-OH group, the skilled worker would have
`understood that a blocked nucleotide is needed to carry out Dower’s process
`(see infra).
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`Columbia did not respond substantively to the patentability challenge
`of claims 1-3 based on Dower under 35 U.S.C. § 102 in their subsequent
`response under 37 C.F.R. § 42.120. The evidence as outlined above
`persuades us that Illumina has met its burden of proof by a preponderance of
`the evidence in showing that claims 1-3 of the ’575 Patent are anticipated by
`Dower under 35 U.S.C. § 102.
`
`Claim 6
`Claim 6 depends from claim 1, and further recites that the sequencing
`method employs a nucleotide which comprises a deazapurine as a base.
`Dower is not said by Illumina to expressly describe a deazapurine base in its
`written disclosures. Rather, Illumina contends a nucleotide with a
`deazapurine is present by virtue of the incorporation by reference to the
`Prober I publication by Dower. “To incorporate material by reference, the
`host document must identify with detailed particularity what specific
`material it incorporates and clearly indicate where that material is found in
`the various documents.” Advanced Display Sys., Inc. v. Kent State Univ.,
`212 F.3d 1272, 1282 (Fed. Cir. 2000). When making such determination,
`the standard “of one reasonably skilled in the art should be” applied. Id. at
`1283.
`
`The following passages were cited in the Decision on Rehearing to
`establish that Dower incorporated Prober I for its teaching a deazapurine
`base.
`
`DNA polymerase, or a similar polymerase, is used to extend the
`chains by one base by incubation in the presence of dNTP
`analogs which function as both chain terminators and
`fluorescent labels. This is done in a one-step process where
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`each of the four dNTP analogs is identified by a distinct dye,
`such as described in Prober et al. Science 238:336-341.
`(Dower, col. 23, ll. 18-24.)
`Fluorescent chain terminators (analogs of dATP, dCTP, dGTP,
`and TP, each labeled with fluorophore preferably emitting at a
`distinguishable wavelength) are added to the reaction at a
`sufficient concentration and under suitable reaction conditions
`(time, temperature, pH, ionic species, etc., See Sambrook et al.
`(1989) Molecular Cloning, vols. 1-3, and Prober et al.).
`(Id. at col. 25, ll. 4-10.)
`(c) An alternative polymer stepwise synthetic strategy
`can be employed. In this embodiment, the fluorophores need
`not be removable and may be attached to irreversible chain
`terminators. Examples of such compounds for use in
`sequencing DNA include, but are not limited to,
`dideoxynucleotide triphosphate analogs as described by Prober
`et al. (1987) Science 238:336-341.
`(Id. at col. 25, ll. 41-47.)
`Upon reconsideration, we agreed with Columbia that Prober I is not
`incorporated by reference into Dower for a teaching a deazapurine base in a
`nucleotide with a reversible 3’-OH cap (Paper 44, Dec. Reh’g 6-9.) The
`primary flaw is that Prober I’s nucleotides with the deazapurine substituent
`have an irreversible 3’-OH blocking group (chain terminating dideoxy
`ddNTPs) because they were employed in chain terminating sequencing.
`Illumina did not identify a teaching in Dower where Dower describes using
`Prober I to modify Dower’s nucleotides with a reversible 3’-OH capping
`group.
`With respect to col 23, ll. 18-24 of Dower, Dr. Trainor testified:
`[T]he material being referenced in Dower in the phrase “where
`each of four dNTP analogues is identified by a distinct dye” is
`only the description of the four distinct dyes used to label four
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`ddNTPs. The only dNTPs described in Prober I are unlabeled
`nucleotides which are used with four labeled ddNTPs in a
`Sanger dideoxy sequencing experiment. Since there is no
`disclosure in Prober I of labeled dNTP analogues, one of
`ordinary skill would not have understood the referenced
`material to be dNTP analogues identified by distinct dyes, but
`only the four dyes used to label the ddNTPs.
`(Ex. 2033, Trainor Decl. ¶ 52.)
`We agree with Dr. Trainor’s analysis and conclusion.
`Similarly, we agree with Dr. Trainor that Dower’s disclosure at
`col. 25, ll. 4-10, is not adequate because it appears to be only a description of
`the conditions that one of ordinary skill in the art would use to accomplish
`the polymerase reaction, and not of using the analogues themselves (Ex.
`2033, Trainor ¶ 54). In addition, the passage cited at column 24, lines 41-
`47, is also inadequate because it only concerns the four fluorescently
`labeled, dideoxy ddNTP chain terminators described in Prober I (id. at ¶ 56).
`
`At col. 25, ll. 41-64, Dower describes an alternative (c). This
`embodiment refers to nucleotides that have irreversible blocking groups on
`the 3’-OH position of the sugar, and thus, do not teach using Prober I’s
`deazapurine in nucleotide with a reversible 3’-OH group as claimed (Ex.
`2033, Trainor ¶ 57).
`Illumina cites to column 15, lines 37-40 of Dower, which states: “In
`contrast to a dideoxy nucleotide, typically the blocking agent will be a
`reversible blocking agent thereby allowing for deblocking and subsequent
`elongation.” Illumina states this disclosure supports the position that Dower
`discloses dNTPs for sequencing synthesis methods (Paper 76, p. 12.) We
`agree with this statement, but the issue is whether the disclosure of SBS
`nucleotides with reversible 3’-OH caps coupled to the reference to Prober’s
`
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`dideoxy irreversibly capped ddNTPs having a deazapurine base is a
`description of the claimed nucleotide analogue having a deazapurine base
`with a reversible 3’-OH cap. Illumina has not pointed to anything
`convincing in Dower that teaches replacing Dower’s dideoxy terminated
`nucleotide with a removable 3’-OH cap or vice-versa.
`Accordingly, we find that Illumina has not established by a
`preponderance of the evidence that Dower anticipates claim 6.
`
`
`IV. TSIEN
`We instituted inter partes review of claims 1-3 based on Tsien as an
`anticipatory publication. Tsien describes a method of sequencing DNA
`(Tsien, p. 6, ll. 28-30). The method involves the sequential addition to a
`primer of labeled nucleotides (dNTP), each with a different detectable label
`attached to it (id. at p. 7, ll. 3-14; p. 10, ll. 7-10; p. 14, ll. 12-26). Tsien
`describes the claimed [1] detectable label attached to a base (id. at p. 10,
`ll. 10-15; Tsien, p. 27, l. 33 to p. 28, l. 2; p. 28, ll. 5-6), in addition to other
`locations on the nucleotide analogue (p. 26, ll. 2-5; p. 26, ll. 17-19). Tsien
`also describes “[2] a small removable chemical moiety capping the 3’-OH
`group of the sugar of the nucleotide analogue” to prevent inadvertent
`multiple additions during the sequencing method (id. at p. 12, ll. 27-29).
`Columbia had argued in the Preliminary Response that “the large
`number of alternative approaches and features disclosed by Tsien form a
`‘genus’ of many possible methods, from which the specific method of claim
`1 cannot be immediately envisaged.” (Paper 22, Preliminary Response 16.)
`We agreed that there were choices to be made, but find that each selection is
`made from a defined set of possible choices. Citing Wrigley, 683 F.3d at
`
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`1361-62, in which anticipation was found where each of the specific
`ingredients in the claimed formula was recited in a longer list of alternative
`agents, we determined that there was a factual and legal basis on which
`Illumina would prevail in establishing anticipation by Tsien of claims 1-3,
`despite the need for choosing (Paper 26, Dec. Pet. 16).
`Columbia did not respond substantively to the patentability challenge
`of claims 1-3 based on Tsien under 35 U.S.C. § 102 in their subsequent
`Patent Owner Response. The evidence as outlined above persuades us that
`Illumina has met its burden of proof by a preponderance of the evidence in
`showing that claims 1-3 of the ’575 Patent are anticipated under 35 U.S.C.
`§ 102 by Tsien.
`
`
`V. TSIEN AND PROBER
`We instituted inter partes review of claim 6 on the grounds that the
`
`Columbia 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 6
`
`Claim 6 is drawn to the nucleic acid sequencing method of claim 1,
`and further recites that at least one of the labeled bases is a “deazapurine.”
`We instituted inter partes review of claim 6 under 35 U.S.C. § 103 as
`obvious in view of Tsien and Prober I.
`A nucleotide analogue of claim 6 has the following structures or
`features: 1) a unique label attached to a base; 2) a removable chemical
`
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`moiety capping the 3’-OH group of the nucleotide sugar; and 3) a deaza-
`substituted base. Features 1) and 2) are said to be described by Tsien.
`Prober I describes deazapurines. The issue to be decided is whether it would
`have been obvious to one of ordinary skill in the art to have used Prober I’s
`deazapurines in Tsien’s sequencing method.
`
`B. Tsien and Prober I disclosures
`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 structures 1) and 2) are described in Tsien (see also Pet. 31-38 (where
`Illumina cited disclosure from Tsien to meet the claim limitations).
`
`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, p. 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
`
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`a 3’-blocked dNTP analogue containing a label such as a
`fluorescent group coupled to a remote position such as the base.
`(Id. at p. 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 p. 28, ll. 5-6.)
`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.
`(Id. at p. 13, ll. 17-19.)
`The coupling reaction generally employs 3’ hydroxyl
`blocked dNTPs to prevent inadvertent extra additions [of
`nucleotides to the 3’-OH end].
`(Id. at p. 20, ll. 25-26.)
`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) (id. at p. 12, ll. 14-18; p. 9, l. 35 to p. 10, 15):
`
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` A
`
` 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:
`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 t
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