Trials@uspto.gov
`572-272-7822
`
`
`
`
`
`
`Paper 140
` 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 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
`
`
`
`
`572-272-7822
`
`
`
`
`
`
`Paper 140
` 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 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
`
`
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`
`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
`
`
`
`2
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`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
`
`
`
`3
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`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
`
`
`
`4
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`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”).
`
`
`
`
`5
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`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.
`
`
`4 IPR2012-00006.
`5 IPR2013-00011.
`
`
`
`6
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`
`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”).
`
`
`
`7
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`
`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
`
`
`
`8
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`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).)
`
`
`
`9
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`
`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
`
`
`
`10
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`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.
`
`
`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
`
`synthesis. As indicated in Illumina’s patentability challenge of claim 12,
`Stemple III describes chain terminating nucleotides that include a blocking
`
`
`
`11
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`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.
`
`
`
`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.
`
`
`
`12
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`
`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.
`
`
`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
`
`
`
`13
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`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.
`
`
`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
`
`
`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).
`
`
`
`14
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`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
`
`
`
`15
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`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.
`
`
`
`16
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`(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
`
`
`
`17
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`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.
`
`
`
`18
`
`
`
`Case IPR2012-00007
`Patent 7,790,869
`
`
`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 before us, we are persuaded that
`Illumina establi
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
