Ariosa Diagnostics, Inc.v.the Board of Trustees of the Leland Stanford Junior University

Patent Trial and Appeal Board

Nov 19, 2014

13452083 (P.T.A.B. Nov. 19, 2014)

Trials@uspto.gov Paper No. 40
571.272.7822 Filed: November 19, 2014

UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________________

ARIOSA DIAGNOSTICS,
Petitioner,
v.
THE BOARD OF TRUSTEES OF THE LELAND
STANFORD JUNIOR UNIVERSITY,
Patent Owner.
____________________

Case IPR2013-00308
Patent 8,296,076 B2
___________________

Before TONI R. SCHEINER, LORA M. GREEN, and
SCOTT E. KAMHOLZ, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

FINAL WRITTEN DECISION
35 U.S.C. § 318(a) and 37 C.F.R. § 42.73

I. INTRODUCTION
A. Background
Petitioner, Ariosa Diagnostics (“Ariosa”), filed a Petition requesting
inter partes review of claims 1–13 (“the challenged claims”) of U.S. Patent
No. 8,296,076 B2 (“the ’076 patent”). Paper 1 (“Pet.”). Patent Owner, The
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Board of Trustees of the Leland Stanford Junior University (“Stanford”), did
not file a Patent Owner Preliminary Response. We determined that the
information presented in the Petition demonstrated that there was a
reasonable likelihood that Petitioner would prevail in challenging claims
1–13 as unpatentable under 35 U.S.C. § 102(e) and 35 U.S.C. § 103(a).
Pursuant to 35 U.S.C. § 314, the Board instituted this proceeding on
November 20, 2013, as to the challenged claims of the ’076 patent. Paper 7
(“Institution Decision”; “Dec. Inst.”).
Patent Owner filed a Response (Paper 15, “PO Resp.”), but did not
file a motion to amend. Petitioner subsequently filed a Reply. Paper 18
(“Reply”). An oral hearing was held on July 11, 2014. The transcript of the
hearing has been entered into the record. Paper 39.
We have jurisdiction under 35 U.S.C. § 6(c). This final written
decision is issued pursuant to 35 U.S.C. § 318(a). Based on the record
before us, we conclude that Petitioner has demonstrated by a preponderance
of the evidence that the challenged claims of the ’076 patent are
unpatentable.

B. Related Proceedings
The ’076 patent is the subject of a civil action, Verinata Health, Inc. v.
Ariosa Diagnostics, Inc., No. 3:12-cv-05501-SI (N.D. Cal.), filed
October 25, 2012. Paper 6.

C. The ’076 Patent
The ’076 patent issued on October 23, 2012, with Hei-Mun Christina
Fan and Stephen R. Quake as the listed co-inventors. The ’076 patent
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“relates to the field of molecular diagnostics, and more particularly to the
field of prenatal genetic diagnosis.” Ex. 1001, col. 1, ll. 36–38.
The ’076 patent teaches that fetal chromosomal aneuploidies may
affect 9 out of every 1000 live births. Id. at col. 1, ll. 49–50. The discovery
of significant amounts of cell-free nucleic acid in the maternal blood stream
has led to the development of non-invasive prenatal tests for a variety of
traits, but measurement of aneuploidy has presented a challenge due to the
high background of maternal DNA, as fetal DNA often constitutes less than
10% of total DNA in maternal cell-free plasma. Id. at col. 1, l. 62–col. 2,
l. 3. Methods that have been used to detect aneuploidy include detecting an
allelic variation between the mother and the fetus, direct shotgun sequencing
followed by mapping of fragments to the chromosome of origin, as well as
enumeration of the number of fragments per chromosome. Id. at col. 2, ll.
4–21.
In a preferred method of the ’076 patent, DNA is obtained from
maternal serum, wherein the DNA is a mixture of maternal and fetal DNA.
Id. at col. 3, ll. 40–47. The DNA is sequenced partially to provide a large
number of short reads, which act as sequence tags, with a significant number
of the short reads being sufficiently unique such that they can be mapped to
specific chromosomes or chromosomal locations of the human genome. Id.
at col. 3, 47–52. “By counting the number of sequence tags mapped to each
chromosome (1–22, X and Y), the over- or under-representation of any
chromosome or chromosome portion in the mixed DNA contributed by an
aneuploid fetus can be detected.” Id. at col. 3, ll. 54–58. As taught by the
’076 patent, the method does not rely on a priori sequence information to
distinguish fetal DNA from maternal DNA. Id. at col. 3, ll. 64–66.
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The ’076 patent also discloses a method for correcting for the
“nonuniform distribution [of] sequence tags to different chromosomal
portions.” Id. at col. 4, ll. 54–55. The ’076 patent discloses a method in
which a large number of windows of defined length are created along
chromosomes of interest, such that the windows cover each chromosome of
interest, except that non-informative regions of the chromosomes, such as
centromere and repetitive regions, are not necessarily included. Id. at col. 4,
ll. 56–62. As taught by the ’076 patent, “[v]arious average numbers, i.e.,
median values, are calculated for different windows and compared. By
counting sequence tags within a series of predefined windows of equal
lengths along different chromosomes, more robust and statistically
significant results may be obtained.” Id. at col. 4, ll. 62–67.
The ’076 patent also provides examples that describe “direct
sequencing of cell-free DNA from plasma of pregnant women with high
throughput shotgun sequencing technology.” Id. at col. 20, ll. 30–32. The
sequences are mapped to specific chromosomal regions, allowing for the
measurement of over- and under-representation of chromosomes from an
aneuploid fetus. Id. at col. 20, ll. 34–36.
The ’076 patent discloses further that “[a]nother method for
increasing sensitivity to fetal DNA is to focus on certain regions within the
human genome,” such as by using sequencing methods that select sequences
that map to a chromosome of interest a priori. Id. at col. 13, ll. 53–56. An
area of focus may be a partial chromosome deletion, such as 22q11 deletion
syndrome. Id. at col. 13, ll. 57–59. Sequence-based methods that may be
used to sequence selected subsequences include sequencing by array, as well
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as using capture beads with specific genomic sequences used as capture
probes. Id. at col. 13, l. 65–col. 14, l. 1.
As taught by the ’076 patent:
The subsequencing method is in one aspect contrary to
conventional massively parallel sequencing methodologies,
which seek to obtain all of the sequence information in a
sample. This alternative method selectively ignores certain
sequence information by using a sequencing method which
selectively captures sample molecules containing certain
predefined sequences. One may also use the sequencing steps
exactly as exemplified, but in mapping the sequence fragments
obtained, give greater weight to sequences which map to areas
known to be more reliable in their coverage, such as exons.
Otherwise, the method proceeds as described below, where one
obtains a large number of sequence reads from one or more
reference chromosomes, which are compared to a large number
of reads obtained from a chromosome of interest, after
accounting for variations arising from chromosomal length,
G/C content, repeat sequences and the like.
Id. at col. 14, ll. 21–39.

D. Illustrative Claims
Claim 1 is the only independent challenged claim. Claims 1–3 and 9
are illustrative of the disclosed invention, and are reproduced below
(emphases added):
1. A method of testing for an abnormal distribution of a
chromosome in a sample comprising a mixture of maternal and
fetal DNA, comprising the steps of:
(a) obtaining maternal and fetal DNA from said sample;
(b) sequencing predefined subsequences of the maternal
and fetal DNA to obtain a plurality of sequence tags aligning to
the predefined subsequences, wherein said sequence tags are of
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sufficient length to be assigned to a specific predefined
subsequence, wherein the predefined subsequences are from a
plurality of different chromosomes, and wherein said plurality
of different chromosomes comprise at least one first
chromosome suspected of having an abnormal distribution in
said sample and at least one second chromosome presumed to
be normally distributed in said sample;
(c) assigning the plurality of sequence tags to their
corresponding predetermined subsequences;
(d) determining a number of sequence tags aligning to the
predetermined subsequences of said first chromosome and a
number of sequence tags to the predetermined subsequences of
the second chromosome; and
(e) comparing the numbers from step (d) to determine the
presence or absence of an abnormal distribution of said first
chromosome.

2. The method of claim 1 wherein the sample is a
maternal serum or plasma sample, wherein the abnormal
distribution of said first chromosome is a fetal aneuploidy, and
wherein said second chromosome is a euploid chromosome.

3. The method of claim 2 wherein the sequencing
comprises massively parallel sequencing of the predefined
subsequences.

9. The method of claim 2 wherein said sequencing
comprises selectively sequencing nucleic acid molecules
comprising the predefined sequences.

Ex. 1001, col. 35, ll. 10–41, col. 36, ll. 8–10.

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E. Instituted Challenges
Claims Basis References
1–5, 7–9, 12, and 13 § 102(e) Lo1
10 and 11 § 103(a) Lo and Brenner2
1–5 and 7–13 § 103(a) Quake3 and Kapur4
6 § 103(a) Lo and Li;
5 and Quake, Kapur, and
Li

II. ANALYSIS
A. Claim Construction
In an inter partes review, claim terms in an unexpired patent are
interpreted according to their broadest reasonable construction in light of the
specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,766
(Aug. 14, 2012). Claim terms also are given their ordinary and customary
meaning, as would be understood by one of ordinary skill in the art in the
context of the entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249,
1257 (Fed. Cir. 2007). If an inventor acts as his or her own lexicographer,

1 Lo et al., Pub. No. US 2009/0029377, published Jan. 29, 2009 (Ex. 1004,
“Lo”).
2 Brenner, Pub. No. US 2006/0177832 A1, published Aug. 10, 2006
(Ex. 1003, “Brenner”).
3 Quake et al., Pub. No. US 2007/0202525 A1, published Aug. 30, 2007
(Ex. 1006, “Quake”).
4 Kapur et al., Pub. No. US 2008/0138809 A1, published Jun. 12, 2008
(Ex. 1005, “Kapur”).
5 Heng Li et al., Mapping Short DNA Sequencing Reads and Calling
Variants Using Mapping Quality Scores, 18 GENOME RESEARCH 1851–1858
(2008) (Ex. 1014, “Li”).
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the definition must be set forth in the specification with reasonable clarity,
deliberateness, and precision. Renishaw PLC v. Marposs Societa’ per
Azioni, 158 F.3d 1243, 1249 (Fed. Cir. 1998). “[A] claim construction that
excludes a preferred embodiment . . . is rarely, if ever correct and would
require highly persuasive evidentiary support.” Epos Tech. Ltd. v. Pegasus
Tech. Ltd., 766 F.3d 1338, 1347 (Fed. Cir. 2014) (alteration in original)
(internal citation and quotations omitted). Moreover, “[u]nder the doctrine
of claim differentiation, dependent claims are presumed to be of narrower
scope than the independent claims from which they depend.” AK Steel
Corp. v. Sollac and Ugine, 344 F.3d 1234, 1242 (Fed. Cir. 2003) (internal
citation omitted).
1. “sequence tag”
The ’076 patent defines “sequence tag” as a “DNA sequence of
sufficient length that it may be assigned specifically to one of chromosomes
1–22, X or Y.” Ex. 1001, col. 8, ll. 57–59. We adopt that construction.
2. “massively parallel sequencing”
Neither party explicitly requests a construction of this term, which is
found in dependent claims 3 and 4, but we set forth the definition provided
by the ’076 patent, as it informs our construction of other portions of the
claim whose construction is at issue. Specifically, the ’076 patent defines
“massively parallel sequencing” as
techniques for sequencing millions of fragments of nucleic
acids, e.g., using attachment of randomly fragmented genomic
DNA to a planar, optically transparent surface and solid phase
amplification to create a high density sequencing flow cell with
millions of clusters, each containing ~1,000 copies of template
per sq. cm. These templates are sequenced using four-color
DNA sequencing-by-synthesis technology.
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Ex. 1001, col. 9, ll. 22–29.
3. “sequencing predefined subsequences”
In the Institution Decision, we construed this term as not limited to
any particular sequencing technique, and thus encompassing the use of
random shotgun sequencing. Dec. Inst. 7–10.
Patent Owner contends that the method claimed by the ’076 patent is
limited to “targeted sequencing, i.e., only certain predefined sequences are
actually sequenced,” which, Patent Owner asserts, excludes the use of
random shotgun sequencing. PO Resp. 7. In particular, Patent Owner
argues that the term “predefined” in the claim excludes random sequencing.
Id. at 8. According to Patent Owner, although the Specification includes
embodiments to both random and targeted sequencing, the ordinary artisan
would understand that the use of the term “predefined” refers to targeted
sequencing. Id. at 10–12.
Relying on the Declaration of Dr. J. Chris Detter, Patent Owner
asserts that “a person of ordinary skill in the art would understand that the
term ‘predefined’ refers to preselecting the nucleic acids to be sequenced
prior to sequencing them.” Id. at 8–9 (citing Ex. 2008 ¶ 48). Patent Owner
argues further that step 1(b) of claim 1 also supports its construction,
because the sequence tags are assigned only to predefined subsequences, and
thus sequence tags that cannot be assigned to the predefined sequences are
not produced. Id. at 9. According to Patent Owner, steps 1(c) and 1(d) of
claim 1 also support its construction. Id. at 10. Specifically, Patent Owner
argues that the use of the term “subsequence,” as well as the term
“predefined,” “confirms that less than all of the chromosomes of interest are
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being sequenced in the claimed method, consistent with targeted
sequencing.” Id.
Petitioner responds that Patent Owner’s construction excludes the
preferred and exemplified embodiments of the ’076 patent, all of which
involve the use of random shotgun sequencing. Reply 2.
We have considered Patent Owner’s contentions carefully, as well as
the evidence cited by Patent Owner, and we decline to adopt its proffered
construction of limiting “sequencing predefined subsequences” to targeted
sequencing. As noted by Petitioner, the term “targeted sequencing” nowhere
appears in the Specification of the ’076 patent. Id. at 1. Moreover, claim
terms are not construed in isolation. Rather, claim terms should be
construed in the context of the claim as a whole, in light of the teachings of
the Specification. See, e.g., Hockerson-Halberstadt, Inc. v. Converse Inc.,
183 F.3d 1369, 1374 (Fed. Cir. 1999) (“Proper claim construction . . .
demands interpretation of the entire claim in context, not a single element in
isolation.”). We find that the rest of claim 1, the dependent claims, and the
Specification support our construction.
The portion of step (b) of claim 1 that includes the disputed phrase
recites (emphasis added) “sequencing predefined subsequences of the
maternal and fetal DNA to obtain a plurality of sequence tags aligning to the
predefined subsequences.” Thus, the claim language associates “sequencing
predefined sequences” with obtaining “sequence tags.” The Specification of
the ’076 patent discusses sequence tags in the context of shotgun
sequencing. See, e.g., Ex. 1001, col. 14, ll. 56–66. As Petitioner notes, there
is no discussion in the Specification of the term “targeted sequencing.”
Reply 1. Instead, the ’076 patent also discloses the use of a large number of
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windows of defined length created along the chromosome, such that the
windows cover each chromosome in question, except for the non-
informative regions of the chromosome, such as centromere and repetitive
regions, may be omitted. Id. at col. 4, ll. 56–62. Thus, “[v]arious average
numbers, i.e., median values, are calculated for different windows and
compared. By counting sequence tags within a series of predefined
windows of equal lengths along different chromosomes, more robust and
statistically significant results may be obtained.” Id. at col. 4, ll. 62–67
(emphasis added). As taught by the ’076 patent, “[e]ach autosome (chr.
1–22) is computationally segmented into contiguous, non-overlapping
windows,” although sliding windows could also be used. Id. at col. 5, ll.
4–9. In addition, as noted above, the ’076 patent also provides examples
that describe “direct sequencing of cell-free DNA from plasma of pregnant
women with high throughput shotgun sequencing technology,” wherein
sequences were mapped to specific chromosomal regions, allowing for the
measurement of over- and under-representation of chromosomes from an
aneuploid fetus. Id. at col. 20, ll. 30–36. Thus, the Specification does not
disclose sequencing only the defined sequences as Patent Owner would have
us construe this phrase, but instead, it discloses sequencing the predefined
sequences along with other sequences, and then using various techniques to
locate the predefined sequences in the material that has been sequenced.
Thus, we conclude that the broadest reasonable interpretation of the
phrase “sequencing predefined subsequences” is that the subsequences may
be predefined through comparison with the predefined windows that are
created along the length of the chromosome. The predefined subsequences
may walk along the entire length of the chromosome. Thus, although one
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predefined subsequence would not include the entire chromosomal
sequence, two or more subsequences may include the entire length of the
chromosomal sequence. That interpretation encompasses the preferred
embodiment of the ’076 patent, whereas Patent Owner’s proffered
construction limiting the method of claim 1 to “targeted” sequencing, as
Patent Owner defines that term, would not
Steps (c) and (d) of claim 1 are not inconsistent with our construction.
Step (c) requires “assigning the plurality of sequence tags to their
corresponding predetermined subsequences” (emphasis added), which
would encompass matching the sequence tag to its corresponding predefined
window. Step (d) requires “determining a number of sequence tags aligning
to the predetermined subsequences of said first chromosome and a number
of sequence tags to the predetermined subsequences of the second
chromosome,” which encompasses counting the number of sequence tags
that match the corresponding predefined window.
Moreover, the doctrine of claim differentiation supports our
construction. Claim 9 requires that “said sequencing comprises selectively
sequencing nucleic acid molecules comprising the predefined sequences.”
Claim 9 depends from claim 2, which depends from claim 1. The claim 9
limitation—that the sequencing step is limited to sequencing only the
predefined sequences—further supports our interpretation that “sequencing
predetermined sequences” is not limited to sequencing only the predefined
sequences, but encompasses sequencing sequences in addition to the
predefined sequences. Although we recognize that the doctrine of claim
differentiation may be more of a “rebuttable presumption” than a “doctrine,”
Retractable Technologies, Inc. v. Becton, Dickinson & Co., 653 F.3d 1296,
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1305 (Fed. Cir. 2011), Patent Owner has not provided evidence or argument
sufficient to rebut the presumption. See also Seachange Intern., Inc. v. C-
COR, Inc., 413 F.3d 1361, 1368-69 (noting that the “doctrine is at its
strongest ‘where the limitation sought to be “read into” an independent claim
already appears in a dependent claim’”).
Thus, consistent with the Institution Decision, we decline to limit
“sequencing predefined sequences” to any particular sequencing method, but
construe the term as encompassing sequencing methods such as random
shotgun sequencing, as well as sequencing by hybridization. Dec. Inst. 7–
10; see also Ex. 1041, 32–34 (District Court claim construction order noting
that claim 1 is not limited to selectively capturing sample molecules, that is,
molecular preselection).
In sum, we construe “sequencing predefined subsequences” as not
limited to targeted sequencing, wherein the sequences are molecularly
preselected, such as by hybridization; but as also encompassing
informationally predefining the subsequences, such as through the use of the
predefined windows taught by the ’076 patent.
4. “predetermined subsequences”
In the Institution Decision, we construed “predetermined
subsequences” as “reference sequence information.” Dec. Inst. 10–11.
Patent Owner contends that step (d) of claim 1 “states that the
‘predetermined subsequences’ are ‘subsequences of said first chromosome’
and subsequences of the second chromosome.’” PO Resp. 15. Thus, Patent
Owner argues that “the predetermined subsequences are not just any
reference sequence information, but rather are reference sequence
information that represent less than all of a chromosome.” Id. Specifically,
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step (d) of claim 1 recites “determining a number of sequence tags aligning
to the predetermined subsequences of said first chromosome and a number
of sequence tags to the predetermined subsequences of the second
chromosome.” Given the explicit language of claim 1 that the sequence tags
are aligned to a “predetermined subsequence” of a chromosome, to read that
limitation as encompassing the entire chromosome would lead the limitation
of “subsequence” out of the claim. Thus, we adopt Patent Owner’s proposed
construction: That is, we construe “predetermined subsequences” as
“reference sequence information that represents less than all of a
chromosome.” Similar to our construction of “sequencing predefined
subsequences,” however, although one predetermined subsequence would
not include the entire chromosomal sequence, two or more predetermined
subsequences may include the entire length of the chromosomal sequence.
5. “polymorphism-independent”
Although the term “polymorphism-independent” does not appear in
claim 1, Patent Owner argues that the claims of the ’076 patent should be
construed “as being directed to polymorphism-independent methods of
detecting fetal aneuploidy.” PO Resp. 15. Patent Owner contends that the
’076 patent “repeatedly makes reference to the fact that the invention is
polymorphism-independent.” Id. Patent Owner does not point us to any
claim language, however, that would limit the claim only to detecting fetal
aneuploidies that are polymorphism-independent. Moreover, Patent Owner
has not explained how the references to “polymorphism-independent” in the
specification amount to a “clear disclaimer” of polymorphism dependent
methods. In re Am. Acad. Of Sci. Tech. Ctr., 367 F.3d 1359, 1369 (Fed. Cir.
2004). Thus, we determine that the broadest reasonable interpretation of the
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method of claim 1 is that it encompasses methods of testing for both
polymorphism dependent, and polymorphism-independent, abnormal
distributions of a chromosome.

B. Patentability
To prevail on its challenges to the patentability of claims, Petitioner
must prove unpatentability by a preponderance of the evidence. 35 U.S.C.
§ 316(e); 37 C.F.R. § 42.1(d).
1. Principles of Law
a. Anticipation
In order for a prior art reference to serve as an anticipatory reference,
it must disclose every limitation of the claimed invention, either explicitly or
inherently. In re Schreiber, 128 F.3d 1473, 1477 (Fed. Cir. 1997). We must
analyze prior art references as a skilled artisan would. See Scripps Clinic &
Res. Found. v. Genentech, Inc., 927 F.2d 1565, 1576 (Fed. Cir. 1991),
overruled on other grounds by Abbott Labs. v. Sandoz, Inc., 566 F.3d 1282
(Fed. Cir. 2009) (to anticipate, “[t]here must be no difference between the
claimed invention and the reference disclosure, as viewed by a person of
ordinary skill in the field of the invention”).
b. Obviousness
A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
between the subject matter sought to be patented and the prior art are such
that 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
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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
nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). An
invention “composed of several elements is not proved obvious merely by
demonstrating that each of its elements was, independently, known in the
prior art.” KSR, 550 U.S. at 418. Moreover, a determination of
unpatentability on the ground of obviousness must include “articulated
reasoning with some rational underpinning to support the legal conclusion of
obviousness.” In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). The
obviousness analysis “should be made explicit” and it “can be important to
identify a reason that would have prompted a person of ordinary skill in the
relevant field to combine the elements in the way the claimed new invention
does.” KSR, 550 U.S. at 418.
2. Patent Owner’s Contention that Petitioner’s Arguments are
Legally Deficient
Patent Owner contends that the expert testimony relied upon by
Petitioner “is legally deficient and does not reflect a proper anticipation or
obviousness analysis.” PO Resp. 16–17. According to Patent Owner, both
of Petitioner’s experts, Dr. Cynthia Casson Morton and
Dr. Robert Nussbaum, “acknowledged that they applied an incorrect and
overly broad understanding of the legal standard for anticipation,” and Dr.
Morton could not “accurately identify a distinction between obviousness and
anticipation.” Id. Patent Owner argues further that the testimony of Dr.
Morton and Dr. Nussbaum is unreliable. PO Resp. 18–19. For example,
Patent Owner argues that Dr. Nussbaum admitted in his deposition that he
had not read the entirety of the ’076 patent, and Dr. Morton admitted that
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she did not review all of the materials cited in her Declaration. Id. at 18-19
(citing Ex. 1038, 9:23–24; Ex. 1037, 37:3–6). We note, however, that it is
within our discretion to assign the appropriate weight to be accorded to the
testimonial evidence of Dr. Morton and Dr. Naussbaum. Thus, we decline
to dismiss testimony of Petitioner’s experts out-of-hand and will give it the
weight we find to be appropriate.
3. Anticipation under 35 U.S.C. § 102(e) of claims 1–5, 7–9,
12, and 13 by Lo
Petitioner contends that Lo anticipates the challenged claims to the
extent that they encompass shotgun sequencing, and also anticipates the
claims to the extent they encompass sequencing of selected targeted
subsequences. Pet. 20. Petitioner also sets forth a claim chart demonstrating
where each element of the claims is taught by the reference, and relies,
initially, on the Declaration of Dr. Morton (Ex. 1008), as well as the
Declaration of Dr. Nussbaum (Ex. 1009). Id. at 21–27; see also Dec. Inst.
11–16 (applying the teaching of Lo to the challenged claims). Patent Owner
disagrees with Petitioner’s assertions (PO Resp. 4–55), and relies on the
Declaration of Dr. Detter (Ex. 2008) as evidence that Lo does not anticipate
the challenged claims.
a. Lo (Ex. 1004)
Lo is drawn to “the diagnostic testing of fetal chromosomal
aneuploidy by determining imbalances between different nucleic acid
sequences, and more particularly to the identification of trisomy 21 (Down
syndrome) and other chromosomal aneuploidies via testing a maternal
sample (e.g.[,] blood).” Ex. 1004 ¶ 3; see also ¶ 46 (defining “chromosomal
aneuploidy” as “a variation in the quantitative amount of a chromosome
from that of a diploid genome”). According to Lo, a number of sequences
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are randomly sequenced, wherein the number is based on the desired
accuracy. Id. ¶ 18. Lo defines “random sequencing” as
sequencing whereby the nucleic acid fragments sequenced have
not been specifically identified or targeted before the
sequencing procedure. Sequence-specific primers to target
specific gene loci are not required. The pools of nucleic acids
sequenced vary from sample to sample and even from analysis
to analysis for the same sample. The identities of the
sequenced nucleic acids are only revealed from the sequencing
output generated.
Id. ¶ 47. Lo notes, however, that “the random sequencing may be preceded
by procedures to enrich a biological sample with particular populations of
nucleic acid molecules sharing certain common features.” Id.
Lo teaches that a biological sample, such as plasma or serum, is
obtained from a pregnant female, wherein the sample contains nucleic acid
fragments from both the fetus and the mother. Id. ¶ 54. The nucleic acid
fragments may then be sequenced, for example, by using massively parallel
sequencing methods. Id. ¶¶ 55–56. Bioinformatics analysis may then be
used to identify those sequence reads which map to a chromosome of
interest. Id. ¶¶ 57–58; see also id. ¶ 70 (noting that sequencing from
“Illumina Genome Analyzer” results in “short sequence tags,” which “were
aligned to the human reference genome sequence[,] and the chromosomal
original was noted”). A second amount of one or more of a second
chromosome is also determined. Id. ¶ 59. By taking into account the
relative amount of the first chromosome to the second chromosome, a
normalized frequency is obtained, which allows for the detection of an
aneuploidy, such as a trisomy. Id. ¶ 69. Lo teaches generating sequence
tags, which may be aligned to each chromosome, and compared to a
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reference chromosome, to allow for the identification of chromosomal gains
or losses. Id. ¶ 70.
Lo teaches that “the number of aligned sequenced tags were counted
and sorted according to chromosomal location.” Id. ¶ 71. As taught by Lo,
“[g]ains or losses of chromosomal regions or whole chromosomes were
determined by comparing the tag counts with the expected chromosome size
in the reference genome or that of a non-disease representative specimen.”
Id.
Lo teaches another embodiment, wherein:
the fraction of the nucleic acid pool that is sequenced in a run is
further sub-selected prior to sequencing. For example,
hybridization based techniques such as oligonucleotide array
could be used to first sub-select for nucleic acid sequences from
certain chromosomes, e.g.[,] a potentially aneuploid
chromosome and other chromosome(s) not involved in the
aneuploidy tested. Another example is that a certain sub-
population of nucleic acid sequences from the sample pool is
sub-selected or enriched prior to sequencing.
Id. ¶ 72.
In particular, Lo teaches that “sequences originating from a potentially
aneuploid chromosome and one or more chromosomes not involved in the
aneuploidy could be enriched by hybridization techniques for example onto
oligonucelotide microarrays,” which sequences would then be subject to
random sequencing. Id. ¶ 79. Lo teaches further that one aspect of this
massively parallel sequencing approach is that representative data from all
of the chromosomes may be generated at the same time. Id. ¶ 80. Lo
explains that although the sequencing is done at random, a database search
may be performed to identify the chromosome from which a particular
fragment originates. Id.
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b. Analysis
Lo teaches a method of testing for an abnormal distribution of a
chromosome, using genomic material obtained from maternal blood. Lo ¶ 3.
Thus, Lo is drawn to a “method of testing for an abnormal distribution of a
chromosome in a sample comprising a mixture of maternal and fetal DNA,”
as well as the step of “obtaining maternal and fetal DNA from said sample”
as required by challenged claim 1.
Lo teaches also that the DNA fragments obtained from the sample
may then be sequenced, for example, by using massively parallel sequencing
methods. Id. ¶¶ 55–56. As taught by Lo, sequence tags are generated,
aligned to each chromosome, and tags identified as originating from a
potentially aneuploid chromosome are compared quantitatively to tags
originating from a reference chromosome, to allow for the identification of
chromosomal gains or losses. Id. ¶ 70. That falls within the scope of the
limitation of step (b) of claim 1 of “sequencing predefined subsequences of
the maternal and fetal DNA to obtain a plurality of sequence tags aligning to
the predefined subsequences, wherein said sequence tags are of sufficient
length to be assigned to a specific predefined subsequence.” That is, as
construed above, the sequencing step is not limited to sequencing only the
predefined subsequences, but encompasses sequencing other portions of the
genome. And, as Lo teaches that the sequence tags are aligned to a
chromosome to allow for the identification of chromosomal gains or losses
(id. ¶ 70), the tags generated must necessarily be of sufficient length to be
assigned to a specific predefined subsequence. See, e.g., Ex. 1008 ¶ 60
(noting that although Lo “does not describe specifically that the sequence
tags were of sufficient length to be assigned to a specific region of the
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genome, one skilled in the art would understand this to be the case, because
the sequence tags used to identify chromosomal origin must have been of
sufficient length to allow assignment to a particular genomic region”).
Moreover, to the extent that the claim encompasses preselecting
sequences, Lo teaches that a fraction of the nucleic acid pool may be further
sub-selected prior to sequencing. Ex. 1004 ¶ 72. As taught by Lo,
hybridization based techniques, such as the use of an oligonucleotide array,
may be used to first sub-select for nucleic acid sequences from certain
chromosomes, such as a potentially aneuploid chromosome, as well as a
second chromosome not involved in the aneuploidy being tested. Id. Thus,
although claim 1 does not specify a pre-selection step, Lo teaches a pre-
selection step, wherein only certain subsequences of the total fraction of
genomic material obtained from the maternal sample is sequenced, wherein
the subsequences are selected for using a hybridization reaction, e.g., such as
hybridization to a DNA array.
In addition, Lo teaches that the sequencing data can be used to
determine an amount of a “first chromosome,” such as the chromosome
being tested for aneuploidy, as well as one or more second chromosomes in
the sample. Id. ¶ 58. As taught by Lo, gains or losses of chromosomal
regions or whole chromosomes may then be determined by comparing the
tag counts with the expected chromosome size in the reference genome to
that of the reference chromosome. Id. ¶ 71. Thus, Lo teaches the limitation
of step (b) of claim 1: “the predefined subsequences are from a plurality of
different chromosomes, and wherein said plurality of different chromosomes
comprise at least one first chromosome suspected of having an abnormal
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distribution in said sample and at least one second chromosome presumed to
be normally distributed in said sample.”
Lo teaches that the sequence tags that are generated are aligned to the
human reference genome sequence in order to determine their chromosomal
origin (id. ¶ 70), and thus discloses a step of “assigning the plurality of
sequence tags to their corresponding predetermined subsequences,” as set
forth in step (c) of claim 1. Although Lo states that the sequences are
aligned with the reference genome sequence to determine their chromosomal
origin, the sequence tags are nucleic acid fragments obtained from the
maternal sample. Ex. 1004 ¶ 54. Thus, as the nucleic sample obtained from
the pregnant female only contains chromosomal fragments, the fragments
necessarily can only be aligned to the subsequence of the chromosome that
corresponds to the sequence of the fragment.
As for step (d) of claim 1, which requires “determining a number of
sequence tags aligning to the predetermined subsequences of said first
chromosome and a number of sequence tags to the predetermined
subsequences of the second chromosome,” Lo discloses tabulating the total
number of individual sequence tags aligned to each chromosome of the
human reference genome sequence. Lo ¶ 70. Finally, Lo also teaches that
“[g]ains or losses of chromosomal regions or whole chromosomes were
determined by comparing the tag counts with the expected chromosome size
in the reference genome or that of a non-disease representative specimen”
(id. ¶ 71), and thus teaches step (e) of claim 1: “comparing the numbers
from step (d) to determine the presence or absence of an abnormal
distribution of said first chromosome.”
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Patent Owner argues that Lo cannot anticipate the challenged claims
as “it does not teach at least the claimed element ‘sequencing predefined
subsequences.’” PO Resp. 20. Patent Owner asserts that Lo teaches only
random sequencing, and that even Petitioner’s expert, Dr. Morton, agrees
that Lo does not teach how to pre-select nucleic acids for sequencing. Id.
(citing Ex. 1037, 71–72). The random sequencing of Lo, Patent Owner
argues, does not anticipate the claims when the claim term “predefined” is
given the meaning of “targeted sequencing.” Id. at 24. That is, the claim
requires “the pre-selection of sequences prior to the sequencing step.” Id. at
25.
Patent Owner asserts further that paragraph 72 of Lo does not teach
“sequencing predefined subsequences,” and that the Declarations of Dr.
Morten and Dr. Nussbaum do not provide any analysis as to why that
paragraph of Lo teaches that limitation. Id. at 20. According to Patent
Owner, Lo at paragraph 72 discloses that hybridization is used to select the
entire chromosome for sequencing. Id. at 22 (citing Ex. 2008 ¶ 66).
Patent Owner contends further that we erred in instituting the
challenge based on Lo. That is, in the Institution Decision, we construed
“sequencing predefined subsequences” as requiring that the subsequences
should uniquely map to a chromosome region of interest (Dec. Inst. 10), but
Lo uses hybridization to select an entire chromosome for sequencing, and
not just a selected subsequence or region of the chromosome. PO Resp. 21–
22. Patent Owner contends that although Lo teaches that sequences from a
potentially aneuploid chromosome, as well as one or more chromosomes not
involved in the aneuploidy, could be enriched by hybridization techniques,
and then subjected to random sequencing, “[a] person of ordinary skill in the
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art would understand that enriching a pool of nucleic acids for sequences
originating from a chromosome is not the same as sequencing only particular
predefined subsequences of the chromosome.” Id. at 23 (citing Ex. 1004 ¶
79; Ex. 2008 ¶ 68). We disagree.
Patent Owner’s arguments are premised primarily on a narrow
construction of “sequencing predefined subsequences” as being drawn to
“targeted sequencing,” wherein “only certain predefined sequences are
actually sequenced”—a construction we have declined to adopt, as discussed
above. See section II.A.3.
Moreover, to the extent that the claim requires preselecting sequences
for sequencing, we do not find convincing Patent Owner’s argument that
paragraph 72 of Lo does not teach a pre-selection step. Specifically, Patent
Owner relies on the Declaration of Dr. Detter, who states that “using an
array to select all fragments associated with an entire chromosome[ ] is not
the same concept as predefining subsequences for sequencing as required by
the claims of the Fan ’076 patent.” Ex. 2008 ¶ 66; see also id. ¶ 68 (noting
that “a person of ordinary skill in the art would understand that enriching a
pool of nucleic acids for sequences originating from a chromosome is not
the same as sequencing only particular predefined subsequences of the
chromosome as in a targeted sequencing approach”).
As noted above, the Specification of the ’076 patent nowhere uses the
term “targeted sequencing.” In addition, although claim 1 uses the term
“predefined subsequences,” neither the language of the claim, nor the
remainder of the Specification, defines how the subsequence is predefined or
predetermined. As discussed above in section II.A.3, although we construed
a single subsequence as not encompassing an entire chromosomal sequence,
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we noted that two or more subsequences can encompass the entire length of
the chromosome.
As taught by Lo (¶ 72), and acknowledged in the Specification of the
’076 patent (Ex. 1001, col. 4, ll. 41–44), the fetal nucleic acids present in
maternal plasma are short fragments. Lo teaches the use of an
oligonucleotide (i.e., a short nucleotide molecule) array to sub-select for
sequences from certain chromosomes. Thus, although Lo may in fact be
using the oligonucleotide array to sub-select for sequences along the entire
length of a desired chromosome, the oligonucleotides that make up the array
are selecting for subsequences of the chromosome, which subsequences may
then be analyzed using massively parallel sequencing. Lo thus teaches
sequencing of predefined subsequences of a chromosome.
Also, our finding that Lo anticipates the method of challenged claim 1
is not inconsistent with our construing “sequencing predefined
subsequences” to mean “sequencing predefined nucleic acid molecules that
uniquely map to a chromosome region of interest in a reference genome.”
Specifically, as discussed above, the fetal nucleic acids that are present in
plasma are short fragments. Lo teaches that the short sequence tags are
aligned to a human reference sequence, and that the chromosomal origin is
noted. Lo ¶ 70. Thus, in the alignment, the sequence tags are necessarily
aligned with a region of the longer chromosome, given that the sequence
tags are short fragments derived from chromosomal DNA.
For similar reasons, Patent Owner contends also that Lo does not
disclose step (d) of claim 1, as “Lo makes it clear that predetermined
sequences are not used in its method.” PO Resp. 28. Lo teaches that after
massively parallel sequencing, the chromosomal location of the sequenced
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tags was determined. Patent Owner argues that Petitioner does not explain
how that “involves determining a number of sequence tags aligning to
predetermined subsequences of chromosomes.” Id. That is, Patent Owner
argues, “the Lo Publication makes clear that ‘massively parallel sequencing
is not dependent on the detection or analysis of predetermined or a
predefined set of DNA sequences.’” Id. at 29 (emphasis omitted) (citing Ex.
1004 ¶ 108).
Again, Patent Owner’s contentions are based, in large part, on a
narrow construction of the term “sequencing predefined subsequences,” a
construction we decline to adopt for the reasons set forth above. Moreover,
to the extent that the claims requires sequencing predefined subsequences,
wherein the sequences are molecularly selected, paragraph 72 of Lo
discusses the use of an oligonucleotide array to sub-select for sequences
from certain chromosomes. In addition, Lo teaches tabulating the total
number of individual sequence tags aligned to each chromosome of the
human reference genome sequence. Id. ¶ 70. Thus, when a potential
aneuploid chromosome and a reference chromosome are preselected using a
DNA array, only those fragments that hybridize to the array are sequenced
and aligned with chromosomal sequences, i.e., the sequence of a potentially
aneuploid chromosome, as well as the sequence of a selected reference
chromosome. Ex. 1043 ¶ 15. That method would meet the limitation of
“determining a number of sequence tags aligning to the predetermined
subsequences” of challenged claim 1.
Patent Owner does not present separate argument as to claims 2, 5, 7–
9, 12, and 13. As to claims 3 and 4, Patent Owner argues that “Lo does not
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disclose the use of a massively parallel sequencing system that sequences
predefined subsequences.” PO Resp. 29–30.
Lo teaches that “the fraction of the nucleic acid pool that is sequenced
in a run is further sub-selected prior to sequencing.” Lo ¶ 72 (emphasis
added). Thus, the sub-selection occurs prior to sequencing. Lo also teaches
that nucleic acid fragments may be sequenced, for example, by using
massively parallel sequencing methods. Id. ¶¶ 55–56. The ordinary artisan
would understand that the sub-selection described by paragraph 72 of Lo
could be performed before performing any of the sequencing methods
disclosed by Lo, including massively parallel sequencing.
c. Conclusion
After considering Petitioner’s and Patent Owner’s positions, as well as
their supporting evidence, we determine that Petitioner has shown by a
preponderance of the evidence that claims 1, 3, and 4 are unpatentable under
35 U.S.C. § 102(e) as anticipated by Lo. In addition, we have reviewed
Petitioner’s position and evidence as to claims 2, 5, 7–9, 12, and 13, and
determine that Petitioner has also shown by a preponderance of the evidence
that those claims are unpatentable under 35 U.S.C. § 102(e) as anticipated by
Lo.

4. Obviousness of Claims 10 and 11 over the Combination of
Lo and Brenner (Ex. 1003)
Petitioner contends that claims 10 and 11 are rendered obvious by the
combination of Lo and Brenner (Pet. 28–29). Patent Owner presents no
evidence or argument demonstrating how Petitioner’s contentions are
incorrect. Upon review of claims 10 and 11, as well as the contentions and
evidence relied upon by Petitioner, we determine that the preponderance of
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the evidence of record demonstrates that those claims are rendered
unpatentable by the combination of Lo and Brenner.

5. Obviousness of Claims 1–5 and 7–13 over the combination
of Quake (Ex. 1006) and Kapur (Ex. 1005)
Petitioner contends that the combination of Quake and Kapur teaches
all the limitations of the challenged claims (Pet. 29–39), and relies, initially,
on the Declaration of Dr. Morton (Ex. 1008), as well as the Declaration of
Dr. Nussbaum (Ex. 1009), for a rationale to combine those elements. Patent
Owner disagrees with Petitioner’s assertions (PO Resp. 30–60) and relies on
the Declaration of Dr. Detter (Ex. 2008) as evidence that it would not have
been obvious for one of ordinary skill in the art to combine the teachings of
the references in the manner set forth by Petitioner.
a. Quake (Ex. 1006)
Quake is drawn to the use of “digital PCR” to detect fetal
aneuploidies, such as Down’s syndrome, which is a chromosomal trisomy.
Ex. 1006 ¶ 9. In the method of Quake, a sample is obtained from the
mother, wherein the sample is preferably maternal peripheral blood of blood
plasma or serum, wherein the sample contains a mixture of maternal and
fetal genetic material. Id. ¶ 26. The genetic material is then distributed into
discrete samples, such that each sample does not contain, on average, more
than one target sequence per sample. Id. ¶ 27. Quake teaches that “[t]he
presence or absence of different target sequences in the discrete samples is
detected; and the results are analyzed whereby the number of results from
the discrete sample will provide data sufficient to obtain results
distinguishing different target sequences.” Id. In addition, Quake uses a
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control sequence to detect an abnormal increase in the target sequence, such
as a trisomy. Id. ¶ 54.
Quake teaches further the quantitative analysis of the detection of
maternal and fetal nucleic acid target sequences, which may “include targets
to different regions such as probes to a target on a chromosome suspected of
being present in an abnormal copy number (trisomy) compared to a normal
diploid chromosome, which is used as a control.” Id. ¶ 61. Specifically,
Quake teaches that detection may “be conveniently . . . carried out by a
sequence specific probe,” or by “directly sequencing a region of interest to
determine if it is the target sequence of interest.” Id. ¶ 84.
Quake teaches that the “method of differential detection of target
sequences may involve direct sequencing of target sequences,” wherein the
sequencing may be of a single molecule, or of an amplified derivative of the
target molecule. Id. ¶ 33. Additionally, Quake teaches the use of massively
parallel sequencing to detect the target sequence. Id. ¶ 120. Quake
describes the use of microfluidics to achieve the digital PCR conditions, but
notes that the sample need not be separated into separate wells, but may be
isolated on different beads, or by adhering to different areas of a substrate.
Id. ¶¶ 112, 116. As taught by Quake, “[o]nly about 30 [base pairs]of random
sequence information are needed to identify a sequence as belonging to a
specific human chromosome,” and teaches that software methods to identify
a sequence to a known genome sequence are known. Id. ¶ 121.
b. Kapur (Ex. 1005)
Kapur discloses a method of enriching a rare cell population, such as
fetal cells from a maternal peripheral blood sample, for the detection and
diagnosis of fetal abnormalities. Ex. 1005 ¶ 5. Kapur teaches that genetic
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conditions that can be determined include trisomy 13, trisomy 18, trisomy
21, Klinefelter Syndrome, dup(17)(11. 2p11. 2) syndrome, as well as Down
syndrome. Id. ¶ 7. Specifically, according to Kapur, a sample from a
pregnant female, such as a blood sample, is enriched for fetal cells. Id. ¶ 11.
Genetic analysis is then performed on the cells, such as by SNP detection or
RNA expression detection. Id. In some embodiments, the genetic analysis
of SNP detection or RNA expression can be done using a microarray,
wherein up to 100,000 SNPs may be detected in parallel, or 10,000
transcripts may be detected in parallel for detecting RNA expression. Id.
¶ 13. According to Kapur, the genetic analysis may be performed on DNA
from chromosomes X, Y, 13, 18, or 21, and may also be performed on a
control sample or reference sample, such as a maternal sample. Id. ¶ 114.
As taught by Kapur, the target cells can be selected and binned,
resulting in the reduction of complexity and/or the total cell number of the
output of the enriched cells. Id. ¶¶ 87–88. In order to analyze the genetic
material, Kapur teaches that “target nucleic acids from a test sample are
amplified and optionally results are compared with amplification of similar
target nucleic acids from a non-rare cell population (reference sample).”
Id. ¶ 109. According to Kapur, the nucleic acid of interest may also be
preamplified, such as by amplification of outer primers in a nested PCR
approach. Id. ¶ 111. The amplified nucleic acids may then be quantified,
for example for determining gene or allele number, such as by using
microarrays. Id. ¶ 112–113.
Kapur teaches:
In some embodiments, analysis involves detecting one or
more mutations or SNPs in DNA from e.g., enriched rare cells
or enriched rare DNA. Such detection can be performed using,
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for example, DNA microarrays. Examples of DNA microarrays
include those commercially available from Affymetrix, Inc.
(Santa Clara, Calif.), including the Gene-Chip™Mapping
Arrays including Mapping 100K Set, Mapping 10K 2. 0 Array,
Mapping 10K Array, Mapping 500K Array Set, and
GeneChip™ Human Mitochondrial Resequencing Array 2.0.
The Mapping 10K array, Mapping 100K array set, and
Mapping 500K array set analyze more than 10,000, 100,000
and 500,000 different human SNPs, respectively. . . . . In some
embodiments, a microarray is used to detect at least 5, 10, 20,
50, 100, 200, 500, 1,000, 2,000, 5,000[,] 10,000, 20,000,
50,000, 1,00[0],000, 200,000, or 500, 000 different nucleic acid
target(s) (e.g., SNPs, mutations or STRs) in a sample.
Id. ¶ 114. Kapur also notes that computer implemented methods for
estimating copy number based on hybridization intensity are known.
Id. ¶ 115.
Kapur provides an exemplary method in Figure 6, which is an
overview of a process of using a SNP detection microarray. Id. ¶ 117.
Figure 7 is an overview of another method of detecting mutations or SNPs
using bead arrays. Id. ¶ 123.
c. Analysis
Petitioner contends that “[i]t would have been obvious to use the
sequencing by array methods taught by Kapur in combination with analysis
of targeted gene loci taught by Quake to identify fetal abnormalities.” Pet.
30. Patent Owner responds that the combination of Quake and Kapur
would not have rendered the method of the challenged claims obvious, as
Kapur does not teach a method of sequencing by array, but in fact teaches a
method of genotyping by single nucleotide polymorphism (“SNP”) analysis
via a hybridization array. PO Resp. 32, 44. Thus, Patent Owner contends,
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the ordinary artisan would not have used the SNP detection array as taught
by Kapur as the sequencing method of Quake. Id. at 51.
According to Patent Owner, in a method of sequencing by array, the
probes on the array “will contain all or most of the possible nucleotide
combinations within a given length,” and the method is thus not sequence-
dependent. Id. at 44; see also id. at 45–46 (describing a method of
sequencing by hybridization). Arrays that are used for SNP detection, Patent
Owner contends, are not the same as those used for sequencing by
hybridization, as the SNP arrays do not contain every possible combination
of nucleotides. Id. at 47–48; see also id. at 46–47 (describing a method of
SNP detection). Patent Owner argues that the ordinary artisan also would
have understood that sequencing by array, and the use of arrays to detect
SNPs, are two separate fields. Id. at 48.
We agree with Patent Owner that, based on the record currently before
us, Petitioner has not demonstrated that the ordinary artisan would have
combined Quake and Kapur as set forth in the Petition (29–39) to arrive at
the method of challenged claim 1.
In particular, Petitioner relies on Figures 6 and 7 of Kapur as teaching
“a method for sequence determination of randomly generated DNA
fragments using arrays having oligonucleotides of known sequence.
Sequencing of a randomly generated genomic fragment via binding to a
predefined sequence on an array aligns a random sequence to a probe
indicative of a specific genomic region.” Pet. 31. The evidence relied upon
by Petitioner does not explain, however, why one would have a used a
method for detecting SNPs as taught by Kapur to perform the sequencing of
Quake. That is, what is lacking in the Petition and accompanying
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Declarations is an “articulated reason[] with some rational underpinning to
support the legal conclusion of obviousness.” Kahn, 441 F.3d at 988.
Petitioner responds that the “sequencing by array technology of
Balasubramanian (US 2003/0022207 A1, published Jan. 30, 2003, Ex. 1040)
is cited in all of Kapur (Ex. 1005 ¶ 163), Quake (Ex. 1006 ¶ 120), and the
‘076 patent (Ex. 1001 at col. 10, lines 50–56).” Paper 34 ¶ 19. Figures 6
and 7 relied upon by Petitioner, however, are drawn to methods of detecting
SNPs, and not to the sequencing array technology of Balasubramanian. In
fact, Petitioner first relies on paragraph 163 of Kapur, which it contends
cites the sequencing array technology of Balasubramanian, in its challenge
of claim 3, which is drawn to the use of massively parallel sequencing.
Petitioner cannot rely upon Balasubramanian in its Reply to make up for the
deficiencies in its Petition. See, e.g., 37 C.F.R. § 42.23(b) (noting that “[a]ll
arguments for the relief requested in a motion must be made in the motion,”
and that a “reply may only respond to arguments raised in the corresponding
opposition or patent owner response”).
Petitioner contends further that “Dr. Detter conceded on cross-
examination that sequencing is detection and Prof. Morton concurs with that
view.” Reply 14 (citing Ex. 2023, 59, ll. 20–23; Ex. 1043 ¶ 50).
Specifically, in response to the question of whether you can detect nucleic
acid by sequencing, Dr. Detter testified “[t]hat is what you detect by
sequencing, is a nucleic acid.” Ex. 2023, 59, ll. 20–23. We do not disagree
with Petitioner that, by virtue of the ability of the nucleic acid to hybridize to
a sequence on the SNP array, the ordinary artisan would have understood
that if the sequence of the sequence on the array is known, one can
determine the sequence of the nucleic acid that hybridized to it. This
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reasoning does not explain, however, why the ordinary artisan would have
used the arrays for detecting SNPs as taught by Kapur in the method of
Quake.
Moreover, in its observations of the cross-examination of Dr. Morton,
Patent Owner argues that “Dr. Morton testified that people of ordinary skill
in the art would not use or understand the term ‘sequencing’ to refer to the
use of SNP detection arrays,” which is consistent with Dr. Nussbaum’s
testimony. Paper 31, 8 (citing Ex. 1051, 139–141; Ex. 1038, 17–18); see
also id. at 10 (noting that Dr. Morton stated on cross-examination that SNP
detection as shown in Figure 6 of Kapur is not a sequencing method, but a
genotyping method (citing Ex. 1051, 143–145)).
Specifically, Dr. Morton testified that SNP detection is “in some
ways . . . sequencing, but not the way we would typically think of
determining perhaps a sequence.” Ex. 1051, 139. According to Dr. Morton,
it would be referred to as genotyping, noting, however, that the genotype is
obtained from the sequence. Id. at 139. When asked whether “[u]sing these
methods for genotyping would not be considered sequencing as you believe
people skilled in the art use the term ‘sequencing,’” Dr. Morton responded:
I think using BeadChips and the Affy chips, people would
typically refer to as genotyping and not sequencing. If I was
going to tell somebody I was going to genotype a sample, they
wouldn't necessarily -- if I was going to -- there wouldn’t be a
confusion between -- if I said I was going to sequence a sample,
they’d think I’m going to get a different output than the
genotyping, because the genotyping, you’re looking for a
specific SNP or to -- to classify that individual. But it is
sequenced. It is nucleotide.

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Id. at 141. Dr. Morton’s testimony further supports our determination that
the ordinary artisan would not have used the method of genotyping using
SNP detection for the sequencing required by the method of Quake.
d. Conclusion
After considering Petitioner’s and Patent Owner’s positions, as well as
their supporting evidence, we determine that Petitioner has not shown by a
preponderance of the evidence that claims 1–5 and 7–13 are unpatentable
under 35 U.S.C. § 103(a) as obvious over Quake and Kapur.

6. Obviousness of Claim 6 over the combination of Lo and Li
(Ex. 1014), and Over Quake, Kapur, and Li
Petitioner contends that claim 6 is rendered obvious by the
combination of Lo and Li, or the combination of Quake, Kapur, and Li (Pet.
58–59). Patent Owner presents no evidence or argument demonstrating how
Petitioner’s contentions are incorrect. Upon review of claim 6, as well as the
contentions and evidence relied upon by Petitioner as to the combination of
Lo and Li, we determine that the preponderance of the evidence of record
demonstrates that the claim is rendered obvious by that combination.
As to the challenge based on the combination of Quake, Kapur, and
Li, we have already determined that Petitioner has not established by a
preponderance of the evidence that the combination of Quake and Kapur
renders independent claim 1 obvious. For the same reasons, we conclude
that Petitioner has not established by a preponderance of the evidence that
the combination of Quake, Kapur, and Li renders claim 6, which is
dependent on claim 1, obvious.

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C. Patent Owner’s Motion to Exclude Evidence (Paper 30)
Patent Owner asks us to exclude the Second Declaration of Dr.
Morton (Ex. 1043), Exhibits 1044–1049, as well as the portions of
Petitioner’s Reply that rely on Exhibit 1043.
We relied only on paragraph 15 of Exhibit 1043, and did not rely on
the remainder of that Declaration, nor did we rely on Exhibits 1044–1049 in
making our final determination. We conclude, therefore, that it is
unnecessary to consider Patent Owner’s objections to the admissibility of
those Exhibits, except to the extent that Patent Owner objects to the
admissibility of paragraph 15 of Exhibit 1043.
As to paragraph 15 of Exhibit 1043, Patent Owner contends that the
figure at the end of the paragraph contains an error. Paper 30, 7. That is,
according to Patent Owner, “[w]hile most of the figure shows the life cycle
of a single strand, the last element of the figure shows obtaining six
sequence tags.” Id. Dr. Morton admitted, however, “that using the
sequencing techniques described in Lo, one would only get a single
sequence tag from a single strand.” Id. Patent Owner contends, therefore,
that “the figure is both irrelevant under FRE 402 and misleading under FRE
403.” Id.
Patent Owner’s objections go more to the weight that paragraph 15 of
Exhibit 1043 should be afforded, rather than to its admissibility. It is within
our discretion to assign the appropriate weight to be accorded to Dr.
Morton’s testimonial evidence. The Board, sitting as a non-jury tribunal
with administrative expertise, is well-positioned to determine and assign
appropriate weight to evidence presented. Gnosis S.P.A. v. S. Alabama
Medical Science Foundation, IPR2013-00118, slip op. at 43 (PTAB June 20,
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2014) (Paper 64). See also Donnelly Garment Co. v. NLRB, 123 F.2d 215,
224 (8th Cir. 1941) (“One who is capable of ruling accurately upon the
admissibility of evidence is equally capable of sifting it accurately after it
has been received.”). We thus decline to exclude paragraph 15 of Exhibit
1043.

III. CONCLUSION
Petitioner has shown by a preponderance of the evidence that claims
1–5, 7–9, 12, and 13 are unpatentable under 35 U.S.C. § 102(e) as
anticipated by Lo;
Petitioner has shown by a preponderance of the evidence that claims
10 and 11 are unpatentable under 35 U.S.C. § 103(a) as obvious over the
combination of Lo and Brenner;
Petitioner has shown by a preponderance of the evidence that claim 6
is unpatentable under 35 U.S.C. § 103(a) as obvious over the combination of
Lo and Li;
Petitioner has not shown by a preponderance of the evidence that
claims 1–5 and 7–13 are unpatentable under 35 U.S.C. § 103(a) over the
combination of Quake and Kapur; and
Petitioner has not shown by a preponderance of the evidence that
claim 6 is unpatentable under 35 U.S.C. § 103(a) over the combination of
Quake, Kapur, and Li.

IPR2013-00308
Patent 8,296,076 B2

38
IV. ORDER
Accordingly, it is hereby:
ORDERED that Petitioner has shown by a preponderance of the
evidence that claims 1–13 of the ’076 patent are unpatentable;
FURTHER ORDERED that Patent Owner’s Motion to Exclude
Evidence is denied to the extent it seeks to exclude paragraph 15 of Exhibit
1043, and dismissed as moot as to the extent it seeks the exclusion of the
remainder of Exhibit 1043, as well as Exhibits 1044–1049, as well as the
portions of Petitioner’s Reply that rely on Exhibit 1043; and
FURTHER ORDERED that because this is a final written decision,
parties to the proceeding seeking judicial review of the decision must
comply with the notice and service requirements of 37 C.F.R. § 90.2.

IPR2013-00308
Patent 8,296,076 B2

39
For PETITIONER:

Greg Gardella
Scott McKeown
Kevin Laurence
OBLON, SPIVAK, McCLELLAND, MAIER & NEUSTADT, L.L.P.
cpdocketgardella@oblon.com
cpdocketmckeown@oblon.com
cpdocketlaurence@oblon.com

Dianna DeVore
ARIOSA DIAGNOSTICS
ddevore@ariosadx.com

Sarah Brashears
CONVERGENT LAW GROUP LLP
sbrashears@covergentlaw.com

For PATENT OWNER:

Robert Huntington
Sharon Crane
ROTHWELL, FIGG, ERNST & MANBECK, P.C.
dhuntington@rfem.com
scrane@rfem.com