IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`C.A. No. 19-1681-CFC-SRF
`
`)))))))))))
`
`
`
`
`
`THE TRUSTEES OF COLUMBIA
`UNIVERSITY IN THE CITY OF NEW
`YORK and QIAGEN SCIENCES LLC,
`
`v.
`
`ILLUMINA, INC.,
`
`Plaintiffs,
`
`Defendant.
`
`
`
`DEFENDANT ILLUMINA, INC.’S INITIAL INVALIDITY CONTENTIONS
`
`Pursuant to the Court’s Scheduling Order (D.I. No. 17) Defendant Illumina, Inc.
`
`(“Illumina”) hereby provides the following Initial Invalidity Contentions for U.S. Patent Nos.
`
`10,407,458 (the “’458 Patent”); 10,407,459 (the “’459 Patent”); 10,428,380 (the “’380 Patent”);
`
`10,435,742 (the “’742 Patent”); and 10,457,984 (the “’984 Patent”) (collectively, the “Patents In-
`
`Suit”), as well as the related invalidating references (e.g., manuals, patents, and publications).
`
`I.
`
`RESERVATION OF RIGHTS
`
`Illumina provides its Contentions subject to the following objections and reservation of
`
`rights:
`
`1.
`
`Discovery in this matter is at a very early stage. Illumina’s investigation regarding
`
`the potential grounds of invalidity is ongoing. The Trustees of Columbia University in the City of
`
`New York (“Columbia”) and Qiagen Sciences, LLC (collectively, “Plaintiffs”) have not yet
`
`produced documents and things relating to the Patents In-Suit. Illumina’s invalidity contentions
`Columbia Ex. 2004
`are given without prejudice to Illumina’s right to supplement or amend as additional facts are
`Illumina, Inc. v. The Trustees
`of Columbia University
`in the City of New York
`IPR2020-01177
`
`
`
`Columbia Ex. 2004
`Illumina, Inc. v. The Trustees
`of Columbia University
`are
`
`
`
`
`ons ascertained, analyses are made, research is completed, contentiin the Cityare ofmade, New and Yorkclaims
`IPR2020-01177
`
`

`

`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`C.A. No. 19-1681-CFC-SRF
`
`)))))))))))
`
`
`
`
`
`THE TRUSTEES OF COLUMBIA
`UNIVERSITY IN THE CITY OF NEW
`YORK and QIAGEN SCIENCES LLC,
`
`v.
`
`ILLUMINA, INC.,
`
`Plaintiffs,
`
`Defendant.
`
`
`
`DEFENDANT ILLUMINA, INC.’S INITIAL INVALIDITY CONTENTIONS
`
`Pursuant to the Court’s Scheduling Order (D.I. No. 17) Defendant Illumina, Inc.
`
`(“Illumina”) hereby provides the following Initial Invalidity Contentions for U.S. Patent Nos.
`
`10,407,458 (the “’458 Patent”); 10,407,459 (the “’459 Patent”); 10,428,380 (the “’380 Patent”);
`
`10,435,742 (the “’742 Patent”); and 10,457,984 (the “’984 Patent”) (collectively, the “Patents In-
`
`Suit”), as well as the related invalidating references (e.g., manuals, patents, and publications).
`
`I.
`
`RESERVATION OF RIGHTS
`
`Illumina provides its Contentions subject to the following objections and reservation of
`
`rights:
`
`1.
`
`Discovery in this matter is at a very early stage. Illumina’s investigation regarding
`
`the potential grounds of invalidity is ongoing. The Trustees of Columbia University in the City of
`
`New York (“Columbia”) and Qiagen Sciences, LLC (collectively, “Plaintiffs”) have not yet
`
`produced documents and things relating to the Patents In-Suit. Illumina’s invalidity contentions
`
`are given without prejudice to Illumina’s right to supplement or amend as additional facts are
`
`ascertained, analyses are made, research is completed, contentions are made, and claims are
`
`
`
`
`
`

`

`construed. Illumina further reserves the right to modify, supplement, amend, or otherwise alter
`
`these disclosures as discovery progresses, as permitted by the Federal Rules of Civil Procedure,
`
`by the Default Standard, or by order of the Court. In particular, Illumina reserves the right to
`
`modify, supplement, amend, or otherwise alter these disclosures following an opportunity for
`
`expert discovery. These disclosures do not encompass patent unenforceability, which Illumina
`
`may allege separately.
`
`2.
`
`In the absence of a claim construction order from the Court, Illumina has relied
`
`upon ordinary meaning of claim terms, definitions in the patents, and Plaintiffs’ apparent claim
`
`construction positions from Plaintiffs’ infringement contentions served on January 17, 2020, to the
`
`extent any such constructions can be discerned. Illumina’s reliance on Plaintiffs’ claim
`
`constructions should not be taken to mean that Illumina in any way agrees with Plaintiffs’ apparent
`
`claim constructions or that Illumina is precluded from propounding alternative claim constructions
`
`or requesting Plaintiffs’ actual claim construction positions in the future. Illumina expressly
`
`reserves the right to propose alternative constructions to those advocated by Plaintiffs.
`
`Furthermore, prior art not included in this disclosure, whether or not known to Illumina, may
`
`become relevant depending upon the claim constructions that Plaintiffs may assert or that the Court
`
`may adopt. Illumina’s investigation is continuing and is likely to uncover additional art. Illumina
`
`will supplement its disclosures at appropriate times in light of newly discovered art or changes in
`
`claim constructions.
`
`3.
`
`The disclosure of a reference as anticipating of a claim includes a disclosure of the
`
`reference for obviousness purposes should any element of the claim be determined by the Court to
`
`be absent from the reference. Moreover, Illumina is at the present time unaware of the extent, if
`
`any, to which Plaintiffs will contend that elements of the claims are not disclosed in references
`
`
`
`
`2
`
`

`

`identified by Illumina as anticipatory. To the extent that Plaintiffs make any such claim with
`
`respect to any limitation, Illumina reserves the right to identify other references which may explain
`
`the inherency of, or make obvious the addition of, the allegedly missing element.
`
`4.
`
`References disclosed as rendering a claim obvious are representative and are not
`
`intended to be exhaustive. Other references disclosing the same or similar elements may be
`
`substituted for the cited references. Additional obviousness combinations of the references
`
`identified below are possible, and Illumina reserves the right to use any such combination(s) in
`
`this litigation. Motivation to combine references can be inferred generally for all references within
`
`the fields of art of the Patents In-Suit. Furthermore, where references refer to or cite one another,
`
`motivation to combine may be specifically inferred whether or not called out in a claim chart.
`
`Lastly, Illumina’s identification of motivation to combine references should not be taken as an
`
`admission or a representation that Illumina will not rely upon other tests for obviousness in view
`
`of KSR Int’l. Co. v. Teleflex Inc., 550 U.S. 398 (2007). This would include showing any of the
`
`following: (1) that the combination of elements was obvious to try; (2) that the combination of
`
`elements according to known methods yielded predictable results; (3) that the substitution of one
`
`known element for another obtained predictable results; (4) that the application of a known
`
`technique to a known device, method, or product ready for improvement yielded predictable
`
`results; or (5) that known work in one field of endeavor prompted variations of such work for use
`
`in either the same field or a different one based on design incentives or other market forces because
`
`the variations are predictable to one of ordinary skill in the art.
`
`5.
`
`The identification of prior art that anticipates and/or renders obvious a particular
`
`claim element in these contentions is not an admission that the claim element satisfies the
`
`requirements of 35 U.S.C. § 112. Where Illumina asserts that a claim is invalid under 35 U.S.C.
`
`
`
`
`3
`
`

`

`§ 112 (such as because of a failure to particularly point out and distinctly claim the alleged
`
`invention, failure to provide written description support, and/or failure to enable one of ordinary
`
`skill in the art to make and use the claimed invention), Illumina has nonetheless provided prior art
`
`that anticipates or renders obvious the claim on the assumption that Plaintiffs will contend that
`
`those claims are definite, supported by an adequate written description, and adequately enabled.
`
`6.
`
`In addition to the prior art identified in these contentions, and any future supplement
`
`to these contentions, Illumina may rely on relevant portions of the Patents In-Suit, the prosecution
`
`histories of the Patents In-Suit, all references listed in the References Cited portion of the Patents
`
`In-Suit, all references cited, documents filed, or arguments made in IPR Nos. 2012-00006, 2012-
`
`00007, 2013-00011, 2018-00291, 2018-00318, 2018-00322, 2018-00385, and 2018-00797, all
`
`references cited or arguments made in Illumina’s Initial Invalidity Contentions from Columbia v.
`
`Illumina, C.A. No. 17-973-GMS served on Plaintiffs on July 13, 2018, and fact and expert
`
`testimony about the prior art.
`
`7.
`
`Illumina objects to the disclosure of information that is protected by the attorney-
`
`client privilege, attorney work-product immunity, the common-interest privilege, or any other
`
`applicable privilege or immunity.
`
`8.
`
`Illumina reserves the right to amend and/or supplement these contentions as fact
`
`and expert discovery and claim construction proceed.
`
`II.
`
`PRIOR ART
`A.
`
`Identification of Prior Art References
`
`Subject to the reservation of rights above, Illumina identifies at least the prior art references
`
`set forth in Appendix A, which alone or in combination, render the asserted claims of the Patents
`
`In-Suit invalid under 35 U.S.C. § 103. This prior art identified is also relevant for their showing
`
`of the state of the art and reasons and motivations for making improvements, additions, and
`
`
`
`
`4
`
`

`

`combinations. Illumina reserves the right to identify additional prior art references as discovery
`
`progresses.
`
`B.
`
`Background of the Prior Art
`
`As shown below, the alleged inventions of the asserted claims of the Patents In-Suit were
`
`well-known in the art prior to the date of their alleged invention. Those skilled in the art were
`
`aware of all of the limitations of the asserted claims of the Patents In-Suit. Thus, many prior art
`
`patents, prior art publications, and combinations thereof, disclose, teach, or embody every
`
`limitation of the asserted claims, and thus invalidate those claims. Examples of these disclosures,
`
`teachings, and embodiments are identified in Appendix A and in the attached Invalidity Claim
`
`Charts set forth in Appendix B.
`
`III.
`
`INVALIDITY BASED ON ANTICIPATION
`
`Illumina contends that the prior art listed in Appendix A render the asserted claims of the
`
`Patents In-Suit anticipated under 35 U.S.C. § 102, as set forth in the claim charts set forth in
`
`Appendix B. The citations to the prior art corresponding to the claim limitations in Appendix B
`
`are merely exemplary and are not intended to be exhaustive. For the claim charts in Appendix B,
`
`Illumina identifies disclosures in the prior art concerning the preamble without regard to whether
`
`the preamble is a claim limitation. Terms in the preamble may not be claim limitations.
`
`The following prior art anticipates each of the ’458 Patent, ’459 Patent, ’742 Patent, or
`
`’984 Patent:
`
`
`
`
`
`
`
`
`
`Certain asserted claims are anticipated by Tsien alone.
`
`Certain asserted claims are anticipated by Dower alone.
`
`Certain asserted claims are anticipated by Stemple I alone.
`
`Certain asserted claims are anticipated by Stemple II alone.
`
`
`
`
`5
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Certain asserted claims are anticipated by Stemple III alone.
`
`Certain asserted claims are anticipated by Cheeseman alone.
`
`Certain asserted claims are anticipated by Prober II alone.
`
`Certain asserted claims are anticipated by Rabani alone.
`
`Certain asserted claims are anticipated by Rosenthal alone.
`
`Certain asserted claims are anticipated by Hobbs II alone.
`
`Certain asserted claims are anticipated by Illumina’s commercial products, which
`
`were on sale before the priority date and/or filing date of the patents, to the extent
`
`Plaintiffs contend any of Illumina’s commercial products embody these patents.
`
`IV.
`
`INVALIDITY BASED ON OBVIOUSNESS
`
`Illumina contends that the prior art listed in Appendix A, whether alone or in combination
`
`with each other, render the asserted claims of the Patents In-Suit obvious under 35 U.S.C. § 103,
`
`as set forth in the claim charts set forth in Appendix B. In particular, each prior art reference may
`
`be combined with: (1) information known to persons skilled in the art at the time of the alleged
`
`invention; (2) any other prior art references; (3) any additional prior art Illumina may identify; and
`
`(4) any additional prior art identified or to be identified in prosecution of the Patents In-Suit or
`
`their related patent applications. The citations to the prior art corresponding to the claim
`
`limitations in Appendix B are merely exemplary and are not intended to be exhaustive. For the
`
`claim charts in Appendix B, Illumina identifies disclosures in the prior art concerning the preamble
`
`without regard to whether the preamble is a claim limitation. Terms in the preamble may not be
`
`claim limitations.
`
`
`
`
`6
`
`

`

`A.
`
`’458 Patent, ’459 Patent, ’380 Patent, ’742 Patent, and ’984 Patent
`1.
`
`Prior Inter Partes Reviews
`
`In IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385, and IPR2018-
`
`00797 the Board determined that Tsien (for the cytosine and thymine claims) or Tsien in view of
`
`Prober I (for the adeine and guanine claims), and, additionally, the combination of Dower, Prober
`
`I, and Metzker, rendered obvious Columbia’s patents that are not patentably distinct to the Patents
`
`In-Suit, with the only additional limitation that the blocking group “is not a –CH2CH=CH2 group”
`
`or “is not … an allyl ether group.” [’458 Patent] [’459 Patent] [’742 Patent] [’984 Patent] at claims
`
`1-2. In those previous IPRs, the Board found that a 3’-O-allyl blocking group was taught by the
`
`prior art and held unpatentable a claimed genus of “small, chemically cleavable, chemical
`
`group[s].” See IPR2018-00291, Paper 67 at 35, 50. Illumina incorporates in full the Final Written
`
`Decision and all invalidity arguments made by Petitioner in IPR2018-00291, IPR2018-00318,
`
`IPR2018-00322, IPR2018-00385, and IPR2018-00797.
`
`The same prior art combinations used before the Board renders the Patents In-Suit invalid.
`
`Tsien/Dower, Prober I, and optionally Metzker, while rendering an allyl group obvious, do not
`
`require the claimed “R” group to contain a ketone or be an allyl, methoxy, or ester group for
`
`practicing Tsien/Dower’s SBS method. Moreover, Dower specifically discloses the desirability
`
`of nucleotides having “small blocking groups” on the 3′-OH. Dower at 25:48-51. Tsien also
`
`“caution[s]” against including “large and bulky” groups in the 3’-blocking group to avoid affecting
`
`incorporation by the polymerase and suggests and desire to “reduce size and minimize steric
`
`interference.” Tsien at 26:13-27:1. Excluding the allyl group in the present claims does not alter
`
`the prior art’s teaching, as appreciated by the Board, of the same genus of “small” blocking groups
`
`as presently claimed or somehow require a person of ordinary skill in the art to now use an
`
`excluded group. Accordingly, the Patents In-Suit’s limitation that the blocking group “is not a –
`
`
`
`
`7
`
`

`

`CH2CH=CH2 group” or “is not … an allyl ether group” still does not avoid a conclusion that the
`
`same prior art renders the present claims obvious.
`
`Further, as explained below in §V.A, Columbia relied upon the specification’s disclosure
`
`of the allyl ether species to overcome the Examiner’s written description rejection of claims that
`
`ostensibly exclude this species. See May 9, 2019 Supplemental Response to First Action Interview
`
`Communication at 8-9. Because Columbia relied upon the allyl ether species in order to establish
`
`written description support of the present claims, the Patents In-Suit are rendered obvious by the
`
`allyl species. In Regents of the Univ. of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir.
`
`1997), the Federal Circuit explained: “Recently, we held that a description which renders obvious
`
`a claimed invention is not sufficient to satisfy the written description requirement of that
`
`invention. . . . Thus, a fortiori, a description that does not render a claimed invention obvious does
`
`not sufficiently describe that invention for purposes of § 112, ¶ 1.” Id. at 1567. Accordingly, the
`
`import of the Federal Circuit’s statements regarding the interplay of the written description
`
`requirement and the law of obviousness is that a description that meets the requirements of § 112,
`
`first paragraph, in support of a claimed invention also renders the claimed invention obvious. By
`
`relying upon the specification’s discussion of the obvious allyl ether species to argue that written
`
`description support exists for the ’458 Patent’s claimed genus and secure issuance of its patent, the
`
`present genus depends upon the allyl ether species for compliance with § 112—regardless of the
`
`exclusion of the allyl either species. See, e.g., Erfindergemeinschaft UroPep GbR v. Eli Lilly and
`
`Company, 276 F.Supp.3d 629, 646–647 (2017) (Bryson, J.) (“Patentees may choose to exclude
`
`from the claims some embodiments supported by the disclosure. In fact, a patentee may choose
`
`to exclude some embodiments in order to avoid double patenting problems, as happened in this
`
`case. But the compounds’ exclusion from the claims does not mean that those individual
`
`
`
`
`8
`
`

`

`compounds are no longer representative of other, non-excluded compounds covered by claim 1.”)
`
`(internal citations omitted). Columbia cannot both rely on the disclosure of the allyl ether species
`
`to provide the claims of the Patents In-Suit with written description support, and simultaneously
`
`argue that the allyl species does not render the claims invalid as obvious. Therefore, either the
`
`claims of the Patents In-Suit are invalid under §103, or they lack written description support under
`
`§112, as explained below in §V.A.
`
`2.
`
`Prior Art Combinations
`
`The following combinations render the ’458 Patent, ’459 Patent, ’380 Patent, ’742 Patent,
`
`and ’984 Patent obvious. These combinations are merely exemplary and are not intended to be
`
`exhaustive:
`
`
`
`
`
`
`
`
`
`Certain asserted claims are rendered obvious by Tsien alone.
`
`Certain asserted claims are rendered obvious by Tsien in combination with (Hiatt,
`
`Kruse, Dower, Greene and Wuts, Stemple I, Stemple II, Stemple III, Cheeseman,
`
`Prober II, Rabani, Rosenthal, Hobbs II, Prober I, Metzker, Garland, Kumar,
`
`Densham, Ansorge, Lynx Therapeutics, Inc.’s Massive Parallel Signature
`
`Sequencing service, alone or in combination).
`
`Certain asserted claims are rendered obvious by Dower alone.
`
`Certain asserted claims are rendered obvious by Dower in combination with (Hiatt,
`
`Kruse, Greene and Wuts, Stemple I, Stemple II, Stemple III, Cheeseman, Prober II,
`
`Rabani, Rosenthal, Hobbs II, Prober I, Metzker, Garland, Kumar, Densham,
`
`Ansorge, Lynx Therapeutics, Inc.’s Massive Parallel Signature Sequencing service,
`
`alone or in combination).
`
`
`
`Certain asserted claims are rendered obvious by Stemple I alone.
`
`
`
`
`9
`
`

`

`
`
`Certain asserted claims are rendered obvious by Stemple I in combination with
`
`(Cheeseman, Prober II, Rabani, Rosenthal, Hobbs II, Prober I, Metzker, Garland,
`
`Kumar, Densham, Ansorge, Lynx Therapeutics, Inc.’s Massive Parallel Signature
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sequencing service, alone or in combination).
`
`Certain asserted claims are rendered obvious by Stemple II alone.
`
`Certain asserted claims are rendered obvious by Stemple II in combination with
`
`(Cheeseman, Prober II, Rabani, Rosenthal, Hobbs II, Prober I, Metzker, Garland,
`
`Kumar, Densham, Ansorge, Lynx Therapeutics, Inc.’s Massive Parallel Signature
`
`Sequencing service, alone or in combination).
`
`Certain asserted claims are rendered obvious by Stemple III alone.
`
`Certain asserted claims are rendered obvious by Stemple III in combination with
`
`(Cheeseman, Prober II, Rabani, Rosenthal, Hobbs II, Prober I, Metzker, Garland,
`
`Kumar, Densham, Ansorge, Lynx Therapeutics, Inc.’s Massive Parallel Signature
`
`Sequencing service, alone or in combination).
`
`Certain asserted claims are rendered obvious by Cheeseman alone.
`
`Certain asserted claims are rendered obvious by Cheesman in combination with
`
`(Prober II, Rabani, Rosenthal, Hobbs II, Prober I, Metzker, Garland, Kumar,
`
`Densham, Ansorge, Lynx Therapeutics, Inc.’s Massive Parallel Signature
`
`Sequencing service, alone or in combination).
`
`Certain asserted claims are rendered obvious by Prober II alone.
`
`Certain asserted claims are rendered obvious by Prober II in combination with
`
`(Rabani, Rosenthal, Hobbs II, Prober I, Metzker, Garland, Kumar, Densham,
`
`
`
`
`10
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`Ansorge, Lynx Therapeutics, Inc.’s Massive Parallel Signature Sequencing service,
`
`alone or in combination).
`
`Certain asserted claims are rendered obvious by Rabani alone.
`
`Certain asserted claims are rendered obvious by Rabani in combination with
`
`(Rosenthal, Hobbs II, Prober I, Metzker, Garland, Kumar, Densham, Ansorge,
`
`Lynx Therapeutics, Inc.’s Massive Parallel Signature Sequencing service, alone or
`
`in combination).
`
`Certain asserted claims are rendered obvious by Rosenthal alone.
`
`Certain asserted claims are rendered obvious by Rosenthal in combination with
`
`(Hobbs II, Prober I, Metzker, Garland, Kumar, Densham, Ansorge, Lynx
`
`Therapeutics, Inc.’s Massive Parallel Signature Sequencing service, alone or in
`
`combination).
`
`Certain asserted claims are rendered obvious by Hobbs II alone.
`
`Certain asserted claims are rendered obvious by Hobbs II in combination with
`
`(Prober I, Metzker, Garland, Kumar, Densham, Ansorge, Lynx Therapeutics, Inc.’s
`
`Massive Parallel Signature Sequencing service, alone or in combination).
`
`A person of ordinary skill in the art would have been motivated to combine the references
`
`listed in Appendix A, because these references share common subject matter and approaches,
`
`discuss related products and technologies, and/or were developed during the same time period.
`
`Most of the references concern methods for producing fluorescently-labeled nucleotides or
`
`nucleotide analogues in enzymatic synthesis of DNA, such as in polymerase-mediated DNA
`
`sequencing reactions.
`
`
`
`
`11
`
`

`

`3.
`
`Motivation To Combine
`a)
`
`’742 Patent and ’984 Patent
`
`Tsien, Hiatt, Dower, Stemple I, Stemple II, Stemple III, Cheeseman, Prober II, Rabani,
`
`Rosenthal, and Hobbs II either disclose or suggest all of the features of Claims 1 and 2. Other
`
`prior art, namely Prober I, Metzker, Kwiatkowski, Hovinen, Greene and Wuts, Garland, Kumar,
`
`Densham, Ansorge, and Lynx Therapeutics, Inc.’s Massive Parallel Signature Sequencing service
`
`disclose various limitations recited in Claims 1 and 2.
`
`For instance, a POSA would have been motivated to select a 3’-O-methoxymethyl (MOM)
`
`ether as a blocking group. Hiatt provides five particularly desirable reversible 3’ protecting groups
`
`that are compatible with DNA and are readily removable under DNA-compatible conditions. Hiatt
`
`also provides a working example of the synthesis of a nucleotide whose 3’-OH is blocked with a
`
`MOM group, one of only three 3’-O-ether blocked nucleotides disclosed. Id. at 30:22-40. Greene
`
`and Wuts further discloses the MOM blocking groups, and demonstrates that mild conditions are
`
`available for its preparation and cleavage. Greene and Wuts at 27-33. A POSA looking to select
`
`a reversible 3’ protecting groups that is incorporated by a DNA polymerase would also look to the
`
`teachings of Dower, Pelletier, and Welch. Dower disclosed the desirability of nucleotides having
`
`“small blocking groups” on the 3′-OH. Dower at 25:48–51. Dower was filed in 1990 and provides
`
`blocking groups that were considered small at that time: “acetyl, tBOC, NBOC, and NVOC.” Id.
`
`at 25:48-51. The desirability of “small blocking groups” was further refined in the decade after
`
`Dower’s publication. In 1994, Pelletier published the crystal structure of a DNA polymerase. See
`
`Pelletier at 1897, 1903. This crystal structure would have informed a POSA in 2000 as to available
`
`space surrounding the 3’-carbon atom in a polymerase active site. See Pelletier at 1897 (Table 3)
`
`(indicating an “[i]nteratomic distance[] of interest” between the 3′-carbon (Atom “C3′”) and a
`
`protein atom (Atom “O” of “residue Phe272”) of 3.2 Å). Other publications touted the use of
`
`
`
`
`12
`
`

`

`coordinates for the active site of a T7 polymerase crystal structure, concluded that certain 3’
`
`blocking groups were too large to fit into the enzyme active site, and recommended modifying
`
`nucleotides based on this insight. See Welch 1999, Abstract, see also 955–56; Stemple at 22:64–
`
`67 (explaining that the space available at the 3’ hydroxyl may limit the groups that could be
`
`attached).
`
`Based on this understanding in 2000 concerning the requirements of a DNA polymerase
`
`for incorporation of a modified dNTP, a POSA would have been motivated to select Hiatt’s MOM
`
`from the list of five particularly desirable reversible 3’ protecting groups since MOM is the
`
`smallest reversible 3’ protecting group that Hiatt teaches is compatible with DNA and readily
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`removable under DNA-compatible conditions. Following the prior art’s teachings on this issue,
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`Columbia admitted during prosecution that “[t]he POSA in October 2000 would have readily
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`known whether any given R when present as OR (a 3′-O capping group) was small” by using the
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`coordinates published by Pelletier and available software such as Chem3D Pro. May 27, 2016
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`Response in Appl. No. 15/167,917 at 3.
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`As a further example, a POSA would have been motivated to select a 3’-O-
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`methylthiomethyl (“MTM”) as a blocking group. Tsien describes a thio-containing ether that is
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`advantageous because it is cleaved with silver ions and Tsien directs the skilled artisan to the Kruse
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`1978 publication as follows: “A wide variety of hydroxyl blocking groups are cleaved selectively
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`using chemical procedures other than base hydrolysis. 2,4-Dinitrobenzenesulfenyl groups are
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`cleaved rapidly by treatment with nucleophiles such as thiophenol and thiosulfate (Letsinger et al.,
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`1964). Allyl ethers are cleaved by treatment with Hg(II) in acetone/water (Gigg and Warren, 1968).
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`Tetrahydrothiofuranyl ethers are removed under neutral conditions using Ag(I) or Hg(II) (Cohen
`
`and Steele, 1966; Cruse [sic Kruse] et al., 1978). These protecting groups, which are stable to
`
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`conditions used in the synthesis of dNTP analogues and in the sequence incorporation steps, have
`
`some advantages over groups cleavable by base hydrolysis – deblocking occurs only when the
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`specific deblocking reagent is present and premature deblocking during incorporation is
`
`minimized.” Tsien at 24:24-25:3. Tsien’s tetrahydrothiofuranyl ether contains a smaller
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`methylthiomethyl (“MTM”) moiety.
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`Kruse further describes the desirability of the MTM blocking group. Kruse is directed to
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`the “Use of (Thio)Acetal Esters as Reagents for the Protection of Alcohols.” Kruse at Title. “The
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`protection of hydroxyl groups, often as mixed acetals, is an extensively used technique in the
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`synthesis of polyfunctional compounds. Recently, several new protecting groups have been
`
`introduced, which can be removed with a highly specific reagent. The methylthiomethyl (MTM)
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`group has been recommended in this respect because of its stability toward both basic and mildly
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`acidic conditions and its easy cleavage under neutral conditions with certain metal ions.” Kruse
`
`at 3548. Additionally, Greene and Wuts describes the preparation and cleavage of MTM under
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`mild conditions. Greene and Wuts at 33-35.
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`Additionally, Tsien discloses that a thio-containing ether is an advantageous capping group
`
`because “deblocking occurs only when the specific deblocking reagent is present and premature
`
`deblocking during incorporation is minimized.” Ex. 1 at 24:29-25:3. Tsien’s disclosure of the
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`desirability of a thio-containing ether blocking group would have motivated a POSA to select and
`
`use the 3’-O-MTM capping group on the nucleotide analogues disclosed by Tsien.
`
`Tsien discloses a [thymine] [cytosine] analogue [(Structure A)] [(Structure B)] having a
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`fluorescent label attached through a linker to the 5-position of the base. Ex. 1 at 30. Tsien discloses
`
`the advantages of labeling [thymine] [cytosine] at the 5-position because it provides “great
`
`flexibility in that the linker can be varied with respect to length or functionality.” Id. at 29:16-19.
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`14
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`It was well-known that attaching substituents to [thymine] [cytosine] nucleotide analogues was
`
`advantageous because substitution at the 5-position “places the linker and reporter in the major
`
`groove” (Ex. 6 at 27:58-59), “minimize[s] interference with hybridization and other processes”
`
`(id. at 27:60-51), and stabilizes the DNA duplex. Ex. 7 at 3051. Tsien cites to Prober I for
`
`“show[ing] enzymatic incorporation” of fluorescently labeled nucleotide analogues (Ex. 1 at
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`28:16-18), including [thymine] [cytosine] analogues having a label attached via a linker of the 5-
`
`position of the base. Id. at 29:12-16 (discussing Structures A & B and citing Prober I). Tsien is
`
`correct that Prober I shows polymerase incorporation of 5-substituted and labeled [thymine]
`
`[cytosine] analogues. Ex. 2 at 337, 340. Thus, there was motivation within Tsien itself and in the
`
`art to label [thymine] [cytosine] with a linker at the 5-position.
`
`Combining the favorable disclosures within Tsien “does not require a leap of
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`inventiveness.” Boston Sci. Scimed, Inc. v. Cordis Corp., 554 F.3d 982, 991 (Fed. Cir. 2009).
`
`Thus, a POSA would have been motivated to combine Tsien’s disclosures to arrive at a [thymine]
`
`[cytosine] nucleotide analogue having a 3’-O-allyl group and a tag attached through a cleavable
`
`linker at the 5-position of the base. Additionally, a POSA would have been motivated to combine
`
`Tsien’s disclosures with Hiatt’s to arrive at a [thymine] [cytosine] nucleotide analogue having a
`
`3’-O-methoxymethyl (MOM) ether group and a tag attached through a cleavable linker at the 5-
`
`position of the base. Furthermore, a POSA would have been motivated to combine Tsien’s
`
`disclosures with Kruse’s to arrive at a [thymine] [cytosine] nucleotide analogue having a 3’-O-
`
`methylthiomethyl group and a tag attached through a cleavable linker at the 5-position of the base.
`
`One of ordinary skill in the art would have been similarly motivated to combine the other
`
`prior art references listed in Appendix A. For instance, the combination of Dower, Prober I, and
`
`Metzker would have had such motivation. Dower discloses most of the features of Claims 1 and
`
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`15
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`2, with the exception of a 5-substituted [cytosine] [thymine]. Prober I discloses 5-substituted
`
`cytosine, and Metzker discloses a 3’-O-allyl ether capping group, as well as other capping groups
`
`that are not a methoxy or an ester/ketone/allyl. A POSA would have recognized the benefits of
`
`combining Dower, Prober I and Metzker.
`
`Dower discloses a nucleotide analogue having a cleavably linked fluorescent label and a
`
`small 3’-OH capping group. Dower expressly cites to the fluorescently labeled nucleotides
`
`described in Prober I, providing direction to turn to Prober I. Ex. 3 at 25:4-12, 25:44-47, 20:39-42,
`
`23:16-26, 28:6-17, 17:35-36. Prober I’s disclosure is beneficial in Dower’s methods for several
`
`reasons. Prober I discloses the 5-position of pyrimidines were reported “to be acceptable for
`
`attaching substituents to chain-propagating substrates (that is, deoxynucleotide triphosphates) for
`
`DNA polymerases.” Ex. 2 at 340. Prober I discloses DNA polymerase maintains the fidelity of
`
`5-substituted [cytosine] [thymine] analogues during polymerase incorporation. Id. at 337, 340. It
`
`was known that linking labels to the 5-position of [cytosine] [thymine] was advantageous because
`
`this “places the linker and reporter in the major groove” (Ex. 6 at 27:58-59), “minimize[s]
`
`interference with hybridization and other processes” (id. at 27:60-61), and stabilizes the DNA
`
`duplex. Ex. 7 at 3051. The ’742 Patent and ’984 Patent each admit polymerases were known “to
`
`recognize nucleotides with extensive modifications with bulky groups such as energy transfer dyes
`
`at the 5-position of the pyrimidines (T and C)”. Ex. 2 a