Ex Parte Kay et al

Patent Trial and Appeal Board

May 9, 2013

10200002 (P.T.A.B. May. 9, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte MARK A. KAY and ANTON McCAFFREY
__________

Appeal 2012-002806
Application 10/200,002
Technology Center 1600
__________

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
SHERIDAN K. SNEDDEN, 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
of reducing viral gene expression. The Examiner denied priority and
rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.

Appeal 2012-002806
Application 10/200,002

2
Statement of the Case
Background
“In the subject methods, an effective amount of an RNAi agent, e.g.,
an interfering ribonucleic acid (such as an siRNA or shRNA) or a
transcription template thereof, e.g., a DNA encoding an shRNA, is
administered to a non-embryonic mammal, e.g., via a hydrodynamic
administration protocol” (Spec. 8, ll. 5-9).
The Claims
Claims 1, 3, 8-11, 47, 49, 50, 53, and 54 are on appeal. Claim 1 is
representative and reads as follows:
1. A method of reducing expression of a coding sequence of
a viral pathogen in a mammalian tissue in a non-embryonic
mammal, said method comprising:
administering to said mammal, in vivo, an effective
amount of an RNAi agent, said RNAi agent being (i) an
interfering ribonucleic acid, (ii) specific for a viral coding
sequence present in a cell of the tissue of the mammal after
infection thereof, and (iii) composed of a sense and an antisense
strand, each 21 nucleotides in length, annealed to form a duplex
structure 19 base pairs in length and having 2-nucleotide
3' overhangs.

The issues
A. The Examiner denied the claim for benefit of priority to US
provisional applications 60/307,411 and 60/360,664 for failure to provide
descriptive support of the claimed invention (Ans. 4-6).
Appeal 2012-002806
Application 10/200,002

3
B. The Examiner rejected claims 1, 3, 8-11, 47, 49, 53, and 54 under 35
U.S.C. § 103(a) as obvious over McSwiggen
1
and Tuschl
2
(Ans. 8-9).
C. The Examiner rejected claim 50 under 35 U.S.C. § 103(a) as obvious
over McSwiggen, Tuschl, and Kay
3
(Ans. 10).
A. Priority
Appellants and the Examiner extensively discuss the priority issues
for the instant Specification and the cited references. In the instant case, in
order for the Examiner to apply McSwiggen and Tuschl as prior art under 35
U.S.C. § 103(a), the references must qualify as prior art under 35 U.S.C. §
102(e) which states that a person shall be entitled to a patent unless:
(e) the invention was described in — (1) an application for patent,
published under section 122(b), by another filed in the United States
before the invention by the applicant for patent or (2) a patent granted
on an application for patent by another filed in the United States
before the invention by the applicant for patent, except that an
international application filed under the treaty defined in section
351(a) shall have the effects for the purposes of this subsection of an
application filed in the United States only if the international
application designated the United States and was published under
Article 21(2) of such treaty in the English language.

(35 U.S.C. § 102(e) (1999)).

1
McSwiggen, J., US 2003/0124513 A1, published Jul. 3, 2003,
filed May 29, 2002, claimed benefit of US provisional 60/294,140,
filed May 29, 2001.
2
Tuschl et al., US 2004/0259247 A1, published Dec. 23, 2004,
filed Nov. 29, 2001, claimed benefit of US provisional 60/279,661,
filed on Mar. 30, 2001.
3
Kay et al., US 6,107,027, issued Aug. 22, 2000, filed Sep. 11,
1995.
Appeal 2012-002806
Application 10/200,002

4
Tuschl
The MPEP § 2136.03 II explains that for international applications
filed after November 29, 2000, which designate the United States, and which
were published in English, “[i]f such an international application properly
claims . . . priority to an earlier-filed U.S. provisional application, apply the
reference under 35 U.S.C. 102(e) as of the earlier filing date, assuming all
the conditions of 35 U.S.C. 102(e) and 35 U.S.C. 119(e), 120, or 365(c) are
met.”
Tuschl‟s application was filed after November 29, 2000, designated
the United States, was published in English, and claims priority to US
provisional application 60/279,661, filed Mar. 30, 2001. There is no dispute
that the remaining conditions are met. Thus, the Examiner may properly
rely upon the disclosure of US 60/279,661 as of Mar. 30, 2001, which is
prior to the earliest filing date of Appellants on July 23, 2001 of US
provisional 60/307,411.
McSwiggen
The MPEP § 2136.03 III states that the “35 U.S.C. 102(e) critical
reference date of . . . U.S. application publications . . . entitled to the benefit
of the filing date of a provisional application under 35 U.S.C. 119(e) is the
filing date of the provisional application with certain exceptions if the
provisional application(s) properly supports the subject matter relied upon to
make the rejection in compliance with 35 U.S.C. 112, first paragraph.”
McSwiggen properly claims priority to US provisional application
60/294,140, filed on May 29, 2001 which is prior to the earliest filing date of
Appeal 2012-002806
Application 10/200,002

5
Appellants on July 23, 2001 of US provisional 60/307,411. Thus the
Examiner may properly rely upon the disclosure of US 60/294,140.
We need not address the issue of whether Appellants are entitled to
priority for their provisional application 60/307,411 since both McSwiggen
and Tuschl claim priority to provisional applications which were filed prior
to the filing date of Appellants earliest filing date. For the prior art
rejections, we will refer to the McSwiggen and Tuschl provisional
applications for their teachings to ensure that we only rely upon subject
matter with descriptive support in the provisional applications.
B. 35 U.S.C. § 103(a) over McSwiggen and Tuschl
The Examiner finds that “McSwiggen claims a method of modulating
HIV expression in an animal (e.g., human) using enzymatic nucleic acid
molecule (19, 20, 21, 22 nucleotides in length) that targets a region of HIV .
. . . McSwiggen teaches modes of administration that would make obvious
intravascularly administering the nucleic acid molecule” (Ans. 8). The
Examiner finds that “Tuschl claims a method of mediating viral gene
expression in a cell of an organism (mammal) using siRNA having 19-25
nucleotides in length (claim 24 and pages 1 and 3). Tuschl teaches using
siRNA having a 2-nucleotide 3' overhang . . . siRNA agents with 2-nt
3'overhangs were efficient in mediating RNA interference” (id.).
The Examiner finds it obvious to “combine the teaching of
McSwiggen and Tuschl, namely to produce siRNA targeting a target viral
gene from a nucleotide sequence and use siRNA to inhibit the viral gene in a
mammal” (id. at 9). The Examiner finds that “one of ordinary skill in the art
would have been motivated to reduce expression of a viral pathogen in a
Appeal 2012-002806
Application 10/200,002

6
juvenile or adult to reduce a viral infection either individual since both are
known by one of ordinary skill in the art to be infected with a virus” (Ans.
9).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner‟s conclusion that the McSwiggen and Tuschl
render claim 1 obvious?
Findings of Fact
1. McSwiggen teaches “a method of treating a patient having a
condition associated with the level of HIV, comprising contacting cells of
the patient with an enzymatic nucleic acid molecule of the invention under
conditions suitable for the treatment” (McSwiggen, US 60/294,140 at 3, ll.
7-9).
2. McSwiggen teaches that “the invention features nucleic acid-
based molecules and methods that modulate the expression of HIV-1 gene . .
. HIV-2 gene . . . LTR . . . nef . . . vif . . . tat . . . and rev” (McSwiggen, US
60/294,140 at 5, ll. 20-27).
3. McSwiggen teaches:
the use of an enzymatic nucleic acid molecule, preferably in
the hammerhead, NCH, G-cleaver, amberzyme, zinzyme
and/or DNAzyme motif, to down-regulate the expression of
HIV genes, or inhibit the replication of HIV.
By “inhibit” or “down-regulate” it is meant that the
expression of the gene, or level of RNAs or equivalent
RNAs encoding one or more protein subunits or
components, or activity of one or more protein subunits or
components, such as HIV protein(s), is reduced below that
observed in the absence of the nucleic acid molecules of the
invention.

Appeal 2012-002806
Application 10/200,002

7
(McSwiggen, US 60/294,140 at 6, ll. 12-18.)
4. McSwiggen teaches that “enzymatic nucleic acid molecules of
the invention are preferably between about 15 and 50 nucleotides in length .
. . triplex forming oligonucleotide molecules of the invention are preferably
between about 10 and 40 nucleotides in length, more preferably between
about 12 and 25 nucleotides in length, e.g., 18, 19, 20, or 21 nucleotides in
length” (McSwiggen, US 60/294,140 at 14, ll. 15-28).
5. McSwiggen teaches that
The negatively charged polynucleotides of the
invention (e.g., RNA, DNA, or analogues thereof) can be
administered and introduced into a patient by any standard
means, with or without stabilizers, buffers, and the like to
form a pharmaceutical composition. When it is desired to
use a liposome delivery mechanism, standard protocols for
formation of liposomes can be followed. The compositions
of the present invention can also be formulated and used as
tablets, capsules or elixirs for oral administration; . . . sterile
solutions; suspensions for injectable administration; and the
other compositions known in the art.

(McSwiggen, US 60/294,140 at 37, ll. 19-25.)
6. McSwiggen teaches that:
Dosage levels of the order of from about 0.1 mg to
about 140 mg per kilogram of body weight per day are
useful in the treatment of the above indicated conditions . . .
.
It is understood that the specific dose level for any
particular patient depends upon a variety of factors including
the activity of the specific compound employed; the age,
body weight, general health, sex, diet, time of
administration, route of administration, and rate of
excretion, drug combination and the severity of the
particular disease undergoing therapy.
Appeal 2012-002806
Application 10/200,002

8
(McSwiggen, US 60/294,140 at 42, ll. 22-31.)
7. Tuschl teaches that “[w]e demonstrate that short 21 and 22 nt
RNAs, when base-paired with 3‟ overhanging ends, act as the guide RNAs
for sequence-specific mRNA degradation” (Tuschl, US 60/279,661 at 2, ll.
27-30).
8. Tuschl teaches
an isolated double-stranded RNA molecule, wherein each
RNA strand has a length from 19-23 nucleotides, wherein
said RNA molecule is capable of mediating target-specific
nucleic acid modifications, particularly RNA interference
and/or DNA methylation. Preferably at least one strand has a
3‟-overhang from 1-5 nucleotides. The other strand may be
blunt-ended or has up to 6 nucleotides 3‟ overhang.

(Tuschl, US 60/279,661 at 3, ll. 12-18.)
9. Tuschl teaches that “it was found that synthetic short double-
stranded RNA molecules particularly with overhanging 3‟-ends are
sequence-specific mediators of RNAi and mediate efficient target-RNA
cleavage, wherein the cleavage site is located near the center of the region
spanned by the guiding short RNA” (Tuschl, US 60/279,661 at 3, ll. 27-31).
10. Tuschl teaches that:
The target gene to which the RNA molecule of the invention
is directed may be associated with a pathological condition.
For example, the gene may be a pathogen-associated gene,
e.g. a viral gene . . . inhibiting the function of such a gene
valuable information and therapeutic benefits . . . in the
medicine or veterinary medicine field may be obtained

(Tuschl, US 60/279,661 at 7, ll. 13-21).
Appeal 2012-002806
Application 10/200,002

9
11. Tuschl teaches that the “dsRNA is usually administered as a
pharmaceutical composition. The administration may be carried out by
known methods, wherein a nucleic acid is introduced into a desired target
cell in vitro or in vivo” (Tuschl, US 60/279,661 at 7, ll. 23-25).
12. Tuschl teaches
RNase III makes two staggered cuts in both strands of the
dsRNA, leaving a 3‟ overhang of about 2 nt. We chemically
synthesized 21 and 22 nt RNAs, identical in sequence to
some of the cloned ~ 21 nt fragments, and tested them for
their ability to mediate target RNA degradation . . . . Under
these conditions, target RNA cleavage is readily detectable.

(Tuschl, US 60/279,661 at 23, ll. 21-28.)
13. Tuschl teaches that:
To test whether siRNAs are also capable of mediating RNAi
in tissue culture, we synthesized 21 nt siRNA duplexes with
symmetric 2 nt 3‟ overhangs directed against reporter genes
coding for sea pansy . . . and two sequence variants of firefly
. . . luciferases . . . . The siRNA duplexes were co-
transfected with the reporter plasmid combinations . . . into
D. melanogaster Schneider S2 cells or mammalian cells
using cationic liposomes. Luciferase activities were
determined 20 h after transfection. In all cell lines tested, we
observed specific reduction of the expression of the reporter
genes in the presence of cognate siRNA duplexes

(Tuschl, US 60/279,661 at 31, ll. 2-11).
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). “If a person of
Appeal 2012-002806
Application 10/200,002

10
ordinary skill can implement a predictable variation, § 103 likely bars its
patentability.” Id. at 417.

Analysis
McSwiggen teaches reducing the expression of a viral pathogen (FF
1) by targeting a coding sequence (FF 2) comprising administering an
effective amount of a nucleic acid agent (FF 3) which may be 21 nucleotides
in length (FF 4). McSwiggen expressly discusses administration of the
nucleic acid as a pharmaceutical agent (FF 5) including useful dosages for
different patient populations (FF 6).
Tuschl teaches inhibiting the function of a viral gene as a medical
therapy (FF 10) using a 21 nucleotide double stranded RNAi agent (FF 7)
with 2 nucleotide overhangs (FF 8, 12) which is specific for the viral coding
sequence in an infected mammal (FF 10). Tuschl teaches that the RNAi
functions in vitro (FF 12) and in cell culture (FF 13). Tuschl teaches
formulation of the RNAi into a pharmaceutical composition (FF 11).
Applying the KSR standard of obviousness to the findings of fact, we
conclude that the person of ordinary skill would have modified
McSwiggen‟s therapeutic inhibition of virus using a nucleic acid (FF 1-6) by
substituting the RNAi of Tuschl (FF 7-13) since Tuschl teaches that the
“target gene to which the RNA molecule of the invention is directed may be
associated with a pathological condition. For example, the gene may be a
pathogen-associated gene, e.g. a viral gene . . . By . . . inhibiting the function
of such a gene . . . therapeutic benefits . . . in the medicine or veterinary
medicine field may be obtained” (Tuschl, US 60/279,661 at 7, ll. 13-21; FF
Appeal 2012-002806
Application 10/200,002

11
10). Such a combination is merely a “predictable use of prior art elements
according to their established functions.” KSR, 550 U.S. at 417.
Appellants contend that their “own provisional applications pre-date
the effective date for McSwiggen as a prior art reference” (App. Br. 11).
We are not persuaded. As we discussed above, McSwiggen properly
receives priority to US provisional 60/294,140, filed May 29, 2001, which
was filed prior to Appellants earliest priority filing date of July 23, 2001 for
US 60/307,411.
Appellants contend that “until Appellants own disclosure, delivery of
effective RNAi agents to living mammals had not been achieved or even
expected to work with known in vitro administration methods, such as lipid /
liposomal delivery to cultured cells” (id. at 12). Appellants contend that
“[g]iven the Tuschl disclosure with its vague description of standard
methods of administration, the skilled artisan would have no expectation of
success in introducing an RNAi agent into a nonembryonic mammal in vivo
and to achieve reduction of expression of a viral pathogen in a mammal”
(id.).
We are not persuaded. Both McSwiggen and Tuschl teach therapeutic
administration of nucleic acids (FF 5-6, 10-11). Tuschl teaches a functional
demonstration of the RNAi in a human cell culture experiment (FF 13).
Appellants do not identify any evidence supporting their position that either
McSwiggen or Tuschl would not have had a “reasonable expectation of
success” in applying their nucleic acid treatments to actual patients. An
“obviousness finding was appropriate where the prior art „contained detailed
enabling methodology for practicing the claimed invention, a suggestion to
Appeal 2012-002806
Application 10/200,002

12
modify the prior art to practice the claimed invention, and evidence
suggesting that it would be successful.”‟ In re Kubin, 561 F.3d 1351, 1360
(Fed. Cir. 2009) (citing In re O’Farrell, 853 F.2d 894, 902 (Fed. Cir. 1988).
Here, Tuschl provides detailed information on the method of making
the RNAi double stranded molecules, the specific targeting information, and
Tuschl demonstrates that RNAi targeting functions in human cell culture (FF
7-13). As stated by the Federal Circuit, “[r]esponding to concerns about
uncertainty in the prior art influencing the purported success of the claimed
combination, this court [in O’Farrell] stated: „[o]bviousness does not require
absolute predictability of success ... all that is required is a reasonable
expectation of success.”‟ Kubin, 561 F.3d at 1360 (citing In re O’Farrell,
853 F.2d at 903-904).
Appellants do not cite declaratory evidence in the evidence appendix,
nor do Appellants point to any other evidence which would demonstrate any
reason to doubt the teachings of McSwiggen and Tuschl regarding in vivo
administration of the RNAi for treatment of viral disease (FF 1-13).
Consequently, balancing Appellants argument against the teachings of
McSwiggen and Tuschl results in a conclusion that there was a reasonable
expectation of success in performing the RNAi viral treatment method
suggested by these references.
Conclusion of Law
The evidence of record supports the Examiner‟s conclusion that the
McSwiggen and Tuschl render claim 1 obvious.

Appeal 2012-002806
Application 10/200,002

13
B. 35 U.S.C. § 103(a) over McSwiggen, Tuschl, and Kay
The Examiner provides sound fact-based reasoning for combining
Kay with McSwiggen and Tuschl. We adopt the fact finding and analysis of
the Examiner as our own. Appellants do not identify any material defect in
the Examiner‟s reasoning for combining Kay with McSwiggen and Tuschl.
Since Appellants only argue the underlying rejection of McSwiggen and
Tuschl which we affirmed above, we affirm this rejection for the reasons
stated by the Examiner.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. §
103(a) as obvious over McSwiggen and Tuschl. Pursuant to 37 C.F.R. §
41.37(c)(1), we also affirm the rejection of claims 3, 8-11, 47, 49, 53, and
54, as these claims were not argued separately.
We affirm the rejection of claim 50 under 35 U.S.C. § 103(a) as
obvious over McSwiggen, Tuschl, and Kay.

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