AVIDITY BIOSCIENCES, INC.

Patent Trials and Appeals Board

Dec 30, 2020

2019004650 (P.T.A.B. Dec. 30, 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 12/30/2020
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
12/30/2020 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 COTTA, Administrative Patent Judges.
CHANG, Administrative Patent Judge.

DECISION ON REQUEST FOR REHEARING

Appellant requests rehearing of the decision entered August 4, 2020
(hereinafter “Decision”), which affirmed the Examiner’s rejections of claims
1–5, 8–11, 13, and 16–22 as obvious.1
We DENY the requested relief.

1 The prior art references discussed in this decision include McSwiggen et al.,
US 2007/0004665 Al, published Jan. 4, 2007 (“McSwiggen”); Colletti et al.,
US 2017/0081425 Al, published Mar. 23, 2017 (“Colletti”); Marcusson et al.,
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DISCUSSION
Appellant asserts that “[t]he Board overlooked and misapprehended
Appellant’s arguments regarding unexpected results.” Reh’g Req. 6.
Appellant further requests that the Board’s affirmance be designated as a
new ground of rejection. Id. We will address these in order.

A. Unexpected Results
Appellant contends that the Board “overlooked and misapprehended
that the additional evidence discussed in the Reply Brief,” namely Examples
10 to 43, “was in response to the arguments made for the first time by the
examiner in the Answer and were thus proper arguments made in Reply
Brief.” Reh’g Req. 7–8.
We are not persuaded. “[A]ny argument not timely presented in the
[P]rincipal Brief, will not be considered when filed in a Reply Brief, absent a
showing of good cause explaining why the argument could not have been
presented in the Principal Brief.” Ex parte Nakashima, 93 USPQ2d 1834
(BPAI 2010); see also Decision 27–28. Appellant contends that it showed
good cause for citing to Examples 10 to 43 in its Reply Brief because it
noted in the Reply Brief that the citation was for the purpose of “pointing
out the ‘additional fallacies of the examiner’s arguments in the Answer.’”
Reh’g Req. 7–8 (quoting Reply Br. 6). This general statement, however,
was not directed in particular to citations to Examples 10 to 43 and is not
sufficiently specific to show good cause for citation to that additional
evidence.

US 2017/0159056 Al, published June 8, 2017 (“Marcusson”); and Ma et al., US
2013/0052731 Al, published Feb. 28, 2013 (“Ma”).
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In the rehearing request, Appellant suggests more specifically that
citation to the additional examples was properly made in response to “[t]he
examiner . . . for the first time assert[ing] in the Answer that the [asserted
unexpected] results were not commensurate in scope with the claims.”
Reh’g Req. 7. This argument was not made in the Reply Brief. Thus, the
Board did not “overlook or misapprehend” the alleged showing of good
cause.
Moreover, in the Advisory Action mailed July 17, 2018, the Examiner
made similar assertions with respect to Appellant’s unexpected results
showing, asserting that “[t]he result from a method using one species cannot
be extrapolated to the genus of complexes in plasma” and that “a person of
ordinary skill in the art cannot ascertain a trend in the data that would allow
him/her to reasonably extend the probative value thereof.”2 Advisory Act.
2–3. Accordingly, we are not persuaded that Appellant has shown good
cause, even in the rehearing request, as to why it could not have cited to
Examples 10 to 43 in the Appeal Brief. This is particularly the case given
that, once the Examiner has established a prima facie case, the burden shifts
to Appellant to produce evidence that its invention possesses unexpected
properties as compared to the prior art, which showing must be
commensurate in scope with the claim. See, e.g., In re Mayne, 104 F.3d
1339, 1343 (Fed. Cir. 1997) (stating that, “[w]ith a . . . prima facie case of
obviousness shown, the burden shifts to applicants to demonstrate that their

2 The Advisory Action, mailed July 17, 2018 (hereinafter “Adv. Act.”) is
not paginated. Thus, page numbers refer to the document as if it were
consecutively paginated beginning on the first page, excluding the cover
sheet.
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claimed fusion proteins possess an unexpected property over the prior art”);
see also In re Dill, 604 F.2d 1356, 1361 (CCPA 1979) (stating that “[t]he
evidence presented to rebut a prima facie case of obviousness must be
commensurate in scope with the claims to which it pertains”).
In any event, contrary to Appellant’s apparent contention in the
rehearing request, the Board did in fact address Appellant’s arguments with
respect to Examples 10 to 43. In particular, the Decision noted that, other
than the comparative data presented in Figures 50A and 50B, which is
described in Example 10 and separately addressed in the Decision, the data
in the cited examples do not compare the properties of the claimed
molecules to their closest prior art counterparts and are thus lacking as
evidence that the unexpected results allegedly shown for two claimed siRNA
constructs may be extrapolated to other molecules encompassed by claimed
formula (I). Decision 28.
Appellant also contends that “the Board overlooked Appellant’s
argument that the order of the components of the claimed molecule matters.”
Reh’g Req. 6. In particular, Appellant contends that
the Board . . . discounted Appellant’s evidence of unexpected
results on the basis that it was unclear 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
delivery and pharmacokinetic properties.” Decision at 28. The
Board also asserted that “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 evidence as to why such data is
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representative for other embodiments falling within claim l.”
Id[.] at 27.
Reh’g Req. 8.
The portion of the Decision cited by Appellant, however, does not
show that we overlooked Appellant’s argument that the order of the
components of the claimed molecule matters. Instead, the Decision merely
points out that Appellant’s evidence of alleged unexpected results is not
commensurate with the scope of claim 1 because (1) Appellant has cited to
comparative data for only two siRNA constructs, without providing
persuasive evidence that these constructs are representative of the large
number of molecules encompassed by claim 1; and (2) as already discussed
above, other than the comparative data for the two siRNA constructs, the
data in Examples 10 to 43 cited in the Reply Brief do not compare the
properties of the claimed molecules to their closest prior art counterparts and
thus do not suffice to show unexpected results for other claimed siRNA
constructs. Decision 27–28.
Appellant contends that “[t]he evidence demonstrates . . . that the
order and the configuration [of the siRNA constructs] matter” and that “the
proper comparison is thus whether conjugates having the configuration of
claim 1 show properties that are different from molecules that have different
configurations.” Reh’g Req. 8. Appellant contends that “[t]o conclude that
because McSwiggen, Col[l]etti, 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, is mere
speculation on the part of the Examiner that the claimed construct would
produce better bioavailability and enable higher target tissue uptake.” Reh’g
Req. 9 (quoting Appeal Br. 13).
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Once again, Appellant does not persuasively explain how the Board
misapprehended or overlooked Appellant’s argument that the order and the
configuration of the siRNA constructs matter. We agree that the conjugates
for which unexpected results must be demonstrated are the claimed
conjugates, i.e., the conjugates having a specific configuration. However, as
discussed above and explained in our Decision, we disagree that Appellant’s
proffered evidence demonstrates that the claimed subject matter
demonstrates unexpected results, because, among other things, the evidence
is not commensurate with the scope of the claim. Decision 25.
Likewise, the Decision explicitly addressed the argument from page
13 of the Appeal Brief quoted in Appellant’s rehearing request, explaining
that, contrary to Appellant’s assertions that the cited prior art references
“describe[] only a portion of the claimed construct” and/or “a nucleic acid
conjugated on both termini in which one terminus is a cap,” “McSwiggen in
fact ‘discloses a composition comprising a siRNA molecule attached to a
conjugate at both termini of the molecule (Figure 65)’” which “has the same
generalized structure as the formula I recited in claim 1.” Decision 21
(quoting Ans. 5). The Decision points out more particularly that claimed
formula I is encompassed by the third structure of McSwiggen’s Figure 65.
Id.
Appellant contends that the Examiner and the Board did not explain
why the unexpected results presented “could not be extrapolated to the
claimed molecule having the specified order” and that “[i]n response to the
Examiner’s weak obviousness rejection . . ., Appellant met its burden of
production by pointing out the evidence of unexpected results in the
specification demonstrating that order matters.” Reh’g Req. 8, 9.
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Appellant further contends that “[n]either the Examiner nor the Board point
to any teaching in the prior art that the configuration and the orientation of
the nucleic acid structures of McSwiggen would result in the difference in
activity shown in the examples.” Id. at 10.
We are not persuaded. As we explained in our Decision, “the burden
of showing unexpected results rests on he who asserts them.” Decision 27
(quoting In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972)). Likewise, “[i]t
is well established that the objective evidence of nonobviousness must be
commensurate in scope with the claims,” i.e., provide a reasonable basis for
concluding that the untested embodiments encompassed by the claims would
behave in the same manner as the tested embodiment(s). In re Lindner, 457
F.2d 506, 508 (CCPA 1972); see also In re Kao, 639 F.3d 1057, 1068 (Fed.
Cir. 2011). As we explained in our Decision and reiterate above, Appellant
has not provided such commensurate evidence of unexpected results.
Decision 25–26.
In short, the Decision makes clear that the Board understood
Appellant’s argument that constructs having the claimed order of
components exhibit unexpected results as compared to similar constructs
having different configurations,3 and considered the evidence of alleged

3 Indeed, in analyzing Appellant’s unexpected results argument, the
Decision notes that Figures 22 and 27 compare “2 different siRNA
constructs having different arrangements of components as well as different
siRNA sequences” and further notes that “Appellant has not explained why
the same double-stranded polynucleotide was not used in the comparison
. . ., 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.” Decision 26, n. 11 (emphasis added). Thus, the
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unexpected results, including Examples 10 to 43, but disagreed that the
evidence cited by Appellant, when considered together with evidence of
obviousness, shows the claims to be non-obvious. While Appellant may
disagree with the conclusion we reached upon weighing the evidence,
Appellant has not shown that we overlooked or misunderstood any issue of
fact or law in reaching that conclusion. Accordingly, we deny the request
for rehearing on this ground.

B. New Ground
Appellant contends that the affirmance of the Examiner’s rejection
should be designated as a new ground a rejection because “the Board relied
on numerous additional facts, as well as provided additional rationale not
relied upon by the Examiner” in the Decision. Reh’g Req. 10. We are not
persuaded.

1. Additional Facts/Citations
Appellant first argue that designation of new ground is appropriate
because “the Decision cites portions of the references relied upon by the
Examiner that were not cited by the Examiner,” specifically paragraphs 15,
61, 106, 489, and 684 of McSwiggen, paragraphs 168, 194, 195, 202, 207,

Board clearly understood and took into account Appellant’s argument that
the order of the components in the constructs matters, even if, ultimately, we
disagreed with Appellant as to whether the evidence of alleged unexpected
results showed the claims to be non-obvious when considered together with
the evidence of obviousness.
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208, 212, 217, and 221 of Colletti, and paragraphs 2, 5, and 9 of Marcusson.
Reh’g Req. 10.
We are not persuaded. While we agree that “[m]ere reliance on the
same statutory basis and the same prior art references, alone, is insufficient
to avoid making a new ground of rejection when the Board relies on new
facts and rationales not previously raised to the applicant by the examiner,”
“[t]he Board need not recite and agree with the examiner’s rejection in haec
verba to avoid issuing a new ground of rejection.” In re Leithem, 661 F.3d
1316, 1319 (Fed. Cir. 2011). Furthermore, “[a] new ground of rejection . . .
generally will not be found based on the Board ‘further explain[ing] the
examiner’s rejection’ or the Board’s thoroughness in responding to an
applicant’s argument.” In re Biedermann, 733 F.3d 329, 337 (Fed. Cir.
2013) (quoting In re Jung, 637 F.3d 1356, 1364–65 (Fed. Cir. 2011)).
Instead, the question is whether the Board’s reliance upon new fact
findings “changes the thrust of the rejection.” Id. Put another way, “the
ultimate criterion of whether a rejection is considered ‘new’ in a decision by
the [B]oard is whether [applicants] have had fair opportunity to react to the
thrust of the rejection.” In re Kronig, 539 F.2d 1300, 1302–03 (CCPA
1976) (holding no new ground of rejection when the Board relied on the
same reasoning advanced by the Examiner).
In this case, Appellant has made no effort to explain how the
Decision’s citation to particular paragraphs of the prior art results in reliance
on “new facts” not previously raised by the Examiner, changes the thrust of
the rejection, or denies Appellant a fair opportunity to respond. We are thus
unpersuaded by Appellant’s argument that the affirmance should be
designated as a new ground. Indeed, as discussed in greater detail below,
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the Decision’s citation to the paragraphs enumerated by Appellant in the
rehearing request does not change the thrust of the Examiner’s rejection.

a) Paragraphs 15, 61, 106, 489, and 684 of McSwiggen
Paragraphs 15 and 61 in McSwiggen are cited in the Decision as
teaching that modified nucleotides may be used to improve characteristics of
nucleic acid molecules, including, e.g., stability, activity, and/or
bioavailability. Decision 8 (FF4, citing McSwiggen ¶¶ 15, 61); see also id.
at 16, 20 and 28 (citing FF4). In rejecting the claims, the Examiner similarly
relies on McSwiggen to show that “[t]he siRNA can have a modified
nucleotide as set forth in instant claims 2-5” and that a cap structure, an
example of a modified nucleotide, “can be used to protect the nucleic acid
molecule from exonuclease degradation, and can help in delivery and/or
localization within a cell.” Final Act. 6 (citing McSwiggen 24, 25, 37, 63,
and 64).4
Paragraphs 106 and 684 are cited in the Decision as teaching siNA
attached to conjugate molecules such as PEG, via covalent bonds or linkers
to either or both ends of the sense or antisense strand, as well as the potential
benefits (e.g., bioavailability) of such modification. Decision 8–9 (FF5,
citing ¶¶106, 684); see also id. at 16, 17–18, 20, 23, and 28 (citing FF5). In
the Answer, the Examiner also cites to McSwiggen for the same teachings,
explaining that “McSwiggen discloses a composition comprising a siRNA
molecule attached to a conjugate at both termini of the molecule,” that “[t]he

4 Claims 2–5 recite specific nucleotide modifications including 2’ modified
nucleotide, a modified internucleotide linkage, and an inverted abasic moiety
(i.e., a cap). Appeal Br. 19.
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conjugate can be . . . selected from a group including antibodies[] and PEG,”
and that some of the structures in Figure 65 of McSwiggen “would be the
same structure as set forth in formula I of instant claim 1.” Ans. 5 (citing
McSwiggen 24, 25, and Fig. 65).5 The Examiner further cites to
McSwiggen as teaching the potential benefits of such conjugates. Id. at 6
(citing pargraph 178 of McSwiggen as evidence that “PEG is known in the
prior art to increase the bioavailability of an oligonucleotide”).
Finally, paragraph 489 is cited in the Decision for McSwiggen’s
teaching that its compounds are useful for introducing nucleic acid
molecules into a cell. Decision 10 (FF7, citing McSwiggen ¶ 489). Once
again, this citation is congruent with the Examiner’s rejection: The
Examiner also cites McSwiggen for teaching that conjugates similar to those
claimed “can be used to protect the nucleic acid molecule from exonuclease
degradation, and can help in delivery and/or localization within a cell.” Ans.
5 (citing McSwiggen 24, 25, 37, 63, and 64).

b) Paragraphs 208, 212, 217, and 221 of Colletti
As an initial matter, the Decision notes that “McSwiggen itself
suggests all the limitations of claim 1 and provides a reason to combine them
in the same manner.” Decision 19. As the Decision also notes, the Board
may rely on less than all of the references relied upon by the Examiner. Id.

5 To the extent Appellant complains that the Examiner’s reasoning in the
Answer differs from that in the Final Office Action such that the Answer
contains an undesignated new ground of rejection, we note that whether an
Answer contains an undesignated new ground of rejection can be reviewed
only by way of petition. 37 C.F.R. § 41.40(a).
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Thus, our affirmance is not reliant on any alleged new fact findings relating
to Colletti. In any event, as discussed below, the alleged new citations to
Colletti do not change the thrust of the Examiner’s rejection.
Paragraph 217 is cited in the Decision for the uncontroversial
proposition, undisputed by Appellant, that the sense strand is the passenger
strand and the antisense strand is the guide strand. Decision 13 (FF14, citing
Colletti ¶ 217); see also id. at 16, 21 (citing FF14). As the Examiner
explains in the Answer, this is well known to a skilled artisan. Ans. 4
(explaining that “siRNA molecules comprise two oligonucleotide
sequences[;] one sequence is the guide strand (antisense strand) and the
other sequence is the passenger strand (sense strand)”).
Paragraphs 168, 207, 208, and 221 of Colletti are cited in the Decision
for teaching a double stranded siRNA wherein targeting ligands and
solubilizing agents are attached via linkers to the same strand or different
strands, and the passenger and/or guide strand, of the siRNA. Decision 12
(FF11, citing Colletti ¶ 208), 13–14 (FF13, citing Colletti ¶ 168; FF17, citing
Colletti ¶¶ 207, 221; FF19, citing Colletti ¶ 208); see also id. at 18 and 20
(citing FF11, FF13, FF17, and FF19). Paragraph 202 and paragraphs 208
and 212 of Colletti are further cited, respectively, for embodiments (1)
wherein the targeting ligand is attached to the passenger strand of a double
stranded siRNA at a terminal 3’ or 5’-position, optionally through a linker;
and (2) having the formula G-L-R-L-X, where G is a targeting ligand, L is a
linker, R is an oligonucleotide or siRNA, and X may be, among other things,
a solubilizing group. Decision 13–14 (FF18, citing Colletti ¶ 202; FF19,
citing Colletti ¶¶ 208, 212); see also id. at 18 and 20 (citing FF18, FF19).
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In the Answer, the Examiner cites to Colletti for similar teachings,
explaining that “Col[l]etti discloses a composition comprising a targeting
ligand linked to an oligonucleotide linked to a peptide and a lipid also linked
to the oligonucleotide, wherein the oligonucleotide can be siRNA,” “[t]he
targeting ligand can be an antibody,” and “[t]he peptide can be PEG.”6 Ans.
5–6 (citing Colletti 1, 3, 12, and 76). The Examiner also cites to Colletti as
disclosing, more specifically, “a complex comprising A-X-B-Y-C (formula
I),” wherein “the variables in Formula can be antibody (A), B can be a
siRNA, and C can be PEG and the linker (X and Y) can be non-polymeric
linkers.” Id. Furthermore, while the Examiner does not specifically cite to
Colletti for attaching conjugates to the passenger strand, both the Decision
and the Examiner cite to McSwiggen for disclosing this limitation. Decision
17 (finding that Figure 65 of McSwiggen discloses a siNA construct wherein
“the conjugates are attached to the two termini of the passenger (i.e., sense)
strand of the siNA”); Ans. 8 (“McSwiggen discloses a composition
comprising a conjugate linked to the 5’ and 3’ terminus of the sense [(i.e.,
passenger)] strand (Figure 65).”). We do not find that the additional citation
to Colletti on this point, which merely supports the disclosure in
McSwiggen, changes the thrust of the rejection so as to warrant designation
of the affirmance as a new ground of rejection.
Paragraphs 194 and 195 are cited in the Decision for the teachings that
solubilizing groups can include PEGs and may “enhance aqueous solubility,
circulation half life and/or cellular uptake.” Decision 13 (FF16, citing

6 As discussed below, Colletti identifies PEG as a solubilizing agent.
Colletti ¶ 194.
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Colletti ¶¶ 194, 195); see also id. at 18, 20, 23 and 28 (citing FF16). Again,
these citations are congruent with the reasoning of the Examiner, who cites
Colletti to show disclosure of a complex comprising A-X-B-Y-C wherein C
can be PEG. Ans. 5–6. Furthermore, although the Examiner does not
specifically cite Colletti for showing the advantages of conjugating a siRNA
molecule with PEG, the Examiner does state in the Answer that “PEG is
known in the prior art to increase the bioavailability of an oligonucleotide.”
Ans. 6 (citing McSwiggen ¶ 178). Thus, the citation of Colletti’s paragraphs
194 and 195 in the Decision does not change the thrust of the rejection.

c) Paragraphs 2, 5, and 9 of Marcusson
Paragraph 2 of Marcusson was cited for teaching antisense
oligonucleotides that inhibit or reduce the expression of a mutant gene;
paragraph 5 was cited for antisense oligonucleotide having at least one
modified internucleoside linkage; and paragraph 9 was cited for
embodiments in which the antisense oligonucleotide includes 2’-modified
sugars. Decision 14 (FF20, citing Marcusson ¶ 2; FF21, citing Marcusson
¶ 5; and FF22, citing Marcusson ¶ 9) 19, 20 and 28 (citing FF21, FF22).
None of the above citations change the thrust of the Examiner’s
rejection. First, as discussed above, our affirmance is not reliant on any
alleged new fact findings relating to Marcusson. Decision 19. Furthermore,
as discussed below, the citations to paragraphs 2, 5, and 9 of Marcusson
tracks the Examiner’s reasoning in the rejection.
In particular, although the Examiner does not specifically cite to
paragraph 2 of Marcusson, the Examiner states in the Answer that, “[a]s
evidenced by the prior art cited in the rejections of record,” a skilled artisan
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would have known at the time of the effective filing date, that “siRNA (a
product embraced by the term double stranded polynucleotide having a
passenger and a guide strand recited in claim 1) . . . reduce[s] expression of a
target gene in a cell.” Ans. 4. Appellant has not disputed that the function
of siRNAs in reducing gene expression is known in the prior art. Spec. ¶ 3
(describing “[g]ene suppression by RNA-induced gene silencing” in the
“Background of the Disclosure”).
Neither do we agree that the Decision’s citation to paragraphs 5 and 9
of Marcusson warrants designating our affirmance a new ground of
rejection. Claim 1 recites a molecule “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.”
Appeal Br. 19 (Claims App.). The Examiner cites to paragraph 55 of
Marcusson for teaching an oligonucleotide having a terminal cap structure,
which Marcusson explains may be an inverted abasic moiety. Final Act. 11;
Marcusson ¶ 55. Thus, both the Examiner and the Decision cite to
Marcusson as teaching the limitation of claim 1 recited above.
Moreover, while the Examiner does not cite specifically to Marcusson
for disclosures of 2’-modified nucleotide or a modified internucleotide
linkage, both the Examiner and the Decision rely primarily on McSwiggen
for disclosure of these modifications. See, e.g., Decision 16; Final Act. 11
(stating that McSwiggen teaches that “siRNA can have a modified
nucleotide as set forth in instant claims 2-5,” which recite a 2’ modified
nucleotide, a modified nucleotide linkage, and a terminal inverted abasic
moiety). Thus, the citations to Marcusson in the Decision merely provide
additional support for the Examiner’s reasoning and do not change the thrust
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of the rejection or deny Appellant a fair opportunity to respond to the
rejection. In this regard, we note that Appellant has not disputed that the
cited prior art combination teaches polynucleotides comprising one or more
of the modifications recited above.
In short, to the extent specific paragraphs cited in the Decision were
not cited by the Examiner in the Final Office Action or the Answer, the
reasoning in the Decision nevertheless remains the same as the reasoning
expressed by the Examiner in rejecting the claims. Accordingly, we deny
Appellant’s request to designate our affirmance as a new ground on the basis
of these citations.

2. New Rationales to Combine
Appellant also argues that “the Decision relies on new rationales in
concluding that there was a reason to combine the references with a
reasonable expectation of success.” Reh’g Req. 10.
Appellant first contends that, although the Examiner relied on
McSwiggen only for disclosing that “[a] cap structure can be incorporate[d]
at either of the siRNA,” the Decision additionally asserts that McSwiggen
teaches that (1) its siRNA may be conjugated to molecules, such as
antibodies, that facilitate its delivery, (2) such chemical modifications may
dramatically increase serum stability, and (3) PEG improves the
pharmacokinetics of the construct and thus increases the construct’s
bioavailability. Reh’g Req. 10–11. Appellant further contends that “[t]he
Board . . . also argued that ‘[a] skilled artisan would have a reason to modify
McSwiggen’s siRNA construct with a 2’-modified nucleotide . . . [to]
increas[e] the serum stability,’ but the Examiner did not mention any
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motivation to modify the siRNA with 2’-modified nucleotide in any part of
the rejection.” Id. at 11.
We are not persuaded. As to (1) and (2), the Examiner states in the
Answer:
It is reiterated that McSwiggen discloses a
composition comprising a siRNA molecule attached to a
conjugate at both termini of the molecule (Figure 65). A
structure in these figures would be the same structure as
set forth in formula I of instant claim 1. See the third and
sixth figure in Figure 65. The conjugates can be used to
protect the nucleic acid molecule from exonuclease
degradation, and can help in delivery and/or localization
within a cell (pages 24, 25, 37, 63, and 64 of
McSwiggen). The conjugate can be a biologically active
agent selected from a group including a ligand for
cellular receptors (including antibodies) and PEG (pages
24-25). Thus, McSwiggen teaches a structure that would
embrace formula I recited in the instant claims.
Ans. 5 (emphasis added). Contrary to Appellant’s argument, therefore, the
Examiner also relied on McSwiggen for teaching that siRNA may be
conjugated to molecules, including antibodies, to facilitate its delivery and
that such conjugation may also increase stability (i.e., by “protect[ing] the
nucleic acid molecule from exonuclease degradation”). As for (3), the
Examiner similarly cites to McSwiggen in explaining that “PEG is known in
the prior art to increase the bioavailability of an oligonucleotide.” Id. at 6.
We are likewise unpersuaded by Appellant’s argument that, in
contrast to the Decision, “the Examiner did not mention any motivation to
modify the siRNA with 2’-modified nucleotide in any part of the rejection.”
Reh’g Req. 11. The Examiner states in rejecting the claims that “[i]t would
have been obvious to use the modifications in instant claims 2-5” — i.e., 2’-
modified nucleotide, modified internucelotide linkage, and a terminal
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inverted abasic moiety — “to increase the stability of the siRNA in a cell.”
Final Act. 7.
Next, Appellant contends that the Decision asserts 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 l”; that “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”; and that “Colletti further teaches that
the targeting ligand may be an antibody and the
solubilizing group may be PEG.”
Reh’g Req. 11. Appellant contends, however, that “[t]he Examiner did not
point to specific portion of . . . Colletti” and “merely stated that ‘Col[l]etti
discloses a complex comprising a siRNA-linker-targeting ligand, wherein
the ligand is an antibody and the linker is a non-polymeric linker.’” Id.
Appellant contends that “[t]he Examiner’s argument does not extend to any
structure of siRNA conjugated with both targeting ligand and solubilizing
agents, let alone on the same or different strands.” Id.
We are not persuaded. As discussed above, the Decision noted that
“McSwiggen itself suggests all the limitations of claim 1 and provides a
reason to combine them in the same manner.” Decision 19. As the Decision
also noted, the Board may rely on less than all of the references relied upon
by the Examiner. Id. Thus, our affirmance is not reliant on any alleged new
rationale based on Colletti.
Moreover, the Examiner states in the Answer that
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Col[l]etti disclose[s] a complex comprising A-X-B-Y-C
(formula I). The composition can be used to provide
effective in vivo delivery, cell uptake and/or endosome
escape of oligonucleotides (page 1 of Col[l]etti). Colletti
discloses a composition comprising a targeting ligand
linked to an oligonucleotide linked to a peptide and a
lipid also linked to the oligonucleotide, wherein the
oligonucleotide can be siRNA (page 3). The peptide can
be PEG (page 12). The targeting ligand can be an
antibody (page 76). A person of ordinary skill in the art
would possess the knowledge that antibodies can be
conjugated to an oligonucleotide and the antibodies are
used to target a desired cell (See Col[l]etti, page 1) and
that PEG is known in the prior art to increase the
bioavailability of an oligonucleotide in a cell line or a
subject (See McSwiggen, paragraph 178).
Both McSwiggen and Col[l]etti disclose that the
variables in Formula can be an antibody (A), B can be a
siRNA, and C can be PEG and the linkers (X and Y) can
be non-polymeric linkers. It would have been obvious to
a person of ordinary skill in the art to attach conjugates to
the termini of the sense strand to avoid processing of the
sense strand instead of the guide strand. It would have
been obvious to a person of ordinary skill in the art to
attach PEG to one end of the siRNA to increase
bioavailability of the siRNA and an antibody to the other
end of the siRNA to assist in delivery of the siRNA to a
target cell.
Ans. 5–6 (emphasis added).
Contrary to Appellant’s arguments, therefore, the Examiner in fact
cited specific portions of Colletti. Similarly, the Examiner explained that
Colletti teaches specific structure(s) of siRNA conjugated with both
antibody (i.e., targeting ligand) and PEG (i.e., solubilizing agent). Finally,
the Examiner explained in the Answer that there is not merely a mention of a
nucleic acid conjugated on both termini in the prior art, because
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“McSwiggen discloses a composition comprising a conjugate linked to the
5’ and 3’ terminus of the sense [(i.e., passenger)] strand (Figure 65).” Ans.
8. Thus, although the Examiner does not specifically cite to Colletti for
conjugating molecules on the sense/passenger strand of siRNA, we do not
find the Decision’s additional citation to Colletti for a similar proposition,
which merely supports McSwiggen’s disclosure, changes the thrust of the
Examiner’s rejection.
Appellant further contends that “the Examiner . . . merely asserted that
Marcusson ‘discloses an oligonucleotide having at least one or more linkers
to both termini ... can have an antibody and the other terminus can have a
cap structure.’” Reh’g Req. 11. Appellant contends that, in contrast, the
Board describes Marcusson as teaching oligonucleotides covalently linked to
conjugate groups, such as antibodies, that “enhance the activity, cellular
distribution, and/or cellular uptake of the resulting . . . oligonucleotides” and
as further teaching “using the polynucleotide modifications recited in claim
1 (i.e., [‘]2’ modified nucleotide, ... modified internucleotide 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.” Reh’g Req. 11–12.
We are not persuaded. As discussed above with respect to Colletti,
the Decision notes that McSwiggen alone suffices to render claim 1 obvious.
Decision 19. Moreover, relying on the same portion of Marcusson cited in
the Decision for the teaching regarding oligonucleotide-antibody conjugates,
the Examiner states in the Answer that “Marcusson discloses that antibodies
can be conjugated to an oligonucleotide and the antibodies are used to target
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a desired cell.” Ans. 7 (citing Marcusson 4, 7). Thus, contrary to
Appellant’s suggestion, the Decision does not provide a new rationale to
combine by describing Marcusson as teaching that antibody-oligonucleotide
conjugates enhance, e.g., cellular uptake.
Similarly, the Examiner cites to paragraph 55 of Marcusson as
teaching “an oligonucleotide having at least one or more linkers to both
termini” wherein “[o]ne terminus can have an antibody and the other
terminus can have a cap structure,” e.g., an inverted abasic moiety. Final
Act. 11; Marcusson ¶ 55 (“Cap structures are well-known in the art and
include, for example, inverted deoxy abasic caps.”). The same paragraph in
Marcusson also teaches the benefits of terminal modifications such as cap
structures, stating that “termination modifications protect the . . .
oligonucleotide . . . from exonuclease degradation, and can help in delivery
and/or localization of the antisense oligonucleotide within a cell.” Id.
Accordingly, we are not persuaded that the Decision’s reference to
Marcusson’s teaching regarding use of polynucleotide modifications to
achieve desirable oligonucleotide characteristics changes the thrust of the
Examiner’s rejection.7

7 We note that, as discussed in the earlier portion of this opinion, both the
Examiner and the Decision primarily cite to McSwiggen for disclosures
regarding the use of polynucleotide modifications to achieve benefits such as
stability and delivery/localization of the nucleic acid molecule within a cell.
See, e.g., Dec. 16; Final Act. 11 (stating that McSwiggen teaches that
“siRNA can have a modified nucleotide as set forth in instant claims 2-5,”
(i.e., 2’ modified nucleotide, modified internucleotide linkage, and inverted
abasic moiety), and further 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 can
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Finally, Appellant contends that,
as to Ma, the Examiner . . . asserted “Ma discloses
making a complex comprising an antibody conjugating to
a siRNA,” but did not provide any arguments on any
purpose of generating the conjugation. In contrast, the
Board argued that “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”. Decision at 19.
Reh’g Req. 12.
We are not persuaded. First, as discussed above with respect to
Colletti and Marcusson, the Decision noted that McSwiggen alone suffices
to render claim 1 obvious. Decision 19. Moreover, the Examiner explains
in the Answer that “McSwiggen taken with Ma make obvious the claimed
product because McSwiggen teaches formula I and [teaches that] antibodies
and PEG can be conjugated to the oligonucleotide,” while “Ma discloses that
antibodies are used to target a desired cell and can be conjugated to a
siRNA.” Ans. 6 (emphasis added). Thus, contrary to Appellant’s argument,
the Examiner points to Ma’s disclosure of a purpose to generate a
conjugation of antibody and siRNA (i.e., to target a desired cell) in rejecting
the claims, and the Decision reiterates that purpose in affirming the
rejection.
Accordingly, for the reasons set forth above, we deny Appellant’s
request to designate our affirmance as a new ground of rejection.

help in delivery and/or localization within a cell”). The Decision’s citation
to Marcusson for similar teachings merely support the disclosures in
McSwiggen cited by the Examiner. For this additional reason, we find that
the Decision to Marcusson does not change the thrust of the rejection.
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CONCLUSION
In summary:
Outcome of Decision on Rehearing:

Claims
Rejected
35 U.S.C. § Reference(s)/Basis  Denied Granted
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

Final Outcome of Appeal after Rehearing:

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
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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).

REHEARING DENIED