Ex Parte Ow

Board of Patent Appeals and Interferences

Nov 24, 2010

10913085 (B.P.A.I. Nov. 24, 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.
10/913,085 08/06/2004 David W. Ow 0129.04 5906
25278 7590 11/24/2010
USDA-ARS-OFFICE OF TECHNOLOGY TRANSFER
PATENT ADVISORS OFFICE
WESTERN REGIONAL RESEARCH CENTER
800 BUCHANAN ST
ALBANY, CA 94710
EXAMINER
HAMA, JOANNE
ART UNIT PAPER NUMBER
1632
MAIL DATE DELIVERY MODE
11/24/2010 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 DAVID W. OW
__________

Appeal 2010-006460
Application 10/913,085
Technology Center 1600
__________

Before ERIC GRIMES, DEMETRA J. MILLS and LORA M. GREEN,
Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL1

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.
Appeal 2010-006460
Application 10/913,085

2
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s rejection of claims 1-16 and 39.2 We have jurisdiction under 35
U.S.C. § 6(b).

STATEMENT OF THE CASE
Claim 1 is the only independent claim on appeal, and reads as follows:
1. A method of obtaining site-specific replacement of a DNA of interest
in a mammalian cell, comprising:
a) providing a mammalian cell that comprises a receptor construct,
wherein the receptor construct comprises a receptor polynucleotide to be
replaced, the receptor polynucleotide being flanked by two or more copies of
a irreversible recombination site (IRS);
b) introducing into the cell a donor construct that comprises a donor
polynucleotide to replace the receptor polynucleotide, the donor
polynucleotide being flanked by two or more of a complementary
irreversible recombination site (CIRS); and
c) contacting the receptor construct and the donor construct with an
irreversible recombinase polypeptide;
wherein the irreversible recombinase catalyzes recombination
between the IRS and the CRIS [sic] and replacement of the receptor
polynucleotide with the donor polynucleotide, thereby forming a
replacement construct.

The following grounds of rejection are before us on review:
I. Claims 1-16 and 39 stand rejected under 35 U.S.C. § 103(a) as
being rendered obvious by the combination of Calos3 and Hasty.4

2 Claims 17-34 and 53-66 are also pending, but stand withdrawn from
consideration. (Amended App. Br. 5.)
3 Calos, U.S. Patent No. 6,632,672 B2, issued October 14, 2003.
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II. Claims 1-16 and 39 stand rejected on the ground of nonstatutory
obviousness-type double patenting as being unpatentable over
claims 1-4 of U.S. Patent No. 6,746,8705 as combined with Hasty.
III. Claims 1-16 and 39 stand rejected under 35 U.S.C. § 103(a) as
being rendered obvious by U.S. Patent No. 6,746,870 as combined
with Hasty.
IV. Claims 1-16 and 39 stand provisionally rejected on the ground of
nonstatutory obviousness-type double patenting as being
unpatentable over claims 61-71 of U.S.S.N. 10/721,980 as
combined with Hasty.
V. Claims 1-16 and 39 stand provisionally rejected on the ground of
nonstatutory obviousness-type double patenting as being
unpatentable over claims 1-3, 6, 20, 21, and 24 of U.S.S.N.
11/209,388 as combined with Hasty.
We reverse all of the appealed rejections.
ISSUE
Has the Examiner established that the combination of any of Calos,
U.S. Patent No, 6,746,870, claims 61-71 of U.S.S.N. 10/721,980, and claims
1-3, 6, 20, 21, 24 of U.S.S.N. 11/209,388, as combined with Hasty, renders
the method of independent claim 1 obvious?

4 Hasty et al., The Length of Homology Required for Gene Targeting in
Embryonic Stem Cells, 11 MOLECULAR AND CELLULAR BIOLOGY 5586-5591
(1991).
5 Ow, U.S Patent No. 6,746,870 B1, issued June 8, 2004.
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Application 10/913,085

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FINDINGS OF FACT
FF1 The Examiner’s statements of rejection may be found in the
Examiner’s Answer.
FF2 Each of Calos, U.S. Patent No, 6,746,870, claims 61-71 of U.S.S.N.
10/721,980, and claims 1-3, 6, 20, 21, and 24 of U.S.S.N. 11/209,388, are
drawn to a method of integrating a polynucleotide of interest into a genome.
As we find that U.S. Patent No, 6,746,870, claims 61-71 of U.S.S.N.
10/721,980, and claims 1-3, 6, 20, 21, and 24 of U.S.S.N. 11/209,388, are
cumulative to the teachings of Calos, we focus our analysis on the Calos
patent.
FF3 Specifically, as taught by Calos, the method of integrating the
polynucleotide of interest comprises:
introducing (i) a circular targeting construct, comprising a first
recombination site and the polynucleotide sequence of interest,
and (ii) a site-specific recombinase into the eucaryotic cell,
wherein the genome of the cell comprises a second
recombination site native to the genome and recombination
between the first and second recombination sites is facilitated
by the site-specific recombinase. . . . The result of the
recombination is site-specific integration of the polynucleotide
sequence of interest in the genome of the eucaryotic cell.

(Calos, col. 2, ll. 55-67.)
FF4 Thus, as taught by Calos, one of the recombination sites is associated
with the polynucleotide to be inserted, and the second recombination site is
present in the genome of the cell into which the polynucleotide is to be
inserted.
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FF5 The Examiner notes that “[w]hile Calos teaches integration of a
heterologous sequence using a single site, Calos does not teach gene
replacement.” (Ans. 4.)
FF6 As to each of U.S. Patent No, 6,746,870, claims 61-71 of U.S.S.N.
10/721,980, and claims 1-3, 6, 20, 21, and 24 of U.S.S.N. 11/209,388, the
Examiner finds that the claims of each “are drawn to method steps of
irreversible site-specific integration of a sequence.” (See Ans. 7, 9, and 11.)
FF7 The Examiner cites Hasty for teaching “that homologous
recombination has been used to introduce site-specific mutations into murine
embryonic stem cells.” (Id. at 4.)
FF8 Specifically, the Examiner relies on Hasty for teaching that “a double
crossover event is a gene replacement event.” (Id. at 5 (citing Hasty, p.
5586, second column).)
FF9 Hasty teaches that “[h]omologous recombination has been used to
introduce site-specific mutations into murine embryonic stem (ES) cells with
both insertion and replacement vectors.” (Hasty, Abstract.) Hasty
“compared the frequency of gene targeting with various lengths of
homology and found a dramatic increase in targeting with an increase in
homology from 1.3 to 6.8 kb.” (Id.)
FF10 Hasty teaches:
In the context of the hypoxanthine phosphoribosyltransferase
(hprt) locus . . . in XY ES cells, all of the targeted clones can be
isolated by selection for hprt inactivity in 6-thioguanine (TG).
We investigated the length of vector homology that is required
for efficient gene targeting with both insertion and replacement
vectors and found a dramatic increase in the absolute targeting
frequency when the length of homology was increased from 1.3
to 6.8 kb. A more detailed analysis of replacement vectors
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showed that homology of less than 1.7 kb was insufficient to
generate targeted events. An additional 225 bp increased the
frequency by at least fivefold. Homology increases from 1.9 to
4.2 kb and from 4.2 to 6.0 kb resulted in 16- and 3-fold,
respectively, increases in the targeting frequency. We have also
determined that the targeting of replacement vectors with just
472-bp sequence homology on the short arm was as efficient as
1.2 kb for a double-crossover (gene replacement) event.

(Id. at 5586, second column (emphasis added).)
FF11 Hasty teaches further that “[r]eplacement vectors usually integrate the
entire vector into the target locus, including the bacterial plasmid.” (Id. at
5591, first column.)
FF12 The Examiner concludes that it would have been obvious to modify a
gene integration system, such as that taught by Calos, into a replacement
system, by using two recombination sites on the host DNA and two
recombination sites on the recipient DNA, as Hasty teaches that a gene
replacement event is a double crossover event. (Ans. 5; see also, Ans. 7-8
(U.S. Patent No, 6,746,870); Ans. 9-10 (claims 61-71 of U.S.S.N.
10/721,980); and Ans. 11-12 (claims 1-3, 6, 20, 21, and 24 of U.S.S.N.
11/209,388).)

PRINCIPLES OF LAW
While the analysis under 35 U.S.C. § 103 allows flexibility in
determining whether a claimed invention would have been obvious, KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), it still requires showing
that “there was an apparent reason to combine the known elements in the
fashion claimed by the patent at issue.” Id. An invention “composed of
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several elements is not proved obvious merely by demonstrating that each of
its elements was, independently, known in the prior art.” Id. “Often, it will
be necessary . . . to look to interrelated teachings of multiple [references] . . .
and the background knowledge possessed by a person having ordinary skill
in the art, all in order to determine whether there was an apparent reason to
combine the known elements in the fashion claimed[.]” Id. “[T]his analysis
should be made explicit,” and it “can be important to identify a reason that
would have prompted a person of ordinary skill in the relevant field to
combine the elements in the way the claimed new invention does.” Id. “We
must still be careful not to allow hindsight reconstruction of references to
reach the claimed invention without any explanation as to how or why the
references would be combined to produce the claimed invention.”
Innogenetics, N.V. v. Abbott Labs., 512 F.3d 1363, 1374 n.3 (Fed. Cir.
2008).

ANALYSIS
Appellant argues that the skilled artisan would not look to a method of
homologous recombination, such as that taught by Hasty, to modify a
method based on site specific recombination, such as that taught by Calos.
(Reply Br. 9.) Specifically, Appellant asserts, site-specific integration, as
evidenced by Calos, requires relatively short, unique DNA sequences, that
are recognized by a site specific recombinase, wherein one site is on the
recipient molecule, and one site is on the donor molecule. (Id. at 10.)
Homologous recombination, Appellant argues, is initiated at double stranded
breaks, and is dependent on the amount of homology between the gene
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targeting vector and the target gene. (Id. at 10-11.) And in homologous
recombination, Appellant argues, it is the cell’s own recombination and
repair proteins that repair the break. (Id. at 11.) Appellant thus asserts, that
when read as a whole, the references as combined do not support the
combination as set forth by the Examiner, and thus the Examiner has failed
to set forth a prima facie case of obviousness. (Id. at 12.)
We agree with Appellant. The Examiner has provided no evidence or
reasoning as to why the ordinary artisan, given the teachings of Calos (as
well as U.S. Patent No, 6,746,870, claims 61-71 of U.S.S.N. 10/721,980,
and claims 1-3, 6, 20, 21, and 24 of U.S.S.N. 11/209,388), wherein one of
the recombination sites is associated with the polynucleotide to be inserted,
and the second recombination site is present in the genome of the cell into
which the polynucleotide is to be inserted (FF3), and the teachings of Hasty,
wherein the gene replacement depends on the amount of homology between
the replacement gene and the target gene (FF9), and wherein the entire
vector is integrated into the target locus, including the bacterial plasmid
(FF11), would arrive at the claimed method of site-specific replacement of a
DNA of interest, wherein the receptor is flanked by two or more copies of a
irreversible recombination site and the donor polynucleotide is flanked by
two or more of a complementary irreversible recombination site. We are
thus compelled to reverse the rejection.

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CONCLUSION OF LAW
We conclude that the Examiner has not established that the
combination of any of Calos, U.S. Patent No, 6,746,870, claims 61-71 of
U.S.S.N. 10/721,980, and claims 1-3, 6, 20, 21, and 24 of U.S.S.N.
11/209,388, as combined with Hasty, renders the method of independent
claim 1 obvious. We thus reverse all of the rejections on appeal.

REVERSED

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USDA-ARS-OFFICE OF TECHNOLOGY TRANSFER
PATENT ADVISORS OFFICE
WESTERN REGIONAL RESEARCH CENTER
800 BUCHANAN ST
ALBANY CA 94710