Ex Parte Dapprich et al

Patent Trial and Appeal Board

Mar 18, 2013

11724043 (P.T.A.B. Mar. 18, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
11/724,043 03/13/2007 INV001Johannes Dapprich Dapprich-10202 1689
14333 7590 03/18/2013
Meagher Emanuel Laks Goldberg & Bovino, LLP
ONE PALMER SQUARE
SUITE 325
Princeton, NJ 08542
EXAMINER
FORMAN, BETTY J
ART UNIT PAPER NUMBER
1634
MAIL DATE DELIVERY MODE
03/18/2013 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte JOHANNES DAPPRICH and MICHELE A. CLEARY
__________

Appeal 2011-007833
Application 11/724,043
Technology Center 1600
__________

Before TONI R. SCHEINER, FRANCISCO C. PRATS, and
STEPHEN WALSH, Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) from the rejection of
claims directed to a method for separating a polynucleotide molecule from a
population of genomic DNA molecules. The Patent Examiner rejected the
claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b). We
affirm.
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STATEMENT OF THE CASE
Claims 21-32 and 34 are on appeal. Claim 21 illustrates the subject
matter on appeal and reads as follows:
21. A method for separating a polynucleotide molecule from a population
of genomic DNA molecules, the method comprising:
(a) providing a population of genomic DNA molecules comprising
said polynucleotide molecule, wherein said polynucleotide molecule
includes a target nucleic acid sequence and a distinguishing element;
(b) contacting said population of genomic DNA molecules with a
targeting element, wherein said targeting element binds specifically to said
target nucleic acid sequence of said polynucleotide molecule;
(c) selectively attaching multiple separation groups to said bound
targeting element, wherein attachment of separation groups occurs, only if
said targeting element is bound to said target nucleic acid sequence, by
extending said targeting element so as to include multiple separation groups;
(d) immobilizing said attached separation groups to a substrate,
thereby forming an immobilized polynucleotide-targeting element-
separation group complex; and
(e) removing said immobilized polynucleotide-targeting element-
separation group complex from said population of genomic DNA molecules,
thereby separating said polynucleotide molecule from said population of
genomic DNA molecules;
wherein the distinguishing element is a polymorphism, the targeting
element is an oligonucleotide that partially overlaps the distinguishing
element, the separation group is an immobilizable, non-terminating
nucleotide, and the 3' -terminus of the oligonucleotide is complementary to
the polymorphism.

The Examiner rejected the claims as follows:
I. claims 21-32 under 35 U.S.C. § 103(a) as unpatentable over Dale1 and
Davis2 or Huang;3 and

1 James Langham Dale et al., US 5,856,092, issued Jan. 5, 1999.
2 Ronald W. Davis et al., US 5,391,480, issued Feb. 21, 1995.
3 Xiaohua Huang et al., US 6,709,816 B1, issued March 23, 2004.
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II. claims 32 and 344 under 35 U.S.C. § 103(a) as unpatentable over
Dale, Davis or Huang, and Lebo.5

I
The Issues
The Examiner’s position is that Dale described a method for
separating a nucleic acid molecule containing a polymorphism from a
population of nucleic acid molecules. (Ans. 4-5.) The Examiner found that
while Dale taught an oligonucleotide primer corresponding to Appellants’
targeting element or oligonucleotide, Dale did not specifically teach that the
3’ terminus of its oligonucleotide primer is complementary to the
polymorphism. (Id. at 5.)
The Examiner further found however that “allele-specific primer sets
having 3’terminal nucleotides complementary to a specific allele were well
known in the art at the time the invention was made as taught by Davis and
Huang.” (Id.) The Examiner concluded: “It would have been obvious to
one of ordinary skill in the art at the time the claimed invention was made to
apply the allele-specific primers of Davis and/or Huang to the point
mutation-specific amplification and detection of Dale.” (Id. at 6.)
Appellants contend the rejection should be reversed because:
(i) “the Examiner fails to provide a sufficient motivation for one of
ordinary skill in the art to combine cited references;” and

4 The rejection includes claim 33, but Appellants state that claim 33 was
cancelled. (App. Br. 5; see also Ans. 2.)
5 Roger V. Lebo, US 5,654,148, issued August 5, 1997.
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(ii) “the combination of the cited references in the manner asserted by
the Examiner would not have arrived at the methods claimed in the present
application.” (App. Br. 17.)

Findings of Fact
1. We adopt the Examiner’s findings of fact concerning the scope and
content of the prior art.

Analysis
Claim 21
Appellants contend there are significant differences between Dale’s
methods and the claimed methods. (App. Br. 19-20.) A first difference is
said to be that Dale uses a primer that anneals adjacent to a polymorphic site,
rather than overlapping and forming a 3’-match with the polymorphism of
interest. (Id. at 19.) The Examiner responds that Dale taught primers
complementary to the sequence of interest. (Ans. 11, citing Dale col. 7.)
The evidence expressly supports the Examiner’s finding. Appellants
acknowledge that Davis taught “[t]he 3’ terminus of the primer overlaps
with the test nucleotide and forms a match or a mismatch with the test
nucleotide” (App. Br. 18), and that Huang taught “an allele-specific primer
that has an allele-specific 3’ end” (id. at 19). The rejection supplied
evidence addressing this difference.
Appellants contend that a second significant difference between
Dale’s methods and the claimed methods is that Dale relied on selective
incorporation of a specific terminating nucleotide, but the claimed methods
“rely on selective extension of the primer in the presence of non-terminating
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nucleotides.” (App. Br. 19.) The Examiner responds that “Dale teaches a
primer extension method using a primer complementary to the sequence of
interest followed by incorporation of nonterminating nucleotides (Column 7,
lines 7-21).” (Ans. 11.) The rejection’s evidence supports the Examiner’s
finding. Further, the Examiner notes that “Dale specifically illustrates the
method using complementary primers and non-terminating nucleotides (Fig.
2b)” (id.), and the evidence again supports the Examiner. While Dale allows
the use of terminating nucleotides in some embodiments, Dale described
embodiments using non-terminating nucleotides. Appellants’ argument for a
significant difference is therefore unpersuasive.
Appellants contend that Dale described methods of “analyzing primer
extension products,” but “[i]t is the polynucleotide molecule originally
present and subsequently separated from a genomic DNA population, rather
than a primer extension product, that the methods claimed in the present
application focus on.” (App. Br. 19-20.) This is not a point of difference
because the claimed separation is achieved by “removing said immobilized
polynucleotide-targeting element-separation group complex from said
population of genomic DNA molecules.” (Claim 21 (e).) Dale’s Figure 2b
supports the Examiner’s finding that Dale’s method removed the complex
from the population of genomic DNA.
In Figure 2b, Dale shows that molecule of interest and the extended
targeting element form a duplex, and the duplex of interest, and other
duplexes present, are precipitated with ethanol, washed, resuspended, and
immobilized to a substrate. The substrate is subjected to a wash. Thus,
unbound genomic DNA will be washed away from the immobilized
polynucleotide-targeting element-separation group complex retained on the
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substrate. At this point, claim 21 step (e) is achieved. Dale indicates using
“high stringency wash,” which means that the immobilized polynucleotide-
targeting element-separation group complex will retain only targets with a
high degree of complementarity (the polynucleotide of interest).
Thus, although Appellants argue for three primary differences
between Dale’s methods and the claimed methods, we find only Dale’s lack
of specificity as to the location of the polymorphisms at the 3’-terminus of
the primer or targeting element is a significant difference. The Examiner
resolved that difference, finding that using allele-specific primer sets having
3’ terminal nucleotides complementary to a specific allele was well known,
as evidenced by Davis or Huang.
Appellants do not dispute that Davis or Huang taught using allele-
specific primer sets having 3’ terminal nucleotides complementary to a
specific allele. Instead, Appellants contend it was error to rely on Davis or
Huang because (i) the combination would change Dale’s principle of
operation, and (ii) the combination would not arrive at the claimed methods.
(App. Br. 20-26.)
Appellants first argument relies again on the contention that Dale
required “at least one terminating ddNTP that complements to the nucleotide
[to be detected],” based on methods illustrated in Dale’s Figures 3a and 3b.
(Id. at 21.) This argument is again unpersuasive because it ignores the other
methods Dale taught that did not use a terminating nucleotide, for example,
the method illustrated in Fig. 2b.
Appellants contend that it was error to rely on a fact disclosed by
Davis because Davis “operates in a way significantly different from Dale.”
(Id. at 21.) According to Appellants, “modifying the method of Dale by
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using the primer of Davis would change the principle of operation of Dale
and eliminate the advantages of having both a capture group and a detection
group in a single oligonucleotide emphasized in Dale.” (Id. at 22.)
Appellants similarly contend that “modifying the method of Dale by using
the primer of Huang would change the principle of operation of Dale.” (Id.)
The Examiner cited Davis and Huang as evidence that making a
primer with the 3’ terminus complementary to a specific allele (aka
polymorphism) was known. (Ans. 5.) The rejection concluded: “It would
have been obvious to one of ordinary skill in the art at the time the claimed
invention was made to apply the allele-specific primers of Davis and/or
Huang to the point mutation-specific amplification and detection of Dale.”
(Id. at 6.) Taking the point literally, Appellants contend that inserting a
Davis or Huang primer into Dale’s method wouldn’t work because the Davis
and Huang primers had additional features incompatible with Dale’s
method. (App. Br. 21-23.) We think Appellants read the conclusion too
literally, without giving due consideration that the claim feature being
addressed is only the obviousness of making a primer with a complementary
nucleotide at the 3’ terminus of Dale’s primer, in order to detect the
polymorphism in the target. As the Examiner explains, this is the point of
difference resolved in the rejection, and the reason for citing Davis or
Huang. (See Ans. 13-14.)
References need not be capable of physical combination in order to
show obviousness. In re Etter, 756 F.2d 852, 859 (Fed. Cir. 1985) (in banc);
see also, In re Nievelt, 482 F.2d 965, 968 (CCPA 1976) (“Combining the
teachings of references does not involve an ability to combine their specific
structures”); In re Andersen, 391 F.2d 953, 958 (CCPA 1968) (“There is a
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distinction between trying to physically combine the two separate apparatus
disclosed in two prior art references on the one hand, and on the other hand
trying to learn enough from the disclosures of the two references to render
obvious the claims in suit. . . . Claims may be obvious in view of a
combination of references, even if the features of one reference cannot be
substituted physically into the structure of the other reference.”).
Appellants further contend that combining the Davis or Haung
disclosure with Dale’s would not have led to the claimed method. (Id. at 24-
25.) These arguments expand on the view that the rejection proposed taking
a primer from Davis or Huang and using it in Dale’s method. As we do not
agree that the rejection proposed a literal substitution, we find these
arguments misdirected.
We conclude that the rejection of claim 21 must be affirmed. Claims
22-30 have not been argued separately and therefore fall with claim 21.
37 C.F.R. § 41.37(c)(1)(vii).
Claim 31
Claim 31 adds to the method of claim 21 by “further comprising
(f) characterizing said polynucleotide molecule separated from said
population of genomic DNA molecules.”
The Examiner found: “Dale teaches characterization of the complex
comprising the template (§ 2) [sic].” (Ans. 8.)
Appellants contend that none of the references suggests “further
characterizing” a polynucleotide molecule isolated from a population of
genomic DNA. (App. Br. 27.) Appellants state that their separation method
“allows a user the flexibility to employ any subsequent assay of choice for
characterization of the original isolated molecule.” (Id.) The claimed
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method merely separates a DNA molecule from genomic DNA, it does not
provide an isolated molecule. Further, the claim does not require that an
assay be done. The Examiner found that the term “characterization” had no
particular meaning, and that therefore any description of the polynucleotide
separated from the genomic population would do. Dale implicitly described
the separated polynucleotide as bound in a complex, e.g., as shown in Figure
2b, which is a characterization of the polynucleotide separated from genomic
polynucleotides. Appellants contend Dale discloses the detection of the
extension products to indicate the presence of the nucleic acid molecule of
interest, but “not the direct characterization of the nucleic acid molecule of
interest from the biological sample.” (Id.) Claim 31 does not require
“direct” characterization, and Appellants does not identify in the
Specification an explanation of “direct.”
Referring to Dale’s Figure 3a and 3b embodiments, Appellants
contend that Dale’s immobilized duplex formed between an extension
product and its polynucleotide template is washed extensively under high
stringency conditions, and argue that “after multiple high stringency washes,
it is very likely that the polynucleotide template is already disassociated
from the extension product before the extension product is assayed for the
presence or absence of the detector group.” (Id. at 28.) Appellants’
references to Dale’s Figure 3a and 3b embodiments are unpersuasive
because they are misdirected to embodiments not relied on in the rejection.
We have agreed with the Examiner that Dale’s Fig. 2b illustrates a method
rendering claim 21 obvious. (See also, the portions of Dale’s text cited in
the rejection.) We also find Appellants’ arguments about washing away the
molecule of interest unpersuasive because they are speculative and not based
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on evidence. In its ordinary usage, high stringency refers to conditions in
which perfect complements will remain bound to each other, while less
perfect matches will wash away. As Dale’s process produces perfect
complements, the molecule of interest is not likely to be washed away as
Appellants argue. Taking into account the Examiner’s reasoning that “any
means of characterization is encompasses by the claim” (Ans. 15), we
conclude that the rejection of claim 31 must be affirmed.
Claim 32
Claim 32 further limits the method of claim 31 by reciting “wherein
step (f) characterizes sites in said polynucleotide molecule that constitute a
haplotype.”
Appellants contend that “none of the cited references mention
haplotyping, in particular not of the original polynucleotide molecule.”
(App. Br. 29.) This argument is unpersuasive because claim 32 does not
require haplotyping. It requires instead that sites that constitute a haplotype
be characterized. Dale separated a polynucleotide having a polymorphism,
i.e., a polynucleotide that is a haplotype, and characterized the molecule, i.e.,
the sites, as bound to a complex. Appellants further contend: “Dale only
describes the detection of the detection groups in extension products to
determine the presence or absence of target polynucleotide molecules in a
sample, but does not teach further characterizing the extension products as to
how many and where the labels are present in the extension products.” (Id.)
This argument is unpersuasive because the claim does not require additional
characterization, and Appellants cite no Specification disclosure suggesting
that any particular kind of characterizing is required. We conclude that the
rejection must be affirmed.
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II
The Examiner’s position is that a method of separating a
polynucleotide more than 100 kbp in length would have been obvious over
Dale’s method and Lebo’s evidence that DNAs of more than 100 kbp were
known targets of interest for genetic testing and haplotyping. (Ans. 9-10.)
According to the Examiner: “It would have been obvious to one of ordinary
skill in the art at the time the claimed invention was made to apply the
targets of Loeb [sic, Lebo] to the genetic detection methods of Dale et al.
One of ordinary skill in the art would have been motivated to do so for the
expected benefit of identifying disease-associated haplotypes as taught by
[Lebo] (Column [9], lines 1-13).” (Id.)
Appellants argue claims 32 and 34 separately.
Claim 32
Claim 32 further limits the method of claim 31 by reciting “wherein
step (f) characterizes sites in said polynucleotide molecule that constitute a
haplotype.”
The rejection proposed to apply Lebo’s targets to Dale’s genetic
detection methods. Appellants argue that the deficiencies argued for the
rejection of claim 32 over Dale and Davis or Huang, are not remedied by the
addition of Lebo. App. Br. 30.) We do not agree that the rejection of claim
32 over Dale and Davis or Huang was deficient, as explained in the
discussion of claim 32 in Part I, above. ) If Lebo’s haplotype target
molecules were separated by Dale’s method, the same result would obtain –
by showing the target molecule as bound in a complex, Dale implicitly
characterized the molecule.
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Claim 34
Claim 34 further limits the method of claim 21 by reciting “wherein
said polynucleotide molecule separated from said population of genomic
DNA molecules is more than 100 kbp in length.”
The rejection proposed to apply Lebo’s targets to Dale’s genetic
detection methods, meaning that one would use Dale’s method to separate a
DNA molecule greater than 100 kbp in length. Appellants contend that
(i) “Lebo relates to multicolor in situ hybridization methods for genetic
testing, and is not closely related to Dale, Davis or Huang, which focuses on
detecting or determining a particular nucleotide at a specific site of interest
in a polynucleotide molecule,” and (ii) “[a]lthough targets of more than 100
kb DNA were known in the art of genetic diagnosis, Lebo does not teach or
suggest how to modify Dale to enable Dale to separate a polynucleotide
molecule more than 100 kbp long from a population of genomic DNA.”
(App. Br. 31.) According to Appellants, “the extension product in Dale is
typically extremely short . . . the binding between the extension product and
its template, the polynucleotide of interest, is far too weak to keep the
molecule of interest reliably bound to the extension product during the
immobilization and subsequent wash steps.” (Id.)
The Examiner responds:
the artisan would have understood that immobilizing the long
templates of Loeb (used for haplotyping) would have required a
longer extension product and therefore would have known to provide
a long extension product using the method of Dale. Appellant has not
pointed to any teaching of Dale that limits the extension as asserted.
In contrast to Appellant's assertion, Dale does not limit the extension
to produce a short extension product. Additionally, as stated in the
Final Office Action, the instant claims are not limited to producing a
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long extension product. The claims do not define any length, long or
short, for the extension. The claims merely define some degree of
separation of a 100kb polynucleotide from a population. As noted by
Appellant, one of ordinary skill would understand the requirements
for such separation. Therefore, one of ordinary skill would have
understood how to apply the method of Dale to obtain the long
templates of Loeb for analysis of the long polynucleotides at the
sequence level using the method of Dale.

(Ans. 17-18.)
Appellants offer no evidence to show that Dale’s methods are size
limited, and no evidence to support the allegations that Dale’s method
doesn’t work for targets longer than 100kbp. What is needed here is
evidence, not attorney argument. “Attorney’s argument in a brief cannot
take the place of evidence.” In re Pearson, 494 F.2d 1399, 1405 (CCPA
1974); In re Geisler, 116 F.3d 1465, 1471 (Fed. Cir. 1997) (same). In the
event Appellants may be relying on Dale’s drawings to infer a size
limitation, we cannot agree that the drawings are limiting. See In re
Heinrich, 268 F.2d 753, 755 (CCPA 1959) (“patent drawings are not
ordinarily considered to be working drawings drawn to scale”); see also In
re Wright, 569 F.2d 1124, 1127 (CCPA 1977) (“Absent any written
description in the specification of quantitative values, arguments based on
measurement of a drawing are of little value.”).
We see no evidence that the Examiner erred in assessing how a person
of ordinary skill would have implemented Dale’s method for separating
Lebo’s target molecules, and conclude the Examiner has the better position.
The rejection of claim 34 is affirmed.
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SUMMARY
We affirm the rejection of claims 21-32 under 35 U.S.C. § 103(a) as
unpatentable over Dale and Davis or Huang.
We affirm the rejection of claims 32 and 34 under 35 U.S.C. § 103(a)
as unpatentable over Dale and David or Huang, and Lebo.
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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