Ex Parte 8558055 et al

Patent Trial and Appeal Board

Oct 22, 2018

90013858 (P.T.A.B. Oct. 22, 2018)

UNITED STATES PATENT AND TRADEMARKOFFICE
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.
90/013,858 11/03/2016 8558055 4438
58249 7590 10/22/2018
COOLEY LLP
ATTN: IP Docketing Department
1299 Pennsylvania Avenue, NW
Suite 700
Washington, DC 20004
EXAMINER
CAMPELL, BRUCE R
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
10/22/2018 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 TRANSPOSAGEN BIOPHARMACEUTICALS, INC.
Patent Owner and Appellant
____________

Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2
Technology Center 1600
____________

Before TONI R. SCHEINER, RICHARD M. LEBOVITZ, and RAE LYNN
GUEST, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This appeal involves claims related to a genetically modified rat or
progeny of the rat, where the rat or its progeny comprise, in at least some of
its cells, a genome comprising a disruption of one or more cytokine genes
that results in their misexpression. The Examiner rejected the claims as
unpatentable under 35 U.S.C. § 103. Pursuant to 35 U.S.C. § 134,
Appellants appeal the rejection of the claims. We have jurisdiction under 35
U.S.C. § 6(b). The rejection is affirmed.

Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2

2
STATEMENT OF THE CASE
This appeal involves U.S. Pat. No. 8,558,055 B2 (“the ’055 patent”)
which issued October 15, 2013. A Request for Ex Parte Reexamination was
filed by a Third-Party Requester on November 3, 2016 pursuant to 35 U.S.C.
§§ 302–307 and 37 C.F.R. § 1.510.
The real party-in-interest is identified in the Appeal Brief (“Br.”) as
Transposagen Biopharmaceuticals, Inc. Br. 2.
Claim 1–7, 9–17, 21–34, and 39–47 stand finally rejected by the
Examiner as obvious under 35 U.S.C. § 103(a) over the following
publications (Final Office Action (“Final Act.”) 5; Examiner’s Answer
(“Ans.”) 2).
1. Cui et al. (“Cui”) U.S. Patent No. 9,206,404 B2, issued Dec. 8,
2015;
2. Timothy J. Aitman et al. (“Aitman”) “MHC2TA is associated with
differential MHC molecule expression and susceptibility to rheumatoid
arthritis, multiple sclerosis and myocardial infarction,” 40 NATURE
GENETICS (5), 516–22 (2008);
3. Amos-Landgraf et al. (“Amos-Landgraf”) “A target-selected Apc-
mutant rat kindred enhances the modeling of familial human colon cancer,”
104 PNAS (10), 4036–41 (2007);
4. Eric M. Ostertag et al. (“Ostertag”) “Mutagenesis in rodent using
the LI retrotransposon,” 8 GENOME BIOLOGY SUPPL 1, S16.1–S16.9 (2007);
5. WO 2009/072882 A1, published June 11, 2009 (“Cuppen”);
6. Maria Swanberg et al. (“Swanberg”) “MHC2TA is associated with
differential MHC molecule expression and susceptibility to rheumatoid
Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2

3
arthritis, multiple sclerosis and myocardial infarction,” 37 NATURE
GENETICS (5), 486–94 (2005);
7. Lilia Bi et al. (“Bi”) “Dominant inhibition of Fas ligand-mediated
apoptosis due to a heterozygous mutation associated with autoimmune
lymphoproliferative syndrome (ALPS) Type lb,” 8 BMC MEDICAL GENETICS
(41) (2007); and
8. Lindsay at al. (“Lindsay”) “The Prevention and Treatment of
Murine Colitis Using Gene Therapy with Adenoviral Vectors Encoding IL-
10,” 166 J. IMMUNOLOGY, 7625–33 (2001).
Independent claim 1 is representative and is reproduced below
(underlining showing language added relative to the original claims):
1. A genetically modified rat or progeny of the rat, wherein
the rat or its progeny comprise in at least some of its cells a
genome comprising a disruption of one or more cytokine genes
that results in the misexpression of the one or more cytokine
genes, wherein the rat or its progeny exhibits a greater
susceptibility to a cytokine-mediated autoimmune and/or
inflammatory disease than a rat or progeny rat not comprising
the genetic mutation, and wherein the disruption comprises a
site-specific nuclease-introduced deletion of DNA.

REJECTION
The Examiner found that Cui describes a method of making a
genetically modified “knockout” rat by deleting genomic DNA using a site-
specific nuclease, the same technique recited in all the rejected claims to
produce the claimed genetically modified rat or progeny of the rat. Final
Act. 8–9. Cui does not describe deleting DNA from a cytokine gene as
required by all of the claims.
Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2

4
The Examiner further found that each of Aitman, Ostertag, Amos-
Landgraf, and Cuppen describe knockout rats produced by methods which
cause a gene to be misexpressed. Final Act. 9. These methods involve a
different technology than the site-specific nuclease technology described in
Cui. Id. The Examiner found that these publications characterized the rats
as useful models for human disease and for testing pharmaceuticals. Id.
The Examiner further found that the prior art “shows that there were
several cytokine genes known to be of interest [in human disease] due to
their association with certain disease states.” Id. at 9–10. These prior art
publications include:1

Cuppen
The Examiner found that Cuppen produced rats with modified
cytokine genes. Final Act. 10. The Examiner acknowledged that “Cuppen’s
knockout was caused by a point mutation which created a stop codon in the
CXCR2 coding sequence [a cytokine gene]” and not a deletion of DNA as
required by the claim, but found that “the skilled artisan would immediately
recognize that Cui’s method of making deletion mutations enables
production of rats with the same phenotype, i.e. no detectable expression of
the CXCR2 protein.” Id. at 8 (fn. 1).

1 A complete discussion of all the cited publications is found on pages 5–9
of the Final Office Action.
Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2

5
Lindsay
The Examiner found that Lindsay describes IL-10 deficient knockout
mice. The gene target-targeted knockout mice develop colitis that resembles
human Crohn’s disease. Lindsay 7625. Lindsay used the mouse model to
test the ability of IL-10 to ameliorate the disease and to determine the
delivery system to do so. Id. at 7632. The Examiner found:
Lindsay does not suggest making genetically modified rats [as
claimed], but motivation to do so can be found in Amos-
Landgraf, which notes that rats have the advantage of being
amenable to endoscopy and virtual colonoscopy so that disease
(or treatment) progression can be studied without sacrificing
test animals (p. 4039, col. 2–p. 440, col. 1).
Final Act. 9

Bi
The Examiner found that Bi describes a human mutation in the Fas
ligand (FasL) gene, which is a cytokine gene (see ’055 patent, col. 11, ll. 1–
2) as claimed. Final Act. 8–9. The gene mutation is associated with
autoimmune lymphoproliferative syndrome (ALPS) Type Ib. Id. at 8. The
Examiner stated:
[It] would have been obvious to make rats having genetic
defects similar to those found to be linked with human disease.
For example, the codon encoding arginine at position 156 of the
FasL protein, which Bi found to be critical for FasL function,
could be deleted.
Ans. 12.

Reason to combine
The Examiner concluded that it would have been obvious to one of
ordinary skill in the art at the time of the invention “that the method of Cui
Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2

6
could be used to produce mutations that would achieve the same phenotype
as any mutation that had already been discovered or made in rats by other
methods.” Ans. 11–12. The Examiner further explained that one of
ordinary skill in the art at the time of the invention “would be motivated to
make these deletions in order to rapidly introduce the mutations into rat
strains having different genetic backgrounds” and “to reproduce in rats any
knockout that had already been made in mice, such as the IL-10 knockout
disclosed by Lindsay, motivation being the art recognized advantages of rats
as models of human disease as taught by Aitman and Ostertag.” Id. at 12.
Thus, based on the cited teachings of Cuppen, Lindsay, Bi, etc., the
Examiner determined that “the skilled artisan would have been motivated to
use the powerful new gene editing method of Cui to create deletions in
cytokine related genes in order to satisfy the long felt need for rat models of
human diseases.” Id.

DISCUSSION
Appellant contends that the nine publications2 cited by the Examiner
are “conflicting” and are “pieced together using Patent Owner’s
specification as a template.” Br. 4. Appellant argues that four of the
publications cited by the Examiner describe randomly introducing mutations
into the rat genome which conflicts with the claimed approach of “targeting
a specific and predetermined gene.” Id. at 4. Appellant further argues that
Cui’s genetically modified rats show a phenotype “opposite” to the claimed
phenotype. Id. at 6. Appellant states that “[n]othing in Cui would have

2 We count only 8 listed on page 2 of the Examiner’s Answer.
Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2

7
motivated a skilled artisan to generate a transgenic rat with the opposite
phenotype, let alone providing a reasonable expectation of success to do so.”
Id. Appellant contends that “the manufacture of genetically modified rats
was a highly complex and unpredictable field” and that no evidence has
been provided that Cui’s teaching of a single knockout rat “provided
sufficient guidance for a skilled artisan to generate a knockout rat of
different genes with an opposite phenotype.” Id. at 7.
These arguments are not persuasive. The Examiner acknowledged
that the prior art had used random mutagenesis to generate mutations in
genes, but concluded that these disclosures are not a “teaching away” or
conflict with the claimed invention. Ans. 9. Rather, the Examiner explained
that Cui’s gene targeting technique had not been previously available and
satisfied a need in the art for a technique to generate rat models for disease
and pharmaceutical testing by targeting genes of interest in a specific and
predetermined way. Id. at 9–10. It was not disputed by Appellant that Cui’s
technique produces the same gene disruption and DNA deletion recited in all
the rejection claims. The Examiner also stated that the cited publications
provide motivation to make mutations in cytokine genes to create rat models
of human diseases and provided persuasive evidence to substantiate this
conclusion. Id. at 10.
As evidence of the need for new technologies to target specific genes
in rats, such as the technology described in Cui, the Examiner cited
Aitman’s summary of the “Recommendations of the 1999 Rat Genome
Priorities meeting” describing the recommendation “to develop new
technologies for site-specific gene targeting” in rats. Aitman 517 (“Box 1”).
Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2

8
Aitman stated that “All of the recommendations of the 1999 meeting have
been exceeded, with the exception of site-specific gene targeting, which is
the ongoing focus of intensive investigation.” Id. at 516. Aitman further
stated that the pace of discovery will depend on various factors, including
“gene targeting.” Id. at 521.
The Examiner also cited the statement in Ostertag of the “need for
new techniques that can rapidly create and map gene knockouts in rats for
the creation of new models of human disease.” Ostertag at S16.5. The
Examiner found that the technology described in Cui satisfied this gene
targeting need in rats. Final Act. 7.
Thus, the Examiner had adequate and substantial factual basis to find
that one of ordinary skill in the art would have had a reason at the time of the
invention to have utilized Cui’s gene targeting technology to target specific
rat cytokine genes, such as those described in Cuppen, Lindsay, and Bi.
Ans. 9–10. The Examiner also found that “the method of Cui satisfied a
long felt need and those skilled in the art would have been eager to use this
technique to generate rats with specific, predetermined mutations, and the
prior art of record shows that they would have been motivated to make
mutations in cytokine genes to create rat models of human diseases.” Ans.
9–10.
Appellant did not identify a persuasive defect in the Examiner’s
substantial evidence.
Appellant argues “none of [the cited publications] teach or suggest a
deletion of DNA in a cytokine gene.” Br. 7. However, the Examiner
specifically addressed this deficiency in finding that Cui provides the sought
Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2

9
after gene technology to target and delete DNA in specific genes in rats.
Ans. 9. The teaching in Cuppen that rats with modified cytokine genes
could be produced with a discernable phenotype (Cuppen 43:17–19; 59
(Table 7) and Cui’s success in rats provided a reasonable expectation that
gene deletions in a cytokine gene could be made successfully in rats.
With respect to Appellant’s contention that the skilled worker would
not have utilized Cui because Cui produced a phenotype opposite to that
which is claimed, the Examiner responded:
This argument is not persuasive because Cui is relied upon
solely for its disclosure of the method for making site-specific
deletions. It was never alleged that the animals produced in
Cui’s working examples meet the limitations of the claims with
regard to the genes mutated or the phenotypes observed.
Ans. 10.
As discussed by the Examiner, Cui teaches that its method has broad
applicability:
As noted above, the disclosed methods and compositions
can be used in any type of rat cell. Progeny, variants and
derivatives of rat cells can also be used.
Applications
The disclosed methods and compositions can be used for
genomic editing of any rat gene or genes. In certain
applications, the methods and compositions can be used for
inactivation of rat genomic sequences.
Cui, col. 20, ll. 27–32.
Thus, a preponderance of the evidence supports the Examiner’s
determination that it would have been obvious to have utilized Cui’s
technology to disrupt a cytokine gene.
Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2

10
Appellant also contends that Cui does not provide sufficient guidance
for the skilled artisan to make the claimed genetically modified rat or
progeny of the rat comprising a genome comprising a disruption of one or
more cytokine genes that results in the misexpression of the one or more
cytokine genes. Br. 6–7.
This argument is not persuasive. Appellant does not identify a
deficiency in Cui that would have made the working example in Cui
insufficient to target and specifically disrupt other genes, including a
cytokine gene as claimed. Appellant did not provide evidence that Cui,
which is presumptively enabled, is not an enabling disclosure for disruption
of a cytokine gene. Ans. 10–11. An argument made by counsel in a brief
does not substitute for evidence lacking in the record. Estee Lauder, Inc. v.
L’Oréal, S.A., 129 F.3d 588, 595 (Fed. Cir. 1997).
Appellant contends that “Cuppen teaches CXCR2 among as one gene
among a laundry list of genes that could be mutated in a rat.” Br. 7.
Appellant also contends that Cuppen “does not disclose any data or
experiments towards generating a genetically engineered rat carrying a
disruption in the CXCR2 gene, let alone teaches the phenotype of such rat.”
Id.
Appellant’s argument is not supported by adequate evidence.
Cuppen teaches ENU mutations in the CXCR2 gene encoding the type 2
interleukin 8 receptor (Cuppen 43:17–19; 59 (Table 7)), which Appellant
does not dispute is a cytokine gene that falls within the scope of the rejected
claims. Cuppen teaches that mutation results in a truncation to the receptor.
Cuppen 69 (Table 7). A truncation to the receptor gene is a disruption to the
Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2

11
gene because it disrupts or interrupts expression of the normal full length
protein. Thus, it is not correct that Cuppen does not describe “a genetically
engineered rat carrying a disruption in the CXCR2 gene.” Br. 7. Cuppen
teaches the phenotype of such rats homozygous for the mutation in CXCR2.
Id. at 66 (Table 9) (“impaired growth”; “enlarged spleen and lymph nodes”;
“No detectable protein”). Accordingly, it also not factually supported that
Cuppen does not teach “the phenotype of such rat.” Br. 7.
Appellant argues “importantly, Cuppen does not teach a deletion of
DNA, as required by the claims, in the CXCR2 gene.” Br. 7. This argument
misconstrues the Examiner’s rejection. The Examiner found it obvious to
have made a targeted specific deletion of a cytokine gene, such as CXCR2,
utilizing the gene targeting technology of Cui. Final Act. 9. Thus,
Appellant’s attempt to distinguish Cuppen has no merit because the
Examiner did not rely on Cuppen for teaching a DNA deletion.

SUMMARY
In sum, we conclude that the Examiner established by a
preponderance of the evidence that claim 1 is obvious in view of Cui,
Aitman, Amos-Landgraf, Ostertag, Cuppen, Swanberg, Bi, and Lindsay.
Claims 2–7, 9–17, 21–34, and 39–47 fall with claim 1 because separate
arguments for their patentability were not provided. 37 C.F.R. §
41.37(c)(1)(iv).

Appeal 2018-007272
Reexamination Control 90/013,858
Patent 8,558,055 B2

12
TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv).

AFFIRMED

PATENT OWNER:
COOLEY LLP
ATTN: IP DOCKETING DEPARTMENT
1299 PENNSYLVANIA AVENUE, NW
SUITE 700
WASHINGTON DC 20004

THIRD PARTY REQUESTER:
CARDINAL LAW GROUP, LLC
1603 ORRINGTON AVENUE
SUITE 2000
EVANSTON, IL 60201

lp