`Tel: 571-272-7822
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`Paper 7
`Entered: December 9, 2013
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`SEQUENOM, INC.
`Petitioner
`
`v.
`
`THE BOARD OF TRUSTEES OF
`THE LELAND STANFORD JUNIOR UNIVERSITY
`Patent Owner
`_______________
`
`Case IPR2013-00390
`Patent 8,195,415 B2
`_______________
`
`
`Before LORA M. GREEN, FRANCISCO C. PRATS, and SCOTT E. KAMHOLZ,
`Administrative Patent Judges.
`
`PRATS, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
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`I. INTRODUCTION
`A. Statement of the Case
`On June 26, 2013, Sequenom, Inc. (“Sequenom”) filed a petition (“Pet.”) to
`institute an inter partes review of claims 1-17, all of the claims, of U.S. Patent No.
`8,195,415 B2 (Ex. 1001, “the ’415 patent”). Paper 1. Patent Owner, The Board of
`Trustees of the Leland Stanford Junior University (“Stanford”), did not file a
`Preliminary Response. We have jurisdiction under 35 U.S.C. §§ 6(b) and 314.
` The standard for instituting an inter partes review is set forth in 35 U.S.C.
`§ 314(a), which states:
`THRESHOLD. -- The Director may not authorize an inter partes
`review to be instituted unless the Director determines that the
`information presented in the petition filed under section 311 and any
`response filed under section 313 shows that there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of
`the claims challenged in the petition.
`
`Sequenom has persuaded us that it has shown, under 35 U.S.C. § 314(a), that
`there is a reasonable likelihood that it would prevail with respect to at least one of
`the claims challenged in its petition. Accordingly, for the reasons below, we grant
`the petition and institute an inter partes review of claims 1-17.
`B. Related Proceedings
`The ’415 patent is asserted in co-pending litigation captioned as Verinata
`Health, Inc. and the Board of Trustees of the Leland Stanford Junior University v.
`Sequenom, Inc. and Sequenom Center for Molecular Medicine LLC, United States
`District Court for the Northern District of California, Case No. 3:12-cv-00865-SI.
`Pet. 1. The ’415 patent is involved also in Interference No. 105,922, declared on
`May 3, 2013. Id.
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`C. Proposed Grounds of Unpatentability
`Sequenom contends that the challenged claims are unpatentable under
`35 U.S.C. §§ 102 and/or 103 on the following specific grounds (Pet. 3-60):1
`Reference[s]
`Basis
`Claims challenged
`Lo II2
`§ 102(e)
`1-6, 8-12
`
`Lo II, Hillier,3 Smith4
`
`Lo II, Wang5
`
`Lo II, Shimkets,6 Dohm7
`
`Lo II, Quake8
`
`§ 103
`
`§ 103
`
`§ 103
`
`§ 103
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`Lo II, Wang, Hillier, Smith
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`§ 103
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`7
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`13, 16
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`14
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`15
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`17
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`Lo II, Wang
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`§ 103
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`1-6, 8-12
`
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`1 Petitioner supports its challenge with a declaration, executed Jun. 26, 2013, by
`Stacey Bolk Gabriel (Ex. 1010).
`2 Lo et al., U.S. Patent App. Pub. No. 2009/0029377 A1 (filed Jul. 23, 2008) (Ex.
`1002).
`3 LaDeana W. Hillier et al., Whole-genome sequencing and variant discovery in
`C. elegans, 5 NATURE METHODS 183-188 (published online Jan. 20, 2008) (Ex.
`1006).
`4 Andrew D. Smith et al., Using quality scores and longer reads improves accuracy
`of Solexa read mapping, 9 BMC BIOINFORMATICS 128 (Feb. 28, 2008) (Ex. 1009).
`5 Tian-Li Wang et al., Digital karyotyping, 99 PNAS 16156-16161 (Dec. 10, 2002)
`(Ex. 1005).
`6 Shimkets et al., U.S. Patent App. Pub. No. 2005/0221341 A1 (published Oct. 6,
`2005) (Ex. 1004).
`7 Juliane C. Dohm et al., Substantial biases in ultra-short read data sets from
`high-throughput DNA sequencing, 36 NUCL. ACIDS RES. e105 (published online
`Jul. 26, 2008) (Ex. 1007).
`8 Quake et al., U.S. Patent No. 7,888,017 B2 (filed Feb. 2, 2007) (Ex. 1008).
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`Lo II, Wang, Hillier, Smith
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`Lo II, Wang, Shimkets,
`Dohm
`Lo II, Wang, Quake
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`Lo I,9 Shimkets
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`§ 103
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`§ 103
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`§ 103
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`§ 103
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`Lo I, Shimkets, Hillier, Smith § 103
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`Lo I, Shimkets, Wang
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`Lo I, Shimkets, Dohm
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`Lo I, Shimkets, Quake
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`§ 103
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`§ 103
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`§ 103
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`7
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`14
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`15
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`1-6, 8-12
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`7
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`13, 16
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`14
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`15
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`17
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`§ 103
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`Lo I, Shimkets, Wang,
`Hillier, Smith
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`D. The ’415 Patent
`The ’415 patent describes prenatal genetic diagnosis methods that allow
`detection of chromosomal aberrations, without the use of invasive techniques such
`as amniocentesis or chorionic villus sampling, which pose potentially significant
`risks to both fetus and mother. See Ex. 1001, col. 1, ll. 30-54. In particular, the
`’415 patent discloses that fetal DNA can constitute nearly ten percent of the cell-
`free DNA in maternal plasma, and, therefore, fetal aneuploidy can be detected by
`determining the sequences of the DNA fragments in the maternal plasma. See id.
`at col. 1, l. 55-col. 2, l. 24. The ’415 patent thus describes “the successful use of
`shotgun sequencing and mapping of DNA to detect fetal trisomy 21 (Down
`syndrome), trisomy 18 (Edward syndrome), and trisomy 13 (Patau syndrome),
`
`
`9 Lo I, et al., U.S. Provisional Patent Application 60/951,438 (filed July 23, 2007)
`(Ex. 1003).
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`carried out non-invasively using cell-free fetal DNA in maternal plasma.” Id. at
`col. 4, ll. 17-21.
`To perform these analyses, the sequences of the DNA fragments in a
`maternal plasma sample are determined by generating sequence tags of sufficient
`length “to be assigned to a chromosomal location with a genome and of a sufficient
`number to reflect abnormal distribution.” Id. at col. 4, ll. 38-40. Once the
`sequence tags are assigned to their chromosomal locations in a reference genome,
`“[o]ne then may determine a first number of sequence tags mapped to at least one
`normally distributed chromosome portion and a second number of sequence tags
`mapped to the specified chromosome portion [suspected of abnormal distribution],
`both chromosomes being in one mixed sample.” Id. at col. 4, ll. 46-50. After
`correcting for “nonuniform distribution [of] sequence tags to different
`chromosomal portions[,]” id. at col. 4, ll. 51-52, a differential is calculated
`“between the first number and the second number which is determinative of
`whether or not the abnormal distribution exists.” Id. at col. 4, ll. 64-67.
`The ’415 patent explains that the methods do not require sequence
`differentiation between fetal and maternal DNA, “because the summed
`contribution of both maternal and fetal sequences in a particular chromosome or
`chromosome portion will be different as between an intact, diploid chromosome
`and an aberrant chromosome, i.e., with an extra copy, missing portion or the like.”
`Id. at col. 3, ll. 56-62. That is, “the method does not rely on a priori sequence
`information that would distinguish fetal DNA from maternal DNA.” Id. at col. 3,
`ll. 62-64.
`Claims 1 and 13, the independent claims of the ’415 patent, are reproduced
`below:
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`(b)
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`1. A method of testing for an abnormal distribution of a
`specified chromosome portion in a mixed sample of normally
`and abnormally distributed chromosome portions obtained from
`a subject, comprising:
`(a)
`sequencing DNA from the mixed sample to obtain
`sequences from multiple chromosome portions,
`wherein said sequences comprise a number of
`sequence tags of sufficient length of determined
`sequence to be assigned to a chromosome location
`within a genome;
`assigning the sequence tags to corresponding
`chromosome portions
`including at
`least
`the
`specified
`chromosome
`by
`comparing
`the
`determined sequence of the sequence tags to a
`reference genomic sequence;
`(c) determining values for numbers of sequence tags
`mapping to chromosome portions by using a
`number of windows of defined length within
`normally and abnormally distributed chromosome
`portions to obtain a first value and a second value
`therefrom; and
`(d) using the values from step (c) to determine a
`differential, between the first value and the second
`value, which is determinative of whether or not the
`abnormal distribution exists.
`
`
`13. A method of determining an abnormally distributed
`chromosome portion of interest in a mixed sample of normally
`and abnormally distributed DNA molecules, comprising:
`(a)
`sequencing DNA in said sample by massively
`parallel sequencing to obtain a number of sequence
`tags;
`specific
`to
`tags
`sequence
`said
`(b) mapping
`chromosome portions, each chromosomal portion
`being comprised
`in a sliding window of a
`predetermined length;
`(c) determining numbers of sequence tags mapped to
`each sliding window on at least each autosome;
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`(e)
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`(d) determining a mean of said numbers for each
`autosome and a second mean for at least all
`autosomes;
`calculating a normalized value from all autosomes,
`using said second mean; and
`comparing normalized values among autosomes to
`determine any abnormally distributed autosomal
`chromosome portion of interest.
`
`(f)
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`E. Claim Interpretation
`Consistent with the statute and legislative history of the America Invents Act
`(AIA), the Board interprets claims using the “broadest reasonable construction in
`light of the specification of the patent in which [they] appear[].” 37 C.F.R.
`§ 42.100(b); see also Office Patent Trial Practice Guide, 77 Fed. Reg. 48756,
`48766 (Aug. 14, 2012). Under that standard, terms in a claim are given the
`“broadest reasonable meaning of the words in their ordinary usage as they would
`be understood by one of ordinary skill in the art, taking into account whatever
`enlightenment by way of definitions or otherwise that may be afforded by the
`written description contained in the . . . specification.” In re Morris, 127 F.3d
`1048, 1054 (Fed. Cir. 1997).
`Sequenom submits proposed constructions for several claim terms. Pet. 8-
`12; see also Ex. 1010 ¶¶ 29-36. Except for the terms “window” and “sliding
`window,” the claim terms construed by Sequenom are defined either expressly in
`the ’415 patent specification, or are defined expressly in the claims in which they
`appear. See Pet. 8-12.
`As to the term “window” (claim 1), Sequenom contends that, based on the
`’415 patent specification, an ordinary artisan “would understand the meaning of
`‘window’ as used in the ’415 patent to mean a predefined subsection of a
`chromosome.” Id. at 10 (citing Ex. 1010 ¶ 31).
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`The ’415 patent explains that, in order to determine how many sequence tags
`obtained from the maternal plasma sample map to any particular chromosomal
`location in the genome, “[e]ach autosome (chr. 1-22) is computationally segmented
`into contiguous, non-overlapping windows. . . . Each window is of sufficient
`length to contain a significant number of reads (sequence tags, having about 20-
`100 [bp (base pairs)] of sequence) . . . .” Ex. 1001, col. 5, ll. 4-8. Thus, by
`dividing the chromosomes into subsections for the purpose of counting the number
`of sequence tags mapping to each chromosome, one ultimately is able to discern a
`differential between normally and abnormally distributed chromosomes in the
`maternal plasma sample. See id. at col. 4, ll. 9-12 (“By analyzing sequence tag
`density in predefined subsections of chromosomes (e.g., 10 to 100 kb windows), a
`normalization constant can be calculated, and chromosomal subsections quantified
`. . . .”).
`
`Accordingly, we interpret “window” in claim 1 to mean a predefined
`subsection of a chromosome of sufficient length to allow determination of an
`abnormal chromosome distribution, if present, based on the number of sequence
`tags mapping to that chromosomal subsection.
`As to the term “sliding window” (claim 13), Sequenom contends that an
`ordinary artisan would broadly construe it to mean a “contiguous, overlapping or
`non-overlapping, predefined subsection[] of a chromosome.” Id. (citing Ex. 1010
`¶32). As Sequenom points out, Pet. 10, the ’415 patent describes using a non-
`overlapping sliding window to determine the number of sequence tags mapping to
`each chromosome:
`Because the distribution of sequence tags across each chromosome
`was non-uniform (possibly technical artifacts), we divided the length
`of each chromosome into non-overlapping sliding window[s] with a
`fixed width (in this particular analysis, a 50 kbp window was used),
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`skipping regions of genome assembly gaps and regions with known
`microsatellite repeats.
`Ex. 1001, col. 23, ll. 15-20.
`Accordingly, we interpret “sliding window” to mean a contiguous,
`overlapping or non-overlapping, predefined subsection of a chromosome of
`sufficient length to allow determination of an abnormal chromosome distribution,
`if present, based on the number of sequence tags mapping to that chromosomal
`subsection.
`
`II. ANALYSIS
`A. Anticipation of claims 1-6 and 8-12 by Lo II
`We have reviewed Sequenom’s contentions and supporting evidence
`regarding the proposed ground of anticipation of claims 1-6 and 8-12 of the ’415
`patent by Lo II, and are persuaded that Sequenom has shown a reasonable
`likelihood of prevailing in accordance with35 U.S.C. §§ 312 and 314.
`As Sequenom contends, Pet. 13-14, Lo II describes a process “for
`determining whether a nucleic acid sequence imbalance (e.g., chromosome
`imbalance) exists within a biological sample obtained from a pregnant female.”
`Ex. 1002 ¶ 14. Lo II discloses that a suitable sample is maternal plasma. Id.
`Accordingly, we agree with Sequenom that Lo II describes a process for detecting
`abnormal chromosome distribution, as required by claim 1, using a sample of the
`type required by the claim.
`Step (a) of claim 1 requires sequencing DNA from the mixed sample by
`obtaining sequences from multiple chromosome portions. Ex. 1001, col. 33, ll. 56-
`57. The obtained sequences must include a number of sequence tags of sufficient
`length, and of determined sequence, to be assigned to a chromosome location
`within a genome. Id. at col. 33, ll. 59-61; see also id. at col. 8, ll. 54-46 (“A
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`‘sequence tag’ is a DNA sequence of sufficient length that it may be assigned
`specifically to one of chromosomes 1-22, X or Y.”).
`As Sequenom contends, Pet. 14, and as required by step (a), Lo II discloses
`that a “portion of the nucleic acid molecules contained in the biological sample are
`sequenced,” Ex. 1002 ¶ 15, and discloses also that the sequencing involves
`obtaining DNA fragments, i.e., sequence tags, of sufficient length to allow
`mapping of a particular fragment to a specific chromosome. See id. at ¶ 80 (“The
`sequencing is done at random and then a database search may be performed to see
`where a particular fragment is coming from.”).
`As Sequenom contends, Pet. 14-15, and as required by step (b) of claim 1,
`Lo II describes assigning the sequence tags obtained from the sample to their
`corresponding locations on chromosomes, including locations on the chromosome
`suspected of abnormal distribution, by comparing the sequences to a reference
`genome. See, e.g., Ex. 1002 ¶ 70 (“The short sequence tags generated were
`aligned to the human reference genome sequence and the chromosomal origin was
`noted.”).
`Step (c) of claim 1 requires “determining values for numbers of sequence
`tags mapping to chromosome portions by using a number of windows of defined
`length within normally and abnormally distributed chromosome portions to obtain
`a first value and a second value therefrom . . . .” Ex. 1001, col. 33, l. 66, through
`col. 34, l. 54. As noted above, we interpret the term “window” to mean a
`predefined subsection of a chromosome of sufficient length to allow determination,
`if present, of an abnormal chromosome distribution, based on the number of
`sequence tags mapping to that chromosomal subsection.
`As Sequenom contends, Pet. 15-16, Lo II discloses that, when determining
`the number of sequence tags that map to a particular chromosome, one may count
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`the numbers of sequence tags mapping to chromosome regions, that is, subsections
`of chromosomes, rather than the entire chromosome. See Ex. 1002 ¶ 60 (“There
`are a number of ways of determining the amounts of the chromosomes, including
`but not limited to counting the number of sequenced tags . . . originating from
`particular chromosome(s) or chromosomal regions.”) (emphasis added).
`Accordingly, we agree with Sequenom that step (c) of claim 1 of the ’415 patent
`encompasses the counting step of Lo II’s process.
`As Sequenom contends further, Pet. 16, and as required by step (d) of claim
`1, Lo II discloses that its process includes the step of determining a differential
`between the numbers of sequence tags mapping to normally and abnormally
`distributed chromosomes, so as to determine whether abnormal chromosomal
`distribution is present. See Ex. 1002 ¶ 16 (“A parameter from the first amount and
`the second amount is then compared to one or more cutoff values. Based on the
`comparison, a classification of whether a fetal chromosomal aneuploidy exists for
`the first chromosome is determined.”).
`Thus, because Sequenom directs us to disclosures supporting a
`determination that Lo II describes a process that includes all of the steps of claim 1
`of the ’415 patent, Sequenom has persuaded us that there is a reasonable likelihood
`it will prevail in its challenge to the patentability of that claim.
`Claim 2 of the ’415 patent reads as follows:
`2. The method of claim 1 wherein to determine a differential
`includes the step of comparing a normalized sequence tag density of
`the specified DNA chromosome portion to a normalized sequence tag
`density of another DNA chromosome portion in said mixed sample,
`wherein all autosomes are used to calculate the normalized sequence
`tag density.
`
`Ex. 1001, col. 34, ll. 59-64.
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`In its challenge to claim 2, Sequenom directs us, Pet. 17-18, to Lo II’s
`disclosure that, as a basis for its ultimate comparison, one may normalize the
`sequence tag density of chromosome 21, a chromosome suspected of abnormal
`distribution, based on its relative size as compared to the other chromosomes:
`By taking into account of the relative size of chromosome 21
`compared with the other chromosomes, one could obtain a normalized
`frequency, within a reference range, of chromosome 21-specific
`sequences from such a sequencing exercise. If the fetus has trisomy
`21, then the normalized frequency of chromosome 21-derived
`sequences from such a sequencing exercise will increase, thus
`allowing the detection of trisomy 21.
`
`Ex. 1002 ¶ 69 (emphasis added). On the present record, we interpret Lo II’s
`disclosure that the size of chromosome 21 is compared with “the” other
`chromosomes as meaning that it is compared with the sizes of all other
`chromosomes, including all the autosomes. Given that disclosure, we are
`persuaded that Sequenom has shown a reasonable likelihood it will prevail in its
`challenge to claim 2 of the ’415 patent.
`
`As required by claim 3, and its dependent claim 6, Lo II describes detecting
`fetal aneuploidies, such as trisomy 21, by analyzing a maternal blood sample. See,
`e.g., Ex. 1002 ¶ 3. As required by claim 4, Lo II discloses that its methods can be
`used to detect chromosomal aberrations in malignant tumors. See id. at ¶ 37 (“Yet
`other examples include sequences which are mutated, deleted, or amplified in a
`malignant tumor, e.g., sequences in which loss of heterozygosity or gene
`duplication occur.”). As required by claim 5, Lo II employs massively parallel
`sequencing as its sequence determination technique. See id. at ¶ 56. Given these
`disclosures, we determine that there is a reasonable likelihood Sequenom will
`prevail in its challenge to these claims as anticipated by Lo II.
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`Claims 8-12 all depend directly or indirectly from claim 3. Ex. 1001, col.
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`35, ll. 12-34. As to claim 8, which recites that the sequence tags are about 25 to
`100 base pairs in length, Lo II exemplifies sequence tags of 36 bp. See Ex. 1002 ¶
`11. As to claim 9, which recites that at least about 1 million sequence tags are
`obtained, Lo II describes generating “in the order of hundred thousands to millions
`or even possibly hundreds of millions or billions” of sequence reads from each
`sample in each run. Ex. 1002 ¶ 57. Given these disclosures, Sequenom has
`persuaded us there is a reasonable likelihood that it will prevail, as well, in its
`challenge to claims 8 and 9 as anticipated by Lo II.
`Claim 10 requires calculating a normalized sequence tag density for the
`chromosome portion suspected of being abnormally distributed, and calculating
`also a normalized tag density for another chromosome from the sample. Ex. 1001,
`col. 35, ll. 16-20. Claim 11, which depends from claim 10, requires, when
`calculating a differential between the normally and abnormally distributed
`chromosome portions, to do so by comparing (a) a normalized sequence tag
`density of the chromosome portion suspected of abnormal distribution to (b) a
`normalized sequence tag density of another chromosome portion in the mixed
`sample, using all autosomes to calculate the normalized sequence tag density. Id.
`at col. 35, ll. 21-28. Claim 12 requires measurement of over- and under-
`representation of a chromosome by determining a sequence tag density for each
`chromosome in the sample, including chromosomes 1-22, X, and Y, if present. Id.
`at col. 35, ll. 29-33.
`As noted above, Lo II describes normalizing the sequence tag density of
`chromosome 21 based on a comparison with the other chromosomes in the sample,
`which would necessarily include all autosomes, Ex. 1002 ¶ 69, and presents data
`for all chromosomes as part of its analysis, id. at Figs. 4A and 4B. Given these
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`disclosures, Sequenom has demonstrated a reasonable likelihood it will prevail in
`its challenge to claims 10-12 as anticipated by Lo II.
`B. Obviousness of claim 7 in view of Lo II, Hillier, and Smith
`We have reviewed Sequenom’s contentions and supporting evidence
`regarding the proposed ground of obviousness of claim 7 of the ’415 patent in view
`of Lo II, Hillier, and Smith, and are persuaded that Sequenom has shown a
`reasonable likelihood of prevailing in accordance with35 U.S.C. §§ 312 and 314.
`Claim 7 recites “[t]he method of claim 3 wherein the step of assigning
`sequence tags to corresponding chromosome portions allows one mismatch.” Ex.
`1001, col. 35, ll. 9-11. As noted above, we agree with Sequenom that there is a
`reasonable likelihood that it will prevail in its challenge of claim 3 as anticipated
`by Lo II, as well as in its challenge under the same ground as to claim 1, from
`which claim 3 depends.
`Sequenom concedes that Lo II “is silent as to whether one mismatch is
`allowed between the sequence tags and the corresponding chromosome portions.”
`Pet. 22. Sequenom contends, see id. at 23, that Hillier teaches, in a study of the
`accuracy of the massively parallel sequencing technique employed in Lo II, that
`about 80 percent “of the reads exhibited 0 or 1 mismatch when uniquely aligned to
`the reference genome.” Ex. 1006 at 185 (Fig. 2 caption). Similarly, as Sequenom
`contends further, Pet. 23, Smith discloses that mapping longer sequence reads,
`while permitting some mismatches, actually increases accuracy. See Ex. 1009 at 4
`(“[W]e see that the combined target region coverage and mapping selectivity is
`maximized when read length is 36 nt [nucleotides] and up to 4 mismatches are
`allowed.”).
`Based on the teachings that sequence reads map to their unique locations
`reliably even when one mismatch is allowed, and that selectivity is maximized
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`when up to four mismatches are allowed, we are persuaded, based on the record
`presently before us, that an ordinary artisan, while mapping sequence reads to a
`reference genome as taught by Lo II, would have been prompted to allow for one
`mismatch, as recited in claim 7. We determine, accordingly, that Sequenom has
`shown a reasonable likelihood that it would prevail in its challenge of claim 7 as
`being obvious over Lo II, Hillier, and Smith.
`C. Obviousness of claims 13 and 16 over Lo II and Wang
`We have reviewed Sequenom’s contentions and supporting evidence
`regarding the proposed ground of obviousness of claims 13 and 16 of the ’415
`patent in view of Lo II and Wang, and are persuaded that Sequenom has shown a
`reasonable likelihood of prevailing in accordance with35 U.S.C. §§ 312 and 314.
`Regarding claim 13, Sequenom contends that Lo II describes a process that
`includes step (a) of the claimed process. Pet. 24. As to step (b), Sequenom
`concedes that Lo II does not disclose mapping its sequence tags to chromosome
`portions comprised of a sliding window of a predetermined length. Id. at 25. As
`Sequenom contends, however, see id., Wang teaches the use of sliding windows to
`measure mapped sequence tag numbers in a digital karyotyping method similar to
`the methods of detecting chromosomal aberrations described in Lo II. See, e.g.,
`Ex. 1005 at 16156 (“Moving windows containing the same number of virtual tags
`as the simulated alteration were used to evaluate tag densities along the genome.”).
`Given Wang’s teaching of the suitability of using sliding windows to map
`sequence tags to a reference genome when performing a method of determining
`chromosomal abnormalities, we determine, on the present record, that an ordinary
`artisan would have considered it obvious to use sliding windows to map sequence
`tags to specific chromosome portions of a reference genome when determining
`chromosomal abnormalities in Lo II’s process, as step (b) of claim 13 requires.
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`Moreover, given the teachings in both Lo II and Wang of determining the sequence
`tag numbers on all chromosomes when evaluating samples for chromosomal
`abnormalities, see, e.g., Ex. 1002, Figs. 4A and 4B; see also Ex. 1005 at 16158
`(Table 2), we determine, again on the present record, that an ordinary artisan
`would have considered it obvious to determine numbers of sequence tags mapping
`to each sliding window of each autosome, as step (c) of claim 13 requires.
`As to step (d) of claim 13, Sequenom contends that Wang describes
`determining an average, or mean, sequence tag density for all chromosomes in its
`sample, see Pet. 27-28 (citing Ex. 1005 at 16157). Sequenom contends further,
`relying on the Gabriel Declaration, that an ordinary artisan would have considered
`it obvious “to use the individual means from each chromosome to calculate a
`second mean as a method for normalizing the data obtained from all of the
`sequenced tags mapped to the chromosome portions.” Pet. 28 (citing Ex. 1010
`¶ 68). As to step (e), Sequenom contends, again relying on the Gabriel
`Declaration, that an ordinary artisan would have considered it obvious
`to use the second mean (i.e., the mean of the individual means) to
`calculate a normalized value for all 22 autosomes because the
`calculation of normalized values is a standard statistical methodology
`for adjusting values measured on different scales (in the conte[x]t of
`the claimed methods, sequenced
`tag densities measured on
`chromosomes of different sizes) to a notionally common scale.
`
`Id. (citing Ex. 1010 ¶69).
`In evaluating Sequenom’s contentions, we note that declarant Gabriel states
`that she earned a Ph.D. in Genetics in 1998, Ex. 1010 ¶ 4, and has extensive
`experience in the field of nucleic acids-based genotyping, including in supervisory,
`editorial, and advisory roles. See id. at ¶¶ 5-16. Dr. Gabriel states that she has
`authored over 90 peer-reviewed publications, most of which “involve the
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`application of sequencing technology to the study of human disease[,]” and has
`published protocols explaining how “to prepare DNA for use in massively parallel
`sequencing.” Id. at ¶ 17.
`Dr. Gabriel’s relevant training and experience satisfy us that she is qualified
`to testify as to the understanding of a person of ordinary skill in the art at the time
`of the invention. Accordingly, we credit Dr. Gabriel’s testimony as to the
`suitability of analytical techniques applicable to the methods described in Lo II and
`Wang. Given Dr. Gabriel’s explanation, see Ex. 1010 ¶¶ 68-69, we are persuaded,
`on this record, that Sequenom has advanced sufficient evidence to show that an
`ordinary artisan practicing the methods of Lo II and Wang would have considered
`it obvious not only to determine a mean value for the number of sequence tags
`mapping to each chromosome, but to determine also, for normalization purposes, a
`mean value of sequence tags that map to all chromosomes, and, therefore, all
`autosomes. We determine, therefore, that Sequenom has shown that there is a
`reasonable likelihood that an ordinary artisan practicing the methods of Lo II and
`Wang would have considered it obvious to apply the analytical steps (d) and (e) of
`claim 13 to the sequence data generated when performing those methods.
`As to step (f) of claim 13, Sequenom argues, see Pet. 29, that having
`normalized the values of sequence tags mapping to autosomes, an ordinary artisan
`detecting abnormal chromosome distribution according to the teachings of Lo II
`would have considered it obvious to compare normalized values among autosomes
`to determine whether any particular autosome had an abnormal distribution. See,
`e.g., Ex. 1002 ¶ 75 (“[T]he fractional count of the amount of sequenced tags from
`chromosome 21 with reference to all or some other sequenced tags could be
`compared to that of other non-aneuploid chromosomes.”); see also id. at Figs. 4A
`and 4B (comparing relative amounts of detected sequence tags in all chromosomes
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`to evaluate trisomy 21). We agree with Sequenom, on the present record, that a
`process having the steps recited in claim 13 would have been obvious to an
`ordinary artisan in view of Lo II and Wang. We are, therefore, persuaded that
`Sequenom has shown a reasonable likelihood that it would prevail in its challenge
`of claim 13 for obviousness over those references.
`As to claim 16, Sequenom argues, see Pet. 30, that because both Lo II and
`Wang include sequence tag data from chromosomes X and Y in their analyses of
`the sequencing results, see, e.g., Ex 1002, Figs. 4A and 4B; also Ex. 1005 at 16158
`(Table 2), an ordinary artisan would have considered it obvious to calculate
`normalized values for those chromosomes as well, as claim 16 requires. We agree
`with Sequenom, on the present record, that a process having the steps recited in
`claim 16 would have been obvious to an ordinary artisan in view of Lo II and
`Wang. We are, therefore, persuaded that Sequenom has shown a reasonable
`likelihood that it would prevail in its challenge of claim 16 for obviousness over
`those references.
`D. Obviousness of claim 14 over Lo II, Shimkets, and Dohm
`Claim 14 recites “[t]he method of claim 3 further comprising the step of
`calculating a relationship between numbers of sequence tags and GC content
`associated with sequence tags in a given window and correcting for a higher or
`lower number of reads resulting from a change in GC content.” Ex. 1001, col. 36,
`ll. 18-22. As noted above, Sequenom has persuaded us that there is a reasonable
`likelihood it would prevail in its challenge to claim 3 as anticipated by Lo II.
`As Sequenom contends, see Pet. 30-31, Shimkets discloses, in a sequencing-
`based karyotyping method similar to that employed in Lo II, that the sequencing
`technique may have “a slight bias in favor of sequences with certain compositional
`characteristics (such as higher or lower GC content, the percentage of nucleotides
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`in a given stretch that are G or C). This bias could be ascertained by calibration
`experiments and th