Ariosa Diagnosticsv.Verinata Health, Inc.

Patent Trials and Appeals Board

Oct 23, 2014

13368035 - (D) (P.T.A.B. Oct. 23, 2014)

Trials@uspto.gov Paper No. 42
571-272-7822 Entered: October 23, 2014
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

ARIOSA DIAGNOSTICS,
Petitioner,

v.

VERINATA HEALTH, INC.,
Patent Owner.
____________

Case IPR2013-00277
Patent 8,318,430 B2
____________

Before TONI R. SCHEINER, LORA M. GREEN, and RAMA G. ELLURU,
Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

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

I. INTRODUCTION
A. Background
Ariosa Diagnostics, Inc. (“Petitioner”) filed a Petition requesting inter
partes review of claims 19–30 of U.S. Patent No. 8,318,430 B2 (Ex. 1001,
“the ’430 patent”) pursuant to 35 U.S.C. §§ 311–319. Paper 1 (“Pet.”).
Verinata Health, Inc., (“Patent Owner”) filed a Preliminary Response. Paper
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9. On the basis of the Petition and the Preliminary Response, the panel
determined that Petitioner had demonstrated a reasonable likelihood of
prevailing with respect to at least one of the challenged claims, and on
October 25, 2013, an inter partes review of claims 19–30 was instituted on
the asserted ground that the claims would have been unpatentable over the
combined teachings of Shoemaker, Dhallan, and Binladen. Paper 10
(“Dec.”).1
After institution of trial, Patent Owner filed a Patent Owner Response
(Paper 19, “PO Resp.”), to which Petitioner filed a Reply (Paper 25). Oral
argument was requested by both parties, and was held on July 16, 2014. A
transcript of the oral hearing is included in the record. Paper 41, “Tr.”
Both parties presented witness testimony via declaration during the
course of the proceeding. Petitioner presented the Declarations of Dr.
Cynthia Casson Morton (Ex. 1002, “Morton Decl.”) and Dr. Robert
Nussbaum (Ex. 1003, “Nussbaum Decl.”) with the Petition.2 Patent Owner
presented the Declaration of Dr. Atul J. Butte (Ex. 2003, “Butte Decl.”) with
its Patent Owner’s Response. Finally, with its Reply, Petitioner presented
the Second Declaration of Dr. Morton. Ex. 1042 (“Second Morton Decl.”).
The Board has jurisdiction under 35 U.S.C. § 6(c). This Final Written
Decision, issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73,
addresses issues and arguments raised during trial. For the reasons
discussed below, we determine that Petitioner has not met its burden to

1 Patent Owner did not address this asserted ground in its Preliminary
Response.
2 All references to Exhibits 1002 and 1003 are to the replacement
Declarations filed on March 31, 2014, unless otherwise indicated.
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prove, by a preponderance of the evidence, that claims 19–30 of the ’430
patent are unpatentable.
B. Related Matters
The ’430 patent is the subject of a civil action, Verinata Health, Inc. v.
Ariosa Diagnostics, Inc., Case No. 3:12-cv-05501-S1 (N.D. Cal.), filed
October 25, 2012. Paper 38. Furthermore, concurrent with the instant
Petition, Petitioner filed another petition challenging claims 1–18 of the ’430
patent, IPR2013-00276.
C. The ’430 Patent
The ’430 patent discloses a method for determining the presence or
absence of fetal aneuploidy—a condition in which a fetus carries an
abnormal number of chromosomes—by determining the relative amounts of
non-random polynucleotide sequences from a chromosome suspected of
being aneuploid, and from a reference chromosome or a chromosome
control region, in a cell-free sample from a pregnant woman. Ex. 1001,
1:23–27, 2:10–11, 13:9–12. The ’430 patent further discloses determining
simultaneously the presence or absence of fetal aneuploidy in pooled,
indexed cell-free samples from a plurality of pregnant women, using
massively parallel sequencing. Id. at 1:23–25, 1:66-67.
Briefly, cell-free samples (e.g., maternal serum or plasma) containing
both maternal and fetal nucleic acid fragments are obtained from a plurality
of pregnant women. Id. at 1:41–44, 1:66-67. In each sample, non-random
polynucleotide sequences from a chromosome suspected of being aneuploid,
and non-random sequences from a reference chromosome or chromosome
control region, are enriched selectively and indexed (i.e., tagged for later
identification as originating from a particular sample). Id. at 22:9–15. The
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enriched, indexed samples are pooled, and the enriched, indexed nucleic
acids are sequenced by massively parallel sequencing to produce sequence
reads. Id. The number of sequence reads from the chromosome suspected
of being aneuploid, and the number of sequence reads from the reference
chromosome or chromosome control region, are counted, i.e, enumerated,
and the two numbers are compared to determine whether there is an
abnormal level of DNA associated with the chromosome suspected of being
aneuploid. Id. at 1:45–48, 17:53–59. As discussed above, indexing allows
results from different samples to be distinguished. Ex. 1001, 22:10–15.
D. Illustrative Claim
Of challenged claims 19–30, claim 19 is the only independent claim.
Claim 19, reproduced below, is illustrative.
19. A method for determining a presence or absence of a fetal
aneuploidy in a fetus for each of a plurality of maternal blood
samples obtained from a plurality of different pregnant women,
said maternal blood samples comprising fetal and maternal cell-
free genomic DNA, said method comprising:
(a) obtaining a fetal and maternal cell-free genomic DNA
sample from each of the plurality of maternal blood samples;
(b) selectively enriching a plurality of non-random
polynucleotide sequences of each fetal and maternal cell-free
genomic DNA sample of (a) to generate a library derived from
each fetal and maternal cell-free genomic DNA sample of
enriched and indexed fetal and maternal non-random
polynucleotide sequences, wherein each library of enriched and
indexed fetal and maternal non-random polynucleotide
sequences includes an indexing nucleotide sequence which
identifies a maternal blood sample of the plurality of maternal
blood samples, wherein said plurality of non-random
polynucleotide sequences comprises at least 100 different non-
random polynucleotide sequences selected from at least one
chromosome region tested for being aneuploid and at least 100
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different non-random polynucleotide sequences selected from at
least one chromosome control region, wherein the at least one
chromosome region tested for being aneuploid and the at least
one chromosome control region are different, and wherein each
of said plurality of non-random polynucleotide sequences is
from 10 to 1000 nucleotide bases in length,
(c) pooling the libraries generated in (b) to produce a pool of
enriched and indexed fetal and maternal non-random
polynucleotide sequences;
(d) performing massively parallel sequencing of the pool of
enriched and indexed fetal and maternal non-random
polynucleotide sequences of (c) to produce sequence reads
corresponding to enriched and indexed fetal and maternal non-
random polynucleotide sequences of each of the at least 100
different non-random polynucleotide sequences selected from
the at least one chromosome region tested for being aneuploid
and sequence reads corresponding to enriched and indexed fetal
and maternal non-random polynucleotide sequences of each of
the at least 100 different non-random polynucleotide sequences
selected from the at least one chromosome control region;
(e) based on the indexing nucleotide sequence, for each of the
plurality of maternal blood samples, enumerating sequence
reads corresponding to enriched and indexed fetal and maternal
non-random polynucleotide sequences selected from the at least
one chromosome region tested for being aneuploid and
sequence reads corresponding to enriched and indexed fetal and
maternal non-random polynucleotide sequences selected from
the at least one chromosome control region; and
(f) for each of the plurality of maternal blood samples,
determining the presence or absence of a fetal aneuploidy
comprising using a number of enumerated sequence reads
corresponding to the at least one chromosome region tested for
being aneuploid and a number of enumerated sequence reads
corresponding to the at least one chromosome control region of
(e).
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E. The Prior Art
Petitioner relies on the following prior art:
Shoemaker US 2008/0090239 A1 Apr. 17, 2008 (Ex. 1008)
Dhallan US 7,332,277 B2 Feb. 19, 2008 (Ex. 1004)
Jonas Binladen et al., The Use of Coded PCR Primers Enables
High-Throughput Sequencing of Multiple Homolog
Amplification Products by 454 Parallel Sequencing, 2 PLOS
ONE 1–9 (2007) (Ex. 1005).
F. Grounds of Unpatentability Instituted for Trial
The Board instituted inter partes review based on the following
ground of unpatentability:
Claims 19–30 under 35 U.S.C. §103(a) as unpatentable over the
combination of Shoemaker, Dhallan, and Binladen.
II. ANALYSIS
A. Claim Construction
In the Decision on Institution, the panel construed several claim terms
(Dec. 7–12), all of which appear in claim 19: (1) “selectively enriching a
plurality of non-random polynucleotide sequences;” (2) “at least 100
different non-random polynucleotide sequences selected from at least one
chromosome region tested for being aneuploid and at least 100 different
non-random polynucleotide sequences selected from at least one
chromosome control region;” (3) “sequence reads corresponding to enriched
and indexed fetal and maternal non-random polynucleotide sequences;” (4)
and “chromosome control region.” We determine it is not necessary to
depart from those claim constructions for purposes of this decision.

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B. Principles of Law
To prevail in its challenge to the patentability of the claims, Petitioner
must prove unpatentability by a preponderance of the evidence. 35 U.S.C.
§ 316(e); 37 C.F.R. § 42.1(d). 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 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, 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
rejection 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.
We analyze the instituted grounds of unpatentability in accordance
with those principles.
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C. Alleged Obviousness over Shoemaker, Dhallan, and Binladen
Petitioner asserts that claims 19–30 of the ’430 patent are
unpatentable under 35 U.S.C. § 103(a) as having been obvious over the
combination of Shoemaker, Dhallan, and Binladen. Petitioner asserts that
the combination of Shoemaker, Dhallan, and Binladen teaches all the
limitations of the claimed subject matter (Pet. 38–53), and relies, initially, on
the Declaration of Dr. Morton (Ex. 1002), as well as the Declaration of Dr.
Nussbaum (Ex. 1003), for a rationale to combine those elements. Patent
Owner disagrees with Petitioner’s assertions (PO Resp. 4–53) and relies on
the Declaration of Dr. Butte (Ex. 2003) as evidence that it would not have
been obvious for one of ordinary skill in the art to combine the teachings of
the references relied on.
1. Shoemaker (Exhibit 1008)
Shoemaker discloses detection and genetic analysis of fetal cells in a
blood sample from a pregnant woman—a maternal blood sample—which
contains both fetal and maternal cells. Ex. 1008 ¶¶ 13, 71. Genetic analysis
of the fetal cells may include determination of the presence or absence of
fetal aneuploidy, such as trisomy of chromosome 21, 18, or 13. Ex. 1001
¶¶ 71, 107, 108. Multiple samples may be obtained from the same
individual at different times during the course of the pregnancy (id. ¶ 108),
but Shoemaker does not disclose pooling the multiple samples with each
other, or pooling samples from other individuals. Nor does Shoemaker
disclose analyzing a cell-free sample.
Specifically, Shoemaker’s method involves enriching fetal cells in the
maternal blood sample and distributing them among an array of discrete,
addressable locations, e.g., the wells of a microtiter plate, such that each well
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contains either one fetal cell, or none at all. Id. ¶¶ 107–110. Genomic
regions, i.e., loci, of interest are chosen “on a chromosome suspected of
trisomy and on a control chromosome,” and the loci are amplified and
tagged with locator elements (short nucleic acid sequences incorporated into
amplification primers). Id. ¶¶ 114–118. The locator elements “make[] it
possible to pool the amplicons from all the discrete locations following the
amplification step and analyze the amplicons in parallel.” Id. ¶¶ 118, 119.
After the amplicons are analyzed—i.e., sequenced—the locator elements of
the tags are used to sort the sequence reads into “bins” which correspond to
the individual wells of the microtiter plate (and thus, the cell(s) in that well),
and the sequence reads from the bins are used to determine allele abundance,
which in turn, is used to determine aneuploidy. Id. ¶¶ 138, 140.
2. Dhallan (Exhibit 1004)
Dhallan discloses non-invasive detection of chromosomal
abnormalities, including fetal aneuploidy, in cell-free maternal blood
samples. Ex. 1004, 5:63–6:14. Dhallan does not disclose indexing the
samples, or pooling samples from multiple individuals.
Briefly, Dhallan’s method involves amplifying loci of interest with
multiple primer sets. Ex. 1004, 47:63-65, 48:64. Loci of interest may be
single nucleotide polymorphisms (SNPs). Id. at 25:1-10. The primers may
be “designed such that one or both primers of the primer pair contain a
sequence in the 5' region for one or more restriction endonucleases
(restriction enzyme).” Id. at 37: 51-54. Following amplification, restriction
digestion of the primer(s) allows creation of a 5' overhang proximal to a
locus of interest, and the sequence of the locus of interest is analyzed by
incorporating fluorescently-labeled nucleotides to fill in the 5' overhang. Ex.
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1004, 7:61–8:8, 19:7–11, 45:43–46, 53:29–31. Hundreds or thousands of
loci of interest on multiple chromosomes are sequenced simultaneously,
their relative amounts are quantitated, and expressed as a ratio. Id. at 7:9–
16.
3. Binladen (Exhibit 1005)
Binladen discloses simultaneous sequencing of homolog amplification
products from the mitochondrial DNA of thirteen mammalian species,
including humans. Ex. 1005, 1, 3.
Binladen’s method involves generating homologous DNA
amplification products with 5'-nucleotide tagged primers from multiple
specimens using conventional PCR, followed by high-throughput
sequencing on a parallel sequencing platform. Each DNA sequence is
subsequently traced back to its individual source through 5'-tag-analysis. Id.
at 1, 3, 5.
4. Analysis
Petitioner’s position, supported by the Morton and Nussbaum
Declarations, is that the method of claim 19 would have been obvious
because “a scientist in this field would have known that Dhallan could be
enhanced through the use of PCR amplification techniques utilizing sample
indices and massively parallel sequencing of pooled samples as discussed in
Binladen” and because “a skilled artisan would also have readily understood
that Shoemaker’s methods for determining the presence of fetal
abnormalities could be carried out with the use of cell-free DNA described
in Dhallan and the multiplexed detection techniques taught in Binladen”
(Pet. 38 (citing Ex. 1002 ¶ 85, Ex. 1003 ¶ 95)).
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Specifically, Dr. Morton explains that:
[A] skilled artisan would read Dhallan in the context of the state
of the art in indexed PCR amplification techniques as discussed
in Binladen. A skilled artisan reading Shoemaker would
understand that the disclosed methods for determining the
presence of fetal abnormalities could be carried out with the
Dhallan/Binladen techniques. It is my view that the state of the
art as reflected by Shoemaker, Dhallan and Binladen makes
obvious the techniques described in claims 19–30 of the ’430
patent.
Ex. 1002 ¶ 85.
Similarly, Dr. Nussbaum explains that:
[T]his combination discloses each element of Claims 19–30 of
the ’430 patent and [I] believe that one skilled in the art would
have been motivated to combine these techniques, as the
combination would clearly result in an enhanced productivity
and increased throughput of sample analysis. The sequencing
and multiplexing technology of Binladen would have made the
procedures of Shoemaker and Dhallan less expensive, faster
and more efficient because one could sequence indexed samples
from many different patients in a single sequencing run instead
of laboriously performing a single sequencing run for the DNA
samples from each patient.
Ex. 1003 ¶ 95.
In addition, Petitioner provides a claim chart detailing where various
elements of the challenged claims can be found in Shoemaker, Dhallan, and
Binladen. Pet. 39–53. For each element or clause of the claims, the claim
chart purportedly identifies where some aspect of that element or clause is
disclosed by one or more of the references. The Morton Declaration and the
Nussbaum Declaration closely correspond to Petitioner’s claim chart in this
respect. Ex. 1002 ¶¶ 86–111, Ex. 1003 ¶¶ 96–142. However, there is no
mention in the Petition or the Declarations of any differences between the
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claimed subject matter and the prior art, beyond a single statement that
“Dhallan does not teach indexing” (Ex. 1002 ¶ 91). Moreover, nowhere is it
explained how one of ordinary skill in the art would go about combining the
disparate elements of the references, nor is it explained what modifications
one of ordinary skill in the art would necessarily have made in order to
combine them.
Patent Owner argues that “[Petitioner] and its experts fail to address
the claims as a whole and instead dissect the claims into artificially
disembodied ‘techniques,’ which they interpret in a vacuum and attempt to
map into the disclosures of Shoemaker, Dhallan and Binladen.” PO Resp. 8.
Patent Owner contends “[t]his piecemeal approach is presented in the
Petition in the form of a claim chart listing quotes from Shoemaker, Dhallan
and Binladen” and “[a] similar piecemeal approach is performed by Drs.
Morton and Nussbaum in their declarations.” PO Resp. 8 (citing Pet. 41–55,
Ex. ¶¶ 98–129, Ex. 1003 ¶¶ 109–165).
Moreover, Patent Owner argues that Petitioner’s failure to explain
how one of ordinary skill in the art would “combine the disparate parts of
these unrelated references in a functional manner” is particularly relevant to
this inter partes review because “a person of ordinary skill in the art could
not actually combine the methods disclosed in the cited references and . . .
would not even attempt the proposed combination.” PO Resp. 2.
Specifically, Patent Owner argues that Binladen’s tagging method
would not have been combinable with Dhallan’s use of restriction digestible
primers. Patent Owner contends “the methods disclosed in Dhallan critically
rely on restriction digestible primers [for amplification] followed by
cleaving the primer sequence by enzyme digestion” (PO Resp. 48). As
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explained by Dr. Butte, Dhallan’s “‘primers are designed such that one or
both primers of the primer pair contain [a] sequence in the 5' region for one
or more restriction endonucleases (restriction enzyme)’” (Ex. 2003 ¶ 204
(quoting Ex. 1004, 37:50–53)), and the primers are “designed so that
digestion occurs proximal to the SNP site” (Ex. 2003 ¶ 206 (citing Ex. 1004,
38:8–5, 38:24–26, Fig. 1A)). Following amplification, restriction digestion
allows creation of a 5' overhang, and the SNP sequence is analyzed by
incorporating fluorescently-labeled nucleotides to fill in the 5' overhang. Ex.
2003 ¶¶ 207, 208 (citing Ex. 1004, 7:61–8:8, 19:7–11, 45–43–46, 53:29–31).
Dr. Butte explains that Dhallan’s “particular primer design approach is
necessary for Dhallan’s goal of limiting sequence identification to one or a
few nucleotides.” Id. ¶ 206 (citing Ex. 1004, 38:8–5, 38:24–26, Fig. 1A).
Binladen, however, teaches the use of tags that are vulnerable to restriction
enzymes because they have restriction enzyme sites. Id. ¶ 211. Thus,
contends Patent Owner, “Binladen[’s] tags could not be incorporated in the
methods described in Dhallan because they would be incompatible with the
restriction digestible primers critical to the process of Dhallan” and “would
simply be cleaved off by the restriction enzyme” (id. at 50 (citing Ex. 2003
¶¶ 211–213)). In support, Dr. Butte testifies that “[o]ne of ordinary skill in
the art would recognize that the Binladen tags could not be incorporated in
the methods described in Dhallan because they would be incompatible with
the restriction digestible primers critical to the process of Dhallan.” Ex.
2003 ¶ 211.
In addition, Patent Owner argues that a skilled artisan would not have
combined the references because Binladen’s high error rate is unsuitable for
detecting fetal aneuploidy. Patent Owner argues that “determination of fetal
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aneuploidy requires not only accurate sequence determination but also
highly precise quantification methods” because “a mistake leading to either
false negative . . . or false positive . . . can be devastating.” PO Resp. 44.
Patent owner contends “Binladen discloses generating a limited amount of
sequences with a large and unpredictable number of sequencing errors” (id.
(emphasis omitted)), as well as “unpredictable variation in sequence
distribution . . . specifically attribute[d] to tag composition” (id. at 47).
Thus, Patent Owner contends, one of ordinary skill in the art would
recognize that “the tags and corresponding methods of Binladen would
simply be unsuitable for use in methods for determining fetal aneuploidy.”
Id. at 45 (citing Ex. 2003 ¶ 192). In Dr. Butte’s opinion, “one of ordinary
skill . . . would not have considered utilizing the Binladen tags in a fetal
aneuploidy determination method” because of the large number of
sequencing errors, an observed bias in sequence read distribution, and
unpredictable variation in sequence distribution, attributed by Binladen to
the composition of the tags. Ex. 2003 ¶¶ 187–192. Dr. Butte asserts that
“high sequencing error rates and inaccuracies in sequence abundance (which
may correlate to chromosome numbers) would be unacceptable” in
determining fetal aneuploidy, which “requires not only accurate sequence
determination but also highly precise quantification methods.” Id. ¶ 188.
On cross-examination, Dr. Morton was unable to recall describing “a
synthesis of how to put [Shoemaker, Dhallan, and Binladen] together”
anywhere in her Declaration (Ex. 2005, 85:12–16), but expressed the
opinion that the three references, taken together, provide “the path to do
what is presented here” (id. at 84:17–19). Dr. Morton testified:
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[W]hen you combine . . . what’s presented in the three
references . . . you recognize from Dhallan that you have the
presence of fetal DNA in the maternal circulation, and that in
Binladen, you can index samples from different individuals and
combine them for sequence analysis, and then you can figure
out the sequence for that particular individual based on the
indexing.
And that in Shoemaker, you can do a similar analysis, except
that you’re using individual cells instead of -- as the source of
DNA, instead of the source being a particular individual, a
pregnant woman that has a mixture of fetal and maternal
sequences in the same sample. Instead, in Shoemaker, you’re
combining single fetal cells and indexing those, and then you
can actually deconvolute the sequence in each one of those. So
in I feel that taken together, the three of them actually show me
the path to do what is presented here.
Id. at 84:1–19.
Nevertheless, Dr. Morton conceded that certain aspects of Dhallan
and Binladen would not be compatible, and “different methods” would have
been required to implement the claimed method. Ex. 2005, 97:16. For
example, Dr. Morton conceded that one “would do a different process to
incorporate the tags” (id. at 97:6–7), and Binladen’s “tagging would not be
the way that that was done, because the method of inserting the tag, the way
it’s done now was not known at that time” (id. at 100:10–13).
In response to Patent Owner’s contentions regarding the unsuitability
of Binladen’s tags due to a high rate of sequencing errors and variation in
sequence distribution, Dr. Morton asserts that “Binladen proposes ‘primer
design guidelines’” and “one of ordinary skill . . . would be able to easily
apply the teachings of Binladen to optimize the tags to decrease the error
rate and increase the accuracy of putative sample tags.” Ex. 1042 ¶¶ 27, 29.
We are not persuaded. We note Dr. Morton’s earlier testimony, in which
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she asserted that, unlike detection of fetal nucleic acids “known a priori to
be physically absent in the mother” (e.g., Y chromosome sequences),
“[d]etection of cell-free fetal nucleic acid sequences that are present in both
the fetus and the pregnant mother presents different technical challenges, as
does the detection of fetal aneuploidies” and “is currently possible only
through the use of highly precise methods for quantification by, e.g.,
amplification of the fetal and maternal nucleic acids in the sample followed
by single molecule sequencing.” Ex. 1002 ¶¶ 22, 23.
Having considered the Petition, and the Declarations of Drs. Morton
and Nussbaum that accompanied it, we conclude that Petitioner has failed to
prove by a preponderance of the evidence that claims 19–30 would have
been unpatentable over Shoemaker, Dhallan, and Binladen. Although the
Petition and accompanying Declarations point to disparate elements of the
three references, and attempt to map them to elements of the challenged
claims, virtually no effort is made to explain how or where the references
differ from the challenged claims, how one of ordinary skill in the art would
go about combining their disparate elements, or what modifications one of
ordinary skill in the art would necessarily have made in order to combine the
disparate elements. What is lacking in the Petition and accompanying
Declarations is an “articulated reason[] with some rational underpinning to
support the legal conclusion of obviousness.” Kahn, 441 F.3d at 988. The
inadequacy of the obviousness analysis in the Petition and accompanying
Declarations is readily apparent when the disparate elements of the
references are scrutinized closely, as in Patent Owner’s response, and we
decline to search through the record and piece together those teachings that
might support Petitioner’s position. Cf. DeSilva v. DiLeonardi, 181 F.3d
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865, 866-67 (Fed. Cir. 1999) (“A brief must make all arguments accessible
to the judges, rather than ask them to play archeologist with the record.”).
To the extent Petitioner’s Reply and Dr. Morton’s Second Declaration
are responsive to specific points raised by Dr. Butte in his Declaration
concerning the combinability of Binladen or Shoemaker with Dhallan, we
are not persuaded. As discussed above, Dr. Morton acknowledged on cross-
examination that Binladen’s indexing (i.e., tagging) scheme could not be
used with Dhallan’s restriction-digestible amplification primers. Dr.
Morton, in her Second Declaration, contends that Dhallan also teaches a
number of amplification and/or detection methods which do not require the
use of restriction digestible primers” (Ex. 1042 ¶¶ 17, 18), but those portions
of Dhallan were not identified or discussed in the Petition or the
accompanying Declarations. Moreover, although Dr. Morton asserts that
“one of ordinary skill in the art would use basic common sense and not
utilize the embodiments of Dhallan where restriction sites are added to the
primers” (id. ¶ 32 (emphasis omitted)), Dr. Morton still does not explain
how these other methods would be combined with Binladen or Shoemaker.
Nor are we persuaded by the belated attempt in the Reply and Dr.
Morton’s Second Declaration to bolster Petitioner’s initial obviousness
challenge by reference to technical advances, e.g., massively parallel
sequencing (MPS), that one of ordinary skill in the art would have been
aware of “in the years between the filing of Dhallan and the earliest claimed
priority date” (Reply 8, 9). For example, Exhibit 1010 was introduced
briefly in Dr. Nussbaum’s Declaration as disclosing “a commercially
available kit for production and analysis of indexed libraries from different
samples of origin” “designed to be used with Illumina’s multiplexed
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sequencing platform, the Illumina Genome AnalyzerTM” (Ex. 1003 ¶ 21). In
her Second Declaration, Dr. Morton asserts:
It is my opinion that one of ordinary skill in January 2010
would not only be aware of the use of next generation,
massively parallel sequencing [e.g., Ex. 1033; Ex. 1036; Ex.
1011; Ex. 1045], but would have been aware of the
commercially-available indexing kit available through Illumina,
Inc. in 2008 [Ex. 1010] that allowed for sequencing of 96
different samples on a single flow cell. Thus, not only was
barcoding or sample indexing known in the art as evidenced by
both Binladen and Shoemaker, but as early as 2008 Illumina,
Inc. offered a sample indexing kit that was compatible with the
Genome Analyzer, the same sequencing system used in
generating the data reported in the ‘430 patent. [Ex. 1001 at col.
18:52-540].
It is my opinion that one of ordinary skill in January 2010
would be motivated to index individual samples and pool them
for sequencing to maximize sequencing capacity and to
minimize sequencing cost. For example, the Illumina, Inc.
product flyer from 2008 [Ex. 1010] states, “[h]arnessing this
sequencing power in a multiplexed fashion increases
experimental throughput while reducing time and cost.”
Ex. 1042 ¶¶ 42–43 (brackets in original).3

3 Exhibit 1010, submitted with the Nussbaum Declaration, Exhibits 1033
and 1036, submitted with the Morton Declaration, and Exhibits 1011 and
1045, submitted with Dr. Morton’s Second Declaration, are as follows:
Multiplexed Sequencing with the Illumina Genome Analyzer
System, Illumina Inc. (2008) (Ex. 1010).
Rossa W.K. Chiu et al., Noninvasive Prenatal Diagnosis of
Fetal Chromosomal Aneuploidy by Massively Parallel Genomic
Sequencing of DNA in Maternal Plasma, 105 PNAS 20458–
20462 (2008) (Ex. 1033).
Rossa W.K. Chiu et al., Noninvasive Pre-natal Diagnosis by
Single Molecule Counting Technologies, 25 Trends in Genetics
324–331 (2009) (Ex. 1036).
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Patent 8,318,430 B2

19
This testimony, in effect, replaces the tagging and sequencing
techniques of Dhallan and Binladen with the Illumina indexing kit and
sequencing platform, but neither Petitioner nor Dr. Morton explains why
Exhibit 1010 could not have been presented as part of the asserted ground of
unpatentability in the first instance with the Petition.4 Therefore we accord
this aspect of Dr. Morton’s testimony no weight.
5. Conclusion
Having considered Petitioner’s and Patent Owner’s positions, as well
as their supporting evidence, we determine that Petitioner has not met its
burden of showing, by a preponderance of the evidence, that claims 19–30
of the ’430 patent are unpatentable as having been obvious over the
combination of Shoemaker, Dhallan, and Binladen.
D. Patent Owner’s Motion to Exclude
Patent Owner, by its Motion to Exclude, seeks to exclude Petitioner’s
Replacement Exhibit 1002, Replacement Exhibit 1003, Exhibits 1014-1040,
portions of Exhibit 1041, Paragraphs 3–46 of Exhibit 1042, Exhibit 1011,
Exhibit 1045, and Exhibit 1046. Paper 29 (“Mot.”).

H. Christina Fan et al., Noninvasive Diagnosis of Fetal
Aneuploidy by Shotgun Sequencing DNA from Maternal Blood,
105 PNAS 16266–16271 (2008) (Ex. 1011).
Lo et al. US 2009/0029377 A1 Jan. 29, 2009 (Ex. 1045)
4 “A reply may only respond to arguments raised in the corresponding . . .
patent owner response.” 37 C.F.R. § 42.23(b). That is, “[r]eply evidence . .
. must be responsive and not merely new evidence that could have been
presented earlier to support the movant’s motion.” Rules of Practice for
Trials before the Patent Trial and Appeal Board, 77 Fed. Reg. 48,612,
48,620 (Aug. 14, 2014).
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Patent 8,318,430 B2

20
As the movant, Patent Owner has the burden of proof to establish that
it is entitled to the requested relief. See 37 C.F.R § 42.20(c). For the
reasons discussed below, Patent Owner’s Motion to Exclude is denied.
1. Replacement Exs. 1002, 1003, and Substitute Exs. 1014–1040
Patent Owner seeks to exclude the replacement Declarations of Drs.
Morton and Nussbaum (Exs. 1002 and 1003), and substitute Exhibits 1014–
1040, filed on March 31, 2014. Mot. 2–3.
Patent Owner contends that it “may incur some prejudice” because
substitute Exhibits 1014–1040 were originally “buried in the record as
attachments to Petitioner’s expert declarations” (id. at 3), and are now
“present[ed] in a new light as separate documents” (id.). Substitute exhibits
1014–1040 were included as attachments to original Exhibits 1002 and 1003
(filed on May 10, 2013), but were not in compliance with 37 C.F.R §
42.63(c). Petitioner was authorized to refile the exhibits that were already
included and listed in the Declarations of Drs. Morton and Nussbaum (Exs.
1002 and 1003, originally filed on May 10, 2013), to bring the exhibits into
compliance with 37 C.F.R § 42.63(c). See Paper 21. The substitute exhibits
were merely renumbered, and the replacement Declarations amended to
reflect the new numbering scheme. We regard the risk of prejudice to Patent
Owner as minimal in this instance.
Accordingly, the Motion is denied with respect to the replacement
Declarations of Drs. Morton and Nussbaum (Exs. 1002 and 1003), and
substitute Exhibits 1014–1040.
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Patent 8,318,430 B2

21
2. Deposition Transcript of Dr. Butte (Ex. 1041); Dr. Morton’s
Second Declaration (Ex. 1042); Fan (Ex. 1011); (Lo Ex. 1045); (Daines Ex.
1046)
Patent Owner argues that portions of Exhibit 1041 relied on by
Petitioner on pages 1, 2, 4, 5, and 14 of its Reply (Paper 26) should be
excluded under Federal Rule of Evidence 4035 because “Petitioner’s
citations to portions of Ex. 1041 omit portions ‘that in fairness ought to be
considered at the same time,’ and inaccurately characterized the testimony
so as to be misleading and unfairly prejudicial to [Patent Owner].” Mot. 4,
6.
Patent Owner also seeks to exclude paragraphs 3–46 of Dr. Morton’s
Second Declaration. Essentially, Patent Owner contends
Dr. Morton’s second declaration is replete with attempted
remedial testimony related to a prima facie case of obviousness
that should have been submitted with the Petition. It is packed
with terms such as “person of ordinary skill,” “motivation to
combine references,” “references considered as a whole,”
“reasonable expectation of success,” and the “relevant field.”
None of these phrases or subjects appear in her first declaration
or in the Petition.
Id. at 7.
Patent Owner further seeks to exclude Exhibits 1011 and 1045 as
“new evidence used to belatedly address knowledge of the person of
ordinary skill in the art during the relevant time period” and “outside the
scope of the Petition.” Id. at 4, 13. Patent Owner seeks to exclude Exhibit
1046 as “a belated identification of challenge.” Id. at 13.

5 As stated in 37 C.F.R. § 42.62, the Federal Rules of Evidence generally
apply in an inter partes review.
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Patent 8,318,430 B2

22
Nevertheless, 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, Case IPR2013-00118, slip op. at 43 (PTAB
June 20, 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.”). In an inter partes review, we regard it as the better
course to have a complete record of the evidence to facilitate public access,
as well as appellate review. See id. (“If the record on review contains not
only all evidence which was clearly admissible, but also all evidence of
doubtful admissibility, the court which is called upon to review the case can
usually make an end of it, whereas if evidence was excluded which that
court regards as having been admissible, a new trial or rehearing cannot be
avoided.”).
To the extent the arguments made in Petitioner’s Reply and Dr.
Morton’s Second Declaration are responsive to arguments made in Patent
Owner’s Response and Dr. Butte’s Declaration, we have considered the
arguments and found them unpersuasive. To the extent the arguments and
evidence presented in Petitioner’s Reply and Dr. Morton’s Second
Declaration are not responsive and could have been presented earlier to
support Petitioner’s challenge, we accord them no weight. Patent Owner’s
Motion to Exclude is denied.

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Patent 8,318,430 B2

23
III. CONCLUSION
We conclude that Petitioner has failed to meet its burden of proof, by
a preponderance of the evidence, that claims 19-30 of the ’430 patent are
unpatentable under 35 U.S.C. § 103 as having been obvious over the
combination of Shoemaker, Dhallan, and Binladen.
IV. ORDER
In consideration of the foregoing, it is hereby:
ORDERED that Petitioner has failed to prove by a preponderance of
the evidence that claims 19-30 of U.S. Patent No. 8,318,430 are
unpatentable;
FURTHER ORDERED that Patent Owner’s Motion to Exclude is
denied; 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.
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Patent 8,318,430 B2

24
For PETITIONER:

Greg Gardella
cpdocketgardella@oblon.com

Scott McKeown
cpdocketmckeown@oblon.com

Kevin Laurence
cpdocketlaurence@oblon.com

Dianna DeVore
DDeVore@ariosadx.com

For PATENT OWNER:

Michael T. Rosato
mrosato@wsgr.com

Maya Skubatch
mskubatch@wsgr.com

Steven Pamelee
sparmelee@wsgr.com