Subramaniam Srikumaran et al.

Patent Trials and Appeals Board

Nov 21, 2019

14815240 - (D) (P.T.A.B. Nov. 21, 2019)

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.
14/815,240 07/31/2015 Subramaniam Srikumaran 12770022C1 3106
30743 7590 11/21/2019
W&C IP
11491 SUNSET HILLS ROAD
SUITE 340
RESTON, VA 20190
EXAMINER
NOBLE, MARCIA STEPHENS
ART UNIT PAPER NUMBER
1632
MAIL DATE DELIVERY MODE
11/21/2019 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 SUBRAMANIAM SRIKUMARAN and
SUDARVILI SHANTHALINGAM
____________

Appeal 2019-000991
Application 14/815,240
Technology Center 1600
____________

Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
JOHN E. SCHNEIDER, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL1
Pursuant to 35 U.S.C. § 134(a), Appellant2 appeals from Examiner’s
decision to reject claims 39–44. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.

1 Oral Hearing held November 5, 2019.
2 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as
“WASHINGTON STATE UNIVERSITY of Pullman, WA” (Appellant’s
July 3, 2018 Appeal Brief (Appeal Br.) 3).
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STATEMENT OF THE CASE
Appellant’s disclosure relates “generally to conditions and/or diseases
associated with M. haemolytica in ruminants, and more particularly to novel
and efficacious compositions and methods for treating or preventing
conditions and/or diseases associated with M. haemolytica in ruminants”
(Spec.3 ¶ 2). Appellant’s independent claims 39 and 42 are representative
and reproduced below:
39. A genetically engineered ruminant animal having a genome
comprising a nucleic acid sequence encoding a ruminant CD18
protein having a cleavable signal peptide with a helix-breaking
amino acid residue at an amino acid positioned 5 residues
upstream of the signal peptide cleavage site, wherein said
nucleic acid sequence has been introduced by homozygous
integration of the nucleic acid sequence into the endogenous
CD18 gene thereby disrupting the expression of native CD18
having an intact signal peptide, wherein the mutant CD18
protein encoded by said nucleic acid sequence is expressed at
least in the animal’s leukocytes, and wherein the genetically
engineered ruminant animal is resistant to, or less susceptible
to, the effects of M. haemolytica, relative to a wild-type control
animal.
(Appeal Br. 18.)
42. A method of providing a genetically engineered ruminant
animal, comprising introduction into the genome of a ruminant
animal, a nucleic acid sequence encoding a ruminant CD18
protein having a cleavable signal peptide with a helix-breaking
amino acid residue at amino acid positioned 5 residues
upstream of the signal peptide cleavage site, wherein said
nucleic acid sequence is introduced by homozygous integration
of the nucleic acid sequence into the endogenous CD 18 gene
thereby disrupting the expression of native CD18 having an
intact signal peptide, wherein the mutant CD18 protein encoded
by said nucleic acid sequence is expressed at least in the

3 Srikumaran et al., US 2015/0327522 A1, published Nov. 19, 2015.
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animal’s leukocytes, and wherein the genetically engineered
ruminant animal is resistant to, or less susceptible to, the effects
of M. haemolytica, relative to a wild-type control animal.
(Id. at 18–19.)

Ground of rejection before this Panel for review:
Claims 39–44 stand rejected under the enablement provision of 35
U.S.C. § 112(a).

ISSUE
Does the evidence of record support Examiner’s conclusion that
undue experimentation would be required to practice the claimed invention?
ANALYSIS
To satisfy the enablement requirement of 35 U.S.C. § 112(a) a patent
application must adequately disclose the claimed invention so as to enable a
person skilled in the art to practice the invention at the time the application
was filed without undue experimentation. Enzo Biochem, Inc. v. Calgene,
Inc., 188 F.3d 1362, 1371–72 (Fed. Cir. 1999). It is important to recognize,
however, that “nothing more than objective enablement is required, and
therefore it is irrelevant whether this teaching is provided through broad
terminology or illustrative examples.” In re Marzocchi, 439 F.2d 220, 223
(CCPA 1971). In this regard, we note that “a patent need not teach, and
preferably omits, what is well known in the art.” Hybritech Incorporated v.
Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384 (Fed. Cir. 1986).
On this record, Examiner finds that “the [S]pecification fails to
provide specific guidance to[:] demonstrate that the in vitro findings taught
by the [S]pecification will predictably result in a phenotype of disease
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resistance in the genetically engineered ruminant animal,” “a method that
will predictably mak[e] the claimed ruminant,” “the making of the claimed
genetically engineered ruminant animal or the ruminant animal proper”
(Ans. 6). Thus, Examiner finds that Appellant’s Specification “fails to
predictably enable a genetically engineered ruminant animal with a disease
resistant phenotype or a method of making such a ruminant animal” (id.)
In defining the breadth of Appellant’s claimed invention, Examiner
finds that, on this record, Appellant’s claims
are fairly narrowly defined to a specific genetic modification
and a specific phenotype. The breath of “ruminant animal”
encompasses any ruminant animal such as cattle, sheep, goats,
camels, llamas, and alpacas. However, the type of genetic
modification claimed is narrowly defined to one particular type
of knock-out of an endogenous CD 18 gene and a knock-in of a
replacement mutant form of CD18. The phenotype conferred
by this genetic modification is also narrowly defined as
resistant or reduces susceptibility to the effect of M.
haemolytica. The “effect of M. haemolytica” encompasses any
effect conveyed by M. haemolytica. As such, overall the claims
are fairly narrow in scope.
(Ans.4 5.)
Appellant discloses that “[t]ransgenic animals are those that carry a
non-native gene that were introduced into the animal using similar
techniques as described herein and those well known in the art” (Spec. ¶ 87;
see generally Ans. 6). In this regard, Appellant discloses that “[g]ene
replacement techniques used in the practice of [A]pplicant’s invention
includes, but is not limited to, the gene replacement techniques described in
Kuroiwa et al., (2004)” (Spec. ¶ 89; see generally Ans. 6).

4 Examiner’s September 19, 2018 Answer.
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This Appeal is based on the claims in Application, 14/815,240, which
is a continuation of the Srikumaran ’925.5 Issued claim 1 of Srikumaran
’925 is reproduced below:
1. A ruminant cell that is genetically engineered to contain a
nucleic acid sequence encoding a ruminant CD18 protein
having a cleavable signal peptide with a helix-breaking amino
acid residue at an amino acid positioned 5 residues upstream of
the signal peptide cleavage site.
(Srikumaran ’925 185: 58–62 (emphasis added).) The ruminant cell of
Srikumaran ’925’s claim 1 contains the same nucleic acid sequence
encoding a ruminant CD18 protein as required by Appellant’s claim 39 and
42 on Appeal.6 Tracking the effective filing date of Appellant’s claimed
invention, we note that Appellant claims benefit of PCT/US10/22932, filed
February 2, 2010, which claims benefit to Provisional Application
61/149,278, filed February 2, 2009. Thus, Examiner finds that the effective
filing date of Appellant’s Application is February 2, 2009 (Ans. 10).
Examiner recognizes that “homologous recombination in primary
fibroblasts followed by somatic cell nuclear transfer was developed and was
the exclusive method for producing a targeted disruption (e.g. gene knock-

5 Srikumaran et al., US 9,102,925 B2, issued Aug. 11, 2015, filed August 2,
2011.
6 Appellant’s independent claim 39 comprises, inter alia, “a nucleic acid
sequence encoding a ruminant CD18 protein having a cleavable signal
peptide with a helix-breaking amino acid residue at an amino acid positioned
5 residues upstream of the signal peptide cleavage site” (see Appeal Br. 18).
Similarly, Appellant’s only other independent claim, claim 42, comprises,
inter alia, “a nucleic acid sequence encoding a ruminant CD18 protein
having a cleavable signal peptide with a helix-breaking amino acid residue at
[an] amino acid positioned 5 residues upstream of the signal peptide
cleavage site” (id.).
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out) in the genome of livestock at the time of [Appellant’s] invention” (Final
Act.7 6; cf. Ans. 12 (Examiner finds that Appellant’s Specification “fails to
provide any specific guidance to a method of disrupting (i.e.-knocking-out)
the endogenous CD18 gene in a ruminant by inserting (i.e.-knocking-in) a
mutated form of the CD18 gene into said endogenous CD18 gene”); see
generally Ans. 12–13). See Hybritech Incorporated v. Monoclonal
Antibodies, Inc., 802 F.2d at 1384 (“a patent need not teach, and preferably
omits, what is well known in the art.”). To be clear, somatic cell nuclear
transfer refers to a method of producing a viable embryo by transferring a
somatic cell nucleus, e.g., a nucleus from a cell encompassed by the
Srikumaran patent, into an enucleated oocyte.
Thus, Examiner concedes, and the evidence of record establishes, that
as of the effective filing date of Appellant’s claimed invention, the
methodology required to produce the targeted ruminant CD18 protein
modification required by Appellant’s claimed invention was well known in
this art (see Final Act 6 (“homologous recombination in primary fibroblasts
followed by somatic cell nuclear transfer was developed and was the
exclusive method for producing a targeted disruption (e.g. gene knock-out)
in the genome of livestock at the time of [Appellant’s] invention”); see also
Laible8 111: col. 2 (“a cell-mediated transgenesis method that could be
applied in farm animals . . . emerged in 1996 with the arrival of the clone
sheep Dolly, the first mammal produced by somatic cell nuclear transfer

7 Examiner’s April 2, 2018 Final Office Action.
8 Laible et al., Improving livestock for agriculture – technological progress
from a random transgenesis to precision genome editing heralds a new era,
10 Biotechnol. J. 109–20 (2015).
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(SCNT)”); see also Srikumaran ’925 185: 58–62 (claim 1 of Srikumaran
’925 setting forth a cell comprising Appellant’s claimed mutation, which
may serve as the source of nuclear material for a somatic cell transfer)).
There is no doubt that Laible’s 2015 post-filing date disclosure
provides evidence of the state of the art prior to Appellant’s filing date that
supports a finding that at the time of Appellant’s claimed invention, the
methodology required to produce the targeted ruminant CD18 protein
modification required by Appellant’s claimed invention was well known in
this art. See In re Hogan, 559 F.2d 595, 605 (Fed. Cir. 1977) (“This court
has approved use of later publications as evidence of the state of art existing
on the filing date of an application.”).
In addition, Beever declares that Appellant’s Specification, “in view
of the knowledge in the art, would have enabled one of ordinary skill in the
art as of the filing date to produce the genetically engineered ruminant
animal of the claimed invention without undue experimentation” (Beever
Declaration9 ¶ 6). See Hybritech Incorporated v. Monoclonal Antibodies,
Inc., 802 F.2d at 1384 (“a patent need not teach, and preferably omits, what
is well known in the art.”). Beever further declares that “as of the filing
date, zinc finger nuclease (ZFN) gene editing technology was a known and
reliable technique for generating genetically engineered animals” (id. (citing
a number of pre-filing date documents for support); see Ans. 23 (“Examiner
does agree that as of the filing date ZFN gene editing [was a] reliable
technique for generating some genetically engineered animals with

9 Declaration of Jonathan E. Beever, Ph.D., signed October 17, 2017.
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particular types of genetic modification, such targeted gene disruptions in
mice and rats were established”)).
Although Examiner appreciates that ZFN technology was well-known
in this art at the time of Appellant’s earliest effective filing date, Examiner
finds that this evidence of the state of the art at the time of Appellant’s
invention does “not provide adequate demonstration of enablement at the
time of filing because they do not . . . produc[e] a knockin ruminant as
[Appellant’s] claimed invention requires” (Ans. 15; see generally id. at 15–
20). Srikumaran declares, however, that “Examiner . . . incorrectly
concluded that because the ZFN technique had not been applied to a
ruminant animal in 2009 that it was not possible” (Srikumaran Declaration10
¶ 2). In this regard, Srikumaran declares that “apart from size, mice and rats
are not all that different from other mammals such as cows” and
“experiments performed in rats and mice can be extrapolated to the not so
evolutionarily distant ruminant animals” (id.). On this record, and in view of
the successful results obtained in non-ruminant animals, we find that
Appellant’s evidence and rationale outweighs Examiner’s intimation that, at
the time of Appellant’s claimed invention, those of ordinary skill in this art
would have found that it would have required undue experimentation to
produce knock-in ruminants.
We are also not persuaded by Examiner’s reliance on Laible’s 2015
post-filing date disclosure “that somatic cell nuclear transfer based gene
targeting proved to be too inefficient to make the introduction of site specific
changes into livestock genomes a routine practice” (Final Act. 7 (citing

10 Declaration of Subramaniam Srikumaran, Ph.D., signed January 25, 2018.
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Laible 114: col. 1, first paragraph); see Ans. 8 (citing Laible 114: col. 1, first
paragraph)). Examiner made no attempt, on this record, to identify whether
the inefficiencies disclosed by Laible were discovered prior to or after the
filing date of Appellant’s application. In this regard, we note that it is not
proper for Examiner to rely upon “a later . . . publication disclosing a
later . . . existing state of the art in testing an earlier . . . application for
compliance with” 35 U.S.C. § 112(a). See In re Hogan, 559 F.2d at 605.
Therefore, Examiner failed to establish an evidentiary basis on this record to
support a finding that Laible supports Examiner’s assertion that “somatic
cell nuclear transfer based gene targeting proved to be too inefficient to
make the introduction of site specific changes into livestock genomes a
routine practice” (Final Act. 7).
We recognize Examiner’s reliance on the Carlson’s 2012 post-filing
date disclosure,11 but find that Examiner failed to establish whether
Carlson’s disclosure relates to “the permissible application of later
knowledge about art-related facts existing on the filing date [or] the
impermissible application of later knowledge about later art-related
facts . . . which did not exist on the filing date” of Appellant’s claimed
invention. In re Hogan, 559 F.2d 605. Therefore, we are not persuaded by
Examiner’s reliance on Carlson to support Examiner’s assertion that
homologous recombination methods used to introduced a
targeted insertion in mice (i.e.-knock-in) were not applicable to
other mammals. As an alternative approach, homologous
recombination in primary fibroblasts followed by somatic cell
nuclear transfer was developed and was the exclusive method
for producing a targeted disruption (e.g. gene knock-out) in the

11 Carlson et al., Efficient TALEN-mediated gene knockout in livestock, 109
PNAS 17382–87 (2012).
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genome of livestock at the time of the invention. However,
generation of knockout cell lines by homologous recombination
was inefficient and the length of time for gestation and
reproductive maturation for livestock represent significant
barrier to homozygous gene inactivation or the engineering
multiple loci.
(Final Act. (citing Carlson 17382: col. 1, first paragraph); see Ans. 8 (citing
Carlson 17382: col. 1, first paragraph).)
Examiner’s reliance on the post-filing date disclosures of Tywman,12
Liu,13 and Gao14 suffers the same deficiency as Carlson (see Ans. 7–9).
Furthermore, Examiner failed to establish a nexus, on this record, between
Tywman’s reported “side effects” associated with “experiments concentrated
on the transfer of growth-related genes” and resistance, or reduced
susceptibility, to the effects of M. haemolytica encompassed by Appellant’s
claimed invention (id. at 7).
For the foregoing reasons, we are not persuaded by Examiner’s
finding that “the post-filing art provide[s] adequate evidence demonstrating
that a great deal of undue experimentation would have been required at the
time of the invention to enable the claims” (id. at 10). See In re Hogan, 559
F.2d at 605 (Examiner’s conclusion is based on “the impermissible

12 Twyman et al., Gene Expression in Recombinant Animal Cells and
Transgenic Animals, Encyclopedia of Industrial Biotechnology: Bioprocess,
Bioseparation, and Cell Technology 1–74 (Michael C. Flickinger ed., John
Wiley & Sons, Inc.) (2013).
13 Liu et al., Zinc-finger nickase-mediated insertion of the lysostaphin gene
into the beta-casein locus in cloned cows, Nature Communications DOI:
10.1038/ncomms3565, www.nature.com/naturecommunications (2013).
14 Gao et al., Single Cas9 nickase induced generation of NRAMP1 knockin
cattle with reduced off-target effects, 18 Genome Biology 1–15 (2017).
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application of later knowledge about later art-related facts . . . which did not
exist on the filing date.”).
In sum, the available evidence on this record supports a finding that
those of ordinary skill in this art, at the time of Appellant’s earliest effective
filing date, would have been able to produce, without undue
experimentation, a ruminant somatic cell that contains the specific CD18
modification required by Appellant’s claimed invention. Examiner fails to
establish an evidentiary basis on this record to support a finding that a
person of ordinary skill in this art would not have been able to produce a cell
(i.e., a somatic cell) that expresses the specific CD18 genetic modification
required by Appellant’s claimed invention without undue experimentation
(see Srikumaran ’925 185: 58–62 (claim 1 of Srikumaran ’925 setting forth a
cell comprising Appellant’s claimed mutation, which may serve as the
source of nuclear material for a somatic cell transfer); cf. Ans. 23 (Examiner
asserts that making Appellant’s “claimed ruminant . . . requires more than a
targeted gene disruption because the claimed ruminant has a gene
replacement, which requires gene disruption, targeted gene insertion in a
manner that successfully results in expression of the inserted gene, and the
development of a phenotype susceptibility or resistance to M. haemolytica)).
The available evidence on this record further supports Examiner’s
finding that “homologous recombination in primary fibroblasts followed by
somatic cell nuclear transfer was developed and was the exclusive method
for producing a targeted disruption (e.g.[,] gene knock-out) in the genome of
livestock at the time of [Appellant’s] invention” (Final Act. 6; see also
Laible 111: col. 2 (“a cell-mediated transgenesis method that could be
applied in farm animals . . . emerged in 1996 with the arrival of the clone
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sheep Dolly, the first mammal produced by somatic cell nuclear transfer
(SCNT)”)).
For the foregoing reasons, we are not persuaded by Examiner’s
assertion that Appellant failed to enable a method of producing an animal
within the scope of their claimed invention (see e.g., Ans. 22).
In addition, Examiner failed to establish an evidentiary basis on this
record to support a finding that an animal produced by somatic cell nuclear
transfer using a cell engineered to contain the genetic modification required
by Appellant’s claimed invention, would not have been reasonably expected,
at the time of Appellant’s claimed invention, to exhibit the phenotype the
animal was engineered to express, i.e. an animal that is resistant to, or less
susceptible to, the effects of M. haemolytica, relative to a wild-type control
animal (see Appeal Br. 18–19; cf. Ans. 22 (Appellant fails to enable “gene
correction in ruminant cells that can be developed into a live ruminant
animal that successfully expresses the corrected gene in a manner that
predictably leads to a specific disease resistance phenotype, as the instant
claimed ruminant animal and methods require”)).
For the foregoing reasons, we find that the weight of the evidence on
this record falls in favor of Appellant.
CONCLUSION
The evidence of record fails to support Examiner’s conclusion that
undue experimentation would be required to practice the claimed invention.
The rejection of claims 39–44 under the enablement provision of 35 U.S.C.
§ 112, first paragraph is reversed.

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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
39–44 112(a) Enablement 39–44

REVERSED