Steven F. Dowdy et al.

Patent Trials and Appeals Board

Jul 22, 2019

11776317 - (D) (P.T.A.B. Jul. 22, 2019)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
11/776,317 07/11/2007 Steven F. Dowdy 00015-047US1 6546
26138 7590 07/22/2019
Joseph R. Baker, APC
Gavrilovich, Dodd & Lindsey LLP
4370 La Jolla Village Drive, Suite 303
San Diego, CA 92122
EXAMINER
SCHNIZER, RICHARD A
ART UNIT PAPER NUMBER
1635
MAIL DATE DELIVERY MODE
07/22/2019 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
_________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
_________________

Ex parte STEVEN F. DOWDY, SCOTT G. PETERSEN,
and BRYAN R. MEADE

_________________

Appeal 2018-002574
Application 11/776,317
Technology Center 1600
_________________

Before DEBORAH KATZ, TAWEN CHANG, and JOHN E. SCHNEIDER,
Administrative Patent Judges.

KATZ, Administrative Patent Judge.

DECISION ON APPEAL

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Appellants1 seek our review, under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claims 13, 15, 16, 18–23, 33, 37, and 38.2
(Appeal Brief filed September 14, 2017 (“App. Br.”) 1.) We have
jurisdiction under 35 U.S.C. § 6(b). We AFFIRM.
Appellants’ Specification explains that RNA interference (RNAi) is a
technique for manipulating cellular phenotypes in a targeted way by
selectively degrading specific mRNAs. (See Specification (“Spec.”) ¶ 5.)
Appellants report that the short interfering RNAs (siRNAs) used in RNAi
are not able to enter cells because of their size and negative (anionic) charge.
(See id.) Appellants propose new compositions and methods for transducing
cells with siRNAs that are “masked” or transiently protected with
protecting/charge neutralizing group. (See id. at ¶ 7.)
Appellants’ claim 13, the only independent claim on appeal, is
directed to a pharmaceutical composition comprising, in part, a double-
stranded oligoribonucleotide or polyribonucleotide having one or more
phosphodiester and/or phosphothioate backbone moieties linked to a
neutralizing group on the backbone. (See App. Br. 3; see App. Br. 17–20.)
The claimed oligoribonucleotide or polyribonucleotide has a net negative
charge, at least one guanine base, and is from 10 to 100 nucleotides long.
(See App. Br. 3; see App. Br. 17–20.) Claim 13 recites:
A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a nucleic acid construct
comprising;

1 Appellants report that the real party in interest is the Regents of the
University of California. (App. Br. 2.)
2 Claims 1–12, 14, 17, 24, and 34–36 were canceled, claims 25–32 were
withdrawn in previous prosecution. (See App. Br. 17–23.)
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a double-stranded oligoribonucleotide or
polyribonucleotide comprising one or more phosphodiester
and/or phosphothioate backbone moieties linked to a
neutralizing group of the oligoribonucleotide or
polyribonucleotide backbone,
wherein the oligoribonucleotide or polyribonucleotide
backbone has a net negative charge,
wherein said oligoribonucleotide or polyribonucleotide
comprises from 10 to 100 nucleotides,
wherein said oligoribonucleotide or polyribonucleotide
backbone comprises at least one guanine nucleotide,
wherein the one or more phosphodiester and/or
phosphothioate backbone moieties together with the
neutralizing group have the structure:

and wherein the oligoribonucleotide or
polyribonucleotide comprises a 2’-W moiety, wherein W is F,
O-Me, or O-alkyl,
wherein X is O (oxygen), S (sulfur) or NR1, where R1 is
H, methyl, ethyl, S-pivaloyl thioethanol, hydroxy, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, heterocyclic, or
substituted heterocyclic;
wherein each R is independently selected from the group
consisting of

wherein R3 is H, hydroxy, alkyl, substituted alkyl,
alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
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substituted aryl, heterocyclic, substituted heterocyclic, halo,
cyano, or nitro,
wherein A1 and A2 are each independently one to seven
atom chains, or substituted one to seven atom chains,

wherein R4 is H, hydroxy, alkyl, substituted alkyl,
alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, heterocyclic, substituted heterocyclic, halo,
cyano, or nitro,
wherein A3 and A4 are each independently one to seven
atom chains, or substituted one to seven atom chains,

wherein R5 is H, hydroxyl, alkyl, substituted alkyl,
alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, heterocyclic, or substituted heterocyclic,
wherein A5 is a one to seven atom chain, or substituted
one to seven atom chain,
wherein X1 is O, S or NR7, and R7 is H, hydroxy, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, heterocyclic, or
substituted heterocyclic, and X2 is S;
and

wherein R6 is H, hydroxy, alkyl, substituted alkyl,
alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,
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alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, heterocyclic, substituted heterocyclic, halo,
cyano, or nitro,
wherein A6 and A7 are each independently one to seven
atom chains, or substituted one to seven atom chains,
wherein X3 is S, and X4 is O, S or NR8, and R8 is H,
hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclic,
or substituted heterocyclic;
wherein each Q is independently selected from the group
consisting of:
Q1,
wherein Q1 is a basic group with a pKa greater than or
equal to 10,

wherein Q2 is a basic group with a pKa greater than or
equal to 10,
wherein A8 and A9 are each independently one to seven
atom chains, or substituted one to seven atom chains,

wherein Q3 is a basic group with a pKa greater than or
equal to 10,
wherein A10 and A11 are each independently one to seven
atom chains, or substituted one to seven atom chains,

wherein Q4 is a basic group with a pKa greater than or
equal to 10,
wherein A12 is a one to seven atom chain, or substituted
one to seven atom chain,
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wherein X5 is O, S or NR9, and R9 is H, hydroxy, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl, substituted aryl, heterocyclic, or
substituted heterocyclic, and X6 is S; and

wherein Q5 is a basic group with a pKa greater than or
equal to 10,
wherein A13 and A14 are each independently one to seven
atom chains, or substituted one to seven atom chains,
wherein X7 is S, and X8 is O, S or NR10, and R10 is H,
hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclic,
or substituted heterocyclic.

(App. Br. 17–20.)
The Examiner rejected claims 13, 15, 16, 18–22, 33, 37, and 38 under
35 U.S.C. § 103(a) as being obvious over Imbach3, Kosonen4, Fosnaugh5,

3 Imbach et al., U.S. Patent 6,124,445, issued September 26, 2000.
4 Kosonen et al., “Hydrolysis and intramolecular transesterification of
ribonucleoside 3'-phosphotriesters: the effect of alkyl groups on the general
and specific acid-base-catalyzed reactions of 5'-O-pivaloyluridin-3'-yl
dialkyl phosphates,” 2 J. CHEM. SOC., PERKIN TRANS. 663–70 (1998).
5 Fosnaugh et al., U.S. Patent Application Publication 2003/0143732 A1,
published July 31, 2003.
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Spinelli6, and Hayakawa7. (Final Office Action issued September 14, 2016
(“Final Act.”) 2–10.) The Examiner rejected claim 23 under 35 U.S.C.
§ 103(a) over Imbach, Kosonen, Fosnaugh, Spinelli, Hayakawa, and
Astriab-Fisher8. (Final Act. 10–11.)
The Examiner’s rejection relies on Imbach for its teaching of DNA
and RNA oligonucleotides that have phosphate groups protected by S-
acylthioethyl (SATE) groups as recited in Appellants’ claims in order to
improve cellular uptake by temporarily masking negative charge of the
phosphate group. (See Final Act. 3.) The rejection cites Imbach for
teaching phosphoramidites comprising 2’[-]F or 2’-O-alkyl groups recited as
the “2’-W moiety in Appellants’ claims, for oligonucleotide synthesis. (See
Final Act. 4.) Kosonen is cited to demonstrate that those skilled in the art
knew that modifying the 2’-OH groups of RNA would stabilize nucleotides
by not allowing reactions with the 3’-phosphotriester. (See Final Act. 5.)
The Examiner relies on Fosnaugh to show that those of ordinary skill knew
that double-stranded RNA oligonucleotides having 2’-O-methyl and 2’-F
and phosphorothioate modifications could be made for improved cellular
uptake and stability. (See Final Act. 6.) The Examiner further cites Spinelli

6 Spinelli et al., “Use of Allylic Protecting Groups for the Synthesis of Base-
Sensitive Prooligonucleotides,” EUR. J. ORG. CHEM. 49–56 (2002).
7 Hayakawa, “Toward an Ideal Synthesis of Oligonucleotides: Development
of a Novel Phosphoramidite Method with High Capability,” 74 BULL. CHEM.
SOC. JPN., 1547–65 (2001).
8 Astriab-Fisher et al., “Conjugates of Antisense Oligonucleotides with the
Tat and Antennapedia Cell-Penetrating Peptides: Effects on Cellular Uptake,
Binding to Target Sequences, and Biologic Actions,” 19 PHARM. RES. 744–
54 (2002).

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to show that it would have been known how to achieve a net negatively
charged double-stranded RNA with SATE phosphotriester modifications, as
claimed, because Spinelli shows that the negative charge is a result effective
variable of the degree of modification. (See Final Act. 7–8.) Finally,
Hayakawa is cited to show protected RNAs within the claimed size range of
10 to 100 nucleotides that include guanosine bases. (See Final Act. 8.)
At the outset, we reject Appellants’ arguments against the Examiner’s
rejection of the claimed composition based on the prior inability to prepare
“meaningful yields” of compositions that could undergo “self-delivery” into
cells in vivo and allow for reduced expression of target proteins in mice.
(See App. Br. 7, citing to Meade et al., 32 NATURE BIOTECH 1256–61
(2014).) This information does not persuade us of the patentability of the
claimed composition because neither specific yields nor a method targeting
protein expression are recited in Appellants’ current claims. Although
Appellants’ claims recite a “pharmaceutical composition,” Appellants do not
direct us to evidence in the Specification or elsewhere that such a
composition is limited to a specific amount of nucleic acid construct.
Furthermore, Appellants’ arguments, on their own, do not present evidence
of unexpected results because they lack a comparison to the closest prior art
and rigorous analysis of any different results.
We agree with the Examiner that Imbach teaches protected forms of
oligonucleotides having at least one phosphate moiety protected with a
removable S-pivaloyl thioethanol group. (See Final Act. 2–3, citing Imbach
Structure I at 2:52–67, Structure II at 3:10–23, and Fig. 3.) Appellants do
not dispute that the protecting groups taught in Imbach fall within the scope
of the claimed protecting groups, including the subgenus recited in claim 15.
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(See Final Act. 3–4.) Appellants acknowledge that Imbach teaches an
approach to preparing phosphate-protected oligonucleotides with
phorphoramidites, including S-acyl thioester (SATE). (See App. Br. 9,
citing Imbach, 17:3–18:12 (Example 12, demonstrating post-synthesis
alkylation) and 16:8–17:2, 22:65–23:61 (Examples 11 and 21, demonstrating
synthesis with SATE or BuSATE).)
We agree with the Examiner that Imbach expressly teaches these
protecting groups can be used with both DNA and RNA poly- and
oligonucleotides. (See Final Act. 4–5.) Imbach teaches:
Various nucleotide units can be can be activated as amidites of
the invention and incorporated in to the oligonucleotides of the
inventions. These include deoxy nucleotides, i.e., wherein Q in the
above structures is H, ribonucleotides, i.e., wherein Q is OH in the
above structures, 2'-alkoxy nucleotides, i.e., wherein Q is O-alkyl in
the above structures, or substituted 2'-O-alkyl nucleotides, i.e.,
wherein Q is substituted-O-alkyl in the above structures. 2'-O-alkyl
nucleotides are described in U.S. Pat. No. 5,466,786, herein
incorporated by reference.

(Imbach 12:20–32 (emphasis added).) Similarly, Imbach expressly provides
that “[a]s practiced herein, the pro-oligonucleotides may be antisense
oligonucleotides of synthetic DNA or RNA or mixed molecules of
complementary sequences to a target sequence belonging to a gene or to an
RNA messenger whose expression they are specifically designed to block or
down-regulate.” (Imbach 9:14–19; see also Imbach 6:4–6 (“Oligonucleotide
as used herein indicates a DNA or RNA polynucleotide in the ribo- (RNA)
or deoxyribo- (DNA), or mixed ribo-deoxyribo, series.”).)
In addition to expressly teaching protected RNA oligonucleotides,
Imbach teaches that the modifications of DNA and RNA poly- and
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oligonucleotides improve stability and cellular uptake. (See Imbach 2:29–
51, 5:5–9; see Final Act. 4.) Imbach explains:
One aspect of this invention is directed to a further approach to
assist cellular uptake of oligonucleotides. In this approach a prodrug
strategy is utilized wherein a prooligonucleotide is formed that
temporarily masks the negative charges of phosphodiester,
phosphorothioate and phosphorodithioate oligonucleotides by the
introduction of a bioreversible group on at least some of phosphate
groups of these oligomers. The resulting neutral prooligos have been
found to be enzymatically stable against nucleases. While we do not
wish to be bound by theory, we believe this will help oligonucleotides
to escape from the endosomes should they become embedded therein
and will present a completely different bioavailability pattern in
relation with their route of administration. A prerequisite of this
approach is that bioreversible groups must be selected that have
stability in culture medium and that have selective intracellularly
hydrolysis after uptake, due to the existence of a greater enzymatic
activity in cytosol than in biological fluids.

(Imbach 5:36–54.) Thus, like Appellants’ claimed composition, the oligo-
or polynulceotides taught in Imbach mask negative charge and allow for
greater bioavailability and stability.
Appellants argue that Imbach “do[es] not provide any teaching or
suggestion that would allow the synthesis of polyribonucleotides including
2' substitution where the 2' position is F, O-Me, or O-alkyl by one of skill in
the art.” (Reply Br. 6.) Similarly, Appellants argue that Imbach does not
“experimentally confirm” that deprotected deoxyguanosine and other
nucleotides could be used to prepare unprotected oligonucleotides without
compromising labile thio groups because Imbach does not demonstrate the
synthesis of an oligonucleotide with the exemplified protecting groups (e.g.,
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isobutyryl, benzoyl, N-nitrophenylsulfenyl, or N-pent-4-enoyl). (App. Br.
10.)
We are not persuaded by these arguments. “All the disclosures in a
reference must be evaluated, including nonpreferred embodiments, . . ., and
a reference is not limited to the disclosure of specific working examples.” In
re Mills, 470 F.2d 649, 651 (CCPA 1972) (citations omitted). The absence
of examples in Imbach of Appellants’ specifically claimed subject matter or
of RNA oligonucleotides, in general, does not render the express teaching or
suggestion to make RNAs in the Imbach specification meaningless. Instead,
Imbach demonstrates that making the claimed modifications in RNA had at
least been considered by those in the art.
Appellants argue that although Imbach teaches removal of SATE or
BuSATE groups from the disclosed compounds, it teaches doing so in total
cell extracts, not in transfected cells. (See App. Br. 10.) Similarly,
Appellants argue that Imbach does not demonstrate suppression of gene
expression because of an inability to prepare an oligonucleotide other than
oligodeoxythymidine. (See id.) These arguments are not persuasive
because Appellants’ claims are not limited to the environment of the claimed
compositions.
The Examiner’s rejection relies on other references to demonstrate
that one of ordinary skill in the art would have known that
oligoribonucleotides having the claimed protection groups could be made
with a guanine base. The Examiner relies on Kosonen to demonstrate
motivation for making RNA oligonucleotides with phosphotriester linkages
for improved uptake and stability. (See Final Act. 5.) We agree with the
Examiner that Kosonen demonstrates that it was understood at the time that
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modifying the 2’-OH groups would render RNA nucleotides more stable by
preventing transesterification reactions between the 2’-OH group and the 3’-
phosphotriester. (See Kosonen abstract and 664.).)
The Examiner also relies on Fosnaugh for its teaching of double
stranded RNA oligonucleotides having 2’-O-methyl and 2’-F and
phosphorothioate modifications. (See Final Act. 6.) We agree with the
Examiner that Fosnaugh demonstrates that those of ordinary skill in the art
would have known of phosphorthioate and 2’-modifications in RNA
oligonucleotides. (See Fosnaugh, Figs. 4 and 5, ¶¶ 18, 19, 34, 35, 165, and
168, Table III at 35.)
Appellants argue that Fosnaugh provides only a “broad generic
disclosure of possible structures” without experimental data, which,
according to Appellants, is nothing more than an invitation to engage in
research to identify embodiments that work. (See App. Br. 11, citing
Fosnaugh ¶¶ 21–66.) Appellants argue further that not all of the structures
taught in Fosnaugh are able to suppress gene expression. (See App. Br. 11,
referring to results shown in Figs. 13A and B and Figs. 14A and B of
Appellants’ Specification.)
Appellants’ argument does not persuaded us that the relevant
structures taught in Fosnaugh fail to demonstrate knowledge in the art about
aspects of Appellants’ claimed structures, even if Fosnaugh also teaches
other structures. See In re Lamberti, 545 F.2d 747, 750 (CCPA 1976)
(explaining that “the fact that a specific symmetric dialkyl is taught to be
preferred is not controlling, since all disclosures of the prior art, including
unpreferred embodiments, must be considered”). As explained above, the
lack of a teaching in the prior art about effects on gene expression has no
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bearing on the patentability of Appellants’ claims because the claims do not
include a limitation regarding suppression of gene expression.
Appellants continue by arguing that Fosnaugh is silent about
nucleoside protecting groups compatible with labile thio groups and that
Kosonen is silent about using reversible groups bound to phosphate or
phosphotioate groups in the context of double-stranded oligonucleotides.
(See App. Br. 11.) We are not persuaded by either of these arguments
because the Examiner’s rejection is based on a combination of the teachings
of Imbach, Kosonen, Fosnaugh, Spinelli, and Hayakawa, not on each
reference taken separately. See In re Merck & Co., Inc., 800 F.2d 1091,
1097 (Fed. Cir. 1986) (“Non-obviousness cannot be established by attacking
references individually where the rejection is based upon the teachings of a
combination of references.”). The Examiner relied on Imbach and
Hayakawa for its teaching of SATE protecting groups and on Fosnaugh for
its teaching to modify double stranded RNA with protecting groups. (See
Final Act. 4 and 7.) Thus, Appellants arguments that each reference fails to
teach all of or a subset of limitations of claim 13 does not persuade us that
the Examiner erred.
The Examiner relied on Hayakawa to show that it was known that
allylic protection could be used with oligoribonucleotides, including those
with guanine bases. (See Final Act. 8; see Ans. 6–7, citing Hayakawa 1553.)
The Examiner also relied on Hayakawa for its teaching of dimedone
deprotection schemes that spare sensitive thio-based groups. (See Ans. 7,
citing Hayakawa 1554.) Appellants argue that Hayakawa does not teach
protection of oligonucleotides with both a guanine base and a sensitive thio-
based group. (See App. Br. 12–13.) According to Appellants, Hayakawa
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teaches double protection with N-AOC groups as the allyl hetroaryl ether,
using SATE phosphotriesters with N-AOC and P-O-allyl protecting groups,
but not with the allyl heteroaryl ether masking strategies. (See App. Br. 13;
see Reply Br. 12–13, citing Hayakawa 1554.) Appellants argue that the
groups used to protect the 2’ position of the oligoribonucleotides in
Hayakawa are functionally and structurally different from those claimed by
Appellants and that, thus, the Examiner has not shown an expectation of
success of using the dimedone deprotection scheme taught in Hayakawa in
Appellants’ claimed compositions. (See Reply Br. 7–9.)
We are not persuaded by Appellants’ arguments.9 Appellants argue
that the guanine ribonucleotides taught in Hayakawa are different from those
claimed, but the Examiner cited art to show that protection with both SATE
phosphotriesters and at the 2’ positions with F, O-Me, or O-alkyl were
known strategies. (See, e.g., Final Act. 3–4, citing Imbach, e.g. at 2:52–67,

9 Appellants attack the Examiner’s reference in the Answer to Guerlavais-
Dagland et al., “Fluoride-Labile Protecting Groups for the Synthesis of
Base-Sensitive Methyl-SATE Oligonucleotide Prodrugs,” EUR. J. ORG.
CHEM. 2327–2335 (2003) (“Guerlavais-Dagland”) in the Answer, arguing
that this citation constitutes a new grounds of rejection and that this
reference does not teach or suggest a 2’-F, -O-Me, or -O-alkyl on the ribose
of a ribonucleoside. (See Reply Br. 9.) Although the Examiner did not cite
Guerlavais-Dagland in the Final Office Action, it is not necessary for the
rejection of Appellants’ claims. Like Hayakawa, Guerlavais-Dagland was
cited merely to show that oligonucleotides comprising SATE modifications
could be made with a guanosine base, without compromising the SATE thiol
group. (See Ans. 7–8.) Because Fosnaugh teaches 2’-F or 2’-O-alkyl
groups on the ribose of a ribonucleotide, Appellants’ argument does not
address the Examiner’s entire rejection. Accordingly, we do not agree that
the Examiner erred in referring to Guerlavais-Dagland.

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3:9–33, and 12:20–32.) Appellants’ Specification states that “[t]he actual
synthesis of the oligonucleotides is well within the talents of those skilled in
the art.” (Spec. ¶ 81.) Despite Appellants’ argument that this passage is
“evidence of the Office's reliance on impermissible hindsight” (App. Br. 15),
the passage tends to support the Examiner’s rejection. That is, although
Appellants argues that the passage means that “given the teachings of the
application in combination with the ordinary knowledge and skill, one of
skill in the art would be able to perform the inventions taught in the
applications as well as obvious modifications thereof” (App. Br. 15), the
passage merely reinforces that deprotection, and other aspects of making the
claimed ribonulceotides, was obvious.
Appellants argue further that, in general, the inventors overcame
“synthetic challenges” and discovered that phenoxyacetyl protecting groups
can be removed from an oligonucleotide or polyribonucleotide without
compromising labile thio groups attached to internucleotide bridging groups.
(See App. Br. 14–15, citing Spec. ¶¶ 28 and 29, Figs. 13A and B, 14A and
B.) Despite this argument, Appellants do not direct us to a disclosure of
specific conditions necessary to deprotect oligonucleotides comprising
phenoxyacetal protecting groups. (See Ans. 8.) Without evidence of what
the specific challenges were and how overcoming such challenges would
have been viewed by those of ordinary skill in light of what was known in
the art, we are not persuaded that the Examiner erred or that the claimed
compositions would not have been obvious.
Appellants argue that because Hayakawa states that the method it
teaches is “not sufficiently effective for the synthesis of rather long
hetereoligomers” it could not be used for preparation of a “pharmaceutical
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composition” as claimed. (See App. Br. 13, citing Hayakawa 1555.) We
note that the statement in Hayakawa was made in regard to an
oligonucleotide with 20 bases, longer than the minimum length (10 bases)
recited in Appellants’ claim 13. (See Ans. 10.) Thus, we are not persuaded
that it would not have been reasonably expected that oligoribonucleotides of
at least 10 nucleotides, as claimed, could be made.
Appellants acknowledge that Spinelli teaches oligoribnucleotides
with selectively attached SATE groups, but argues that none of these
oligoribonucleotides have a guanosine nucleobase. (See App. Br. 11.)
Appellants argue that guanine containing phosporamidites differ from the
compounds exemplified in Spinelli because they include a nucleobase
doubly protected with N-AOC group as an allyl heteroaryl ether and that,
like Hayakawa, Spinelli fails to confirm that O-allyl-protected guanine can
be unmasked in an oligonucleotide without compromising sensitive thio-
based groups. (See App. Br. 12, citing Spinelli Fig. 4.) The Examiner relies
on Spinelli for its teaching that replacing of all of the phosphotriesters with
SATE decreases aqueous solubility of the analogs and that solubility can be
optimized by incorporating only some of these modified linkages to produce
a net negative charge. (See Spinelli 53-54; see Final Act. 8.) Thus, we agree
with the Examiner that Spinelli demonstrates it was known in the art that a
net negative charge is a result effective variable of modification of some
phosphotriester residues. (See Final Act. 8.) Because, as explained above,
the Examiner cites Hayakawa to show deprotection of guanine residues
without compromising thiol groups, we are not persuaded that the Examiner
erred.
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Appellants argue that given that Imbach was available many years
before Fosnaugh, and, thus, the reversible groups taught by Imback were
known, the failure of Fosnaugh to mention the reversible groups taught in
Imbach indicates that one skilled in the art at the time would not have
considered the modifications of Imbach to have been suitable for use in
siRNA. (See App. Br. 13–14.) We are not persuaded by this argument.
Even if Fosnaugh did not mention the findings of Imbach, “[o]ne of ordinary
skill in the art is a person who is presumed to know the relevant prior art and
includes, as asserted by the parties, formulation specialists in the field of the
invention.” In re GPAC, 57 F.3d 1573, 1579, (Fed. Cir. 1995). Regardless
of what the Fosnaugh inventors chose to include, we agree with the
Examiner that the teachings of Fosnaugh demonstrate that those of ordinary
skill in the art knew that double-stranded RNAs could be modified with 2’-
O-methyl and 2’-F as well as phosphorothioate modifications improve
cellular uptake and stability. (See Final Act. 6.)
After considering all the evidence cited and each of Appellants’
arguments, we are not persuaded that the Examiner erred in rejecting claim
13 as being obvious. Appellants do not argue for the separate patentability
of claims 15, 16, 18–22, 33, 37, or 38, which were rejected along with claim
13. These claims therefore fall with claim 13. 37 C.F.R. § 41.37(c)(1)(iv).
Claim 23
The Examiner rejected claim 23 as being obvious over Imbach,
Kosonen, Fosnaugh, Spinelli, and Hayakawa, in addition to Astriab-Fisher.
(See Final Act. 10–11.) Appellants argue only that Astraib-Fisher does not
cure the deficiencies of Imbach, Kosonen, Fosnaugh, Spinelli, and
Hayakawa argued in regard to the Examiner’s rejection of claims 11, 13, 15,
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16, 18–22, 33, 37, and 38. (See App. Br. 15–16.) For the reasons discussed
above, we do not agree that there was any deficiency in the rejection of those
claims. Accordingly, we are not persuaded that the Examiner erred in
rejecting claim 23.
Conclusion
Upon consideration of the record and for the reasons given, the
rejections of claims 13, 15, 16, 18–23, 33, 37, and 38 under 35 U.S.C.
§ 103(a) are sustained.
Therefore, we affirm the decision of the Examiner.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136.

AFFIRMED