Trials@uspto.gov
`Tel: 571-272-7822
`
`Paper 16
`Entered: August 8, 2016
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`
`
`ILLUMINA, INC.,
`Petitioner,
`
`v.
`
`CORNELL RESEARCH FOUNDATION, INC.,
`Patent Owner.
`
`Case IPR2016-00553
`Patent 8,288,521 B2
`
`
`Before TONI R. SCHEINER, JACQUELINE WRIGHT BONILLA, and
`SUSAN L. C. MITCHELL, Administrative Patent Judges.
`
`MITCHELL, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`

`
`IPR2016-00553
`Patent 8,288,521 B2
`
`A. Background
`
`I. INTRODUCTION
`
`Petitioner Illumina Inc. (“Petitioner”) filed a Petition (Paper 1, “Pet.”)
`
`requesting an inter partes review of claims 1–32 (the “challenged claims”)
`
`of U.S. Patent No. 8,288,521 B2 (Exhibit 1001, “the ’521 patent”). See 35
`
`U.S.C. §§ 311–319. Patent Owner Cornell Research Foundation, Inc.
`
`(“Patent Owner”) filed a Preliminary Response, which relies on testimonial
`
`evidence. Paper 7 (“Prelim. Resp.”). Petitioner was granted the right to file
`
`a Reply to the Preliminary Response (Paper 12), and did so. Paper 13
`
`(“Reply”).
`
`
`
`We have jurisdiction under 35 U.S.C. § 314. To institute an inter
`
`partes review, we must determine that the information presented in the
`
`Petition shows “a reasonable likelihood that the petitioner would prevail
`
`with respect to at least 1 of the claims challenged in the petition.” 35 U.S.C.
`
`§ 314(a). For the reasons set forth below, we conclude that Petitioner has
`
`not established a reasonable likelihood that it would prevail in showing the
`
`unpatentability of at least one of the challenged claims of the ’521 patent.
`
`Therefore, we deny institution of an inter partes review for claims 1–32 of
`
`the ’521 patent.
`
`B. Related Proceedings
`
`Four patents, including the ’521 patent, were asserted against
`
`Petitioner in Cornell University v. Illumina, Inc., No. 10-433-LPS-MPT
`
`(D. Del.). Pet. 1; Paper 6, 3. On the same day it filed the Petition at issue in
`
`this case, Petitioner also filed Petitions for inter partes review of claims in
`
`the remaining three patents asserted against it. Pet. 1; Paper 6, 2 (IPR2016-
`
`2
`
`

`
`IPR2016-00553
`Patent 8,288,521 B2
`
`00559 (U.S. Patent No. 8,624,016), IPR2016-00557 (U.S. Patent No.
`
`8,597,891), IPR2016-00549 (U.S. Patent No. 8,703,928)).
`
`C. The ’521 Patent (Ex. 1001)
`
`The ’521 patent involves the detection of nucleic acid sequence
`
`differences of one or more single base changes, insertions, deletions, or
`
`translocations in target nucleic acid sequences using a method including a
`
`ligation phase, a capture phase, and a detection phase. Ex. 1001, 1:23–25,
`
`5:33–38. The claims of the ‘521 patent are drawn to kits for identifying one
`
`or more of a plurality of sequences differing by single-base changes,
`
`insertions, deletions, or translocations in a plurality of target nucleotide
`
`sequences that include capture oligonucleotides that differ in nucleotide
`
`sequence by at least 25% when aligned to another capture oligonucleotide.
`
`See Ex. 1001, 59:59–63, 62:9–14.
`
`D. Illustrative Claims
`
`Claims 1 and 18 are independent claims of the ’521 patent. Claims 2–
`
`17 depend directly or indirectly from claim 1, and claims 19–32 depend
`
`directly or indirectly from claim 18. Claim 1 and 18 are illustrative of the
`
`challenged claims and recite:
`
`1. A kit for identifying one or more of a plurality of sequences
`differing by single-base changes, insertions, deletions or
`translocations in a plurality of target nucleotide sequences
`comprising:
`
`a ligase;
`
`a collection of oligonucleotide probe sets, each set
`characterized by (a) a first oligonucleotide probe
`comprising a target-specific portion and (b) a second
`oligonucleotide probe comprising a target-specific
`portion and a further portion, wherein the further portion
`
`3
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`

`
`IPR2016-00553
`Patent 8,288,521 B2
`
`comprises a nucleic acid sequence of greater than sixteen
`nucleotides that differs for each different target-specific
`portion, and wherein the nucleic acid sequence of a
`complement to one further portion differs from the
`nucleic acid sequence of a complement to another further
`portion in the collection by at least 25%, when aligned to
`each other.
`
`Ex. 1001, 59:58–63, 60:57–63.
`
`18. A kit for identifying one or more of a plurality of target
`nucleotide sequences in a sample comprising:
`
`a ligase;
`
` a
`
` plurality of oligonucleotide probe sets, each set characterized
`by (a) first oligonucleotide probe, having a target-specific
`portion and an address-specific portion and (b) a second
`oligonucleotide probe, having a target-specific portion;
`and
`
`a collection of capture oligonucleotides wherein each type of
`capture oligonucleotide in the collection comprises a
`nucleotide sequence complementary to an address-
`specific portion, wherein the address-specific portion is
`comprised of a nucleotide sequence which is distinct
`from that of the target-specific portions, and wherein
`each type of capture oligonucleotide in the collection
`hybridizes to its complement under uniform
`hybridization conditions but differs by at least 25% in
`nucleotide sequence, when aligned to another type of
`capture oligonucleotide in the collection.
`
`
`
`
`
`Id. at 61:57–61, 62:1–14.
`
`E. The Asserted Grounds of Unpatentability
`
`Petitioner contends that the challenged claims are unpatentable based
`
`on the following grounds. Pet. 25.
`
`4
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`

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`IPR2016-00553
`Patent 8,288,521 B2
`
`References
`
`Basis
`
`Claims Challenged
`
`Landegren,1 Wallace,2 Davis,3 and
`Wetmur4
`Landegren, Wallace, Davis, Wetmur,
`and Van Ness5
`Landegren, Wallace, Davis, Wetmur,
`and Fodor II6
`
`§ 103 1–2, 7, 9–24, and 27–32
`
`§ 103
`
`3–6 and 25–26
`
`§ 103
`
`8
`
`Petitioner relies also on the Declaration of Ralph M. Sinibaldi, Ph.D.
`
`Pet. 2–60; see Ex. 1002.
`
`A. Claim Interpretation
`
`II. ANALYSIS
`
`In an inter partes review, claim terms in an unexpired patent are given
`
`their broadest reasonable construction in light of the specification of the
`
`patent in which they appear. 37 C.F.R. § 42.100(b); Cuozzo Speed Techs.,
`
`LLC v. Lee, 136 S.Ct. 2131, 2144–46 (2016). Under the broadest reasonable
`
`interpretation approach, claim terms are given their ordinary and customary
`
`meaning as would be understood by one of ordinary skill in the art in the
`
`
`1 U.S. Patent No. 4,988,617, issued Jan. 29, 1991 (Ex. 1039, “Landegren”).
`2 PCT App. WO 93/25563, published Dec. 23, 1993 (Ex. 1006, “Wallace”).
`3 PCT App. WO 90/11372, published Oct. 4, 1990 (Ex. 1007, “Davis”).
`4 James G. Wetmur, DNA Probes: Applications of the Principles of Nucleic
`Acid Hybridization, 26 CRITICAL REVIEWS IN BIOCHEMISTRY AND
`MOLECULAR BIOLOGY 227–259 (1991) (Ex. 1008, “Wetmur”).
`5 European Pat. App. 0 455 905 A2, published Nov. 13, 1991 (Ex. 108, “Van
`Ness”).
`6 Stephen P. A. Fodor et al., Multiplexed Biochemical Assays with Biological
`Chips, 364 NATURE 555–556 (1993) (Ex. 1010, “Fodor II”).
`
`5
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`IPR2016-00553
`Patent 8,288,521 B2
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`context of the entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249,
`
`1257 (Fed. Cir. 2007).
`
`Petitioner asserts that we need not construe expressly any claim term
`
`at issue. Pet. 15; Reply 2–3. Patent Owner offers that the ’521 patent shows
`
`that “uniform hybridization conditions” means “common conditions at
`
`which different oligonucleotides are capable of hybridizing to
`
`complementary nucleic acids.” Prelim. Resp. 20. Being able to use uniform
`
`hybridization conditions, Patent Owner asserts, allows multiple sequences to
`
`be hybridized accurately and simultaneously in the same detection reactions,
`
`“thus allowing the performance of multiplex hybridization of multiple
`
`oligonucleotides to their complements in the same hybridization solution.”
`
`Id. at 20–21.
`
`Petitioner points out that neither its declarant nor Patent Owner’s
`
`declarant provides an express construction of “uniform hybridization
`
`conditions,” Reply 2, yet both were able to apply the term in discussing why
`
`or why not the prior art renders the challenged claims unpatentable. Id.
`
`(citing Ex. 1002 ¶¶ 89, 108; Ex. 2032 ¶¶ 9, 11, 14, 15, 17, 19, 20).
`
`For purposes of this decision, we do not need to interpret expressly
`
`the claim term “uniform hybridization conditions.” See, e.g., Wellman, Inc.
`
`v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011) (“[C]laim
`
`terms need only be construed ‘to the extent necessary to resolve the
`
`controversy.’”) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`
`200 F.3d 795, 803 (Fed. Cir. 1999)).
`
`B. Principles of Law
`
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`
`differences between the claimed subject matter and the prior art are such that
`
`6
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`IPR2016-00553
`Patent 8,288,521 B2
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`the subject matter, as a whole, would have been obvious at the time the
`
`invention was made to a person having ordinary skill in the art to which said
`
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`
`(2007). The question of obviousness is resolved on the basis of underlying
`
`factual determinations including: (1) the scope and content of the prior art;
`
`(2) any differences between the claimed subject matter and the prior art;
`
`(3) the level of ordinary skill in the art; and (4) objective evidence of
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`nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`
`In that regard, an obviousness analysis “need not seek out precise
`
`teachings directed to the specific subject matter of the challenged claim, for
`
`a court can take account of the inferences and creative steps that a person of
`
`ordinary skill in the art would employ.” KSR, 550 U.S. at 418; see
`
`Translogic, 504 F.3d at 1259. A prima facie case of obviousness is
`
`established when the prior art itself would appear to have suggested the
`
`claimed subject matter to a person of ordinary skill in the art. In re Rinehart,
`
`531 F.2d 1048, 1051 (CCPA 1976). We are mindful that the level of
`
`ordinary skill in the art also is reflected by the prior art of record.7 See
`
`Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001); In re GPAC
`
`
`7 Petitioner states that the level of skill in the art at the time of the invention
`is a person who “held a doctoral degree in biology, genetics, biochemistry,
`or a closely related discipline, and had at least one year of post-doctoral
`training or industry experience related to nucleic acid assays.” Pet. 14;
`Ex. 1002 ¶ 15. Patent Owner asserts that one of skill in the art is a person
`who “held a bachelor’s degree in one of the biological sciences disciplines
`(for example, cell biology, molecular biology or biochemistry) and at least
`two years of post-graduate practical experience with molecular biology,
`nucleic acid and enzyme biochemistry, nucleic acid hybridization and
`detection, and nucleic acid array technology.” Prelim. Resp. 19. For
`purposes of this decision, we apply Petitioner’s stated level of ordinary skill
`
`7
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`

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`IPR2016-00553
`Patent 8,288,521 B2
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`Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995); In re Oelrich, 579 F.2d 86, 91
`
`(CCPA 1978).
`
`We analyze the asserted ground of unpatentability in accordance with
`
`the above-stated principles.
`
`C. Obviousness over Landegren, Wallace, Davis, and Wetmur
`
`Petitioner contends that claims 1–2, 7, 9–24, and 27–32 are
`
`unpatentable under 35 U.S.C. § 103 as obvious over Landegren, Wallace,
`
`Davis, and Wetmur. Pet. 12, 18–57. Petitioner begins its analysis of
`
`unpatentability with independent claims 1 and 18. Petitioner asserts that
`
`Landegren discloses kits having a ligase and oligo-nucleotide probe sets
`
`with target-specific portions. Id. at 19–20, 37–39. Landegren also discloses,
`
`according to Petitioner, use of a plurality of oligonucleotide probe sets to
`
`simultaneously test multiple target sequences. Id. at 21. Petitioner asserts
`
`that Wallace teaches all the remaining claim limitations of claims 1 and 18.
`
`Id. 21–25. Specifically with regard to the limitation that each capture
`
`oligonucleotide “differs by at least 25% in nucleotide sequence, when
`
`aligned with another type of capture oligonucleotide in the collection,”
`
`Petitioner relies on statements from Wallace, Davis, and Wetmur. Id. at 28,
`
`41–42. Petitioner also provides citation to the references for the additional
`
`limitations of the remaining dependent claims 2, 7, 9–17, 19–24, and 27–32.
`
`Id. at 47–48, 51, 53–58.
`
`
`
`
`in the art, which is supported by Dr. Sinibaldi, because of the sophistication
`of the technology and the educational level of those who work in this area.
`See In re GPAC, 57 F.3d 1573, 1579 (Fed. Cir. 1995).
`
`8
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`IPR2016-00553
`Patent 8,288,521 B2
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`Patent Owner asserts that Petitioner’s obviousness challenge is
`
`unavailing because
`
`Illumina’s suggestion that one skilled in the art can pick
`up a property from one set of sequences in one reference, pick
`another particular property from a different set of sequences in
`another reference—without any indication as to why these
`properties would be combined—and expect to successfully
`arrive at the claimed invention of the ’521 patent does not
`comport with the very real challenges facing scientists when the
`present invention was made.
`
`Id. at 4. Patent Owner relies on its own declarant, John D. Sutherland,
`
`Ph.D., to support its position. See Ex. 2032 (Dr. Sutherland’s Declaration).
`
`We find that the Patent Owner has the better argument. Because we agree
`
`with Patent Owner that the cited references do not teach capture
`
`oligonucleotides that differ “by at least 25% in nucleotide sequence, when
`
`aligned to another type of capture oligonucleotide in the collection,”8 we
`
`address the references Petitioner asserts teach this limitation. Pet. 24–28,
`
`41–45.
`
`1. Wallace (Ex. 1006)
`
`Wallace describes a method for detecting the presence or absence of
`
`any specific target nucleic acid sequence contained in a sample that is
`
`relatively pure in form or that is a mixture of different nucleic acids. Ex.
`
`1006, Abstract. Wallace further states that the “invention also relates to
`
`
`8 Claim 1 states this limitation in different terms, but the limitation conveys
`the same meaning as found in the limitation of claim 18 recited here. See
`Ex. 1001, 60:59–63 (stating “wherein the nucleic acid sequence of a
`complement to one further portion differs from the nucleic acid sequence of
`a complement to another further portion in the collection by at least 25%”).
`
`9
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`IPR2016-00553
`Patent 8,288,521 B2
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`discriminating between sequences which differ from each other by as a little
`
`as a single nucleotide.” Id. at 1.
`
`To achieve this goal, Wallace describes a primer design in which the
`
`primer is composed of two portions, where the 3ʹ portion is specific for the
`
`target nucleic acid, and the 5ʹ portion is complementary to a preselected
`
`nucleic acid sequence. Id. This preselected nucleic acid sequence is
`
`preferably immobilized on a solid support and arranged in a particular
`
`pattern with different primers. Id. at 7.
`
`In Figure 2, Wallace describes identifying and discriminating between
`
`two allelic nucleic acid sequences in a sample that differ by a single
`
`nucleotide. Id. at 8. The primer hybridizes to one of the allelic nucleic acid
`
`sequences and is extended and labeled by an allele specific primer extension.
`
`Id. The labeled primer then hybridizes to a preselected oligonucleotide that
`
`is on an array. Id. The example further provides
`
`Each location on the array of sequences contains a different
`preselected oligonucleotide. The solid support may be of any
`size with any desired number of locations. The preselected
`oligonucleotides immobilized at each of the grid locations are
`preferably at least 10–100, preferably 15 to 25 nucleotides in
`length. Hybridization preferably, but not necessarily, occurs
`under substantially the same conditions at each location on the
`array.
`
`Id.; see also id. at Fig. 3 (stating that “each location of the array contains a
`
`unique preselected nucleic acid sequence”).
`
`
`
`In Example IV, Wallace teaches a general approach for the design of
`
`grid oligonucleotide sequences. Id. at 14. Wallace states that these grid
`
`oligonucleotides are 20 nucleotides in length and 50% G+C. Id. Wallace
`
`explicitly states that “[t]his design allows hybridization reactions to be
`
`carried out with a single hybridization temperature for all sequences.” Id. at
`
`10
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`

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`IPR2016-00553
`Patent 8,288,521 B2
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`14–15. Wallace used a program to randomize the sequences. Id. at 15.
`
`Each sequence was generated by randomizing the previously generated
`
`sequence. Id. The sequences that resulted from this exercise are listed in
`
`Table 2. Id. at 15. Wallace notes that additional grid oligonucleotides can
`
`be generated using this method. Id. at 16.
`
`Both parties agree that the 20 sequences generated in Example IV, as
`
`presented in Table 2, are at least 25% different from each other. Pet. 21–23
`
`(citing Ex. 1002 ¶ 72); Prelim. Resp. 31 (“Even if the exemplary sequences
`
`listed in Table 2 differ by at least 25%, Wallace’s teaching that sequences
`
`should be generated by ‘randomizing’ sequences with 50% G+C content
`
`does not impose a 25% difference requirement.”) (citing Ex. 2032 ¶ 16). To
`
`reach such a conclusion, however, requires analysis of the 20
`
`oligonucleotides using sequence alignment software, such as SIM. Pet. 22
`
`(citing SIM software data); Ex. 1002 ¶ 74. Wallace does not disclose
`
`conducting such an analysis.
`
`2. Davis (Ex. 1007)
`
`Davis describes detecting the presence or absence of a nucleotide at a
`
`specific location on a strand of DNA using a “special primer capable of
`
`pairing with the strand of DNA and capable of initiating the formation of an
`
`extension product if there is a base pair match at the nucleotide of interest.”
`
`Ex. 1007, 1, 2–3.
`
`Davis explains that
`
`Preferably, the presence or absence of the extension
`product is determined according to a novel method that requires
`an oligonucleotide primer having attached to it a unique tail
`sequence non-complementary with the test DNA. If an
`extension product is formed, that product will include the
`extension portion, the primer, and the non-complementary,
`
`11
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`IPR2016-00553
`Patent 8,288,521 B2
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`unique tail sequence. The extension product then is applied to a
`substrate carrying an oligonucleotide at least in part
`complementary to the unique tail sequence under conditions
`that allow the unique tail sequence of the extension product to
`hybridize to the complementary oligonucleotide on a substrate.
`Preferably, the oligonucleotide complementary to the tail
`comprises repeating units of complementation to the tail. This
`favorably affects the kinetics of hybridization, increasing the
`speed and the sensitivity of the test.
`
`
`Id. at 5.
`
`Davis further explains that a particular extension product will
`
`attach to the substrate at only one location because of hybridization of
`
`the unique tail of the primer and the complementary oligonucleotide
`
`found only at that location. Id. at 6. In defining what is meant by a
`
`“unique” tail, Davis explains that “it is meant that a sequence
`
`complementary to one tail will not hybridize with the other tail.” Id.
`
`at 23. Davis further explains that
`
`It is believed that a single nucleotide substitution on an
`oligonucleotide 14 nucleotides long is sufficient to prevent
`cross hybridization. Preferably there are at least two nucleotide
`substitutions to distinguish each tail. As is understood by those
`skilled in the art, the synthesis of a set of thousands of such
`unique tails 14 nucleotides long is possible.
`
`Id. at 23–24.
`
`
`
`Davis describes an advantage of his invention is “that by using unique
`
`tails, any number of alleles or loci may be tested for simultaneously. Thus,
`
`tests for different genes and tests for multiple alleles on different genes may
`
`be accomplished simultaneously . . . .” Id. at 26. Davis describes primers in
`
`Example 4 where the tails are made using a 14 nucleotide repeat that are at
`
`least 140 nucleotides long that differ from each other by 25%. Id. at 48–49.
`
`12
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`IPR2016-00553
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`3. Analysis
`
`Petitioner asserts that “[i]t was also appreciated at the time that
`
`minimizing cross-hybridization in these assays was a critical component of
`
`using universal arrays, and well-known principles for minimizing cross-
`
`hybridization, such as increasing sequence differences between capture
`
`oligonucleotide sequences, were utilized in the design of these universal
`
`arrays.” Pet. 12 (citing Ex. 1002 ¶¶ 49–54). Petitioner points to 20
`
`exemplary capture oligonucleotide sequences disclosed in Table 2 of
`
`Wallace to assert that Wallace teaches that capture oligonucleotides differ by
`
`25%. Id. at 28, 42; see Ex. 1002 ¶¶ 91–92). To support this assertion,
`
`Petitioner relies on an assessment of the degree of similarity between the
`
`sequences as determined by a sequence alignment software program, as
`
`opposed to any explicit teaching in Wallace. See Ex. 1002 ¶ 92.
`
`Petitioner relies on Davis for the teaching that “increasing the
`
`sequence differences between capture oligonucleotides on an array would
`
`avoid cross-hybridization.” Id. at 32 (citing Ex. 1002 ¶¶ 94–99; Ex. 1007,
`
`23–24). Petitioner’s declarant, Dr. Sinibaldi, explains that “one of ordinary
`
`skill in the art would have been motivated to increase the difference in
`
`sequences of the capture oligonucleotides to minimize cross-hybridization
`
`on universal arrays, as evidenced by Davis.” Ex. 1002 ¶ 98, cited in Pet. 33.
`
`Petitioner concludes that
`
`Davis discloses avoiding cross-hybridization by using
`capture oligonucleotides with ‘at least two nucleotide
`substitutions to distinguish each tail’, and in particular discloses
`an example in which two tail sequences differ by 4 out of 14
`nucleotides (28%). This need to prevent cross-hybridization
`would have motivated one of ordinary skill in the art to make
`the array-specific tail sequences (and their corresponding
`complementary capture oligonucleotides) with significant
`
`13
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`IPR2016-00553
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`sequence variation (e.g., at least 2 and as many as 4 out of 14
`bases), understanding that the greater the differences between
`array-specific tail sequences, the less cross-hybridization there
`would be.
`
`Pet. 33–34 (citing Ex. 1002 ¶ 99).
`
`
`
`Petitioner also relies on Wetmur for the teaching that “the kinetics
`
`underlying the well-known principle that increasing the number of
`
`mismatches between two oligonucleotide sequences reduces cross-
`
`hybridization by depressing melting temperature and by decreasing
`
`hybridization rate constants. Where mismatches are increased to 30%,
`
`hybridization rate constants can be reduced to zero when hybridization
`
`conditions are optimized.” Pet. 35 (citing Ex. 1002 ¶¶ 106–107). Petitioner
`
`concludes that “[g]iven the teachings in Wallace, Davis, and Wetmur, one of
`
`skill in the art would have had a reason to reduce cross-hybridization
`
`between capture oligonucleotides on universal arrays, such as Wallace’s
`
`universal arrays, by using capture oligonucleotides whose nucleotide
`
`sequence differed from each other by at least 25%,” id. at 35–36, and one of
`
`skill in the art would have had a reasonable expectation of doing so. Pet.
`
`36–37.
`
`
`
`Patent Owner counters that the obviousness analysis must center on
`
`the features of the capture oligonucleotides as claimed, “a combination of
`
`ligase with capture oligonucleotides or portions that are at least 25%
`
`different in sequence in combination with either the additional property of
`
`being greater than 16 nucleotides in length or having the ability to hybridize
`
`under uniform hybridization conditions.” Prelim. Resp. 2, 50. Patent Owner
`
`contends that “[i]t is not sufficient for each property to be considered in
`
`isolation—each must be found in the same set of sequences.” Id. at 51, 3
`
`14
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`(stating each claim requires that the capture oligonucleotides
`
`“simultaneously must have the properties of 25% difference when aligned
`
`and length (greater than 16 nucleotides), or 25% difference when aligned
`
`and ability to hybridize under uniform hybridization conditions, or all
`
`three”). Patent Owner concludes that “[t]hese combinations applied to the
`
`same set of oligonucleotide sequences, combined further with a ligase, are
`
`not taught, suggested or made obvious by the prior art.” Id. at 3.
`
`
`
`Focusing on the second feature of the capture oligonucleotides listed
`
`above, Patent Owner asserts that Wallace’s use of the word “unique” in
`
`reference to capture oligonucleotides in Figure 3 did not indicate to an
`
`ordinary artisan that there needed to be at least 25% difference in sequence
`
`from its neighbor on the solid support. Id. at 32. In addressing the 20
`
`oligonucleotide sequences listed in Table 2 of Wallace, Patent Owner states
`
`Even if the exemplary sequences listed in Table 2 differ by at
`least 25%, Wallace’s teaching that sequences should be
`generated by “randomizing” sequences with 50% G+C content
`does not impose a 25% difference requirement.
`
`Prelim. Resp. 32–33 (citing Ex. 2032 ¶ 16). Patent Owner notes that this
`
`randomizing of sequences with 50% G+C content will inevitably generate
`
`sequences that are less than 25% different from each other, and Wallace
`
`does not teach that such sequences should be excluded. Id. at 33. Patent
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`Owner concludes that “[j]ust because the randomly generated exemplary
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`sequences in Table 2 happen to be greater than 25% different does not teach
`
`the requirement that additional random sequences be at least 25% different.”
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`Id.
`
`
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`Patent Owner also asserts that the random sequences generated in
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`Wallace are not suitable for multiplex analysis. Id. at 34. For instance,
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`transient hairpins may form that can be extended in a primer extension
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`reaction with no target nucleotide, or transient hybridization may occur
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`between two different oligonucleotides adding a labeled nucleotide without a
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`target sequence. Id. at 34–35. Patent Owner also points out two capture
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`oligonucleotide sequences in Table 2 of Wallace whose complements, which
`
`would be appended to a target-specific portion, would hybridize to each
`
`other. Id. at 35–36.
`
`
`
`In addressing Davis, Patent Owner asserts that Davis teaches away
`
`from a 25% difference between neighboring capture oligonucleotides. Id. at
`
`38. Patent Owner concludes that “[n]owhere does Davis teach that
`
`oligonucleotide sequences should be at least 25% different. In fact, the
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`express teaching of Davis is that sequences that are much more similar than
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`that, such as 14-base sequences differing by a single nucleotide (i.e.
`
`sequences that are only 7%), would be suitable for specific detection.” Id. at
`
`39.
`
`
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`In addressing the teachings of Wetmur, Patent Owner states, “the
`
`teachings of Wetmur that [Petitioner] relies on, taken from a description of
`
`hybridization in the liquid phase, do not apply to the hybridization of
`
`oligonucleotides, with or without mismatches, on a solid support. The prior
`
`art does not lead a POSA to the understating that a 25% difference among
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`nucleotides in an oligonucleotide of at least 16 nucleotides long will be
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`effective.” Id. at 44–45.
`
`We find that Petitioner’s unpatentability position relies on ex post
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`reasoning or impermissible hindsight to read into the prior art the teachings
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`of the ’521 patent. See KSR Internat’l Co. v. Teleflex Inc., 550 U.S. 398,
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`421 (2007). Patent Owner correctly points out that the features of the
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`capture oligonucleotides as claimed encompass “a combination of ligase
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`with capture oligonucleotides or portions that are at least 25% different in
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`sequence in combination with either the additional property of being greater
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`than 16 nucleotides in length or having the ability to hybridize under
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`uniform hybridization conditions.” Prelim. Resp. 2, 50. Petitioner does not
`
`persuade us that any of the cited references, alone or in combination, teaches
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`or suggests these requirements in relation to capture oligonucleotides used
`
`on a solid support.
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`More particularly, we find that none of the references teaches or
`
`suggests differences of at least 25% between capture oligonucleotides on
`
`adjacent positions on a solid support. Petitioner’s arguments in relation to
`
`Wallace in light of the teachings of Davis and Wetmur are unavailing.
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`Nowhere in Wallace, Davis, or Wetmur is there an explicit teaching that
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`capture oligonucleotides on adjacent positions on a solid support should be
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`at least 25% different from each other.
`
`Petitioner’s reliance on Wallace’s Example IV, which teaches a
`
`general approach for the design of grid oligonucleotide sequences, Ex. 1006,
`
`14, to show the required 25% difference is unavailing. Wallace talks about
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`having “different” or “unique” capture oligonucleotides, id. at 8 and Fig. 3,
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`but never defines what is meant by “different” or “unique.” As Patent
`
`Owner points out, “different” or “unique” could mean any difference
`
`between oligonucleotides including differing by one nucleotide. See Prelim.
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`Resp. 32, 40.
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`Petitioner necessarily relies on its expert conducting further analysis
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`on the exemplary oligonucleotides in Example IV, all of which have
`
`differing degrees of uniqueness. Pet. 24–25 (citing Ex. 1002 ¶¶ 91–92;
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`Ex. 1030). Petitioner does not explain adequately why an ordinary artisan
`
`would have conducted such an analysis (when Wallace did not, for
`
`example). Moreover, even assuming one would have conducted such an
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`analysis, Petitioner does not explain adequately why an ordinary artisan
`
`would have concluded that capture oligonucleotides should differ from an
`
`adjacent oligonucleotide by 25% based on results of that analysis. Petitioner
`
`relies on impermissible hindsight from the teachings of the ’521 patent in
`
`this regard.
`
`
`
`Neither Davis nor Wetmur cures this deficiency. Davis teaches that a
`
`difference of only one nucleotide between oligonucleotides that are 14
`
`nucleotides in length (a 7% difference) can be detected, although Davis
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`prefers at least a two nucleotide difference (a 14% difference). See Ex.
`
`1007, 23–24. According to Davis, as long as there is at least one nucleotide
`
`difference in 14, no cross-hybridization will occur. Id. at 23. We agree with
`
`Patent Owner that this would not suggest to one of ordinary skill in the art
`
`that a 25% difference, especially for a nucleotide that is at least 16
`
`nucleotides long, is desired. It is true that Davis also describes primers in
`
`Example 4 that are made using a 14 nucleotide repeat that are about 140
`
`nucleotides long that differ from each other by 28%. Id. at 48–49. This
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`example, however, would not lead one of skill in the art to require at least a
`
`25% difference in capture oligonucleotides in light of the express teaching of
`
`Davis that as little as a 7% difference is enough.
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`We also agree with Patent Owner that there would be no reason for a
`
`person of skill in the art, reading Wetmur, to arrive at the specific
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`combination of diversity and length or hybridization properties recited in
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`claims 1 and 18. See Prelim. Resp. at 41. Wetmur discloses that
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`Mismatches of up to 10%, although easily measured as a
`9
`depression in T∞
` have essentially no effect on hybridization
`M,
`rates at the temperature of the maximum rate and may be
`ignored. Thus, most of the modifications used for labeling
`probes described below in Section II, even if they significantly
`
`decrease T∞M and TM,10 have little or no effect on k2.11 As
`mismatching is increased to 20 and to 30%, where T∞
`M is
`12
`nearing the normally optimum hybridization temperature, k'N
`falls to half and then to zero.
`
`Ex. 1008, 238. Wetmur refers to an “optimum hybridization
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`temperature” for use with mismatches of 20 and 30% to reduce the
`
`rate constant for hybridization reactions to ze