Ex Parte Rademacher et al

Patent Trial and Appeal Board

Aug 31, 2016

11597215 (P.T.A.B. Aug. 31, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
111597,215 12/18/2007 Thomas William Rademacher
110 7590 08/31/2016
DANN, DORFMAN, HERRELL & SKILLMAN
1601 MARKET STREET
SUITE 2400
PHILADELPHIA, PA 19103-2307
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
0380-P04231USO/PJH 3493
EXAMINER
EPPS -SMITH, JANET L
ART UNIT PAPER NUMBER
1633
MAILDATE DELIVERY MODE
08/31/2016 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 THOMAS W. RADEMACHER, MANUEL MARTIN-LOMAS,
SOLEDAD PENADES, RAFAEL OJEDA, AFRICAN G. BARRIENTES,
and KHALID GUMAA1
Appeal2014-008179
Application 11/597 ,215
Technology Center 1600
Before FRANCISCO C. PRATS, JACQUELINE WRIGHT BONILLA, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
NEWMAN, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to the use of
nanoparticles having a metal atom-containing core linked to a double-
stranded RNA ligand that are used for downregulating a target gene. The
Examiner entered rejections for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
1 Appellants identify the Real Party in Interest as Midatech Ltd.,
Oxfordshire, UK. App. Br. 1.
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Application 11/597 ,215
STATEMENT OF THE CASE
Background
The Specification discloses:
[T]he present invention relates to nanoparticles [] having a core
including metal and/or semiconductor atoms, the core being
linked to RNA ligands. The RNA ligands are typically short
RNA sequences designed to mimic small interfering RNA
(siRNA) and micro-RNA sequences (miRNA). The
nanoparticles can be used to deliver the RNA ligands and have
applications in a wide range of applications, in in vitro systems
and for therapeutic or diagnostic applications.
Spec. 2:27-3: 1.
Generally speaking, the present invention provides the use of
nanoparticles as described herein for down regulating a target
gene. In this application, the down regulation may be in vitro,
for example to study gene expression, or in vivo, either in an
experimental system of interest or for medical use, that is the
nanoparticles may be employed for the preparation of a
medicament for the treatment of a condition which is
ameliorated by the down regulation of expression of the target
gene by the RNA or for the treatment of a condition associated
with over expression of a target gene.
Id. at 16:27-17:3.
The Specification discloses that the claimed nanoparticles "provide a
delivery system for the RNA" that allows the use oftransfection agents to be
avoided. Id. at 22: 1-2. The Specification states this "is a desirable
advantage as the transfection agents may themselves cause changes in
protein expression in the cells being tested." Id. at 22:3---6.
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The following rejection is before us to review (Ans. 2):
Claims 82, 83, 91-95, 98, and 101-103 under 35 U.S.C. § 103(a) as
obvious over Mirkin2 and Penades3 in view of Rana '521 4 and Rana '651 5
(Final Action 2-7). Claim 82 illustrates the appealed subject matter and
reads as follows:
82. A method for down regulating a target gene, the method
compnsmg:
contacting cells containing the target gene with
nanoparticles which comprise a core including metal atoms,
wherein the core is covalently linked to a plurality of ligands
which comprise at least one double-stranded RNA ligand
selected from the group consisting of: siRNA, miRNA and
shRNA wherein the double-stranded RNA comprises a sense
strand and an antisense strand, and wherein the nanoparticle is
covalently linked to the RNA ligand via a thiol linker present at
the 3' end of the sense strand of the RNA ligand,
whereby the gene is targeted and down regulated by the
RNA ligand.
OBVIOUSNESS
In rejecting claims 82, 83, 91-95, 98, and 101-103 for obviousness
over Mirkin, Penades, Rana '521, and Rana '651, the Examiner cited Mirkin
as teaching oligonucleotides covalently attached to nanoparticles and that the
nanoparticle-oligonucleotide conjugate "can bind to a plurality of
oligonucleotides or nucleic acids having the complementary sequence."
2 US 2002/0127574 Al, published Sept. 12, 2002.
3 WO 02/32404 A2, published Apr. 25, 2002.
4 US 2005/0020521 Al, published Jan. 27, 2005.
5 US 2004/0152651 Al, published Aug. 5, 2004.
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Mirkin i-fi-f 114--115. The Examiner finds Mirkin also teaches that these
conjugates can be used for various purposes, including nanoparticle-based
gene chips (i-f 99) and in diagnostic methods (i-f 4).
The Examiner cited Penades as teaching nanoparticles made of metal
or semiconductor atoms that link to ligands comprising "carbohydrate
groups alone or in combination with peptides, protein domains, nucleic acid
segments or fluorescent groups." Penades 3:23-28. The Examiner finds
Penades also discloses that the ligand link disclosed can be "via a sulphide
[(thiol)] group" (e.g., a covalent link). Id. at 36:18-20.
The Examiner finds Rana '521 discloses chemical modification of
siRNA, including at the 3' terminus to effect covalent attachment of the
RNA to a nanoparticle while maintaining its activity and ability to be taken
up by a cell (Rana '521 i141). According to the Examiner, Rana '521
discloses an "siRNA derivative that includes an siRNA having two
complementary strands of nucleic acid, such that the two strands are
crosslinked, a 3' OH terminus of one of the strands is modified, or the two
strands are crosslinked and modified at the 3 'O OH terminus" (i-f 42). The
Examiner further finds Rana '521 discloses that the siRNA derivative can
have "a nanoparticle" at the 3' terminus. Id.
The Examiner cites Rana '521 's disclosure as teaching gene down-
regulation:
The invention also includes a method of inhibiting expression
of an RNA ... includ[ing] the steps of introducing into a cell an
siRNA derivative such as those described herein, and such that
the siRNA derivative is targeted to the RNA.
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The invention also includes a method that includes the step of
contacting a cell with a concentration of an siRNA derivative
sufficient to inhibit expression of a target gene.
Id. iTiT 43--44.
The Examiner further finds Rana '521 discloses that siRNA molecules
can be "highly sequence specific" and that "siRNA containing a nucleotide
sequence[] identical to a portion of the target gene are preferred for
inhibition" (i-f 71 ). The Examiner further finds Rana '521 discloses that
siRNA derivatives can be combined with linkers that are "heterofunctional"
such that they react to specific compounds (e.g., amine, thiol) to improve
cellular uptake of the resulting siRNA derivative and stability within the
cell. iT 99. The Examiner finds Rana '521 discloses that the 3' terminus of
siRNA can be labeled with "nanoparticle structures that can enhance cellular
targeting activities without causing any known toxic effects." Id. at iT 100.
The Examiner cites Rana '521 as teaching that its methods "can
be used to reduce HIV infectivity and to regulate genes involved in
cell proliferation and differentiation" including genes related to
disease (i-f 13 8).
The Examiner finds Rana '651 discloses agents including
siRNA and shma (small hairpin RNA) molecules and their use for
regulating improper or undesirable gene expression associated with
disease (Abstract) and teaches "[n]anoparticles ... can also be used to
deliver siRNA into animals" (i-f 103).
Based on the references' teachings, the Examiner reasoned that an
ordinary artisan would have considered it obvious "to combine the teachings
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of the cited references to design the modified nanoparticles according to the
present invention and further to use them in methods for down regulating the
expression of a target gene." Ans. 8. Specifically, the Examiner found that
an ordinary artisan would have found it obvious to combine the teachings of
Penades on nanoparticles made of metal or semiconductor atoms (such as
gold) that link to ligands with Mirkin's teachings on covalent attachment
(using a thiol linker) of any oligonucleotide (DNA or RNA) to obtain a
nanoparticle having a metallic core with a covalently linked oligonucleotide
(RNA). Id. The Examiner found Penades' teachings on potential uses of the
disclosed nanoparticles would have motivated a skilled artisan to pursue the
combination, such as Penades' suggestion to "use ligand-derivatized
nanoparticles for the treatment of conditions associated with said ligand,"
including by "preparation of a medicament for the treatment of a condition
ameliorated by the administration of the ligand attached to the nanoparticle
core." Id. at 5, 8.
The Examiner found that although Mirkin and Penades do not teach
the covalent attachment of siRNA to nanoparticles with a metallic core,
Rana '5 21 "describes the covalent attachment of siRN A to nanoparticles via
thiol linkage" (id. at 9) and that both Rana '521 and Rana '651 teach that
"attachment of siRNA to nanoparticles functions to enhance the cellular
properties of the siRNA by increasing cellular uptake of the siRNA, and
improving the overall cellular stability of the siRNA." Id. The Examiner
concludes these teachings provide a reasonable expectation of success in
achieving the claimed combination (id. at 8-9).
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Based on these teachings, the Examiner finds the ordinary artisan
would have found it obvious "to substitute metal core containing
nanoparticles covalently liked [sic linked] via a thiol linkage to nucleic acid
(including RNA, disclosed in Penades et al. and Mirkin et al.) that are
biocompatible and suitable for therapeutic use, for the nanoparticles used in
the methods disclosed in Rana (both references) in the preparation of the
claimed invention." Id.. at 8-9. Further, the Examiner finds that an ordinary
artisan would have a reasonable expectation of success "in substituting the
metallic core nanoparticles" disclosed in Mirkin and Penades "into the
structures and methods of use disclosed in" both Rana '521 and Rana '651,
to obtain nanoparticles for use in the claimed method. Id. at 8-9. The
Examiner found specific motivation for the combination and guidance in
doing in the teachings of Rana '521 and Rana '621, which provide "explicit
suggestion to modify siRNA by covalently attaching the siRNA to a
nanoparticle for delivery of the siRNA into animals" combined with the
teachings of Mirkin and Penades on creating nanoparticles "that are
biocompatible and suitable for therapeutic use" (id. at 8-9).
As stated inin re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden ... of presenting a
prim a facie case of unpatentability ....
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
We select claim 82 as representative of the claims subject to this
ground of rejection. 37 C.F.R. § 41.37(c)(iv). Appellants' arguments do not
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persuade us that a preponderance of the evidence fails to support the
Examiner's prima facie case as to claim 82.
Appellants argue that Mirkin "discloses nanoparticle-bound
oligonucleotides which are intended for use in methods of detecting nucleic
acids and separating selected nucleic acids from other nucleic acids. In
various embodiments, the oligonucleotides are attached to metallic or
semiconductor nanoparticles." App. Br. 4. The oligonucleotides disclosed
are "single-stranded oligonucleotides." Id.
Appellants argue Penades "discloses nanoparticles comprising clusters
of metal or semiconductor atoms which can be employed as a substrate for
immobilizing a plurality of ligands comprising carbohydrate groups." Id.
Appellants argue the disclosure teaches use in "the study of carbohydrate-
mediated interactions, e.g., with other carbohydrates or proteins, and as
therapeutic and diagnostic reagents." Id.
Appellants argue these references do not mention "gene down-
regulation, gene silencing, sense strands or anti-sense strands of nucleic
acid" and are "silent regarding any in vivo application of the nanoparticles
described therein" aside from "a passing comment about detecting nucleic
acids directly in cells and tissue samples." Id. at 5. Appellants argue "these
references provide no teaching, suggestion or motivation that would lead the
artisan of ordinary skill to use the nanoparticles described therein to carry
out appellants' method." Id.
Appellants argue Rana '521 "is concerned with in vivo gene silencing
using, among other agents, chemically modified siRNA" and that the
modifications relied on by the Examiner include "'the 3' terminus has a
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covalently linked group or compound (e.g., a nanoparticle or a peptide).'"
App. Br. 5. According to Appellants, Rana '521 does not contain a working
example "describing the covalent linking of a nanoparticle of any kind to the
3' terminus of siRNA." Id.
Appellants argue the sole peptide modification of a 3' terminus
(Example XVIII of Rana '521, i-fi-1328-333) "involves (i) adding a cysteine
residue to the amino terminus of the peptide; (ii) synthesizing siRNA having
3 '-end amino groups; and (iii) using NHSester-maleimide crosslinkers for
conjugating the synthesized siRNA to the Tat peptide." Id. at 6. Appellants
argue that although Rana '521 states that "nanoparticle-RNA conjugates can
be prepared using such methods," no experimental evidence is disclosed to
support the statement. Id. Appellants cite to paragraph 10 of the
Declaration of Dr. Thomas Rademacher, 6 the lead inventor, which states:
"the use ofNHS-maleimide conjugated RNA in Rana '521 could not be
readily adapted to metal core nanoparticle embodiments without 'a very
radical change of linker chemistry."' Id. Appellants argue this statement
supports Rana '521 's failure to disclose a working example of covalent
linking of a nanoparticle to the 3' terminus of siRNA. Id. Appellants
further cite Dr. Rademacher's declaration: "neither Mirkin nor Rana '521
disclose the specific combination of attachment of double-stranded siRNA to
the nanoparticle core via the 3' end of the sense strand" as evidence in
support of their argument against the rejection. Id. at 9-10.
6 Declaration of Dr. Thomas W. Rademacher Ph.D, dated April 29, 2013.
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Appellants argue the prior art cited by Rana '521 for support relating
to preparation of nanoparticle-bound RNA do not teach preparation of
nanoparticle-bound RNA and none of these polymeric nanoparticles is
covalently linked to the associated oligonucleotides. Id. at 6. According to
Appellants, "nanoparticles having metallic cores were not contemplated to
be within the scope of the alleged invention of Rana '521" and therefore
Rana '521 's reference to nanoparticles cannot suggest or teach the use of
nanoparticles having a metal atom-containing core in the gene silencing
method. Id. at 7.
Appellants additionally argue that any suggestion in Rana '651 "to
attach a nucleic acid to a nanoparticle does not include covalent linking to
nanoparticle cores comprising metal atoms" and that Rana '651 suffers from
the same deficiencies as Rana '521. Id.
Appellants' arguments do not persuade us that the Examiner erred in
finding that Mirkin, Penades, Rana '521 and Rana '651 would have
prompted an ordinary artisan to prepare nanoparticles containing a core
including metal atoms covalently linked at the 3' end of the sense strand to
double-stranded RNA ligands for use in a method of downregulating a target
gene, as required by claim 82.
Mirkin describes oligonucleotides covalently attached to nanoparticles
and discloses the use of nucleic acids with a complementary sequence as the
oligonucleotides. i-fi-f 114--115. Mirkin also teaches that these conjugates can
be used for various purposes, including nanoparticle-based gene chips (i-f 99)
and in diagnostic methods (i-f 4).
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Penades describes nanoparticles made of metal or semiconductor
atoms that link to ligands that can include nucleic acid segments. 3 :23-28.
Further, Penades discloses a thiol linkage. Id. at 36:18-20. Penades
suggests its nanoparticles could be used for treatment methods including
targeting specific diseases with ligands attached to the nanoparticle core.
36:4--7.
Rana '521 and '651 disclose multiple specific teachings that would
have motivated one of skill in the art to combine such teachings with those
of Mirkin and Penades to achieve the invention of claim 82: Rana '521
teaches chemical modification of siRNA, including at the 3' terminus to
effect covalent attachment of the RNA to a nanoparticle while maintaining
its activity and ability to be taken up by a cell (i-f 41 ); use of a nucleic acid as
the siRNA through 3' linkage of an RNA strand (i-f 42); that the siRNA
derivative can have "a nanoparticle" at the 3' terminus; an siRNA derivative
can be used in vivo to inhibit expression of a target gene (i-fi-f 43--44);
heterofunctional linkers to improve cellular uptake of siNRA derivatives (i-f
99); and use of the disclosed methods to regulate disease genes (i-f 138).
Rana '651 discloses and delivery of siRNA into animals using nanoparticles
(i-f l 03).
Thus, Mirkin and Penades advised an ordinary artisan that
nanoparticles made of metal or semiconductor atoms (such as gold) could be
made to link to ligands of any oligonucleotide using Mirkin's teachings on
covalent attachment to obtain a nanoparticle having a metallic core with a
covalently linked oligonucleotide (RNA). Penades suggested to the artisan
that such a nanoparticle could be used to target specific medical conditions.
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Rana '521 and Rana '651 further advised the artisan that chemical
modification of siRNA could be achieved to effect covalent attachment of
the RNA to a nanoparticle while maintaining its biological activity and
ability to be taken up by a cell. Rana '521 and Rana '651 further advised the
artisan regarding methods to regulate diseases genes, including
downregulation. Accordingly, given these teachings, we agree with the
Examiner that an ordinary artisan would have been prompted to combine the
teachings ofMirkin, Penades, Rana '521, and Rana '651 to create
nanoparticles for use in the claimed methods.
Appellants' arguments largely regard the failure of the individual
references to teach all elements of the claimed methods. Those arguments
are unpersuasive as the Examiner's rejection is based on the combined
teachings ofMirkin, Penades, Rana '521 and Rana '651. (See Ans. 2).
Nonobviousness cannot be established by attacking the references
individually when the rejection is predicated upon a combination of prior art
disclosures. In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986); see
also In re Keller, 642 F.2d 413, 426 (CCPA 1981) (finding "one cannot
show nonobviousness by attacking references individually where, as here,
the rejections are based on combinations of references" (citations omitted)).
Thus, whether any individual reference fails to teach nanoparticles designed
to carry out Appellants' method is not dispositive to the sufficiency of the
rationale underlying the rejection. As stated above, we find the Examiner
sufficiently establishes that an ordinary artisan reading Mirkin, Penades,
Rana '521 and Rana '651 would have reasonably been led to create
nanoparticles designed to carry out Appellants' method.
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It might be true that, as Appellants argue, Rana '521 does not contain
a working example "describing the covalent linking of a nanoparticle of any
kind to the 3' terminus of siRNA" as required by claim 82. App. Br. 5.
Given Rana '521 's identification of nanoparticles and 3' thiol covalent
linkages (see Rana '521i-fi-199-100), we are not persuaded that Rana '521
would have failed to prompt an ordinary artisan to link a nanoparticles made
of metal or semiconductor atoms as disclosed by Penades to create
compounds for use in the invention of claim 82. Moreover,"[ o ]bviousness
does not require absolute predictability of success .... For obviousness
under§ 103, all that is required is a reasonable expectation of success." In
re O'Farrell, 853 F.2d 894, 903---04 (Fed. Cir. 1988).
Finally, the Rademacher declaration is not persuasive because it fails
to establish that the entirety of the prior art cited by the Examiner does not
render the claimed methods obvious. Dr. Rademacher' s declaration that
neither Mirkin nor Rana '521 discloses the specific combination of
attachment of double-stranded siRNA to the nanoparticle core via the 3' end
of the sense strand does not address the cited combination of Mirkin,
Penades, Rana '521 and Rana '651, and is therefore insufficient to rebut the
finding of obviousness. Keller, 642 F.2d at 426. Similarly, Dr.
Rademacher's declaration that the use ofNHS-maleimide-conjugated RNA
in Rana '521 could not be readily adapted to metal core nanoparticle
embodiments without a very radical change of linker chemistry does not
address the entirety of the teachings in Rana '521, but rather focuses on one
disclosed example, the "use ofNHS-maleimide conjugated RNA." App. Br.
6. The Rana '521 reference is applicable in an obviousness rejection for its
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entire scope of disclosure: "It is well settled that a prior art reference is
relevant for all that it teaches to those of ordinary skill in the art." In re
Fritch, 972 F.2d 1260, 1264 (Fed. Cir. 1992) (citation omitted).
In further support of their contention that the combined disclosures
do not provide a reasonable expectation of success in practicing the
Appellants' claimed method, Appellants argue that one of skill in the art
would be motivated to use the disclosure of the prior art (e.g., Lambert),
rather than the guidance provided by Mirkin because these nanoparticle-
bound oligonucleotides "would presumably be more susceptible to the
siRNA dissociation event required for gene silencing to occur, than would
an oligonucleotide covalently linked to a nanoparticle, per Rana '521." App.
Br. 8. Appellants provide no specific persuasive evidence in support of this
argument. Without such evidence, this attorney argument is unpersuasive.
See In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) ("Attorney's
argument in a brief cannot take the place of evidence.").
Appellants further argue that their claimed method is more efficient
without the use of a transfection reagent. App. Br. 8. Appellants claim this
feature must be considered as a basis for patentability despite that it is not
recited in Appellants' claims. Id. Appellants argue that the disclosure in
Rana '521 of siRNA modification without a transfection agent is supported
by "scant data" and that the result is attributable to the function of the Tat-
peptide in the embodiment. Id.
These arguments are unpersuasive. To begin, claim 82 is not
commensurate in scope with Appellants' apparent assertion of unexpected
results, because claim 82 encompasses the use of a transfection reagent,
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based on Appellants' use of "comprising," absent a negative limitation. See
In re Muchmore, 433 F.2d 824, 827 (CCPA 1970) (finding that the basis for
a commensurate in scope requirement is that a claim that reads on both
obvious and nonobvious subject matter is unpatentable under § 103).
Appellants also have not demonstrated that use of the method without
a transfection agent represents an advantage sufficient to overcome a finding
of obviousness. See Ex parte Quadranti, 25 USPQ2d 1071 (BP AI 1992)
(prima facie obviousness not overcome by alleged synergism because
applicants presented no evidence that data represent true, practical
advantage; there is no objective evidence that results were unexpected; and
values cannot be presumed to be statistically significant).
Even if use without a transfection agent did provide an advantage,
Appellants have failed to provide the type of evidence necessary to
demonstrate that their "superior" results (Reply Br. 5) are significant as
compared to the closest prior art. "[W]hen unexpected results are used as
evidence of nonobviousness, the results must be shown to be unexpected
compared with the closest prior art." In re Baxter Travenol Labs., 952 F.2d
388, 392 (Fed. Cir. 1991). Appellants' arguments without more do not meet
this requirement. See In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997)
(" [A ]ttomey argument [is] not the kind of factual evidence that is required to
rebut a prima facie case of obviousness").
Finally, Appellants argue that the final rejection is based on
impermissible hindsight because
Mirkin reveals not the slightest suggestion to use what is
disclosed therein (use of nanoparticle with bound
oligonucleotides for separating nucleic acid) in conjunction
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with what is disclosed in Penades (nanoparticle with bound
carbohydrate groups for use in studying carbohydrate mediated
interactions and as therapeutic and diagnostic reagents).
Similarly, there is no suggestion to use what is disclosed in
either Rana '5 21 or Rana '651 (gene silencing using chemically
modified siRNA) in conjunction with what is disclosed in
Mirkin and/or Penades.
App. Br. 12.
Appellants continue this argument in their Reply brief:
Without the benefit of hindsight knowledge of the invention,
the person of ordinary skill in the art would understand
"nanoparticle" as taught in Rana ('521) as a large, unidentified
and unpredictable class, save perhaps the P ACA nanoparticles
specifically taught in Rana ('521) at paragraph [0156]. The
skilled artisan would have neither the motivation nor the
expectation of success in using the metallic nanoparticles of
Penades et al. and Mirkin et al., both of which describe
completely different utilities for the metallic nanoparticles and
do not teach or suggest the use of metallic nanoparticles in
methods of gene regulation.
Reply Br. 4.
We are not persuaded. "In determining whether the subject matter of
a patent claim is obvious, neither the particular motivation nor the avowed
purpose of the patentee controls. What matters is the objective reach of the
claim. If the claim extends to what is obvious, it is invalid under § 103."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007). Moreover, rather
than impermissibly relying on Appellants' disclosure, the teachings
identified by the Examiner in the cited references, for the reasons discussed
above, would have provided an ordinary artisan sufficient reason to prepare
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nanoparticles containing a core including metal atoms covalently linked at
the 3' end of the sense strand to double-stranded RNA ligands for use in a
method of downregulating a target gene, as required by claim 82.
SUMMARY
For the reasons discussed, we affirm the Examiner's rejection of claim
82 under 35 U.S.C. § 103 for obviousness over Mirkin, Penades, Rana '521
and Rana '651. Claims 83, 91-95, 98, and 101-103 have not been argued
separately and therefore fall with claim 82. 37 C.F.R. § 41.37(c)(l)(vii).
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).
AFFIRMED
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