Ex Parte Seitz

Patent Trial and Appeal Board

Jan 28, 2016

12095485 (P.T.A.B. Jan. 28, 2016)

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.
12/095,485 09/19/2008 Alexander Seitz SONN:1007 2259
34725 7590 01/28/2016
CHALKER FLORES, LLP
14951 North Dallas Parkway, Suite 400
DALLAS, TX 75254
EXAMINER
CHUNDURU, SURYAPRABHA
ART UNIT PAPER NUMBER
1637
MAIL DATE DELIVERY MODE
01/28/2016 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 ALEXANDER SEITZ1
__________

Appeal 2013-008548
Application 12/095,485
Technology Center 1600
__________

Before ERIC B. GRIMES, ULRIKE W. JENKS, and
RICHARD J. SMITH, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for amplifying polynucleotides, which have been rejected as obvious. We
have jurisdiction under 35 U.S.C. § 6(b).
We reverse.

1 Appellant identifies the Real Party in Interest as Lexogen GmbH. (Appeal
Br. 2.)
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STATEMENT OF THE CASE
“Studying the genome (DNA), transcriptome (RNA), and proteome
(protein)” has led to various techniques to assess differential expression of
RNA in cells. (Spec. 1.) Several “differential display (DD)” techniques are
known (id. at 2) but the Specification states that all of them suffer from the
drawback of “giv[ing] the investigator only part of the mRNA sequence that
is differentially expressed” (id. at 3).
The Specification states that “[a] goal of the present invention is to
provide a method that can amplify (enrich for) defined subpopulations of
transcripts in their entire length with full coverage of all mRNA molecules
present in the sample.” (Id.)
Claims 1, 3–7, 11, 13, 14, 16–18, 22, 25, 26, 33, and 35–39 are on
appeal. Claim 1 is illustrative and reads as follows (emphasis added):
1. A method for amplifying a pool of polynucleotide molecules
comprising the steps of:
obtaining a RNA;
reverse transcribing the RNA using one or more reverse transcription
primers, thereby creating a full length cDNA or obtaining a full length
cDNA;
adding a polynucleotide tail at a 3' end of the full length cDNA;
amplifying the full length cDNA using a pair of amplification primers,
wherein the amplification primers comprise a first 3' amplification primer
that hybridizes to a 5' end of the full length cDNA, and a second 5'
amplification primer that hybridizes to both at least a part of the
polynucleotide tail and a part of the cDNA, wherein the second 5' primer
hybridizes to one to ten nucleotides upstream of the 3' polynucleotide tail of
the cDNA.

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The claims stand rejected under 35 U.S.C. § 103(a) as follows:
Claims 1, 3–5, 7, 13, 14, 16, 18, 22, 26, 33, and 35–38 as obvious
based on Fry2 and Weinstein3 (Ans. 5);
Claims 6 and 25 as obvious based on Fry, Weinstein, and Brennan4
(Ans. 6); and
Claims 11, 17, and 39 as obvious based on Fry, Weinstein, and
Slepnev5 (Ans. 7).
DISCUSSION
The Examiner has rejected all of the claims on appeal as obvious
based on Fry and Weinstein, by themselves or combined with either Brennan
or Slepnev. The same issue is dispositive for all of the rejections.
The Examiner finds that Fry discloses all of the limitations of claim 1
except that it “does not expressly teach a second amplification primer that
hybridizes to both the added polynucleotide tail and specific section of the
cDNA.” (Ans. 5.) The Examiner finds that Weinstein “teaches the concept
of adding specific nucleotides complementary to the original target nucleic
acid sequence to the 3' end of a 5' ‘universal’ primer in order to amplify
specific sequences within an mRNA/cDNA pool.” (Id. at 5–6.) The
Examiner concludes that it would have been obvious “to incorporate specific
nucleotides to the 3' end of a 5' ‘universal’ amplification primer in Fry since

2 Fry et al., US 6,114,149 issued September 5, 2000.
3 Weinstein et al., US 6,270,966 B1 issued August 7, 2001.
4 Brennan et al., US 6,632,461 B1 issued October 14, 2003.
5 Slepnev, WO 03/035841 A2 published May 1, 2003.
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Weinstein suggests such a modification to allow for amplification of specific
sequences in a mRNA/cDNA pool.” (Id. at 6.)
The Examiner elaborates on this rationale, explaining that it would
have been obvious “to incorporate one aspect of the Weinstein method (i.e.
the use of specific primer nucleotides at the 3' end of a primer) into the Fry
method in order to obtain a desirable, predictable result (i.e. the production
of specific full-length cDNAs).” (Id. at 9.) The Examiner also reasons that
[t]he prior art makes clear study of both pools of transcripts and
specific transcripts were of interest at the time of invention.
Thus, clearly a skilled practitioner would have seen the benefit
of adjusting the Fry method to focus on specific full-length
transcripts in contrast to proceeding with amplification of the
entire full-length library only to have to isolate specific
transcripts from the pool when needed for study with additional
downstream method(s).
(Id. at 10.)
Appellant argues that “there is no motivation to combine the
references as suggested.” (Appeal Br. 13.) Appellant points out that “Fry
teaches a method for ‘non-specifically amplifying’ RNA or DNA (col. 2,
line 17)” and teaches use of primers that amplify full-length products. (Id.)
Appellant argues that Weinstein, by contrast, digests cDNA with restriction
enzymes and amplifies subsets of the fragments using primers specific for
the ends of the fragments, including nucleotides adjacent to added adapters.
(Id. at 14.) Thus, Appellant argues, “the proposed modification would
render Weinstein unsatisfactory for its intended purpose.” (Id.)
Appellant also argues that “[t]he Examiner’s Answer suggests that the
supposed motivation to combine the elements comes from the supposed
desire of the skilled practitioner to have the elements combined. This
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reasoning is circular reasoning.” (Reply Br. 8.) Appellant also argues that
“[t]he supposition that a skilled practitioner would ‘have seen the benefit’ of
the combination of elements that are set forth in the present invention is not
a fact. It is merely an assumption. . . . Such a test also fails to meet the
Supreme Court’s ‘rational underpinning’ requirement to support the legal
conclusion of obviousness.” (Id. at 8–9.)
We agree with Appellant that the Examiner has not established that
the cited references would have led a person of ordinary skill in the art to
combine their respective teachings. “In rejecting claims under 35 U.S.C.
§ 103, the examiner bears the initial burden of presenting a prima facie case
of obviousness.” In re Rijckaert, 9 F.3d 1531, 1532 (Fed. Cir. 1993).
“Obviousness requires more than a mere showing that the prior art
includes separate references covering each separate limitation in a claim
under examination.” Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352,
1360 (Fed. Cir. 2011). “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.
In this case, Fry discloses a “method for non-specifically amplifying
RNA or DNA fragments non-specifically, i.e., without regard to fragment
sequence.” (Fry 2:17–19.) Fry states that “a more specific object of the
invention [is] to provide such a method which allows successful library
clone formation from small quantities of RNA.” (Id. at 2:20–22.) Fry’s
method includes the “obtaining,” “reverse transcribing,” and “adding” steps
of claim 1 on appeal. (See id. at 4:33–62.)
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Fry’s method also includes amplifying the full-length cDNA using
two amplification primers, one of which hybridizes to a 5' end of the full-
length cDNA (“Primer 2” in Fry’s Fig. 1), and one of which hybridizes to at
least a part of the polynucleotide tail (“Primer 1” in Fry’s Fig. 1). However,
Fry’s primer that hybridizes to the polynucleotide tail does not “hybridize[]
to one to ten nucleotides upstream of the 3' polynucleotide tail of the
cDNA,” as required by claim 1 on appeal.
Weinstein states that “there is a need to increase the specificity of
detection of mRNA species in a sample to allow more accurate detection of
mRNA content that is characteristic of the cell, tissue or other samples” and
that a “method that produces a more specific differential display is generally
useful for medical or forensic applications that require characterization of a
cell or tissue sample.” (Weinstein 4:5–8, 13–16.) Weinstein discloses that
its method (“restriction display-polymerase chain reaction (RD-PCR)”)
“us[es] adaptor sequences that anneal to restriction enzyme recognition sites
in the amplified cDNA” (id. at 4:18–21) and “primer DNA sequences [that]
have at least one nucleotide at the 3' end that specifically hybridizes to a
subset of cDNA molecules” (id. at 4:38–40).
More specifically, Weinstein’s method involves
PCR amplification of the cDNA fragments using sets of primers
based on the adaptor sequences and adjacent bases. In this way,
the cellular mRNA is divided into multiple portions (e.g., 196
portions) for identification of different subsets of the mRNA
that are transcribed into cDNA, amplified and detected by any
of a variety of well known methods.
(Id. at 6:47–53.) In the embodiment shown in Weinstein’s Figure 2, “PCR is
performed with primers. . . including one, two, or three specific ‘nesting’
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bases . . . at the 3' end. These nesting bases add specificity to the differential
display produced because they hybridize to a selected subset of the cDNA
produced.” (Id. at 12:26–32.)
Thus, Fry describes its method as one that non-specifically amplifies
RNA or DNA fragments in order to allow formation of a library of clones
from small quantities of RNA, while Weinstein describes its method as one
that produces a display of the mRNA content that is characteristic of a
particular cell or tissue for medical or forensic applications that require
characterization of a cell or tissue sample. Weinstein states that its method
provides more specificity by amplifying different subsets of the expressed
mRNAs, those subsets being determined by one or more “nesting” bases on
the PCR primers.
Given the different purposes of Fry and Weinstein, the Examiner has
not adequately explained why Weinstein’s suggestion of adding nesting
bases to its PCR primers “to allow for amplification of specific sequences in
a mRNA/cDNA pool” (Ans. 6) would have been an obvious modification of
Fry’s method of non-specifically amplifying nucleic acid fragments to form
a library of clones.
The Examiner reasons that incorporating Weinstein’s use of specific
nucleotides at the 3' end of a primer into Fry’s method would provide the
“desirable, predictable result” of producing specific full-length cDNAs. (Id.
at 9.) However, the Examiner does not explain why such a result would
have been considered desirable by a skilled artisan in light of the full
teachings of the references.
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Finally, the Examiner states that “[t]he prior art makes clear study of
both pools of transcripts and specific transcripts were of interest at the time
of invention.” (Id. at 10.) While this is true, the context is important to the
conclusion of obviousness: Fry is interested in pools of transcripts for the
purpose of constructing clone libraries, while Weinstein is interested in
specific subsets of transcripts for the purpose of identifying cells or tissues
based on their characteristic expression patterns.
The Examiner reasons that “a skilled practitioner would have seen the
benefit of adjusting the Fry method to focus on specific full-length
transcripts in contrast to proceeding with amplification of the entire full-
length library only to have to isolate specific transcripts from the pool when
needed for study.” (Id.) This reasoning also does not persuade us that a
conclusion of obviousness is supported by the evidence.
The modification of Fry’s method that the Examiner proposes would
not, in fact, result in amplification and cloning of “specific full-length
transcripts” (id.) but would result in amplification of randomly determined
subsets of the non-specific library described by Fry. That is, adding a
particular nucleotide (A, for example) to the 3' end of Fry’s Primer 1 would
result in amplification of transcripts that contained a complementary
nucleotide (T), rather than one of the three other possible nucleotides, in that
position. The result would be a library containing a randomly determined
subset of Fry’s desired full library. The Examiner has not explained how
such a subset library would avoid any additional cloning steps that would
otherwise be required in order to further study the clones in Fry’s library.
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The Examiner has also rejected claims 6, 11, 17, 25, and 39 as
obvious based on Fry and Weinstein, further combined with either Brennan
or Slepnev. These rejections rely on the combination of Fry and Weinstein.
(See Ans. 6–7.) We therefore reverse these rejections as well, for the
reasons discussed above.
SUMMARY
We reverse all of the rejections on appeal.

REVERSED

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