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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 IPR2012-00007
`Patent 7,790,869 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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`Illumina Ex. 1021
`IPR Petition - USP 10,435,742
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`Patent 7,790,869
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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 12, 13, 15-17, 20-26, 28,
`29, 31, and 33 of U.S. Patent 7,790,869 B2 (“the ’869 Patent”) pursuant to
`35 U.S.C. §§ 311-319. The owner of the ’869 Patent is The Trustees of
`Columbia University in the City of New York (“Columbia”). On March 12,
`2013, the Board instituted inter partes review as to claims 12, 13, 15-17, 20-
`26, 28, 29, 31, and 33 on four grounds of unpatentability (Paper 38, Decision
`on Petition (“Dec. Pet.” 2)). In a subsequent Decision on Illumina’s Request
`for Rehearing (Paper 40), the Board modified two of the grounds of
`unpatentability by substituting a different patent publication for one of the
`cited patent publications, where both publications had the same inventors
`and shared specifications and disclosures (Paper 54, Dec. Pet. Reh’g 18).
`After institution of the inter partes review, Columbia filed a response
`
`under 37 C.F.R. § 42.120 to the decision instituting inter partes review
`(Paper 78, “PO Resp.). Columbia also filed a Motion to Amend Claims
`(Paper 79) and a Motion to Exclude Evidence (Paper 122). Illumina filed a
`reply to Columbia’s response under 37 C.F.R. § 42.120 (Paper 83, Pet’r
`Reply and a Motion to Exclude Evidence (Paper 119 (redacted); Paper 100
`(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
`Illumina. Dr. Trainor has a Ph.D. in Organic Chemistry and experience in
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`DNA sequencing (Ex. 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 12, 13,
`15-17, 20-26, 28, 29, 31, and 33 of the ’869 Patent are unpatentable.
`
`B. The ’869 Patent
`The ‘869 Patent issued September 7, 2010. The named inventors are
`Jingyue Ju, Zengmin Li, John Robert Edwards, and Yasuhiro Itagaki. The
`invention of the ’869 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 (’869 Patent, col. 3, ll. 1-3).
`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. 8-12).
`All the claims at issue in this inter partes review are drawn to a
`nucleotide analogue, which comprises: 1) a base that is attached to a
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`detectable label through a cleavable linker; and 2) a cleavable chemical
`moiety capping the 3’-OH group. 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 (’869 Patent, col. 2, ll. 34-38). 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 ’869 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 (’869 Patent, col. 2, ll.
`58-66). 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. 67 to col. 3, l. 3). According
`to the ’869 Patent, the prior art teaches attaching the label to the 3’-OH
`group. The ’869 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.
`In summarizing the state of the art in Columbia’s Patent Owner
`Response, Columbia states that, “[d]uring the 1990s, despite some interest in
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`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 78, PO Resp. 9.)
`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 Stemple III,2
`cited in this inter partes review, and Dower,3 which is cited in related
`proceedings, describe SBS methods which use base-label 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
`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 disclosure in the
`prior art where a nucleotide analogue with a label on the base and removable
`
`1 Roger Tsien et al., WO 91/06678 (May 16, 1991), Exhibit 1002 (“Tsien”).
`2 Derek Stemple et al., U.S. Patent 7,270,951 B1 (September 18, 2007),
`Exhibit 1008 (“Stemple III”).
`3 William Dower et al., U.S. Pat. No. 5,547,839 (August 20, 1996), Exhibit
`1005 (“Dower”).
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`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 three publications of a label on the nucleotide
`base and of 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 ’869 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
`(Petition 3-4). According to Illumina, Columbia alleges in that proceeding
`that Illumina has infringed, and continues to infringe, the ’869 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. Patent No. 7,713,698 B2 (“the ’698 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. Patent 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 ’869
`patent. We instituted inter partes review on March 12, 2013.
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`4 IPR2012-00006.
`5 IPR2013-00011.
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`D. The Alleged Grounds of Unpatentability
`We instituted inter partes review on the following four grounds of
`
`unpatentability:
`I. Claims 12, 13, 17, 20-26, 28, 29, 31, and 33 under 35 U.S.C.
`§ 102(b) as anticipated by Tsien.6
`II. Claims 15 and 16 under 35 U.S.C. § 103(a) as obvious in view of
`Tsien and Prober I.7
`III. Claims 12, 13, 17, 20-23, 25, 26, 28, 29, and 31 under 35 U.S.C.
`§ 102(a) as anticipated by Stemple III.8
`IV. Claims 15 and 16 under 35 U.S.C. § 103(a) as obvious in view of
`Stemple III and Anazawa.9
`
`E. Claims
`The ’869 Patent was granted with 33 claims. Illumina challenges the
`patentability of independent claim 12, and dependent claims 13, 15-17, 20-
`26, 28, 29, 31, and 33. Claims 12 and 15 are reproduced below (bracketed
`numbering 1-4 added to emphasize certain limitations in the claim):
`
`12. A nucleotide having [1] a base that is attached to a
`detectable label through a cleavable linker, wherein the
`
`6 Roger Tsien et al., WO 91/06678 (May 16, 1991), Exhibit 1002 (“Tsien”).
`7 James Prober et al., A System for Rapid DNA Sequencing with Fluorescent
`Chain-Terminating Dideoxynucleotides, 238 SCIENCE 336 (1987), Exhibit
`1003 (“Prober I”).
`8 Derek Stemple et al., U.S. Patent No. 7,270,951 B1 (September 18, 2007),
`Exhibit 1008 (“Stemple III”).
`9 Takeshi Anazawa et al, WO 98/33939 (August 6, 1998), Exhibit 1010,
`citations are to an English translation, Exhibit 1011 (“Anazawa”).
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`nucleotide has [2] a deoxyribose comprising a cleavable
`chemical group capping the 3’ OH group, wherein [3] 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
`[4] 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.
`
`15. The nucleotide of claim 12, wherein the base is a
`deazapurine.
`
`
`PATENTABILITY CHALLENGES
`II. TSIEN
`Illumina contends in their Petition for Inter Partes Review that Tsien
`describes all the limitations of the nucleotide of claim 12 and the limitations
`of dependent claims 13, 17, 20-26, 28, 29, 31, and 33 (Petition 21-27).
`Claim 12 is directed to a nucleotide comprising the following features:
`(1) a base that is attached to a detectable label; (2) through a cleavable
`linker; and (3) a deoxyribose comprising a cleavable chemical group
`capping the 3’ OH group. The means for cleaving the linker and group are
`“selected from the group consisting of one or more of a physical means, a
`chemical means, a physical chemical means, heat, and light.”
`Tsien is a published PCT international patent application which
`discloses a sequencing by synthesis method in which 3’ OH blocked and
`fluorescent labeled nucleotides are sequentially added to a primer during
`sequencing of a template DNA strand (Tsien, p. 6, l. 34 to p. 7, l. 34; p. 10, l.
`1-15). Tsien teaches using nucleotides with 3’-OH capping groups and
`methods for removing the capping group (id. at p. 21, ll. 9-33; p. 23, l. 28 to
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`p. 25, l. 25) and thus describes “a cleavable chemical group capping the 3’
`OH group” as recited in claim 12.
`
`In order to detect the incorporated nucleotide, Tsien describes using a
`detectable label (id. at p. 26, ll. 1-26). In the Petition, Illumina cited explicit
`disclosure in Tsien of incorporating a detectable fluorescent label into a
`base:
`
`The C-8 position of the purine [base] structure presents an ideal
`position for attachment of a label. Sarfati et al. (1987) describes
`a derivatization of deoxyadenosine at C-8 of the purine to
`prepare, ultimately, an 8-substituted biotin aldylamino dATP.
`The Sarfati et al. (1987) approach can be used to prepare the
`appropriate fluorescent, rather than biotinylated, analogues. 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. 3-14 (emphasis added).)
`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.
`(Id. at p. 27, l. 33-p. 28, l. 4 (emphasis added).)
`The “methods described below” teach attaching the label through a
`cleavable linker:
`One method involves the use of a fluorescent tag attached to the
`base moiety. The tag may be chemically cleaved (either
`separately from or simultaneously with the deblocking step)
`and measured either in the reaction zone before deblocking or
`in the reaction [eluent] after cleavage.
`(Id. at p. 28, ll. 5-10 (emphasis added).)
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`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.
`(Id. at p. 28, ll. 19-23 (emphasis added).)
`
`There is no express statement in Tsien to use the cleavable linker to
`attach the fluorescent label to the base. However, in the Decision to Institute
`Inter Partes Review, we found that such configuration would have been
`envisaged clearly by one of ordinary skill in the art upon reading the Tsien
`disclosure (Dec. Pet. 10-11). We found that Tsien describes linkers as useful
`to attach a label to a nucleotide (Tsien, p. 28, ll. 19-23). The base of the
`nucleotide is also expressly taught as a position where labels can be attached
`(Tsien, p. 29, ll. 3-14; p. 27, l. 33-p. 28, l. 4). Consequently, we determined
`that the skilled worker would have been guided to use the cleavable linker to
`attach the fluorescent label to the base of the nucleotide (Dec. Pet. 10-11).
`In reaching this determination, we found that although there was no specific
`example of a base that is attached to a detectable label through a cleavable
`linker, specific examples are not necessary to establish anticipation when
`there is a small genus disclosed and each member can be at once envisaged,
`the factual scenario we found to be the case here (id. at 7-8). In re Petering,
`301 F.2d 676, 681 (CCPA 1962); Bristol-Myers Squibb Co. v. Ben Venue
`Labs., Inc., 246 F.3d 1368, 1380 (Fed. Cir. 2001).
`
`With respect to the claimed cleaving means, Tsien discloses use of
`“3’-O-acyl blocking groups and other blocking groups [which are]
`hydrolysable under basic conditions.” (Tsien, p. 22, l. 34 to p. 23, l. 2).
`Tsien further discloses removal of 3’-OH blocking groups using other
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`chemistries, light, and enzymes (id., p. 23, l. 27 to p. 25, l. 34), making any
`one of the three choices anticipatory.
`Columbia challenged Illumina’s contentions in their preliminary
`response, but we found their arguments to be unpersuasive and instituted the
`trial on Tsien as an anticipatory publication (Dec. Pet. 11). In the response
`under § 42.120, Columbia did not address further the anticipation rejection
`based on Tsien, but rather indicated that challenged claims had been
`cancelled in a motion to amend the claims (Paper 78, PO Resp. 13). The
`motion is a contingent motion and has not been granted. Illumina’s
`patentability challenge of claim 12 based on Tsien as an anticipatory
`publication is supported by a preponderance of the evidence as explained
`above. We find it fully persuasive for the reasons stated here and in the
`Decision to Institute Inter Partes Review.
`With respect to claims 13, 17, 20-26, 28, 29, 31, and 33, Illumina
`identified specific disclosure in Tsien where each limitation is found
`(Petition 22-26). We find Illumina’s assertions to be supported by a
`preponderance of the evidence.
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`III. STEMPLE
`We instituted inter partes review of claims 12, 13, 17, 20-23, 25, 26,
`28, 29, and 31 on the grounds that these claims would have been anticipated
`under 35 U.S.C. § 102(a) by Stemple III (Dec. Pet. 17-19; Dec. Reh’g 12-
`13).
`Stemple III is a U.S. patent that describes DNA sequencing by
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`synthesis. As indicated in Illumina’s patentability challenge of claim 12,
`Stemple III describes chain terminating nucleotides that include a blocking
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`group at the 3’-OH of the ribose (limitation (2) of claim 12) and a
`fluorescent label attached to the nucleotide base (limitation (1) of claim 12)
`(Petition 48). To illustrate this teaching, Illumina relied upon Figure 1B of
`Stemple III. Figure 1B, as annotated by Illumina with arrows and boxes, is
`reproduced below.
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`
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`Figure 1B shows the following elements of claim 12.
`A base (“Base”) attached to a detectable label (“Fluorochrome”)
`through a cleavable linker (“Photolabile linker”); and a deoxyribose
`(“Ribose”) comprising a cleavable chemical group capping the 3’-OH group
`(“Photolabile terminator”). The claimed “cleavable linker” and “cleavable
`chemical group” correspond to Stemple III’s Photolabile linker and
`Photolabile terminator, respectively, and are each described as being
`removable by illumination (Stemple III, col. 22, ll. 53-57) and, thus, are
`cleavable by light as recited in claim 12. Stemple III also discloses that
`“[t]he labeling group and the 3’ blocking group can be removed
`enzymatically, chemically, or photolytically” (Stemple III, col. 3, ll. 34-36;
`Petition 49) as in claim 12, making any one of three choices anticipatory.
`Thus, Illumina’s contention in the Petition that claim 12 is anticipated by
`Stemple III is supported by a preponderance of the evidence.
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`Columbia did not challenge Illumina’s contentions in their
`preliminary response (Paper 27). In their Patent Owner Response (Paper
`78), Columbia did not address the anticipation rejection of claim 12 based on
`Stemple III, but rather indicated that challenged claim had been cancelled by
`a motion to amend the claims (Paper 78, PO Resp., p. 13). The motion is a
`contingent motion and has not been granted. Illumina’s patentability
`challenge of claim 12 based on Stemple III is supported by a preponderance
`of the evidence as explained above. We find it persuasive for the reasons
`stated here and in the Decision to Institute Inter Partes Review.
`With respect to claims 13, 17, 20-26, 28, 29, 31, and 33, Illumina
`identified specific disclosure in Stemple III where each limitation is found
`(Petition 22-26). We find Illumina’s assertions to be supported by a
`preponderance of the evidence.
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`IV. STEMPLE AND ANAZAWA
`We instituted inter partes review of claims 15 and 16 on the grounds
`that these claims would have been obvious under 35 U.S.C. § 103 in view of
`Stemple III and Anazawa (Dec. Pet. 30; Dec. Reh’g 18).
`Claim 15 depends on claim 12, and recites that the base is a
`deazapurine, further limiting the claim. In the Petition, Illumina cited
`Anazawa, an international PCT application published in Japanese, for its
`teaching of a deazapurine base coupled to a detectable label.
`Figure 7 of Anazawa shows a nucleotide 7-deazaguanine (natural
`nitrogen at position 7 replaced with a carbon) labeled with the fluorescent
`marker Texas Red at the 7-position (Anazawa, Fig. 7 and p. 6, ll. 5-7).
`Anazawa teaches that the labeled nucleotide “can be incorporated by
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`polymerase-based complementary-chain elongation reactions, as has been
`confirmed by various experiments” (id. at p. 6, ll. 10-12), providing an
`expectation that it could be used successfully in sequencing by synthesis
`methods. The marker or label can be dissociated by photo-irradiation (id. at
`p. 5), and is, therefore, photolabile.
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`Stemple III provides a reason to have modified its nucleotides with
`Anazawa’s teachings10 (Petition 55). Stemple III teaches:
`In an alternative configuration a photolabile group is attached to
`the 3’-OH using succinimide or other chemistry and a
`fluorochrome-photolabile linker conjugate is attached directly
`to the base of the nucleotide as described by Anasawa [sic,
`Anazawa] et al., WO 98/33939. The 3’ attached photolabile
`group will serve as a reversible chain terminator . . . and the
`base-attached fluorochrome-photo labile linker will serve as a
`removable label. In this configuration with each cycle both
`photolabile groups will be removed by photolysis before further
`incorporation is allowed. Such a configuration may be preferred
`if it is found that steric hindrance of large fluorochrome groups
`attached to the 3’-OH of the nucleotide prevent the nucleotide
`from entering the polymerase.
`(Stemple III, col. 22, ll. 52-67).
`
`Based on the suggestion of Stemple III to use the photolabile linkers
`described in Anazawa, the skilled worker would have had reason to have
`turned to the Anazawa publication and to have replaced the natural nitrogen
`base of Stemple III’s nucleotide with a deazapurine as in Anazawa, where
`the latter base comprises a photolabile linker. Even absent this disclosure, it
`would have been obvious to one of ordinary skill in the art to have used
`Anazawa’s deazapurine labeled nucleotide for its known use in DNA
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`10 In addition to the deazaguanine, Anazawa teaches other base types and
`base labeled nucleotides (Anazawa, p. 6, ll. 7-9; 12-16 and 30-34).
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`sequencing (Anazawa, pp. 5-6). It would have been obvious to one of
`ordinary skill in the art to have used a material for its known and expected
`function. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007) (“. . . a
`court must ask whether the improvement is more than the predictable use of
`prior art elements according to their established functions.”)
`
`Relying on the Declaration of Dr. Trainor, Columbia argues that
`Stemple III describes nucleotides with detectable labels at the 3’-OH
`capping group and an alternate structure where the label is attached to the
`base (Ex. 2033, Trainor Decl. ¶ 89). Dr. Trainor testified that the starting
`point would have been the nucleotide analogue with the label on the 3’-OH
`group because this is the only synthesis which is exemplified (id. ¶¶ 90, 91,
`and 95). Dr. Trainor also testified about reasons why one of ordinary skill in
`the art would have preferred to use nucleotides with the label attached to the
`3’-OH (id. ¶¶ 92-93). Dr. Trainor states there are deficiencies in the
`descriptions of the labeling chemistries in Stemple III and Anazawa, making
`it even less likely that label on the base would have been a starting point (id.
`¶ 96, n.7).
`Dr. Trainor’s testimony is not persuasive. Figure 1B of Stemple III
`shows a nucleotide with a removable blocking group on the 3’-OH group,
`which has all the features of claim 15 except for the deazapurine base.
`Although there may be other preferred nucleotides, the presence of other
`examples, which differ in structure from Figure 1B, would not have led the
`skilled worker away from the nucleotide in Figure 1B because it is expressly
`described by Stemple III as a choice to use in Stemple’s sequencing method
`(Stemple III, col. 3, ll. 56-58). With respect to replacing the naturally
`occurring base in Stemple III with a deazapurine base comprising the
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`photolabile linker, there are two publications cited for base labeling
`chemistry – Anazawa in Stemple III at columns 21 and 22; and Prober I in
`Anazawa at page 5, line 40 – indicating that one of ordinary skill in the art
`would have known how to accomplish the desired result, even if certain
`deficiencies were present in one of the publications. Stemple III’s statement
`that Anazawa’s teaching about photolabile linkers could be applied to
`Stemple III’s nucleotides strongly suggests that it was within the purview of
`the ordinary skilled worker to have made such chemical modifications. Dr.
`Trainor’s testimony about how to design new chemical procedures to
`convert Stemple III’s 3’-OH labeled nucleotides into the nucleotide of claim
`15 (Ex. 2033, Trainor Decl. ¶ 107) is unavailing because Figure 1B of
`Stemple III would not have required such changes.
`
`Dr. Trainor also testified that if the starting point were the nucleotide
`of Figure 1B, then four differences from the claimed invention at issue
`would need to be addressed:11
`1. replace the photocleavable linker (described in both
`Stemple Figure 1B and in Anazawa) on the base with a
`linker cleavable by a means other than light;
`
`2. include at 3’-OH position of the nucleotide analogue a
`capping group that is cleavable by means other than light;
`3. change the purine base to a deazapurine base; and
`4. retain the property of being incorporated onto a primer
`extension strand.
`
`
`11 Differences (1) and (2) do not appear in either claim 1 or claim 15, but
`rather appear in claim 34 which was proposed in Columbia’s contingent
`Motion to Amend Claims in which claim 15 was narrowed by canceling
`light as a cleaning means from the recited Markush group (Paper 79). This
`motion has not been entered. However, since the other means involving
`physical and chemical are recited in the claim, we shall address Dr.
`Trainor’s arguments.
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`(Ex. 2033, Trainor Decl. ¶ 108).
`With regard to changes (1) and (2), Stemple III discloses that “[t]he
`labeling group and the 3’ blocking group can be removed enzymatically,
`chemically, or photolytically” (Stemple III, col. 3, ll. 34-36; Petition 49).
`Thus, reason exists to have used any of the three cleaving techniques to
`remove the label and capping group from the nucleotide analogue.
`Columbia contends that a person of ordinary skill
`would not know how to arrive at a nucleotide analogue which
`includes a cleavable chemical group capping the 3’-OH group,
`wherein the cleavable linker is cleaved by a means other than light or
`a base that is a deazapurine and is attached to a detectable label
`through a cleavable linker, where the cleavable linker is cleaved by
`means other than light, from the combined descriptions of Stemple III
`and Anazawa.
`(Ex. 2033, Trainor Decl. ¶ 136). Dr. Trainor cites Stemple III’s lack of any
`working example other than light as the cleaving agent (id. ¶ 137).
`
`This argument is not persuasive. Illumina met its burden in
`establishing that the claimed limitation was met by showing express
`disclosure in Stemple of cleaving the claimed linker by chemical means
`(Stemple III, col. 3, ll. 34-36; Petition 49). Columbia appears to be arguing
`that Stemple III’s disclosure is not enabling, but this argument is not
`supported by convincing evidence. As discussed above, Columbia argues
`that Stemple III only shows photocleavable groups (Ex. 2033, Trainor Decl.
`¶¶ 136-137), but Columbia did not provide evidence that utilizing chemical
`means requires anything more than conventional techniques within the
`purview of the ordinary skilled worker.
`Columbia also argues that there would not have been a reasonable
`expectation of success that the claimed nucleotide could be incorporated by
`
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`polymerase (Ex. 2033, Trainor Decl. ¶¶ 87, 90, 92, and 135). Dr. Trainor
`stated that were “no reports of successful incorporation by a polymerase of a
`nucleotide analogue that had been modified both by placing a removable
`capping group at the 3’-OH position of the sugar and by placing any label,
`let alone a label through a chemically linker, on the base.” (Id. ¶ 92). Dr.
`Trainor cited published reports that he testified establish unpredictability
`about the polymerase activity on nucleotide analogues with the claimed
`features (id. at ¶ 135).
`
`However, Stemple III gives an example of a modified nucleotide
`comprising a 3’-OH cap and base label (Fig. 1B) that can be used its
`sequencing, indicating a reasonable belief that such a nucleotide is a viable
`substrate for DNA polymerase. There is no other purpose for which it is
`disclosed. Moreover, Stemple stated:
`The 3’ attached photolabile group will serve as a reversible
`chain terminator . . . and the base-attached fluorochrome-photo-
`labile linker will serve as a removable label. In this
`configuration with each cycle both photolabile groups will be
`removed by photolysis before further incorporation is allowed.
`Such a configuration may be preferred if it is found that steric
`hindrance of large fluorochrome groups attached to the 3’-OH
`of the nucleotide prevent the nucleotide from entering the
`polymerase.
`(Stemple III, col. 22, ll. 57-67; underlining added).
`It is evident from the passage that Stemple III had considered the
`question of whether a nucleotide with a cap on the 3’ end and label on the
`base would serve as a polymerase substrate and had found it “preferred” in
`some cases over a modified nucleotide with the label on the 3’ end. Stemple
`III expressed no reservation that a nucleotide with the claimed features
`would work.
`
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`
`The claimed nucleotide also incorporates a deazapurine base into the
`nucleotide, another source of unpredictability alleged by Columbia.
`However, Anazawa teaches that nucleotides with a label attached to the base
`are effective polymerase substrates, including a nucleotide with a
`deazapurine base (Fig. 7):
`As seen in the substance diagrammed in Fig. 7, substances
`labeled at the position of the base of the nucleotide can be
`incorporated by polymerase-based complementary-chain
`elongation reactions, as has been confirmed by various
`experiments. It has been confirmed, for example, that dideoxy
`nucleotide ddNTPs, the positions of the bases whereof are
`labeled by various fluorophores, that is, that the terminators of
`the complementary chain synthesis, are incorporated by
`complementary chain synthesis (Nucleic Acids Respectively.
`20, 2471 – 2483 (1992)).
`(Anazawa, p 6, ll. 10-16).
`
`In sum, based on the evidence