Ex Parte Oliphant et al

Patent Trial and Appeal Board

Nov 22, 2016

13689206 (P.T.A.B. Nov. 22, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/689,206 11129/2012
118418 7590
Mintz Levin-Roche/ Ariosa
One Financial Center
Boston, MA 02111
11/25/2016
FIRST NAMED INVENTOR
Arnold Oliphant
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
50876-511C02US 4635
EXAMINER
HAMMELL, NEIL P
ART UNIT PAPER NUMBER
1636
NOTIFICATION DATE DELIVERY MODE
11/25/2016 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
IPDocketingBOS@mintz.com
IPFileroomBOS@mintz.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ARNOLD OLIPHANT, ANDREW SPARKS,
KEN SONG, and JOHN STUELPNAGEL
Appeal2015-006686
Application 13/689,206
Technology Center 1600
Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
RICHARD J. SMITH, Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL 1
This appeal under 35 U.S.C. § 134(a) involves claims 1-3, 6-12, 14--
23, and 37--46 (App. Br. 4). Examiner entered rejection under 35 U.S.C.
§ 103(a). We have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.
1 Appellants identify the real party in interest as "Ariosa Diagnostics, Inc."
(App. Br. 2).
Appeal2015-006686
Application 13/689,206
STATEMENT OF THE CASE
Appellants' disclosure "relates to diagnosis of genetic abnormalities
and assay systems for such diagnosis" (Spec. i-f 2). Claim 1 is representative
and reproduced below:
1. An assay method for providing a statistical likelihood of
the presence or absence of a fetal aneuploidy comprising:
providing a maternal sample comprising maternal and
fetal cell free DNA;
interrogating less than 2000 selected polymorphic nucleic
acid regions from a first chromosome using sequence-specific
oligonucleotides;
isolating the selected polymorphic nucleic acid regions
from the first chromosome;
detecting each isolated selected polymorphic nucleic acid
region from the first chromosome on average at least 100 times;
quantifying total allele counts to determine a relative
frequency of alleles from the isolated selected polymorphic
nucleic acid regions from the first chromosome;
interrogating less than 2000 selected polymorphic nucleic
acid regions from a second chromosome using sequence-
specific oligonucleotides;
isolating the selected polymorphic nucleic acid regions
from the second chromosome;
detecting each isolated selected polymorphic nucleic acid
region from the second chromosome on average at least 100
times;
quantifying total allele counts to determine a relative
frequency of the isolated selected polymorphic nucleic acid
regions from the second chromosome;
interrogating less than 2000 selected polymorphic nucleic
acid regions from at least one chromosome different from the
first and second chromosome using sequence specific
oligonucleotides;
2
Appeal2015-006686
Application 13/689,206
isolating the selected polymorphic nucleic acid regions
from the at least one chromosome different from the first and
second chromosome;
detecting each isolated selected polymorphic nucleic acid
region from the at least one chromosome different from the first
and second chromosome on average at least 100 times;
identifying low frequency alleles from the at least one
chromosome different from the first and second chromosome
using polymorphic regions where the maternal DNA is
homozygous and the fetal DNA is heterozygous;
computing a sum of low frequency alleles from the
isolated selected polymorphic nucleic acid regions from the at
least one chromosome different from the first and second
chromosome; and
calculating a statistical likelihood of the presence or
absence of a fetal aneuploidy in the maternal sample, wherein
the relative frequency of total alleles from the isolated selected
polymorphic nucleic acid regions from the first chromosome,
the relative frequency of total alleles from the isolated selected
polymorphic nucleic acid reg10ns from the second
chromosome, and the sum of the 10\~1 frequency alleles from the
isolated selected polymorphic nucleic acid regions from the at
least one chromosome different from the first and second
chromosome are used to calculate statistically significant
differences in chromosomal frequencies for the first and second
chromosomes, and wherein a statistically significant difference
in chromosomal frequency provides a statistical likelihood of
the presence of a fetal aneuploidy.
(App. Br. 29--31.)
3
Appeal2015-006686
Application 13/689,206
The claims stand rejected as follows:
Claims 1-3, 6-12, 14--23, and 37--46 stand rejected under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Lo '847, 2 Porreca, 3 Van
Opstal, 4 and Lo '353. 5
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
Examiner makes the following findings:
FF 1. Lo '84 7 discloses "methods for providing a statistical likelihood of
the presence or absence of a fetal aneuploidy" from the analysis of "a
maternal sample [] comprising maternal and fetal cell free DNA" using
"massively parallel sequencing" (Ans. 2, citing Lo '847 i-fi-1240, 262, 263,
266, 267, and 271).
FF 2. Lo '84 7 discloses
that it is desirable to specifically target polymorphic loci and
count fetal-specific alleles and common alleles from the
polymorphic nucleic acid region because this informs the
determination of the fractional concentration of fetal DNA[],
which is used to adjust the reference range for expected
2 Lo et al., US 2009/0087847 Al, published Apr. 2, 2009.
3 Gregory J Porreca, et al., Multiplex amplification of large sets of human
exons, 4 NATURE METHODS 931-936 (2007).
4 Diane Van Opstal et al., Rapid aneuploidy detection with multiplex
ligation-dependent probe amplification: a prospective study of 4000
amniotic fluid samples, 17 European Journal of Human Genetics 112-121
(2009).
5 Lo et al., US 2011/0105353 Al, published May 5, 2011.
4
Appeal2015-006686
Application 13/689,206
sequence reads for a given chromosome to inform the diagnosis
of a fetal aneuploidy.
(Ans. 5, citing Lo '847 i-fi-1267 and 278; see also Ans. 7, citing Lo '847 i1278
("Lo [']847 teaches identifying polymorphic sites at which [a] pregnant
woman is homozygous and the fetus is heterozygous," wherein "the amount
of the fetal-specific allele (i.e. low frequency allele) can be compared with
the amount of the common allele to determine the fractional concentration of
fetal DNA (i.e. percent fetal cell free DNA)" and "determining the amount
of the fetal-specific allele"); Ans. 7-8, citing Lo '847 i1267 (Lo '847
discloses "identifying fetal aneuploidy by comparing the relative frequency
of the nucleic acid regions to a reference range and that 'the reference range
is adjusted according to the fractional concentration of fetal DNA in a
particular maternal plasma sample"').)
FF 3. Lo '84 7 discloses "that it was known to specifically target
approximately 500 polymorphic nucleic acid regions per potentially
aneuploidy chromosome and then to base the determination of a
chromosomal imbalance on the SNP allelic ratios for these polymorphic
nucleic acid regions" (Ans. 5, citing Lo '847 i18; see also Ans. 7).
FF 4. Lo '847 discloses the use of "sequence-specific oligonucleotides to
interrogate nucleic acid regions" on "potential[] aneuploidy chromosomes of
interest includ[ing] chromosome 21, chromosome 19, or chromosome 13"
(Ans. 3, citing Lo '847 i-fi-1264, 266, 269, and 273; see also Ans. 5; Ans. 3
(Lo '847 ("suggests [the] use [of] oligonucleotide-based hybridization
techniques to first sub-select for nucleic acid sequences from certain
chromosomes")).
FF 5. Lo '84 7 discloses "targeting polymorphic sites at which the pregnant
woman is homozygous and the fetus is heterozygous and that the amount of
5
Appeal2015-006686
Application 13/689,206
the fetal-specific allele can be compared with the amount of the common
allele (i.e. quantifying a relative frequency of each allele) to determine the
fractional concentration of fetal DNA (i.e. percent fetal cell free DNA)"
(Ans. 5---6, citing Lo '847 i-f 278).
FF 6. Lo '847 discloses the identification of "allelic imbalance using a
Bayesian-type statistical likelihood method" (Ans. 8, citing Lo '847 i-f 88;
see also Ans. 8, citing Lo '84 7 (Lo '84 7 discloses "that it was known to infer
a fetal chromosomal imbalance by detecting a statistically significant
difference between the SNP ratios between two chromosomes")).
FF 7. Lo '847 fails to disclose the interrogation of "less than 2000
polymorphic nucleic acid regions using sequence-specific oligonucleotides"
or the "combination of interrogating polymorphic nucleic acid regions from
a first, second, and third chromosome and further quantifying the total
alleles form the polymorphic nucleic acid regions from the first and second
chromosomes" (Ans. 3 and 5).
FF 8. Porreca discloses "that front-end methods to reduce the complexity
of the mammalian genome to isolate subsets of interest can reduce massively
parallel sequencing costs by several orders of magnitude" (Ans. 3, citing
Porreca Abstract).
FF 9. Porreca discloses the use of "oligonucleotides to specifically
hybridize, capture, and amplify a subset of the genome in a single multiplex
reaction for massively parallel sequencing" (Ans. 3, citing Porreca Abstract,
931: col. 2, second paragraph, 932: col. 1, last paragraph, and Figure 3; see
also Ans. 7, citing Porreca 932: col. 1, last paragraph ("Porreca explicitly
teaches targeting 480 target sites (i.e. less than 2000) for massively parallel
sequencing")).
6
Appeal2015-006686
Application 13/689,206
FF 10. Van Opstal discloses a "method for diagnosing fetal aneuploidy by
using an oligonucleotide ligation-based assay" and to disclose "that the
relative amount of PCR product is proportional to the amount of target
sequence" amplified (Ans. 3--4, citing Van Opstal Abstract, 113: col. 1, last
paragraph, 118: col. 2, second paragraph, and Table 5; see also Ans. 6).
FF 11. Van Opstal suggests the use of "oligonucleotides to specifically
target eight sites (i.e. less than 2000) per aneuploid chromosome to diagnose
fetal aneuploidy" (Ans. 7, citing Van Opstal 114: col. 1, last paragraph).
FF 12. Lo '353 discloses "a method for target-enrichment and targeted
massively parallel sequencing for non-invasive prenatal diagnosis" and "that
target enrichment is an efficient way of estimating the fractional fetal DNA
concentration compared with whole-genome sequencing" (Ans. 4, citing Lo
'353 iii! 239 and 240).
FF 13. Lo '84 7 fails to disclose "that the relative frequency of total alleles
from the two chromosomes are used to calculate statistically significant
differences in chromosomal frequencies between the first and second
chromosomes" as it relates to fetal aneuploidy (Ans. 8).
FF 14. Lo '847 discloses "an embodiment in which the sequencing
technique is used to detect plasma cell-free DNA in blood to detect cancer,"
wherein "the relative frequency of sequence reads between chromosomes
[were directly compared] to identify chromosomal gains or losses" (Ans. 8,
citing Lo '847 if 280).
ANALYSIS
Based on the combination of Lo '84 7, Porreca, Van Opstal, and Lo
'3 5 3, Examiner concludes that, at the time Appellants' invention was made,
it would have been prima facie obvious to use "oligonucleotides [that]
7
Appeal2015-006686
Application 13/689,206
specifically target and enrich for particular subsets of the genome" in Lo
'84 7 's "methods for providing a statistical likelihood of the presence or
absence of a fetal aneuploidy," because, as Lo '353 discloses, "such
enrichment is an efficient way of estimating the fractional fetal DNA
concentration as compared to whole-genome sequencing" (Ans. 4--5).
In this regard, Examiner reasons that
it would have been obvious to one of ordinary skill in the art at
the time [Appellants' claimed] invention was made to have
interrogated [less than 2000] polymorphic nucleic acid regions
from [three] chromosomes because it would have merely
amounted to a simple combination of prior art elements
according to known methods to yield predictable results.
(Ans. 6 and 7 .) Examiner further reasons that those of ordinary skill in this
art "would have been motivated to have interrogated polymorphic nucleic
acid regions because Lo '847 teaches that analyzing polymorphic nucleic
acid regions of interest are useful because they can be used to determine the
fractional concentration of fetal DNA in a maternal sample" (id. at 7 and 8).
Specifically, Lo '84 7 discloses the determination of "tag counts for the
nucleic acid regions from the sequencing reaction," the "amount of a fetal-
specific allele and the amount of the common allele," therefore, Examiner
concludes,
one [of ordinary skill in this art] would have quantified the total
allele counts by determining the tag counts from the massively
parallel sequencing corresponding to the polymorphic nucleic
acid regions and the relative amount of such amplified products
would have been proportional to the amount of target sequence
as taught by Van Opstal.
(Ans. 6, citing Lo '847 i-fi-1272, 278 and Van Opstal 113: col. 1, last
paragraph.)
8
Appeal2015-006686
Application 13/689,206
Appellants contend that their
Invention approaches the challenge of non-invasive, prenatal
testing completely differently as compared to Lo [']847.
Instead of sampling nucleic acids randomly or as an 'enriched
population' as in Lo [']847 ... , [Appellants'] invention samples
2000 or less targeted loci per chromosome on at least three
chromosomes using sequence-specific oligonucleotides, and
instead of sampling loci at a depth of coverage of less than Ix,
the present invention interrogates each individual locus at a
much greater depth of coverage, e.g., on average lOOx.
(App. Br. 17; see Reply Br. 5 ("Lo [']847 []does not clearly teach
comparison of total counts from two chromosomes to identify chromosomal
losses or gains" and "does not teach comparison of total counts from two
chromosomes in any embodiment describing determination of fetal
aneuploidies"); see also Reply Br. 4).
When the combination of Lo '847, Porreca, Van Opstal, and Lo '353,
as relied upon by Examiner, is considered as a whole, we find that the
weight of the evidence falls in favor of Appellants. In this regard; we agree
with Appellants' contention
that the scant teaching of Lo [']847 at i-f 280 in relation to
cancers-i.e., one line: "Direct comparisons or comparisons to
a reference chromosome may be used[]"-and the silence of Lo
[']847 regarding comparison of empirically obtained sequence
counts from loci on two different chromosomes for
determination of fetal aneuploidy is not a clear teaching that
would lead one of ordinary skill in the art to apply Lo' s cancer
monitoring methods to detect fetal aneuploidies with any
reasonable expectation of success.
(App. Br. 20; cf Ans. 8, citing Lo '847 i-f 280 ("Lo [']847 teaches an
embodiment in which the sequencing technique is used to detect plasma cell-
free DNA in blood to detect cancer").) Obviousness requires more than a
mere showing that the prior art includes separate references covering each
9
Appeal2015-006686
Application 13/689,206
separate limitation in a claim under examination. KSR Int'! Co. v. T'elejlex
Inc., 550 U.S. 398, 418 (2007). Rather, obviousness requires the additional
showing that a person of ordinary skill at the time of the invention would
have selected and combined those prior art elements in the normal course of
research and development to yield the claimed invention. Id. at 421.
CONCLUSION OF LAW
The preponderance of evidence relied upon by Examiner fails to
support a conclusion of obviousness.
The rejection of claims 1-3, 6-12, 14--23, and 37--46 under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Lo '847, Porreca, Van
Opstal, and Lo '353 is reversed.
REVERSED
10