Ex Parte Kiefer et al

Board of Patent Appeals and Interferences

Jun 8, 2012

11959251 (B.P.A.I. Jun. 8, 2012)

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.
11/959,251 12/18/2007 Michael C. Kiefer GHI-003/US/CON1 2424
80811 7590 06/11/2012
Genomic Health, Inc. (Bozicevic, Field & Francis)
c/o Kathleen Determann
301 Penobscot Road
Redwood City, CA 94063
EXAMINER
MUMMERT, STEPHANIE KANE
ART UNIT PAPER NUMBER
1637
MAIL DATE DELIVERY MODE
06/11/2012 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MICHAEL C. KIEFER and KENNETH W. HOYT
__________

Appeal 2011-012626
Application 11/959,251
Technology Center 1600
__________

Before TONI R. SCHEINER, MELANIE L. McCOLLUM, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for preparing fragmented RNA for gene expression. The Examiner rejected
the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We
reverse.

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Application 11/959,251

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Statement of the Case
Background
“The present invention provides a sample preparation method that
enables global amplification of even very small or very fragmented RNA
samples. . . . the methods of the invention permit the measurement of mRNA
levels of all expressed genes including fragmented and/or blocked mRNA
species in archived paraffin-embedded tissue samples” (Spec 2 ¶ 0007).
The Claims
Claims 2-4, 14, 16, 22, 24, 31, 56 and 57 are on appeal. Claim 56 is
representative and reads as follows:
56. A method for preparing fragmented RNA comprising a
multiplicity of RNA species for gene expression analysis
comprising the steps of:
(a) producing randomly primed first strand cDNA from
total RNA obtained from a fixed paraffin-embedded tissue
(FPET) sample obtained from a human subject, using reverse
transcriptase and random primers;
(b) tailing said randomly primed first strand cDNA to
produce tailed first strand cDNA, wherein said tailing is done
using poly(A) polymerase or terminal transferase;
(c) converting said tailed first strand cDNA to double
stranded cDNA using a primer that anneals to said tail and
contains a promoter sequence for an RNA polymerase;
(d) transcribing said double stranded cDNA using said
RNA polymerase to produce amplified RNA;
(e) reverse transcribing said amplified RNA using a
reverse transcriptase and random primers to produce a nucleic
acid sample comprising amplified cDNA and amplified RNA;
and
(f) degrading said amplified RNA in said nucleic acid
sample, thereby producing a DNA sample comprising amplified
cDNA.

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Application 11/959,251

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The issues

A. The Examiner rejected claims 2, 3, 14, 16, 22, 24, 31, 56, and 57
under 35 U.S.C. § 103(a) as obvious over Lin
1
and Fry
2
(Ans. 5-8).
B. The Examiner rejected claim 4 under 35 U.S.C. § 103(a) as obvious
over Lin, Fry, and Ohara
3
(Ans. 8-9).
A. 35 U.S.C. § 103(a) over Lin and Fry
The Examiner finds that “Lin teaches a method for preparing
fragmented RNA comprising a multiplicity of RNA species for gene
expression analysis comprising the steps of: (a) producing randomly primed
first strand cDNA from total RNA obtained from fixed, paraffin embedded
tissue . . . where the first strand is synthesized using poly dT, which falls
within the scope of a random primer” (Ans. 6). The Examiner finds that Lin
teaches tailing the cDNA, converting the tailed cDNA to double stranded
cDNA, transcribing the cDNA and reverse transcribing the amplified RNA
(Ans. 6). The Examiner finds that Fry teaches a method of “degrading said
amplified RNA in said nucleic acid sample, thereby producing a DNA
sample comprising amplified cDNA” (Ans. 8).
The Examiner finds it obvious “to extend the teachings of Lin to
combine these two known prior art methods together to produce a
predictable result of single-strand antisense cDNAs as directed by Fry”
(Ans. 8).

1
Lin et al., US 2003/0022318 A1, published Jan. 30, 2003.
2
Fry et al., US 6,114,149, published Sep. 5, 2000.
3
Ohara et al., One-sided polymerase chain reaction: The
amplification of cDNA, 86 PROC. NAT‟L ACAD. SCI. USA 5673-
5677 (1989).
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Appellants contend that “the term „random primers‟ refers to a
mixture of primers of different sequences that hybridize at random positions
in mRNA. Extension of random primers produces a randomly-primed
product. Oligo-(d)T primers, on the other hand, contain a string of T‟s.”
(App. Br. 6). Appellants contend that “Random primers and oligo(d)T
primers are not used interchangeably in these disclosures” (App. Br. 6).
Appellants contend that “in the claimed method, the amplified RNA is
not „re-amplified‟ using an RNA polymerase and then reverse transcribed, as
is done in Lin‟s method” (App. Br. 9).
Appellants contend that the “Cronin Declaration also provides data to
demonstrate that the claimed method works unexpectedly well relative to
commercially available methods representative of those available in the art,
including methods that have steps in common with the claimed method”
(App. Br. 11).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner‟s conclusion that Lin and Fry render the method of
claim 1 obvious?
Findings of Fact
1. The Specification teaches “a random primed (hexamers) cDNA
synthesis that generates cDNA with a free 3‟ OH on the terminal nucleotide
of the FPET cDNA” (Spec. 20 ¶ 0087).
2. Lin teaches that the “nucleic acid sequences can be prepared
from a plurality of fixed cells. . . Those fixed cells are also subjected to
permeabilisation for better enzyme penetration, including . . . paraffin-
embedded tissues on slides” (Lin 4 ¶ 0054).
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3. Figure 1 of Lin is reproduced below:

“FIG. 1 is an illustration of the preferred embodiment of RNA-polymerase
chain reaction” (Lin 4 ¶ 0061).
4. Fry teaches that if “the tailing reaction is performed with
RNA/cDNA fragments, the duplex fragments are next digested with RNase
to remove the sense-strand RNA” (Fry, col. 5, ll. 8-11).
Principles of Law
“The protocol of giving claims their broadest reasonable interpretation
during examination does not include giving claims a legally incorrect
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interpretation. This protocol is solely an examination expedient, not a rule of
claim construction.” In re Skvorecz, 580 F.3d 1262, 1267 (Fed. Cir. 2009).
Analysis
The first step of claim 56 requires the use of “random primers”.
While the Examiner is correct that the Specification does not define the term
“random primers” (see Ans. 10), the Specification does teach the use of
random hexamers (FF 1).
The Examiner is also correct that the USPTO should apply the
broadest reasonable interpretation. In re Morris, 127 F.3d 1048, 1054-56
(Fed. Cir. 1997). However, the word “reasonable” is key. We agree with
Appellants that no ordinary artisan would consider the oligo (dT) primers of
Lin or Fry to be “random primers”. The Examiner has not identified any
evidence in the record, whether from a definition in the Specification to a
definition or teaching in the prior art, which would support the interpretation
of oligo (dT) primers as “random primers”. Since an oligo (dT18) primer
would compose a minor fraction (1 part in 68,719,476,736 parts) of an 18
nucleotide random primer mix, we do not find it reasonable to treat an oligo
dT primer as a random primer. There is abundant prior art which shows that
“random primers” are not oligo (dT) primers (see App. Br., Exhibits A and
B).
Conclusion of Law
The evidence of record does not support the Examiner‟s conclusion
that Lin and Fry render the method of claim 1 obvious.

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B. 35 U.S.C. § 103(a) over Lin, Fry, and Ohara
This rejection relies upon the underlying obviousness rejection over
Lin and Fry which we reversed above. Having reversed the obviousness
rejection over Lin and Fry for a failure to present a prima facie case of
obviousness, we necessarily reverse this obviousness rejection further
including Ohara, as Ohara is not relied upon for the use of a random primer.

SUMMARY
In summary, we reverse the rejection of claims 2, 3, 14, 16, 22, 24, 31,
56, and 57 under 35 U.S.C. § 103(a) as obvious over Lin and Fry.
We reverse the rejection of claim 4 under 35 U.S.C. § 103(a) as
obvious over Lin, Fry, and Ohara.

REVERSED

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