Ex Parte Gmeiner

Board of Patent Appeals and Interferences

Nov 18, 2010

11704090 (B.P.A.I. Nov. 18, 2010)

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.
11/704,090 02/08/2007 William H. Gmeiner 9151-63 6307
20792 7590 11/18/2010
MYERS BIGEL SIBLEY & SAJOVEC
PO BOX 37428
RALEIGH, NC 27627
EXAMINER
STEELE, AMBER D
ART UNIT PAPER NUMBER
1639
MAIL DATE DELIVERY MODE
11/18/2010 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 WILLIAM H. GMEINER
__________

Appeal 2010-004807
Application 11/704,090
Technology Center 1600
__________

Before BRADLEY R. GARRIS, LINDA M. GAUDETTE, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

McCOLLUM, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to a nucleic
acid generation method. The Examiner has rejected the claims on appeal as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.
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STATEMENT OF THE CASE
Claims 1, 2, 5, 6, 9-18, 21, 24-32, and 34 are on appeal. Claims 3, 4,
7, 8, 19, 20, 22, and 23 are also pending but have been withdrawn from
consideration by the Examiner. (App. Br. 3.) We will focus on claims 1, 11,
and 17, which read as follows:
1. A method of generating a nucleic acid of interest, which nucleic
acid specifically binds to an extracellular surface protein expressed by a cell
of interest, and which nucleic acid is capable of being internalized by said
cell of interest, said method comprising the steps of:
combining a first pool comprising different nucleic acids with said
extracellular surface protein;
selecting a first subpopulation of nucleic acids from said first pool,
said first subpopulation comprising at least one nucleic acid that specifically
binds to said extracellular surface protein;
amplifying said at least one nucleic acid of said first subpopulation;
and
selecting a second subpopulation comprising at least one nucleic acid
species from said first subpopulation which is internalized by said cell of
interest, wherein said selecting step is performed by fluorescence
microscopy or flow cytometry.
11. The method of claim [1, wherein said nucleic acid comprises
cytotoxic nucleotides, said cytotoxic nucleotides comprise poly-FdUMP,
and] said poly-FdUMP comprises FdUMP[9] or FdUMP[10].
17. A method of generating a nucleic acid of interest, which nucleic
acid specifically binds to an extracellular surface protein expressed by a cell
of interest, which nucleic acid is capable of being internalized by said cell of
interest, and which nucleic acid comprises one or more types of compounds
of interest to be delivered to said cell of interest, said method comprising the
steps of:
combining a first pool comprising different nucleic acids with said
extracellular surface protein;
selecting a first subpopulation of nucleic acids from said first pool,
said first subpopulation comprising at least one nucleic acid that specifically
binds to said extracellular surface protein;
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amplifying said at least one nucleic acid of said first subpopulation;
selecting a second subpopulation comprising at least one nucleic acid
species from said first subpopulation which is internalized by said cell of
interest;
determining a first chemical structure of a nucleic acid from said
second population;
determining a second chemical structure of a nucleic acid which is an
analog of said nucleic acid from said second population, said analog
comprising one or more types of said compounds of interest;
analyzing the folding properties of said first chemical structure;
analyzing the folding properties of said second chemical structure;
comparing the folding properties of said first chemical structure with
that of said second chemical structure; and
generating a nucleic acid of interest based upon said comparing.
Claims 1, 2, 5, 6, and 9-16 stand rejected under 35 U.S.C. § 103(a) as
obvious over Stanton et al. (US 2004/0249130 A1, Dec. 9, 2004) and
Gmeiner (US 6,342,485 B1, Jan. 29, 2002) (Ans. 4).
Claims 1, 2, 5, 6, 9-18, 21, 24-32, and 34 stand rejected under
35 U.S.C. § 103(a) as obvious over Stanton, Gmeiner, and Shi et al.
(US 2005/0282190 A1, Dec. 22, 2005) (Ans. 6-7).
PRINCIPLES OF LAW
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Obviousness
“analysis need not seek out precise teachings directed to the specific subject
matter of the challenged claim.” Id. at 418. Instead, it proper to “take
account of the inferences and creative steps that a person of ordinary skill in
the art would employ.” Id. “A person of ordinary skill is also a person of
ordinary creativity, not an automaton.” Id. at 421.
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I
In rejecting claim 1, for example, the Examiner relies on Stanton for
teaching
methods of generating nucleic acids of interest comprising
preparing a pool of nucleic acids (i.e. aptamers), combining the
aptamers with an extracellular surface protein of interest,
selecting aptamers that bind to the extracellular surface protein
of interest, amplifying the aptamers, utilizing a cell expressing
the extracellular surface protein of interest to select an aptamer
that is internalized by the cell.
(Ans. 4-5.) In addition, the Examiner finds that “the aptamer can be
conjugated to toxins including fluorouracil” (id. at 5).
The Examiner relies on Gmeiner for teaching “FdUMP[9] or
FdUMP[10] as toxins that can be utilized to treat cancer alone or in
combination with fluorouracil and analysis via flow cytometry” (id.).
The Examiner concludes that it would have been obvious “to modify
the toxins utilized in the method taught by Stanton et al. with the FdUMP[9]
or FdUMP[10] taught by Gmeiner” (id.). The Examiner additionally
concludes that “the claims would have been obvious because . . . flow
cytometry to detect fluorescence[] was recognized as part of the ordinary
capabilities of one skilled in the art” (id. at 6).
Appellant argues:
the combination of Stanton et al. and Gmeiner neither teaches
nor directs one of ordinary skill in the art to select a second
subpopulation comprising at least one nucleic acid species from
said first subpopulation which is internalized by said cell of
interest, wherein said selecting step is performed by
fluorescence microscopy or flow cytometry.
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(App. Br. 7.) In particular, Appellant argues that “a particular known
technique being ‘part of the ordinary capabilities’ of one of ordinary skill in
the art does not show motivation for one of ordinary skill in the art to
perform this technique in order to arrive at Appellant’s claimed invention”
(id.).
Appellant also argues that, with regard to the elected species,
“FdUMP[9], one of ordinary skill in the art is . . . not directed down the path
to modify Stanton et al. with the particular toxins found in the Gmeiner
reference” (id.). In particular, Appellant argues that “Fluorouracil (5-4
fluorouracil, in particular) is found among a general listing of known
chemotherapeutic agents in paragraph [0232] of Stanton et al., and one of
ordinary skill in the art is not directed to fluorouracil, or to specific
variations thereof, in particular” (id. at 8).
Issues
Does the evidence support the Examiner’s conclusion that it would
have been obvious to use flow cytometry to select nucleic acids in Stanton’s
method?
Does the evidence support the Examiner’s conclusion that it would
have been obvious to link FdUMP[9] to Stanton’s aptamer?
Analysis
Stanton discloses that “[a]ptamer selection is accomplished by passing
a solution of oligonucleotides through a column containing the target
molecule” (Stanton, ¶ [0117]). Stanton also discloses that
“[p]harmacokinetics and biodistribution of aptamer conjugates in biological
samples are quantified radiometrically and by a hybridization-based dual
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probe capture assay with enzyme-linked fluorescent readout” (id. at
¶ [0186]). However, we agree with the Examiner that it would have been
obvious to select aptamers by flow cytometry, as disclosed in Gmeiner. We
are not persuaded by Appellant’s argument to the contrary because the
Examiner provides reasons to combine the references in the Examiner’s
Answer at pages 12-13 and Appellant has not adequately explained why
these reasons are inadequate.
In addition, Stanton discloses “linking a nucleic acid aptamer to
cytotoxic agents and delivering the aptamer-toxin conjugate to a target”
(Stanton, ¶ [0002]). Stanton also discloses that “[e]xamples of suitable
toxins include, e.g., chemotherapeutic agents,” such as 5-4 fluorouracil (id.
at ¶ [0232]). Gmeiner discloses the use of homo-oligomeric FdUMP as
cytotoxic agents in the treatment of cancer (Gmeiner, col. 1, ll. 12-21, &
col. 2, ll. 4-6). In particular, Gmeiner discloses a “homooligomer of FdUMP
[that] ranges from about 9-11 monomers” (id. at col. 2, ll. 63-65). We agree
with the Examiner that it would have been obvious to link homooligomers of
FdUMP ranging from 9-11 monomers, including FdUMP[9] and
FdUMP[10], recited in claim 11, to Stanton’s aptamers as the cytotoxic
agent. We are not persuaded by Appellant’s argument to the contrary
because we conclude that the selection of a known toxin, as disclosed in
Gmeiner, is prima facie obvious over the teaching in Stanton of a broad
range of toxins.
Conclusion
The evidence supports the Examiner’s conclusion that it would have
been obvious to use flow cytometry to select nucleic acids in Stanton’s
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method. The evidence also supports the Examiner’s conclusion that it would
have been obvious to link FdUMP[9] to Stanton’s aptamer. We therefore
affirm the obviousness rejection of claim 1 over Stanton and Gmeiner.
Claims 2, 5, 6, and 9-16 have not been argued separately and therefore fall
with claim 1. 37 C.F.R. § 41.37(c)(1)(vii).
II
In rejecting claim 17, for example, the Examiner additionally relies on
Shi for teaching “methods of analyzing the folding properties of nucleic
acids including aptamers with the Mfold program by Zuker” (Ans. 8). The
Examiner concludes that it would have been obvious “to modify . . . the
method taught by Stanton et al. with . . . the folding analysis taught by Shi”
(id.).
Appellant argues:
[I]t is unreasonable to conclude that one of ordinary skill in art
would be motivated to analyze the folding properties of an
aptamer made according to the teachings of Stanton et al. No
mention is made in Stanton et al. of a problem with the folding
properties of the aptamers such that one of ordinary skill in the
art would have been motivated to analyze the nucleic acid
structure/folding. Indeed, the toxin in Stanton et al. is
conjugated to an aptamer by way of a linker (see, e.g.,
Example 5), which serves to physically separate the aptamer
from the toxin and preserve the toxin’s pharmacological activity
(see paragraph [0309]). This physical separation negates a need
or motivation to analyze the folding structure in Stanton et al.
(App. Br. 10).
Appellant also argues:
[N]o mention is made of “an analog” of the nucleic acid
“comprising one or more types of said compounds of interest”
in any of these references, which is recited in Appellant’s
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claim 17. As is known in the art, an analog is a compound
which is structurally similar. The Advisory Action of
February 26, 2009, on Page 6 states that analogs are found in
Stanton et al. However, a motivation for one of ordinary skill
in the art to use an analog in the same way as the claimed
methods is not articulated.
(Id.)
Issue
Does the evidence support the Examiner’s conclusion that it would
have been obvious to compare the folding properties of a nucleic acid
selected by Stanton’s method to the folding properties of an analog of the
selected nucleic acid that comprises a compound of interest?
Analysis
Shi discloses “a method of using a multivalent nucleic acid aptamer to
bring a first and second target molecule into proximity of one another” (Shi,
¶ [0014]). Shi also discloses:
This method involves providing a multivalent aptamer
comprising first, second, and third aptamer sequences, wherein
the first and second aptamer sequences are operably linked by a
three-way junction, and the third aptamer sequence is operably
linked to the first and second aptamer sequences, and wherein
each of the first and second aptamer sequences is capable of
binding the first target molecule, and the third aptamer
sequence is capable of binding the second target molecule,
which is different from the first target molecule.
(Id.) In addition, Shi discloses “FIG. 3B shows a construct (SEQ ID
NO: 17) designed by fusing together through stems one reduced RA1-HSF
with two reduced S1’s. . . . The secondary structure depicted here has been
checked by Mfold . . . to ensure the correct folded form of each aptamer
components in this composite structure.” (Id. at ¶ [0022].)
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Stanton discloses linking a compound of interest, that is, a cytotoxic
agent, to a nucleic acid aptamer to form an aptamer-toxin conjugate
(Stanton, ¶ [0002]). We agree with the Examiner that it would have been
obvious to compare the secondary structure of the aptamer to the secondary
structure of the conjugate, which is an analog of the aptamer comprising a
compound of interest, to ensure that the aptamer of the conjugate has the
correct folded form.
We are not persuaded by Appellant’s argument to the contrary
because we agree with the Examiner that Stanton discloses an analog, i.e.,
the conjugate, and Shi teaches that it is desirable to check the secondary
structure of an aptamer “to ensure the correct folded form of each aptamer
components in this composite structure” (Shi, ¶ [0022]). In order to confirm
that the aptamer of the conjugate has the correct folded form, it would be
obvious to compare it to the aptamer that has not been linked to the toxin to
form a conjugate. Even if physical separation between the aptamer and the
toxin diminishes the need to analyze the folding structure in Stanton, we
agree with the Examiner that one of ordinary skill in the art would still
consider it helpful to confirm that the secondary structure is correct.
Conclusion
The evidence supports the Examiner’s conclusion that it would have
been obvious to compare the folding properties of a nucleic acid selected by
Stanton’s method to the folding properties of an analog of the selected
nucleic acid that comprises a compound of interest. We therefore affirm the
obviousness rejection of claim 17 over Stanton, Gmeiner, and Shi.
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Claims 1, 2, 5, 6, 9-16, 18, 21, 24-32, and 34 have not been argued
separately and therefore fall with claim 17. 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

cdc

MYERS BIGEL SIBLEY & SAJOVEC
PO BOX 37428
RALEIGH, NC 27627