Ex Parte van der Lelie

Patent Trial and Appeal Board

Feb 19, 2013

11925382 (P.T.A.B. Feb. 19, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte DANIEL VEN DER LELIE
__________

Appeal 2011-013187
Application 11/925,382
Technology Center 1600
__________

Before TONI R. SCHEINER, STEPHEN WALSH, and
ULRIKE W. JENKS, 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 single point genome signature tag method for analyzing
the variety of organisms in a sample. 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
“The present invention relates to a method for analyzing the nucleic
acid prepared from a specimen to establish the organismic complexity of the
sample.” (Spec. 4, ¶ [0011].) More particularly, the method is said to
involve “analyzing organismic complexity through the identification and
analysis of single point genome signature tags (SP-GSTs).” (Id. at 6, ¶
[0012].)
Claims 50-55 and 95-98 are on appeal. Claim 50 is representative and
reads as follows:
50. A method for analyzing the variety of members of specific phyla or
families of organisms contained in a sample using single point genome
signature tags comprising the steps of:
a) providing a sample containing one or more organisms;
b) isolating the DNA from the organisms in the sample;
c) contacting the DNA with a fragmenting enzyme under
conditions appropriate for substantially complete digestion of the DNA
thereby generating a plurality of DNA fragments, each having
complementary cohesive termini, said fragmenting enzyme being a type II
restriction endonuclease which does not cleave within conserved segments
of a gene of focus, said gene of focus being a gene containing segments that
are highly conserved across a phylum or a family of organisms and segments
that are species-specific across the phylum or family of organisms;
d) incubating the DNA fragments of step c) with a molar excess of
a duplex linker having a type IIS restriction enzyme recognition sequences
and one cohesive terminus compatible with termini generated by the
fragmenting enzyme of step c), under conditions appropriate for ligating one
duplex linker to each cohesive terminus of the DNA fragments thereby
generating a plurality of DNA fragment-duplex linker species;
e) amplifying a portion of a specific subset of DNA fragment-
duplex linker species using a pair of primers comprising a first primer
specific for the duplex linker and an anchoring primer, said anchoring
primer being specific for a conserved segment of the gene of focus and
which anchoring primer is covalently modified with a first member of a
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specific binding pair, thereby generating a mixture of unamplified DNA
fragment-duplex linker species and amplified portions of a subset of the
DNA fragment-duplex linker species, said amplified portions comprising
sequences that are conserved across the phylum or family and sequences that
are species-specific and which species-specific sequences contain the single
point genome signature tags;
f) capturing the amplified portions of the subset by contacting the
mixture of step e) with a solid support having an attached second member of
the specific binding pair;
g) incubating the solid support and captured amplified portions of
step f) with the type IIS restriction enzyme, under conditions appropriate for
substantially complete digestion thereby releasing the duplex linkers, each
having an appended single point genome signature tag (SP-GST);
h) recovering the released duplex linkers and appended SP-GSTs;
i) incubating the recovered linkers and SP-GSTs of step h) with a
molar excess of an amplification adapter, the amplification adapter having
one terminus compatible with the termini of the appended SP-GSTs, the
incubation being carried out under conditions appropriate for ligating one
amplification adapter to each appended SP-GST;
j) recovering the ligation product of step i);
k) determining the nucleotide sequence of a statistically significant
number of appended SPGSTs to generate a listing of SP-GSTs; and,
l) relating the listing of SP-GSTs of step k) to DNA sequences in
databases to determine analyze the variety of members of specific phyla or
families of organisms contained in the sample.

The Examiner rejected all the claims under 35 U.S.C. § 103(a) as
unpatentable over Ryo,1 Zhou,2 Spinella,3 Velculescu,4 Tucholski,5 and
Ahmadian.6

1 Akihide Ryo et al., A Modified Serial Analysis of Gene Expression
That Generates Longer Sequence Tags by Nonpalindromic Cohesive Linker
Ligation, 277 ANAL. BIOCHEM. 160-162 (2000).
2 J. Zhou et al., Molecular characterization and diversity of thermophilic
iron-reducing enrichment cultures from deep subsurface environments, 90 J.
APPLIED MICROBIOL. 96-105 (2001).
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OBVIOUSNESS
The Issues
The Examiner concluded that it would have been obvious to apply
Ryo’s analytical method, with some modifications, to Zhou’s objective of
identifying microbial strains in a sample containing multiple taxonomic
units.
Appellant disputes the Examiner’s conclusion, arguing that (i) Zhou
“did not make such substitution and then utilize the methods of Ryo,
Spinella, Velculescu, Tucholski and Ahmadian;” (ii) Zhou “could not use
the earlier teachings of Ryo, Spinella, Velculescu, Tucholski and
Ahmadian;” and (iii) “the teachings of Ryo and the others could not be
applied by Zhou et al., to accomplish the analysis the variety of members of
specific phyla or families in the mixed sample.” (App. Br. 6.)

Findings of Fact
1. We adopt the Examiner’s findings concerning the scope and content
of the prior art, and repeat the following findings for discussion
purposes.
2. Ryo stated:

3 Dominic G. Spinella et al., Tandem arrayed ligation of expressed sequence
tags (TALEST): a new method for generating global gene expression
profiles, 27 NUC. ACIDS. RES. e22 i-viii (1999).
4 Victor E. Velculescu et al., Serial Analysis of Gene Expression, 270
SCIENCE 484-487 (1995).
5 Janusz Tucholski et al., MmeI, a class-IIS restriction endonuclease:
purification and characterization, 157 GENE 87-92 (1995).
6 Afshin Ahmadian et al., Single-Nucleotide Polymorphism Analysis by
Pyrosequencing, 280 ANAL. BIOCHEM. 103-110 (2000).
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The serial analysis of gene expression (SAGE) method is a
highly efficient method for systematically analyzing the pattern of
gene expression in tissues or cells, SAGE has been shown to provide a
means for the quantitative cataloging of expressed genes in various
physiological, developmental, and pathological states. However,
because of the difficulty of preparing SAGE, libraries and several
drawbacks, especially the very short sequence tags generated, fewer
groups have successfully applied this method to biological analyses
than another related technique, DNA microarray . . . , regardless of its
potential advantages. To circumvent this, we attempted modifications
of the SAGE procedure.

(Ryo 160, footnotes and citations omitted.)
3. Ryo stated: “In principle, SAGE should be a powerful tool and it will
be applied to a variety of biological studies. The present drastic
modifications should provide SAGE analysis with feasibility and
reproducible outcomes.” (Ryo 162.)
4. Zhou stated: “There is mounting evidence of very high microbial
diversity in environmental samples that may offer a largely untapped
store of organisms of potential use in biotechnology.” (Zhou 96.)
5. Zhou stated:
the molecular analysis of the differentially grown thermophilic
Fe(III)-reducing bacterial cultures provided important information on
microbial community structure. The sequence information will
facilitate the design of appropriate molecular probes in future analysis
of dynamic changes in the Fe(III)-reducing community that can lead
to a more precise identification of various Fe(III)reducing bacteria in
different environments.
If high diversity is a common feature of enrichment cultures,
this phenomenon should be considered in the isolation of bacteria for
biotechnology applications. Divergence of 1-5% in l6S rDNA
sequence is relatively small from a microbial phylogenetic viewpoint,
but these small differences may indicate larger differences in other
important physiological aspects. Differences in kinetics, substrates
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used and products produced could be critical in determining the utility
of a strain for biotechnology applications. Thus, it might be wise to
attempt to obtain and screen more isolates, even if they are 'closely'
related, in order to obtain strains with different physiological
properties.

(Zhou 104.)

Principles of Law
Patentability is not imparted where “the prior art would have
suggested to one of ordinary skill in the art that this process should be
carried out and would have a reasonable likelihood of success, viewed in
light of the prior art.” In re Dow Chemical Co., 837 F.2d 469, 473 (Fed. Cir.
1988).

Analysis
The rejection is organized in two parts. In the first part, the Examiner
makes the findings required by steps one and two of the Graham analysis,
i.e., (1) determining the scope and content of the prior art, and
(2) identifying the differences between Appellant’s invention and the prior
art. The findings are presented as a step-by-step comparison of claim 50’s
12-step method to prior art methods of genetic analysis. (Ans. 7-18.) In the
second part, the rejection presents reasons why (i) it would have been
obvious to apply Ryo’s modified method for serial analysis of genetic
expression (SAGE) to Zhou’s subject - the analysis of variety of phyla or
family members in a sample of organisms, and (ii) other modifications to
Ryo’s method would have been obvious, such as the particular endonuclease
used in step c). (Id. at 18-31.)
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The genetic material that Ryo, Velculescu, and Spinella each analyzed
was from a single species; none of them described analyzing the variety of
organisms in a sample, which was taught by Zhou. More specifically, Ryo
used its method “to demonstrate an example of gene expression profiles in
human hepatocellular carcinoma (HCC) and adjacent noncancerous liver
tissue (NCL).” (Ans. 7; Ryo 161.) In Velculescu’s paper describing SAGE,
“[a]s a demonstration of this approach, SAGE was used to characterize gene
expression in the human pancreas.” (Velculescu 485.) Spinella
demonstrated its process on human lung tissue. (Spinella ii.) Ryo,
Velculescu, and Spinella did not apply their methods to analyzing the variety
of members of a phyla or family of organisms in a sample, but claim 50’s
steps e) through h) involve molecules from plural7 species. (Ans. 11-12.)
Zhou taught analyzing the variety of members of specific families of
organisms contained in a sample and isolating “the total community DNA.”
(Ans. 12.) Zhou described the significance of analyzing the variety of
genetic material in samples containing plural organisms. (E.g., FF 4 and 5.)
For example, Zhou stated that the genetic analysis of cultures provided
“important information” on microbial community structure. (FF 4.)
According to Zhou, the obtained sequence information would “facilitate the
design of appropriate molecular probes in future analysis of dynamic
changes in the Fe(III)-reducing community,” which would “lead to a more

7 Although claim 50 at step a) includes analyzing a sample “containing one
or more organisms,” thus indicating that the method may cover analyzing a
sample with only one organism, step b) recites isolating DNA from
“organisms.”
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precise identification of various Fe(III)reducing bacteria in different
environments.” (FF 5.)
Given the significance of Zhou’s objective, the Examiner concluded it
would have been obvious “to provide Ryo’s methods of a modified serial
analysis of gene expression that generates longer sequence tags by
nonpalindromic cohesive linker ligation in Zhou's methods for analyzing the
variety of members of specific phyla or families of organisms contained in a
sample.” (Ans. 18.) Ryo indicated that “SAGE should be a powerful tool
and it will be applied to a variety of biological studies.” (Ans. 19; see FF
3.) Zhou indicated that environmental samples “offer a largely untapped
store of organisms of potential use in biotechnology . . . . it might be wise
to attempt to obtain and screen more isolates … in order to obtain strains
with different physiological properties.” (Ans. 19-20; see FF 5.) We agree
with the Examiner that Zhou’s suggestion of further analysis, and Ryo’s
indication that its method could be used for a variety of studies, would have
suggested applying Ryo’s powerful method to Zhou’s objective.
The Examiner further noted that Ryo’s method was successfully
demonstrated on closely related cells. (Ans. 20.) Zhou suggested screening
even “closely related” samples (FF 5), and we agree with the Examiner that
this evidence supports a reasonable expectation of success in applying Ryo’s
method to Zhou’s samples. The same evidence supports the Examiner’s
finding that substitution of Zhou’s community DNA for the samples Ryo
analyzed “would have yielded predictable results,” including the successful
analysis of Zhou’s samples. (Ans. 19.)
Appellant disputes the Examiner’s conclusions but does not take issue
with the factual findings concerning the scope and content of the prior art,
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and the differences between the invention and the prior art. Importantly,
Appellant contends that Zhou is the closest prior art “because the analysis
produces a listing of ‘operational taxonomic units’ (OTUs) and in some
cases identification of specific families, phyla and species of iron-reducing
organisms after analyzing a sample containing a mixture of organisms.”
(App. Br. 5.) Appellant focuses on the rejection’s proposal to substitute
Zhou’s sample of organisms for Ryo’s separate samples of normal versus
cancerous liver cells. (Id.)
Appellant does not agree that such a substitution would have been
obvious, and further argues that (i) Zhou “did not make such substitution and
then utilize the methods of Ryo, Spinella, Velculescu, Tucholski and
Ahmadian;” (ii) Zhou “could not use the earlier teachings of Ryo, Spinella,
Velculescu, Tucholski and Ahmadian;” and (iii) “the teachings of Ryo and
the others could not be applied by Zhou et al., to accomplish the analysis the
variety of members of specific phyla or families in the mixed sample.” (Id.
at 6.) Appellant contends that if Appellant’s invention had been obvious,
Zhou would have used it, but did not:
if the presently claimed invention was obvious to those of skill in the
art, Zhou, et al. should have been able to make use of the substitution
and then the combined teachings of Ryo, Spinella, Velculescu,
Tucholski and Ahmadian so as to then analyze only a small portion of
the 16S rDNA sequences of the organisms rather than amplifying and
doing RFLP analysis on the entire 16S rDNA region. Instead, they did
not.

(Id.)
These arguments are unpersuasive. First, the relevant time for
assessing obviousness is the effective filing date of Appellant’s application
(either 2004 or 2002), not the date of Zhou’s publication in 2001. Second,
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Zhou apparently submitted its paper to the journal April 3, 2000. (See Zhou
96, editor’s notes.) As Ryo’s work was published in 2000, Appellant may
be correct that Zhou “could not use” Ryo’s method, but the reason is the
unavailability of the Ryo information while Zhou was doing its work, not
because Zhou could not have applied Ryo’s method if it had been available.
As all the applied references were available by 2002, Appellant’s earliest
possible effective filing date, we assess obviousness according to what was
known in 2002.
Appellant similarly contends that “if the presently claimed invention
was indeed obvious through the combination of Ryo, Spinella, Velculescu,
Tucholski and Ahmadian, Zhou et al. or others could and would have made
the combination long before the present inventors did so.” (App. Br. 6.)
This argument is also unpersuasive. First, this is not the kind of undisputed
fact appropriate for taking notice. In re Kahn, 441 F.3d 977, 990 (Fed. Cir.
2006). Second, precedent requires that the applicant submit actual evidence
of long-felt need as opposed to argument. This is because “[a]bsent a
showing of long-felt need or the failure of others, the mere passage of time
without the claimed invention is not evidence of nonobviousness.” Id. at
990-91 (quotations and citations omitted). See also, In re McGuire,
416 F.2d 1322, 1327-28 (CCPA 1969) (“Appellants argue the century-old
status of the references but this argument does not impress us, absent some
showing that the art tried and failed to solve some problem notwithstanding
its presumed knowledge of the references. For aught that appears, as soon as
the need for an inside tubing cutter was perceived it was produced out of the
accumulated skill of the art.”).
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Appellant contends that “[f]ormulation of an obviousness rejection
based upon the predictability of substitution of one known element for
another in the inherently unpredictable biological sciences is arguably
questionable.” (App. Br. 7.) Obviousness requires only a reasonable
expectation of success; “arguably questionable” is not the standard. The
Examiner directed attention to Ryo’s statement that SAGE was a “highly
efficient method for systematically analyzing the pattern of gene
expression in tissues or cells.” (See Ans. 22; FF 2.) Ryo supports the
finding and further explains that “SAGE has been shown to provide a means
for the quantitative cataloging of expressed genes in various physiological,
developmental, and pathological states.” (FF 2.) The Examiner found, and
Appellant does not dispute, that Ryo’s powerful method worked for closely
related DNAs. (Ans. 19.) Appellant provides no evidence that a person of
ordinary skill in the art would have doubted the likely success of applying
Ryo’s modified method to Zhou’s screening. We conclude that the
Examiner’s evidence is sufficient to shift the burden to Appellant to do more
that say success was “arguably questionable.”
Appellant notes other substitutions to Ryo’s method the Examiner
concluded would have been obvious, but does not show that the Examiner
erred in the findings or conclusions. (App. Br. 8-9.) We have reviewed the
evidence concerning each of these features. We find the evidence supports
the Examiner’s findings and that the Examiner reasonably explained the
conclusion of obviousness for each proposed change to Ryo’s method.
Claims 51-55 and 95-98 have not been argued separately and
therefore fall with claim 50. 37 C.F.R. § 41.37(c)(1)(vii).

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SUMMARY
We affirm the rejection of claims 50-55 and 95-98 under 35 U.S.C.
§ 103(a) as unpatentable over Ryo, Zhou, Spinella, Velculescu, Tucholski,
and Ahmadian.
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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