Ex Parte Bischoff et al

Board of Patent Appeals and Interferences

May 31, 2012

11692115 (B.P.A.I. May. 31, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte FARIDEH Z. BISCHOFF and JOE LEIGH SIMPSON
____________

Appeal 2011-009875
Application 11/692,115
Technology Center 1600
____________

Before DONALD E. ADAMS, ERIC GRIMES, and
FRANCISCO C. PRATS, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims 8, 11, 14, and 16
(App. Br. 2; Reply Br. 2; Ans. 2). We have jurisdiction under 35 U.S.C.
§ 6(b).
STATEMENT OF THE CASE
The claims are directed to a method of estimating the probability of a
test maternal whole blood sample representing a trisomy 21 fetal pregnancy.
Claim 8 is representative and is reproduced in “Appendix A” of Appellants‟
Brief.
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2
Claims 8, 11, 14, and 16 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over the combination of Bischoff,
1
Vintzileos,
2
and Genbank.
3

We affirm.
ISSUE
Does the preponderance of evidence on this record support a
conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Bischoff suggests a PCR method “to quantify fetal and total
(maternal and fetal) DNA sequences in maternal plasma” (Bischoff 1
4
: 1-2;
see generally Ans. 4-6).
FF 2. Bischoff quantified total DNA levels “for four different, non-
chromosomal 21, loci” including beta-globin, which resides “on 11q21” (id.
at 2: 5-8; see generally Ans. 4-6).
FF 3. Bischoff established that the multiplicity of median (MoM) levels
“of total DNA measured for the beta-globin sequence” correlated to a
“higher 1
st
trimester risk” of trisomy 21 (Bischoff 2: 12 - 3: 2 (emphasis
added); see generally Ans. 4-6).

1
Farideh Z. Bischoff, et al., Elevated Beta-globin DNA levels in dried
maternal blood spots from first trimester pregnancies with trisomy 21:
Advancement toward generalized prenatal screening, Abstract Presented at
52
nd
Annual Society for Gynecologic Investigation Meeting (2005).
2
Vintzileos et al., US 5,622,176, issued April 22, 1997.
3
GenBank GI:29440,
http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?29440:OLDID:18657,
accessed October 14, 2008.
4
The three page Bischoff Abstract of record is not paginated. Accordingly,
we refer to page numbers as if Bischoff was paginated consecutively starting
with the first page.
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FF 4. While Bischoff established that “a statistically significant difference
in the MOMs (multiplicity of the medians) for levels of β-globin between
the test subjects . . . and controls” existed, Bischoff did not determine “a
probability or an „appropriate cut-off value‟” (Ans. 6).
FF 5. Vintzileos suggests that “determining . . . a probability for trisomy
21 based on other test results was common in the art” (id.).
FF 6. Bischoff does not suggest “primers corresponding to SEQ ID NOs 7
and 8,” however GenBank “discloses the sequence of the human β-globin
gene, which contains within its sequence the sequences of SEQ ID NO:[ ]7
and 8” (id. at 6-7; see also App. Br. 6 (Wherein Appellants concede that,
prior to the date of Appellants‟ claimed invention, Appellants‟ SEQ ID NO:
7 and SEQ ID NO: 8 were known to be useful as primers for the β-globin
sequence); Reply Br. 6; App. Br. 10 (“the current claims are directed to a
specific preexisting primer pair”)).
FF 7. Lo suggests that “[a]bnormally high concentrations of circulating
fetal DNA are found in a proportion of women carrying fetuses with trisomy
21” (Lo,
5
1747: col. 1, ll. 29-31).
FF 8. Lo utilized “Y-chromosomal sequences in male fetuses . . . as
molecular markers for fetal DNA in maternal plasma” (id. at 1748: col. 2, ll.
7-8).
FF 9. Lo utilized “the β-globin gene . . . as a positive control for the
amplifiability of . . . plasma samples” (id. at ll. 14-17; see also e.g., id. at
1749: col. 1, ll. 6-8 (“As a quality control, real-time quantitative PCR for the

5
Y.M. Dennis Lo et al., Increased Fetal DNA Concentrations in the Plasma
of Pregnant Women Carrying Fetuses with Trisomy 21, 45(10) CLIN. CHEM.
1747-1751 (1999).
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the β-globin gene was performed, which demonstrated the existence of
amplifiable DNA in all samples”)).
FF 10. Lo reported “[n]o significant correlation between the plasma Y-
chromosomal and β-globin sequence concentrations was observed among
the 50 samples obtained from pregnant women bearing male fetuses” (id. at
ll. 47-10).
FF 11. The Bischoff Declaration states that “[i]f the tested Beta-globin
target‟s concentrations [in Lo] were also elevated in a way correlated to
Trisomy 21 samples, they would likewise co-correlate as elevated along with
the elevated Y-chromosome DNA levels. This would be quite self[-]evident
to one of ordinary skill in the art as it is simply common sense” (Bischoff
Declaration
6
2-3: ¶ 8).
FF 12. Lo suggests that “[t]he main limitation of quantitative analysis of Y-
chromosomal sequences in maternal plasma is that this approach can only be
used in pregnancies involving male fetuses. The extension of this type of
study to pregnancies involving female fetuses would require the
development of quantitative assays for autosomal or X-chromosomal
polymorphisms” (Lo 1750: col. 1, ll. 41-47).
ANALYSIS
Based on the combination of Bischoff, Vintzileos, and Genbank
Examiner concludes that, at the time of Appellants‟ claimed invention, it
would have been prima facie obvious to a person of ordinary skill in this art
“to select appropriate primers from the known β-globin sequence,” such as
SEQ ID NOs: 7 and 8, which were known in the art as useful primers for
amplifying the β-globin sequence, “to carry out the method taught by

6
Declaration of Farideh Z. Bischoff, executed on November 30, 2009.
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Bischoff” as modified by Vintzileos to estimate a probability of a test
maternal whole blood sample representing a trisomy 21 fetal pregnancy
(Ans. 6-7).
Appellants contend that Bischoff refers to “the Beta-globin locus on
11q21,” which “is a genomic region encompassing the multigene globin
complex,” not “the beta-globin gene” (App. Br. 6; see also Bischoff
Declaration 2: ¶ 4 (“It is well understood in the art that the Beta-globin locus
refers to a multigene complex spanning a significantly larger genomic region
than that of the beta-globin gene alone”); App. Br. 7 (Bischoff “discloses the
much larger Beta-globin locus”); Reply Br. 6). We are not persuaded.
Bischoff refers to beta-globin and three other genes that exist on a
chromosome other than chromosome 21 (FF 2). In this regard, Bischoff
describes a method making multiple references to “the beta-globin
sequence” (see e.g., FF 3; see also e.g., Bischoff, Title (“Elevated Beta-
globin DNA levels in dried maternal blood spots from first trimester
pregnancies with trisomy 21”).). Therefore, when taken as a whole,
notwithstanding Appellants‟ contentions to the contrary, Bischoff directs a
person of ordinary skill in this art to the beta-globin sequence.
Appellants concede that SEQ ID NOs: 7 and 8 were known primers
for the beta-globin sequence. Accordingly, Appellants‟ contentions
regarding Examiner‟s reliance on hindsight to select SEQ ID NOs: 7 and 8
to amplify the beta-globin sequence are not persuasive (see, e.g., App. Br. 7-
8).
Appellants contend that Lo teaches away from Appellants‟ claimed
invention because Lo suggests that “[n]o significant correlation between the
plasma Y-chromosomal and β-globin sequence concentrations was observed
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among the 50 samples obtained from pregnant women bearing male fetuses”
(App. Br. 9-10; see also Reply Br. 4; FF 10). In this regard, the Bischoff
Declaration states that “[i]f the tested Beta-globin target‟s concentrations
were also elevated in a way correlated to Trisomy 21 samples, they would
likewise co-correlate as elevated along with . . . [Lo‟s] elevated Y-
chromosome DNA levels” (FF 11). We are not persuaded.
Notwithstanding Appellants‟ contention to the contrary, Lo does not
compel a person of ordinary skill in this art to assume that “Beta globin
sequence does not vary between Euploid and Trisomy 21 pregnancies”
(App. Br. 10; Cf. FF 7). As Appellants recognize, Lo did not make this
determination (Reply Br. 4 (“Examiner is literally accurate that Lo (1999)
does not expressly and directly correlate β-globin levels to Trisomy 21”)).
Taken as a whole, Lo suggests only that a correlation between a
marker contributed solely by the fetus (Y-chromosome) and a marker
contributed by both the mother and the fetus (β-globin) was not considered
significant (FF 8-10). Lo does not elaborate on this point and we decline to
infer or assume more than what Lo itself suggests. Instead, we direct
attention to Bischoff, which published after Lo, performed the assay missing
in Lo, and suggested that “total DNA measured for the beta-globin
sequence” correlated to a “higher 1
st
trimester risk” of trisomy 21 (FF 3).
We are not persuaded by Appellants‟ contentions relating to Lo‟s
suggestion to develop an assay based on an autosomal marker, such as beta-
globin, and long-felt need (App. Br. 9-11; Reply Br. 5). The preponderance
of evidence on this record suggests that Appellants‟ asserted long-felt need
was satisfied by Bischoff‟s recognition that “total DNA measured for the
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beta-globin sequence” correlated to a “higher 1
st
trimester risk” of trisomy
21 (FF 3).
For the foregoing reasons we are not persuaded by Appellants‟
contention that Bischoff “in concert with the prior art, does not provide
adequate basis for alleging a reasonable expectation of success because it
does not enable the instantly claimed methods” (App. Br. 7; Reply Br. 6-7).
For the same reasons, we are not persuaded by Appellants‟ contention that
Examiner‟s prima facie case is rooted in hindsight (App. Br. 8; Reply Br. 7).
CONCLUSION OF LAW
The preponderance of evidence on this record supports a conclusion
of obviousness. The rejection of claim 8 under 35 U.S.C. § 103(a) as
unpatentable over the combination of Bischoff, Vintzileos, and Genbank is
affirmed. Claims 11, 14, and 16 are not separately argued and fall together
with claim 8 (App. Br. 4 (“All claims stand and fall together”)). 37 C.F.R.
§ 41.37(c)(1)(vii).

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

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