AVIDITY BIOSCIENCES, INC.

Patent Trials and Appeals Board

Aug 4, 2020

15476849 - (D) (P.T.A.B. Aug. 4, 2020)

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.
15/476,849 03/31/2017 Andrew John GEALL 45532-707.201 1073
21971 7590 08/04/2020
WILSON, SONSINI, GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO, CA 94304-1050
EXAMINER
WHITEMAN, BRIAN A
ART UNIT PAPER NUMBER
1635
NOTIFICATION DATE DELIVERY MODE
08/04/2020 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
patentdocket@wsgr.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ANDREW JOHN GEALL,
VENKATA RAMANA DOPPALAPUDI, DAVID SAI-HO CHU,
MICHAEL CARAMIAN COCHRAN, RACHEL ELIZABETH JOHNS,
PALANI BALU, ROB BURKE, and BEATRICE DIANA DARIMONT
Appeal 2019-004650
Application 15/476,849
Technology Center 1600
Before FRANCISCO C. PRATS, TAWEN CHANG, and
DAVID D. COTTA, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1–5, 8–11, 13, and 16–22. We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 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 Avidity
Biosciences LLC. Appeal Br. 3.
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BACKGROUND
“Gene suppression by RNA-induced gene silencing provides several
levels of control: transcription inactivation, small interfering RNA (siRNA-
induced mRNA degradation, and siRNA-induced transcriptional
attenuation.” Spec. ¶ 3. Thus, RNA interference (RNAi) “represents a
viable method useful for drug target validation, gene function analysis,
pathway analysis, and disease therapeutics.” Id. According to the
Specification, however, nucleic acid therapy such as RNAi therapy may be
“hindered by poor intracellular uptake, limited blood stability and non-
specific immune simulation.” Id. ¶ 135. Further according to the
Specification, the invention explores “various modifications of the nucleic
acid composition . . . , such as for example, novel linkers for better
stabilizing and/or lower toxicity, optimization of binding moiety for
increased target specificity and/or target delivery, and nucleic acid polymer
modifications for increased stability and/or reduced off-target effect.” Id.
CLAIMED SUBJECT MATTER
The claims are directed to a molecule having a recited formula. Claim
1, the only independent claim, is illustrative:
1. A molecule of Formula (I):
A-X-B-Y-C
Formula I
wherein,
A is an antibody or its binding fragments thereof;
B consists of a double-stranded polynucleotide
consisting of a passenger strand and a guide strand;
C consists of a polymer;
X is a bond or first non-polymeric linker; and
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Y is a bond or second non-polymeric linker;
wherein the double-stranded polynucleotide comprises at
least one 2’ modified nucleotide, at least one modified
internucleotide linkage, or at least one inverted abasic
moiety;
wherein A and C are not attached to B at the same
terminus; and wherein A-X and Y-C are conjugated to
the passenger strand.
Appeal Br. 19 (Claims App.).
REJECTIONS
A. Claims 1–5, 8, 9, 13, and 16–22 are rejected under 35 U.S.C. § 103 as
being unpatentable over McSwiggen2 and Colletti.3 Final Act. 6.
B. Claims 10 and 11 are rejected under 35 U.S.C. § 103 as being
unpatentable over McSwiggen, Colletti, and either Bettencourt4 or
Xie.5 Final Act. 10.
C. Claims 1–5, 8, 9, 13, 16–19, and 21 are rejected under 35 U.S.C.
§ 103 as being unpatentable over McSwiggen and Marcusson.6 Final
Act. 11.
D. Claims 1–5, 8, 9, 13, and 16–22 are rejected under 35 U.S.C. § 103 as
being unpatentable over McSwiggen and Ma.7 Final Act. 13.

2 McSwiggen et al., US 2007/0004665 A1, published Jan. 4, 2007.
3 Colletti et al., US 2017/0081425 A1, published Mar. 23, 2017.
4 Bettencourt et al., WO 2013/166004 A2, published Nov. 7, 2013.
5 Xie et al., WO 2009/108217 A2, published Sep. 3, 2009. Both the
Examiner and Appellant refers to this reference as “Liu.”
6 Marcusson et al., US 2017/0159056 A1, published June 8, 2017.
7 Ma et al., US 2013/0052731 A1, published Feb. 28, 2013.
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E. Claims 10 and 11 are rejected under 35 U.S.C. § 103 as being
unpatentable over McSwiggen, Ma, and either Bettencourt or Xie.
Final Act. 16.
OPINION
A. Issues
The Examiner rejects independent claim 1 as obvious over
McSwiggen and one of Colletti, Marcusson, or Ma. The same issues are
dispositive for all of the rejections, and Appellant does not separately argue
the rejections. We therefore consider the rejections together.
The Examiner finds that McSwiggen teaches “a composition
comprising a chemically modified siRNA molecule attached to PEG or a
targeting ligand via a linker.” Final Act. 6. The Examiner finds that
McSwiggen teaches that “[a] cap structure can be incorporate[d] at either
end of the siRNA molecule and can be used to protect the nucleic acid
molecule from exonuclease degradation[] and . . . help in delivery and/or
localization within a cell.” Id. The Examiner finds that McSwiggen teaches
“attaching a protecting group to the 5’ end of the siRNA or a targeting agent
or PEG to the 3’ end of the siRNA.” Id.
The Examiner finds that “McSwiggen does not specifically disclose
formula I in instant claim 1.” Final Act. 6. However, the Examiner finds
that (1) Colletti teaches “a complex comprising a siRNA-linker-targeting
ligand, wherein the ligand is an antibody and the linker is a non-polymeric
linker”; (2) Marcusson teaches “an oligonucleotide having at least one or
more linkers to both termini” where “[o]ne terminus can have an antibody
and the other terminus can have a cap structure”; and (3) Ma teaches “a
complex comprising an antibody conjugating to a siRNA,” wherein siRNA
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may be chemically modified, “[t]he antibody [may be] linked to the siRNA
using a 6-hydrazinonicotinamide (HyNic) linker and . . . a succinimidyl-4-
formyl benzoate analog,” “[t]he complex can . . . be an electrostatic
antibody-9R-siRNA complex,” and “[a]n endosome escape agent maybe
administered with the complex.” Id. at 6, 11, 13–14.
The Examiner concludes that it would have been obvious to a skilled
artisan to combine the teachings of McSwiggen with those of Colletti to
arrive at the claimed invention:
One of ordinary skill in the art would have been motivated to
combine the teaching[s] to study the function, effectiveness or
marketability of the complex in a cell line. “The combination
of familiar elements according to known methods is likely to be
obvious when it does no more than yield predictable results.”
See KSR v. Teleflex, 550 U.S. 398, 82 USPQ2d 1385 (2007).
It would have been obvious to one of ordinary skill in the art to
attach the antibody to one terminus of the passenger strand and
the PEG to other terminus of the passenger to reduce off-target
effect of the passenger strand being processed instead of the
guide strand. It would have been obvious to make the complex
where conjugating the antibody and PEG to either terminus of
the passenger strand to determine if there is a different activity
when using either terminus for A or C. One of ordinary skill in
the art would understand C1 is a non-sterically hindering group
and can be used as the linker. One of ordinary skill in the art
would have been motivated to attach PEG to the product to
increase the bioavailability of the product in a cell line or cell of
a subject. It would have been obvious to use the modifications
in instant claims 2-5 to increase the stability of the siRNA in a
cell. It would have been obvious to use monoclonal antibodies
for site-specific delivery of the product. It would have been
obvious to one of ordinary skill in the art to add an
endosome[o]lytic moiety either the A or C component of the
complex to assist in the delivery of the siRNA to a cell.
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Final Act. 6–7. The Examiner relies on similar reasoning in
concluding that it would have been obvious to a skilled artisan to
combine the teachings of McSwiggen with those of Marcusson or Ma
to arrive at the claimed invention. Id. at 12, 14–15.
Appellant contends that the Examiner has not identified “a reason
with rational underpinnings that would have prompted the ordinary artisan to
combine the elements of McSwiggen with each of Colletti, Marcusson and
Ma ‘in the fashion claimed by the patent at issue’.” Appeal Br. 12.
Appellant contends that the Examiner failed to consider “the totality of the
evidence of record” and improperly relied on inherency arguments. Id. at
12–15. Finally, Appellant contends that the Examiner failed to properly
consider evidence of unexpected results. Id. at 15–17.
Appellant does not separately argue the claims. We therefore focus
on independent claim 1 as representative. The issues with respect to the
rejections are (1) whether a skilled artisan would have had reason to
combine McSwiggen with Colletti, Marcusson, or Ma to arrive at the
invention of claim 1, with a reasonable expectation of success and, if so, (2)
whether Appellant has pointed to persuasive evidence, such as evidence of
unexpected results, that, when considered together with evidence of
obviousness, shows claim 1 to be non-obvious.
B. Findings of Fact
1. McSwiggen teaches “methods and reagents useful in
modulating gene expression,” specifically “synthetic chemically modified
small nucleic acid molecules such as short interfering nucleic acid (siNA),
short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-
RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of
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mediating RNA interference (RNAi) against target nucleic acid sequences.”
McSwiggen Abstract, ¶ 11.
2. McSwiggen teaches that the siNA can be “a double-stranded
polynucleotide molecule comprising self-complementary sense and
antisense regions, wherein the antisense region comprises nucleotide
sequence that is complementary to . . . a target nucleic acid molecule . . . and
the sense region . . . correspond[s] to the target nucleic acid sequence.” Id. ¶
183.
3. McSwiggen teaches that “[i]n one embodiment, [its] invention
features chemically modified siNA constructs having specificity for target
nucleic acid molecules in a cell,” wherein examples of the chemical
modifications include “phosphorothioate internucleotide linkages, 2’-O-
methyl ribonucleotides, 2’-deoxy-2’-fluoro ribonucleotides, 2’-deoxy
ribonucleotides, “universal base” nucleotides, 5-C-methyl nucleotides, and
inverted deoxyabasic residue incorporation.” Id. ¶ 14. McSwiggen teaches
that “[t]hese chemical modifications, when used in various siNA constructs,
are shown to preserve RNAi activity in cells while at the same time,
dramatically increasing the serum stability of these compounds.” Id.; see
also id. ¶¶ 532–533 (nucleotide modifications may be introduced to enhance
their nuclease stability), ¶¶ 535–537 (teaching SiNA molecule comprising
one or more 5’ and/or a 3’ cap structure on either or both of the siNA
strands, where the cap structure “protect the nucleic acid molecule from
exonuclease degradation, . . . can help in delivery and/or localization within
a cell,” and may be an inverted abasic moiety), ¶ 540 (teaching siNA
molecules with phosphate backbone modifications).
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4. McSwiggen further teaches that
the introduction of chemically-modified nucleotides into
nucleic acid molecules provides a powerful tool in overcoming
potential limitations of in vivo stability and bioavailability
inherent to native RNA molecules that are delivered
exogenously. For example, the use of chemically-modified
nucleic acid molecules can enable a lower dose of a particular
nucleic acid molecule for a given therapeutic effect since
chemically-modified nucleic acid molecules tend to have a
longer half-life in serum. Furthermore, certain chemical
modifications can improve the bioavailability of nucleic acid
molecules by targeting particular cells or tissues and/or
improving cellular uptake of the nucleic acid molecule.
Therefore, even if the activity of a chemically-modified nucleic
acid molecule is reduced as compared to a native nucleic acid
molecule, for example, when compared to an all-RNA nucleic
acid molecule, the overall activity of the modified nucleic acid
molecule can be greater than that of the native molecule due to
improved stability and/or delivery of the molecule. Unlike
native unmodified siNA, chemically-modified siNA can also
minimize the possibility of activating interferon activity in
humans.
Id. ¶ 61; see also id. ¶ 15 (explaining that “modified nucleotides can be used
to improve in vitro or in vivo characteristics such as stability, activity, and/or
bioavailability”).
5. McSwiggen teaches an embodiment comprising
a chemically-modified short interfering nucleic acid molecule
(siNA) capable of mediating RNA interference (RNAi) . . . ,
wherein the chemical modification comprises a conjugate
attached to the chemically-modified siNA molecule. The
conjugate can be attached to the chemically-modified siNA
molecule via a covalent attachment. . . . . In one embodiment,
the conjugate molecule is attached at the 3’-end of either the
sense strand, the antisense strand, or both strands of the
chemically-modified siNA molecule. In another embodiment,
the conjugate molecule is attached at the 5’-end of either the
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sense strand, the antisense strand, or both strands of the
chemically- modified siNA molecule. In yet another
embodiment, the conjugate molecule is attached both the 3’-end
and 5’-end of either the sense strand, the antisense strand, or
both strands of the chemically-modified siNA molecule, or any
combination thereof. In one embodiment, the conjugate
molecule of the invention comprises a molecule that facilitates
delivery of a chemically-modified siNA molecule into a
biological system, such as a cell. In another embodiment, the
conjugate molecule attached to the chemically-modified siNA
molecule is a poly ethylene glycol, human serum albumin, or a
ligand for a cellular receptor that can mediate cellular uptake.
. . . The type of conjugates used and the extent of conjugation
of siNA molecules of the invention can be evaluated for
improved pharmacokinetic profiles, bioavailability, and/or
stability of siNA constructs while at the same time maintaining
the ability of the siNA to mediate RNAi activity. As such, one
skilled in the art can screen siNA constructs that are modified
with various conjugates to determine whether the siNA
conjugate complex possesses improved properties while
maintaining the ability to mediate RNAi . . . .
Id. ¶ 106; see also id. ¶ 177 (describing embodiment featuring siNA
constructs comprising one or more chemical modifications that increases its
bioavailability, for example by attaching polymeric conjugates such as PEG
or equivalent that improve its pharmacokinetics, or conjugates targeting
specific tissue or cell types), ¶ 684 (teaching that conjugated siNA constructs
show “vastly improved liver PK compared to the unconjugated siNA
construct”).
6. McSwiggen teaches that PEG “can be covalently attached to
siNA compounds of [its] invention” and that “[t]he attached PEG can be any
molecular weight, preferably from about 2,000 to about 50,000 daltons.” Id.
¶ 181; see also id. ¶ 488.
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7. McSwiggen teaches embodiments of its invention featuring
conjugates of siNA molecules that
can be used to facilitate delivery of siNA molecules into a
biological system, such as a cell. The conjugates and
complexes provided by the instant invention can impart
therapeutic activity by transferring therapeutic compounds
across cellular membranes, altering the pharmacokinetics,
and/or modulating the localization of nucleic acid molecules of
the invention. The present invention encompasses the design
and synthesis of novel conjugates and complexes for the
delivery of molecules, including . . . antibodies, . . . negatively
charged polymers and other polymers, for example, . . .
polyethylene glycols . . . , across cellular membranes. . . . .
These compounds are expected to improve delivery and/or
localization of nucleic acid molecules of the invention into a
number of cell types originating from different tissues.
Id. ¶ 314; see also id. ¶ 178 (teaching that an antibody may be attached to an
siNA molecule to improve its bioavailability), ¶ 489 (explaining that
compounds and methods of its invention are useful for introducing nucleic
acid molecules into a cell).
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8. Figure 65 of McSwiggen is reproduced below:

Id. at Fig. 65. Figure 65 of McSwiggen depicts “various generalized siNA
conjugates of the invention in which various linker chemistries and/or
cleavable linkers can be utilized at different positions of a double stranded
siNA molecule.” Id. ¶ 279.
9. Colletti teaches that
[d]rugs used in antisense, RNAi, and gene therapies are
relatively large hydrophilic polymers and are frequently highly
negatively charged. These physical characteristics severely
restrict their direct diffusion across the cell membrane. For this
reason, the major barrier to polynucleotide therapeutic efficacy
is the delivery of the polynucleotide across a cell membrane to
the cell cytoplasm or nucleus.
. . . .
. . . . Small interfering RNAs (siRNA) can achieve
selective knockdown of therapeutic targets by degradation of
specific messenger RNA, provided the siRNA reaches the RNA
Induced Silencing Complex (RISC) in the cell cytosol.
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Receptor-targeted siRNA constructs can be taken up by cell
surface receptors and accumulate in subcellular vesicles termed
endosomes. A small fraction of the siRNA traverses the
endosomal membrane to reach the cytosol. The process, termed
endosomal escape, is a major barrier to cytosolic delivery and
higher potency of siRNA therapeutics.
There remains a need for additional compositions . . . or
delivery methods that can provide effective in vivo delivery, cell
uptake and/or endosomal escape of oligonucleotides.
Colletti ¶¶ 1–4.
10. Colletti teaches
a peptide containing conjugate comprising (P)c-(L)d-(G)e,
wherein P is a peptide . . . ; L is an optional linker . . . ; G is a
targeting ligand . . . ; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and
e is independently 1, 2, 3, 4, 5 or 6. The conjugate can be
administered to a subject either alone or in combination with a
composition comprising R-(L)a-(G)b, wherein R is an
oligonucleotide as defined herein, to inhibit expression of a
gene of the subject.
Id. at Abstract.
11. Colletti teaches that its invention “features a modular
composition, comprising an oligonucleotide or siRNA (R), one or more
targeting ligands (G), one or more peptides (P), one or more optional linkers
(L), and one or more optional ligands (X), solubilizing groups (X),
pharmacokinetics enhancing agents (X), lipids (X), and/or masking agents
(X).” Id. ¶ 208.
12. Colletti teaches that its invention can “provide effective in vivo
delivery of the conjugate and/or the oligonucleotide.” Id. ¶ 13.
13. Colletti teaches an embodiment in which the oligonucleotide is
a double stranded siRNA (ds siRNA). Id. ¶ 168.
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14. In a double stranded siRNA, the sense strand is the passenger
strand and the antisense strand is the guide strand. Id. ¶ 217; see also Ma ¶
41.
15. Colletti teaches that “[t]he compositions and peptide conjugates
of [its] invention may comprise a targeting ligand,” which is selected from a
group consisting of, among other things, an antibody. Colletti ¶ 182.
16. Colletti teaches that “[t]he R-(L)a-(G)b composition . . . may
further comprise one or more solubilizing agents that may enhance aqueous
solubility, circulation half life and/or cellular uptake” and that these
solubilizing agents can include “PEG, e.g., PEG-0.5K, PEG-2K, PEG-5K,
PEG-10K, PEG-12K, PEG-15K, PEG-20K, PEG-40K.” Id. ¶ 194. Colletti
specifically teaches an embodiment wherein “the solubilizing group is PEG
0.5K to 30K.” Id. ¶ 195.
17. Colletti teaches an embodiment where “the oligonucleotide or
siRNA is double stranded and optional targeting ligands, solubilizing agents,
pharmacokinetics enhancing agents, lipids, and/or masking agents are
attached to the same or different strands via linkers.” Id. ¶ 207. Colletti
teaches that a skilled artisan “will recognize that a variety of permutations
for placing the desired components on the passenger and guide strand exist.”
Id. ¶ 221.
18. Colletti teaches an embodiment in which “the oligonucleotide
or siRNA is double stranded and there is one targeting ligand which is
attached to the passenger strand at a terminal 3’ or 5’-position, optionally
through a suitable linker.” Id. ¶ 202.
19. Colletti teaches an embodiment wherein the oligonucleotide
composition has the formula G-L-R-L-X, wherein G is a targeting ligand, L
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is a linker, R is an oligonucleotide or siRNA, and X is a ligand, solubilizing
group, pharmacokinetics enhancing agent, lipid, and/or masking agent. Id.
¶¶ 208, 212.
20. Marcusson teaches “antisense oligonucleotides that hybridize to
the mRNA from a mutant activin A receptor type-1 (ACVR1) gene and
inhibit or reduce the expression of the mutant ACVR1 gene.” Marcusson
Abstract; see also id. ¶ 2.
21. Marcusson teaches embodiments where “the antisense
oligonucleotide includes at least one modified internucleoside linkage.” Id.
¶ 5; see also id. ¶ 54. Marcusson teaches that “[m]odified internucleoside
linkages may help to improve the stability of the antisense oligonucleotides
to nucleases and enhance cellular uptake.” Id. ¶ 65.
22. Marcusson teaches embodiments in which the antisense
oligonucleotide includes a modified sugar selected from a group consisting
of, among other things, a 2’-O-methoxyethyl modified sugar, a 2’-methoxy
modified sugar, and a 2’-O-alkyl modified sugar. Id. ¶ 9; see also id. ¶¶ 54,
61. Marcusson teaches that “modified sugars may help to improve the
stability of the antisense oligonucleotides to nucleases, increase binding
affinity of the antisense oligonucleotides to their target nucleic acids, and
decrease off-target binding of the antisense oligonucleotides.” Id. ¶ 61.
23. Marcusson teaches embodiments in which its antisense
oligonucleotides are “modified to have one or more stabilizing groups that
are generally attached to one or both termini of antisense oligonucleotides to
enhance properties such as, for example, nuclease stability.” Id. ¶ 55.
Marcusson further teaches that “[s]tabilizing groups include, e.g., cap
structures” and that “[t]hese terminal modifications protect the antisense
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oligonucleotide having terminal nucleic acid from exonuclease degradation,
and can help in delivery and/or localization of the antisense oligonucleotide
within a cell.” Id. Marcusson teaches that “[c]ap structures include . . .
inverted deoxy abasic caps.” Id.
24. Marcusson teaches embodiments in which its antisense
oligonucleotides are covalently linked to one or more moieties or conjugates
which “enhance the activity, cellular distribution, and/or cellular uptake of
the resulting antisense oligonucleotides.” Id. ¶ 55. Marcusson teaches that
conjugate groups may include antibodies. Id.
25. Ma teaches that exogenous, double-stranded RNAs, such as
siRNA, may be introduced into a cell to “specifically destroy a particular
mRNA or block its expression, thereby diminishing or abolishing gene
expression.” Ma ¶ 2.
26. Ma teaches that “it would be useful to develop RNAi delivery
methods that target specific cells, thereby minimizing or avoiding potential
side effects caused by delivery of RNA interference into non-target cells.”
Id. ¶ 4.
27. Ma teaches “methods for covalently . . . conjugating an
antibody . . . with an siRNA molecule,” which methods “may include . . .
modifying an antibody . . . with a linker to provide a linker-modified
antibody, combining a target siRNA with a disulfide containing aldehyde
linker to provide a linker-modified target siRNA[,] and combining the
linker-modified target siRNA with linker-modified antibody to form an
antibody-siRNA complex,” as well as methods of using an antibody-siRNA
conjugate to suppress or silence STAT3 protein expression in a cancer cell.
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Id. at Abstract; see also, e.g., id. ¶¶ 5–6, 9, 10, 14, 17, 24, 39, 72–74, Figs. 1,
5, 8, 15, 30.
C. Analysis
We agree with the Examiner that claim 1 is obvious over the
combination of McSwiggen and either Colletti, Marcusson, or Ma.
In particular, McSwiggen teaches siNAs that are double-stranded
polynucleotides having “self-complementary sense and antisense regions”
(i.e., a passenger strand and a guide strand). FF1, FF2, FF14. McSwiggen
teaches an embodiment of its invention that features chemically modified
siNA constructs, wherein examples of the chemical modifications include 2’
modified nucleotides (e.g., 2’-O-methyl ribonucleotides), a modified
internucleotide linkage (e.g., phosphorothioate internucleotide linkages),
and/or an inverted abasic moiety. FF3. McSwiggen teaches that such
chemical modifications may, among other things, preserve RNAi activity in
cells while “dramatically increasing the serum stability” of the siNA
constructs. FF3, FF4.
McSwiggen further teaches a siNA wherein the chemical modification
comprises conjugates “attached to the chemically-modified siNA molecule.”
FF5. In this regard, McSwiggen teaches that PEG (i.e., a polymer) can be
covalently attached to siNA constructs of its invention to improve the
pharmacokinetics of the construct and, thus, increases the construct’s
bioavailability. FF5, FF6. McSwiggen further teaches that its siNA may be
conjugated to molecules that facilitate its delivery into a biological system
such as a cell. FF7. McSwiggen teaches that such molecules include, for
example, antibodies. Id.
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Finally, McSwiggen teaches that conjugates may be attached to the
3’-end, the ’5-end, or both ends of either the sense (i.e., passenger) strand or
the antisense (i.e., guide) strand via covalent bonds or linkers. FF5, FF6,
FF8. In particular, McSwiggen teaches the following generalized siNA
conjugate, among others:

The figure above is one of the generalized siNA conjugate design depicted
in McSwiggen’s Figure 65. FF8. In this design, the conjugates are attached
to the two termini of the passenger (i.e., sense) strand of the siNA.
We find that it would have been obvious to a skilled artisan to prepare
a construct encompassed by claim 1 by modifying the above generalized
siNA conjugate from McSwiggen Figure 65, by attaching an antibody and a
polymer (e.g., PEG), respectively, to the 5’-end and the 3’-end of the sense
(i.e., passenger) strand, or vice versa, wherein the siNA also comprises at
least a 2’ modified nucleotide, modified internucleotide linkage, or an
inverted abasic moiety, particularly when McSwiggen is considered together
with any one of Colletti, Marcusson, or Ma.
A skilled artisan would have had reason to modify McSwiggen’s
siNA construct with a 2’ modified nucleotide, modified internucleotide
linkage, or an inverted abasic moiety, because McSwiggen teaches that such
chemical modifications can “preserve [the siNA constructs’] activity in cells
while at the same time . . . increas[e] the serum stability” of the constructs.
FF3. Likewise, a skilled artisan would have had reason to attach an antibody
and a polymer to the generalized siNA construct disclosed in McSwiggen
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because McSwiggen teaches that conjugating an antibody to a siNA
construct can improve its delivery into a biological system and similarly
teaches that conjugating a polymer such as PEG to a siNA construct can
increase the construct’s bioavailability. FF5–FF7. Finally, a skilled artisan
would have had reason to attach the antibody and polymer to the construct
via a covalent bond or linkers McSwiggen, because McSwiggen teaches that
conjugates may be attached to a nucleic acid via either covalent bond or
linkers. FF5, FF8.
The disclosure of Colletti also supports the Examiner’s rejection of
claim 1 as obvious over McSwiggen and Colletti. In particular, Colletti
teaches a double-stranded oligonucleotide or siRNA, wherein targeting
ligands and solubilizing agents, among other things, are optionally attached
to the same or different strands via linkers, including an embodiment in
which a targeting ligand is attached to the passenger strand as recited in
claim 1. FF17, FF18. More particularly, Colletti teaches an embodiment
wherein the oligonucleotide composition has the formula G-L-R-L-X,
wherein G is a targeting ligand, L is a linker, R is an oligonucleotide or
siRNA, and X may be a solubilizing group. FF19. Colletti further teaches
that the targeting ligand may be an antibody and the solubilizing group may
be PEG. FF15, FF16. Thus, Colletti suggests a molecule having the same
general arrangement of antibody – linker – double-stranded polynucleotide –
linker – polymer as the molecule of Formula (I) recited in instant claim 1.
Likewise, the disclosure of Marcusson supports the Examiner’s
rejection of claim 1 as obvious over McSwiggen and Marcusson. In
particular, Marcusson teaches using the polynucleotide modifications recited
in claim 1 (i.e., “2’ modified nucleotide, . . . modified internucleotide
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linkage, or . . . inverted abasic moiety”) to achieve various desirable
characteristics of oligonucleotides, including, e.g., improved stability,
cellular uptake, and binding affinity to target nucleic acids, as well as
decreased off-target binding. FF21–FF23. Marcusson also teaches
oligonucleotides covalently linked to conjugate groups that “enhance the
activity, cellular distribution, and/or cellular uptake of the resulting . . .
oligonucleotides,” and further teaches that such conjugate groups may
include antibodies. FF24.
Finally, the disclosure of Ma supports the Examiner’s rejection of
claim 1 as obvious over McSwiggen and Ma. For example, Ma teaches
introducing double-stranded RNAs, such as siRNA, into cells to modify
gene expression and further teaches conjugating an antibody with a siRNA
molecule in order to improve delivery to specific target cells. FF25–FF27.
Ma also teaches that conjugates may be attached to a nucleic acid via either
covalent bond and/or linkers. FF27.
Appellant asserts that there is no reason to combine the cited
references in any of the pending rejections. Appeal Br. 11. We are not
persuaded. As discussed above, McSwiggen itself suggests all the
limitations of claim 1 and provides a reason to combine them in the same
manner. See generally In re Bush, 296 F.2d 491, 496 (CCPA 1961)
(explaining that the Board may rely on less than all of the references relied
upon by the Examiner). Moreover, a skilled artisan would have had reason
to combine the teachings of McSwiggen with the teachings of Colletti,
Marcusson, or Ma discussed above, because each of the references are
concerned with increasing the stability, bioavailability, and/or targeted
delivery into cells of small nucleic acid molecules, particularly those useful
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in modulating gene expression, such as siNA, and the teachings recited
above are all directed towards achieving such enhancement.
To the extent Appellant’s contention is that there is no reason to
combine the reference in such a way as to arrive at the claimed invention, we
are likewise unpersuaded: McSwiggen teaches an siNA construct having the
same general structure as recited in claim 1—namely a construct wherein
conjugates are attached via linkers to the 3’- and 5’-end of the passenger
strands, FF8, and the prior art combinations further teaches (1) modifications
to the double-stranded polynucleotide that are recited in claim 1, such as 2’
modified nucleotide, modified internucleotide linkage, and inverted abasic
moiety, increase nuclease stability, see, e.g., FF3, FF4, FF21–FF23 and (2)
conjugates that may be used in the construct to improve bioavailability
and/or targeted delivery into cells, including antibodies and polymers such
as PEG, see, e.g., FF5–FF7, FF10, FF11, FF15–FF19, FF24, FF27.8 “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).
Appellant next cites the Board decision in Ex parte Ballance, 2018
WL 1378083, Appeal No. 2016-005026 (PTAB Mar. 8, 2018) and argues
that the rejection fails to consider the totality of the evidence of record.

8 In the Reply Brief, Appellant argues that the Examiner’s stated reasons to
combine the prior art are conclusory and unsupported. Reply Br. 6–7. We
are not persuaded. The Examiner’s reasoning is supported by the prior art
as discussed above in this opinion.
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Appeal Br. 12–14. Appellant argues that, analogous to the situation in
Ballance,
[t]o conclude that because McSwiggen, Colletti, Marcusson,
and Ma each describes only a portion of the claimed construct
or because Marcusson describes a nucleic acid conjugated on
both termini in which one terminus is a cap, it is mere
speculation on the part of the Examiner that the claimed
construct would produce better bioavailability and enable
higher target tissue uptake.
Appeal Br. 13.
We are not persuaded. As the Examiner pointed out in response to
arguments in the Appeal Brief, McSwiggen in fact “discloses a composition
comprising a siRNA molecule attached to a conjugate at both termini of the
molecule (Figure 65).” Ans. 5. As discussed above, this molecule has the
same generalized structure as the formula I recited in claim 1.
In the Reply Brief, Appellant acknowledges Examiner’s citation to
Figure 65 of McSwiggen. Reply Br. 8. However, Appellant contends that
“[n]one of the six structure in Figure 65 . . . are the same as the formula (I)
recited in Claim 1.” Id. More particularly, in arguing that “[a]ll the
structures [of McSwiggen’s Figure 65] are different from the claimed
formula 1,” Appellant contends that “in the third structure, the conjugate is
attached at the 3’ end and 5’ end of the sense strand.” Reply Br. 9.
To the extent Appellant is arguing that claimed formula 1 is not
encompassed by the third structure of McSwiggen’s Figure 65, we are not
persuaded. As taught in Colletti and Ma, the sense strand is the passenger
strand. FF14.
Appellant also contends, however, that “none of the structures
disclose having an antibody and a polymer each on a different terminus of
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the double stranded polynucleotide.” Id. at 9. Citing Takeda Chemical Ind.,
Ltd. v. Alphapharm Pty., Ltd., 429 F.3d 1350 (Fed. Cir. 2007), Appellant
argues that the claimed molecule would not have been “obvious to try”
within the meaning of KSR so as to render claim 1 obvious, because
“McSwiggen does not provide a ‘finite number of identified, predictable
solutions,’ but a broad selection of chemical formulas containing a siNA”
that can “cover a broad selection of modifications to the siNA,” together
with “an open-ended laundry list of conjugates that can be attached to
siNA.” Appeal Br. 7–8, 10. Appellant further argues that the cited prior art
references do not “provide any motivation or reasons as to how one of
ordinary skill[] in the art would arrive at the presently claimed molecule of
formula (I),” including because “[t]he examiner failed to show any reason
for one of ordinary skill[] in the art to select any particular chemical formula
out of the hundreds of chemical formula disclosed in McSwiggen for
modification.” Id. at 7–10.
Although we agree that Figure 65 does not explicitly teach that the
conjugates on the termini of the polynucleotide should be an antibody and a
polymer, respectively, we are not persuaded that this renders claim 1 non-
obvious when considered together with the remaining disclosures in
McSwiggen and Colletti, Marcusson, or Ma, for the reasons already
discussed above: Each of the prior art combinations suggests the use of
antibodies and polymer as conjugates to improve bioavailability and/or
targeted delivery into cells, and attaching them to the generalized structure
disclosed in Figure 65 of McSwiggen is no more than the combination of
familiar elements according to known methods.
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We also find Ex parte Ballance to be inapposite in this case. In that
case, claim 61, the independent claim on appeal, is directed to
[a]n albumin fusion protein comprising a Factor IX polypeptide
fused to an albumin polypeptide, wherein said albumin
polypeptide has the ability to prolong the serum half-life of the
fused Factor IX polypeptide compared to the unfused Factor IX
polypeptide, wherein said fused Factor IX polypeptide has
Factor IX clotting activity, wherein said Factor IX polypeptide
is fused at the N-terminus of the albumin polypeptide, wherein
said albumin polypeptide and Factor IX polypeptide are further
defined by, e.g., their amino acid sequences.
Ex Parte Ballance, 2018 WL 1378083 at *1 (PTAB March 8, 2018).
The Board in Ballance found that, although “claim 61 would have
been prima facie obvious,” other evidence tilts the decision in Appellants’
favor in that case:
Although Fleer teaches albumin fusions and suggests use with
factors involved in coagulation, coagulation factors encompass
dozens of potential polypeptides. App. Br. 6-7. Also, the
functionally closest peptide tested in Fleer, von Willebrand
factor (vWF), which can reasonably be characterized as a
coagulation factor, did not exhibit clotting/coagulant activity as
recited in the claims. Id. at 8. And, as we discuss in greater
detail below, Appellants provided persuasive and
countervailing objective evidence of nonobviousness,
particularly unexpected, orientation-dependent results -- with
fusions of Factor IX at the N-terminus of albumin.
Id. at *4.
In contrast, as discussed further below, Appellant has not provided
similarly persuasive evidence of nonobviousness. Also unlike the situation
in Ballance, the prior art in this instance explicitly suggests conjugating PEG
and antibodies to siNA. See e.g., FF5, FF6, FF16. Finally, unlike claim 61
in Ballance, nothing in the prior art or other evidence of record shows that
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the molecule suggested by the prior art and recited in claim 1 would not
function as expected (see infra pp. 24–28 (discussing unexpected results).
Finally, in Ballance the claim recited a functional limitation (i.e., “wherein
said albumin polypeptide has the ability to prolong the serum half-life of the
fused Factor IX polypeptide compared to the unfused Factor IX
polypeptide” and “wherein said fused Factor IX polypeptide has Factor IX
clotting activity”); no such functional limitations requiring inherency
arguments are present in claim 1 on appeal. Ex parte Ballance, 2018 WL
1378083 at *1, *7.9
Neither are we persuaded by Appellant’s argument that the Examiner
is relying on “impermissible inherency arguments in order to make the
obviousness rejections.” Appeal Br. 14. Appellant contends that the
Examiner acknowledges that “none of McSwiggen, Colletti, Marcusson, [or]
Ma disclose claimed Formula 1.” Appeal Br. 15. As discussed above,
however, in the Answer the Examiner points to Figure 65, which has the
same generalized structure as claimed Formula 1. Ans. 5. To the extent
Appellant’s argument is that there were no working examples in the prior art
of “a conjugate combining antibody, siRNA, and polymer,” see, e.g., Appeal
Br. 15, we note that “‘all disclosures of the prior art, including unpreferred
embodiments, must be considered’ in determining obviousness.” In re
Burckel, 592 F.2d 1175, 1179 (CCPA 1979).
Finally, Appellant argues that the subject matter exhibits unexpected
results. Appeal Br. 15–17; Reply Br. 10–14. Appellant cites to Figures

9 We also note that, as Appellant acknowledges, Ex parte Ballance has not
been designated as informative or precedential and is thus not binding
authority on this panel.
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50A, 50B, 22, and 27 in the Specification as showing that an siRNA
construct having the claimed formula (i.e., a construct in which the siRNA
has the formula A-X-B-Y-C) exhibits unexpected results. Appeal Br. 15–17.
We find that Appellant has not demonstrated results commensurate
with the scope of the claim and thus agree with the Examiner that Appellant
has not shown evidence of unexpected results that, when considered together
with evidence of obviousness, shows claim 1 to be non-obvious.10 In re
Lindner, 457 F.2d 506, 508 (CCPA 1972) (“It is well established that the
objective evidence of nonobviousness must be commensurate in scope with
the claims.”).
In particular, claim 1 broadly encompasses any molecule having the
formula A-X-B-Y-C, where (1) A is an antibody or antibody fragment; B is
a double-stranded polynucleotide consisting of a passenger strand and a
guide strand and comprising at least one of the recited modifications; C is a
polymer; and X and Y are bonds or non-polymeric linkers; and (2) the
antibody A and polymer C are conjugated to different termini of the
passenger strand of the polynucleotide B. Appeal Br. 29 (Claims App.).
However, the results Appellant cites to show unexpected results provide data
for only two claimed siRNA constructs, PSMA-Ab(Cys)-EGFR-PEG5k and

10 We do, however, agree with Appellant’s contention that, to show
unexpected results, Appellant needs only compare the claimed molecule to
the closest prior art, not to a molecule rendered obvious by the combination
of prior art but not actually disclosed therein. Appeal Br. 16. We also agree
with Appellant that “[t]here is no requirement that evidence of unexpected
results for a product be presented for every possible use of the product.”
Reply Br. 12.
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EGFR-Ab-KRAS-PEG5k.11 Neither has Appellant provided persuasive
evidence of an “adequate basis to support the conclusion that other
embodiments falling within the claim will behave in the same manner” as
the siRNA constructs for which data of alleged unexpected results is
provided.12 See In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011).
In the Reply Brief, Appellant first argues that “the Examiner does not
provide any reason as to why the results could not be extrapolated” and
improperly “failed to consider Appellant’s rebuttal evidence.” Reply Br. 11.
We are not persuaded. While we agree that, “[c]onsistent with the rule that

11 Figures 50A and 50B compares, respectively, the percentage of EGFR
mRNA expression and siRNA concentration in tumor and liver for 3
different siRNA constructs: PSMA-Ab(Cys)-EGFR (i.e., A-X-B), PSMA-
Ab(Cys)-EGFR-PEG5k (i.e., the claimed A-X-B-Y-C), and PSMA-
Ab(Cys)-PEG5k-EGFR (i.e., A-X-C-Y-B). Figures 22 and 27 compare,
respectively, the siRNA concentration over time in plasma and 2 different
types of tissue (tumor and liver) for 2 different siRNA constructs having
different arrangements of components as well as different siRNA sequences:
EGFR-Ab-KRAS-PEG5k (i.e., the claimed A-X-B-Y-C) and EGFR-Ab-
PEG5k-EGFR siRNA (A-X-C-Y-B). We note that Appellant has not
explained why the same double-stranded polynucleotide was not used in the
comparison illustrated in Figures 22 and 27, or why the difference in plasma
and tissue concentrations observed between the two constructs are due to the
different arrangements of antibody, polynucleotide, and polymer, rather than
the different polynucleotides used.
12 We note, for instance, that the Specification provides some evidence that
the molecular weight of the polymer conjugated to a siRNA may have some
effect on the rate of clearance of an siRNA construct from the plasma, even
if the siRNA construct discussed in that portion of the Specification do not
have the formula recited in claim 1. Spec. ¶ 567 (stating that “the molecular
weight of the PEG linker does not have a large impact on the plasma PK,
except for the 10kDa PEG leads to a faster siRNA clearance (i.e. lower
plasma concentrations at later times).”).
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all evidence of nonobviousness must be considered when assessing
patentability, the PTO must consider comparative data in the specification in
determining whether the claimed invention provides unexpected results,” it
is well settled that “unexpected results must be established by factual
evidence” and “[m]ere argument or conclusory statements in the
specification does not suffice.” In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995)
(internal quotation marks omitted). Moreover, “the burden of showing
unexpected results rests on he who asserts them.” In re Klosak, 455 F.2d
1077, 1080 (CCPA 1972). Here, as discussed above, Appellant has cited to
comparative data for two siRNA constructs as evidence of unexpected
results for a claim having a much broader scope and encompassing a “great
number and variety” of molecules, without providing persuasive evidence as
to why such data is representative for other embodiments falling within
claim 1. See In re Lindner, 457 F.2d at 508. Thus, having considered the
rebuttal evidence, we agree with the Examiner that the evidence of
unexpected results, when considered together with the evidence of
obviousness, does not show claim 1 to be obvious.
In the Reply Brief, Appellant also cites to Examples 10 to 43 for the
first time as supporting Appellant’s unexpected results argument. Reply Br.
13–14. As an initial matter, to the extent Appellant did not cite to these
examples in the Appeal Brief,13 Appellant has not explained why they could
not have been raised in the Appeal Brief. Arguments relating to such
examples are thus considered waived. See Ex parte Nakashima, 93 USPQ2d

13 Example 10 describes the data presented in Figures 50A and 50B, which
has been discussed above.
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1834 (BPAI 2010) (informative); Ex parte Borden, 93 USPQ2d 1473, 1477
(BPAI 2010) (informative).
Moreover, with the exception of the comparative data discussed
above, Appellant does not explain how the data in examples 10 to 43
compares the claimed molecules to the closest prior art. Instead, Appellant
merely states the examples “demonstrate[] . . . that a large number of
molecules encompassed by the claimed formula (I) all have superior
pharmacokinetic properties such as tumor tissue specific accumulation and
maintenance of target tissue concentration over time.” Reply Br. 13.
Appellant argues that “the large number of molecules tested in the example
section and their generally improved tumor tissue specific accumulation and
pharmacokinetic properties are sufficient to support an extrapolation of the
improved properties for the claimed formula (I).” Id. at 13–14. Appellant
does not explain, however, how the “generally improved tumor tissue
specific accumulation and pharmacokinetic properties” of the claimed
molecules would be unexpectedly superior to the prior art siRNA constructs,
which are similarly expected to provide improved target cell delivery and
pharmacokinetic properties (FF3–FF7, 12, 16, 21–24, 26). “Attorney’s
argument in a brief cannot take the place of evidence.” In re Pearson, 494
F.2d 1399, 1405 (CCPA 1974).
Accordingly, we affirm the Examiner’s rejection of claim 1 as
obvious over McSwiggen and Colletti, Marcusson, or Ma. Claims 2–5, 8, 9,
13, and 16–22, which were not separately argued, fall with claim 1.
Appellant does not make any additional arguments with respect to the
rejections of claims 10 and 11 over either the combination of McSwiggen,
Colletti, and Bettencourt or Xie, or the combination of McSwiggen, Ma, and
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Bettencourt or Xie. We therefore affirm these rejection for the same reasons
discussed above.
CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1–5, 8, 9,
13, 16–22
103(a) McSwiggen,
Colletti
1–5, 8, 9,
13, 16–22

10, 11 103(a) McSwiggen,
Colletti, Bettencourt
10, 11
10, 11 103(a) McSwiggen,
Colletti, Xie
10, 11
1–5, 8, 9,
13, 16–19,
21
103(a) McSwiggen,
Marcusson

1–5, 8, 9,
13, 16–19,
21

1–5, 8, 9,
13, 16–22
103(a) McSwiggen, Ma

1–5, 8, 9,
13, 16–22

10, 11 103(a) McSwiggen, Ma,
Bettencourt
10, 11
10, 11 103(a) McSwiggen, Ma,
Xie
10, 11
Overall
Outcome
1–5, 8–11,
13, 16–22

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). See 37 C.F.R.
§ 1.136(a)(1)(iv).

AFFIRMED