Ex Parte Farokhzad et al

Patent Trial and Appeal Board

Jun 25, 2018

12376005 (P.T.A.B. Jun. 25, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/376,005 02/05/2010
23579 7590 06/25/2018
Pabst Patent Group LLP
1545 PEACHTREE STREET NE
SUITE 320
ATLANTA, GA 30309
FIRST NAMED INVENTOR
Omid C. Farokhzad
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.
MIT 12320 3214
EXAMINER
SHIN,DANAH
ART UNIT PAPER NUMBER
1674
MAILDATE DELIVERY MODE
06/25/2018 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 OMID C. FAROKHZAD, ETGAR LEVY-NISSENBAUM,
ROBERTS. LANGER, and FRANK ALEXIS 1
Appeal2016-003540
Application 12/376,005
Technology Center 1600
Before DEBORAH KATZ, JOHN E. SCHNEIDER, and TIMOTHY G.
MAJORS, Administrative Patent Judges.
KATZ, Administrative Patent Judge.
DECISION ON APPEAL
Appellants seek our review, under 35 U.S.C. § 134(a), of the
rejections of claims 1-6, 9-13, 29-33, 35-37, and 402. (See Appeal Brief
1 The real parties-in-interest are reported to be Massachusetts Institute of
Technology, Brigham and Women's Hospital, Inc., and Bind Biosciences,
Inc. (App. Br. 2.)
2 Appellants note that claims 34, 38 and 39 have been withdrawn. (See App.
Br. 1.) Accordingly, we do not consider them. Appellants also assert that
claims 12 and 40 have been cancelled by an amendment accompanying their
Appeal2016-003540
Application 12/376,005
filed July 13, 2015 ("App. Br.") 1.) An Oral Argument was held on June 13,
2018.
We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM.
35u.s.c.§112
The Examiner rejected Appellants' claim 40 as failing to comply with
the written description requirement of 35 U.S.C. § 112, first paragraph.
(Final Office Action, mailed November 7, 2014 ("Final Act.") 4--5.)
Appellants assert that claim 40 was canceled by an amendment entered with
the Appeal Brief. (See App. Br. 5.) Nevertheless, because the Examiner has
not entered the amendment and Appellants do not argue that the rejection
was made in error, we summarily affirm the rejection. See 37 C.F.R.
§ 41.37(c)(iv) ("The arguments shall explain why the examiner erred as to
each ground of rejection contested by appellant. Except as provided for in
[the rules regarding reply briefs, oral hearing, and rehearing], any arguments
or authorities not included in the appeal brief will be refused consideration
by the Board for purposes of the present appeal.").
35 u.s.c. § 103
The Examiner also rejected claims 1---6, 9-13, 29-33, 35-37, and 40
under 35 U.S.C. § 103(a) as being rendered obvious by Ohuchi3, Shadidi4,
Appeal Brief. (See id.) Because the amendment has not been entered by the
Examiner (see Ans. 2), we consider claims 12 and 40 to be pending.
3 Ohuchi et al., "Selection of RNA aptamers against recombinant
transforming growth factor-B type III receptor displayed on cell surface," 88
Biochimie 897-904 (2006).
4 Shaddid and Sioud, "Selection of Peptides for Specific Delivery of
Oligonucleotides Into Cancer Cells," 252 Methods in Mol. Biol. 569-580
(2004).
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Wu5, Diener6, Farokhazad7, in view ofLiu8, Hasan9, Doyle 10, Lupold 11 ,
Cload 12, and Gorenstein 13 . (Final Act. 47 .)
Appellants' claim 1 is directed to selecting oligonucleotides that are
internalized by targeted cell types using iterative rounds of negative and
positive selection. (See App. Br. 35, Claims App'x.) Claim 1 recites:
A method of selecting oligonucleotides which are selectively
internalized by targeted cell types, the method comprising
(i) contacting a plurality of oligonucleotides with at least one
non-target cell type, and collecting the unbound oligonucleotides,
(ii) contacting the unbound oligonucleotides with at least one
target cell type under conditions that allow for internalization of
oligonucleotides within the at least one target cell type,
(iii) selecting oligonucleotides that preferentially internalize in
the target cell type and not in the non-target cell type,
(iv) optionally repeating (i) one or more times, and
(v) repeating (ii) and (iii) one or more times;
5 Wu et al., "Selection of Oligonucleotide Aptamers with Enhanced Uptake
and Activation of Human Leukemia B Cells," 14 Human Gene Therapy
849-860 (2003).
6 Diener et al., U.S. Patent Application Publication No. 2007/0041901 Al,
published Feb. 22, 2007.
7 Farokhzad et al., "Nanoparticle-Aptamer Bioconjugates: A New Approach
for Targeting Prostate Cancer Cells," 64 Cancer Res. 7668-7672 (2004).
8 Liu and Marks, U.S. Patent 7,335,744 B2, issued Feb. 26, 2008.
9 Hasan, International Patent Application Publication WO 2006/133271 A2,
published Dec.14, 2006.
10 Doyle and Murphy, U.S. Patent Application Publication US
2005/0142582 Al, published June 30, 2005.
11 Lupold et al., U.S. Patent Application Publication US 2002/0119473 Al,
published Aug. 29, 2002.
12 Cload and Ferguson, U.S. Patent Application Publication US
2003/0228603 Al, published Dec. 11, 2003.
13 Gorenstein et al., U.S. Patent Application Publication US 2005/0239134
Al, published Oct. 27, 2005.
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(Id.)
wherein the number of each targeted cell type is decreased
between one or more successive rounds of (iii), and
wherein the incubation time with each targeted cell type is
decreased between one or more successive rounds of (iii).
The method of claim 1 includes a first step of contacting
oligonucleotides to a non-target cell and collecting oligonucleotides that do
not bind - a "negative selection" step. The method includes a second step of
contacting the unbound oligonucleotides collected from the first step to a
target cell and selecting those that preferentially internalize in a target cell-
a "positive selection" step. (See id.) The method of claim 1 further provides
that the negative selection step may be repeated and that the positive
selection step must be repeated. Each time the positive selection step is
repeated, the number of target cell types and the incubation times are
decreased. (See id.)
Appellants do not present separate arguments for the patentability
under 35 U.S.C. § 103 of claims 2---6, 9-13, 29-33, 35-37, and 40. 14
Accordingly, we focus on claim 1 in our review. See 37 C.F.R.
§ 41.37(c)(iv).
14 Appellants argue that claim 9 is not obvious over the cited references
because "the references considered alone or in combination, do not suggest
or contemplate using a plurality of consecutive incubations with at least one
type of non-cancer cell and collecting unbound oligonucleotides." (App. Br.
33-34; see also Reply Br. 14.) Because this argument merely recites the
elements of claim 9, it is not a separate argument. See 3 7 C.F .R.
§ 41.37(c)(iv) ("A statement which merely point out what a clam recites will
not be considered an argument for the separate patentability of the claim.").
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Findings of Fact
1. Ohuchi teaches selecting or enriching target-specific aptamers 15
with an iterative selection process (called "SELEX"), which includes
contacting an RNA pool to non-target cells, collecting the unbound RNA in
a negative selection step, using the collected RNA to contact target cells, and
collecting the RNA bound to the target cells in a positive selection step.
(See Ohuchi Fig. 1; Non-Final Office Action mailed May 29, 2014 ("Non-
Final Act.")
5-6.)
2. Ohuchi teaches a negative-positive selection scheme for cell-
bound oligonucleotides, but not does not describe the oligonucleotides as
being internalized.
3. Shadidi teaches selecting peptides that internalize into target
cancer cells by first contacting non-target, normal cells with a peptide
library, collecting the unbound peptides, in a negative selection step, and
then incubating them with target cancer cells under conditions (including
37° C) allowing for internalization and subsequent removal of surface-
bound (non-internalized) peptides in a positive selection step. (See Shadidi,
Fig. lB; Non-Final Act. 6.)
4. Shadidi teaches a negative-positive selection scheme for
internalized peptides, but not for oligonucleotide aptamers.
15 Ohuchi defines "aptamers" as "artificial molecules isolated from large
combinatorial nucleic acid libraries by their high affinity to a target
molecule." Ohuchi 897. This meaning is consistent with the uses of the
term in the other cited references and by Appellants and the Examiner.
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5. Wu teaches selecting internalized oligonucleotide aptamers
after multiple rounds of positive selection by incubating target cells with a
plurality of oligonculeotides at 37° C for 1-2 hours and then removing non-
internalized oligonucleotides. (See Wu 850; Non-Final Act. 7.)
6. Wu teaches a positive selection scheme for internalized
oligonucleotide aptamers, but not a negative-positive selection scheme.
7. Diener teaches selecting RNA aptamers specific for prostate
cancer cells that express a specific protein (PMSA) by performing multiple
rounds of negative selection, wherein PMSA-negative cells are contacted
with a pool of aptamers, and positive selection, wherein PMSA-positive
cells are contacted with the aptamer pool. (See Diener i-fi-1258-263, Fig. 8A;
Non-Final Act. 7.)
8. Diener teaches a negative-positive selection scheme for cell-
bound oligonucleotide aptamers, but not for internalized oligonucleotide
aptamers.
9. Farokhazad teaches that certain RNA aptamers are selectively
internalized into prostate cancer cells that express a protein, PSMA, when
the RNA aptamers are incubated with the cells for 75 minutes to 16 hours at
37° C. (See Farokhazad 7669, 7670-71, Figs. 4A-4B; Non-Final Act. 8.)
10. Doyle relates to magnetic separation to select DNA aptamers
using magnetic beads and teaches that the "[t]he stringency of the selection
can be controlled by adjusting the target protein concentrations, the
incubation times, the concentrations of solutions and the washes." (Doyle
abstract, ,-r 67.)
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11. Doyle teaches using additional rounds of selection reducing the
amounts of protein (by half for rounds 2-10 and by half again for rounds 11-
15) and reduced incubation times. (Doyle i-f 97.)
12. Lupold relates to methods for generating nucleic acid ligands of
the prostate specific protein PMSA using the negative-positive selection
SELEX scheme to isolate nucleic acid ligands, wherein the amount of
PSMA-magnetic beads are decreased in subsequent rounds of selection.
(Lupold abstract, i-f 81.)
13. Cload teaches negative and positive selection steps to aptamers
that selectively recognize caffeine and artificial sweeteners, wherein the
incubation time of subsequent steps is decreased in half. (Cload i-fi-161, 185;
see also i-fi-1128-156 describing SELEX procedures.)
14. Gorenstein teaches selection and isolation of thioaptamers that
target the signaling protein TGF-B 1, wherein the amount of protein in
subsequent rounds is reduced. (See Gorenstein abstract, i-f 74.)
Analysis
Appellants admit that the prior art shows that aptamers that selectively
bind different cell types can be made and that the prior art shows some
aptamers are internalized by cells. (See App. Br. 7.) According to
Appellants, though, "[n]one of the prior art ... leads one skilled in the art to
have a reasonable expectation that one could quickly, relatively
inexpensively, and predictably obtain aptamers that selectively bind different
cell types AND are internalized, allowing their use for the delivery of drug-
loaded nanoparticles to specific cells, even less so how this could be
achieved." (App. Br. 7.)
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At the outset, we agree with the Examiner that Appellants' claims
recite selecting oligonucleotides that are selectively internalized by targeted
cell types, but do not have any limitations regarding the delivery of drugs.
(See Ans. 3.) Thus, we consider Appellants' arguments regarding the lack of
teaching or suggestion in the art to obtain aptamers that selectively bind to
and be internalized by different cells types for delivery of drug to be
unpersuasive.
The Examiner's rejection is based on the findings that the prior art
demonstrates ordinarily skilled artisans would have known how to select
cancer target cell-specific ligands, either aptamers or peptides, through
iterative selection schemes. (See Non-Final Act. 9.) We agree that Ohuchi,
Shadidi, and Diener support this finding because each teaches performing a
first negative selection step, using non-target cells, collecting the unbound
aptamers or peptides, and incubating the collected aptamers or peptides with
a target cell for a second positive selection step. (See FFs 1-2 and 5-8.)
The Examiner's rejection is also based on the finding that the prior art
demonstrates ordinarily skilled artisans would have known that internalized
aptamers and peptides can be selected in a positive selection step by
incubating at 37° C for a sufficient time. (See Non-Final Act. 9.) We agree
that Shadidi and Wu support this finding because they teach selecting
peptides (Shadidi) and aptamers (Wu) after incubation and multiple rounds
of positive selection of internalized molecules. (See FFs 3---6.)
Furthermore, the Examiner's rejection is based on the finding that the
conditions for internalization of the PSMA aptamers into cells were known
to those of ordinary skill in the art. (See Non-Final Act. 10.) We agree that
Farokhazad supports this finding because it teaches incubating unbound
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RNAs in PSMA-expressing target cells for 75 minutes to 16 hours at 37° C
to achieve internalization. (See FF 9.)
The Examiner finds that because of the normal desire of an ordinarily
skilled artisan to improve on existing protocols, it would have been obvious
for the artisan to combine the known steps from the cited prior art for an
improved way of selecting for oligonucleotides that are selectively
internalized by target cells. (See Final Act. 8.) In support the Examiner
cites to KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007), which
explains:
When there is a design need or market pressure to solve a
problem and there are a finite number of identified, predictable
solutions, a person of ordinary skill has good reason to pursue
the known options within his or her technical grasp. If this leads
to the anticipated success, it is likely the product not of
innovation but of ordinary skill and common sense. In that
instance the fact that a combination was obvious to try might
show that it was obvious under § 103.
(See Final Act. 8.)
The Examiner also finds that because all of the method steps recited in
Appellants' claim 1 were taught in the prior art, the prior art provides
evidence that the steps would have been within the technical skills of the
ordinarily skilled artisan. The Examiner concludes that, therefore, there
would have been a reasonable expectation of success in the claimed method.
(See Non-Final Act. 10-11.)
Appellants argue that the prior art does not describe each claim
element. (See App. Br. 12-13.) Although Appellants acknowledge the
rejection is for obviousness, not anticipation, Appellants' arguments are that
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the combination of elements is not taught in the prior art, not that any
individual step is not taught. For example, Appellants argue that none of the
cited prior art teaches "[u]sing a process with progressively shorter
incubation times in combination with internalization by increasingly fewer
cell types." (App. Br. 13.) Similarly, Appellants argue that none of the cited
prior art teaches using repeated positive and negative selection steps. 16 (See
App. Br. 13.) Appellants also argue that the claimed method requires a
comparison of the internalization of oligonucleotides by different cell types.
(App. Br. 14.)
These arguments are not persuasive because even though a single
prior art reference does not teach the combination of elements recited in
Appellants' claims, the steps were each known and the Examiner has
provided a sufficiently persuasive rationale explaining why the steps would
be combined. For example, the art teaches using progressively shorter
incubation times (see Cload, FF 13) and increasingly fewer cells (see
Gorenstein, FF 14). The art also teaches using multiple rounds of negative
selection (see Diener, FF 7) and multiple rounds of positive selection (see
Wu, FF 5). And, the art teaches selection of internalized aptamers (see Wu,
FF 5) and the use of different cell types (see Diener, FF 7). Appellants'
arguments do not address why one of ordinary skill in the art would not have
considered the combination of these steps to have been obvious.
16 We note that a repeated negative selection step in Appellants' claim 1 is
optional and, thus, does not have to be taught in the art for the method to
have been obvious.
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Many of Appellants' other arguments similarly focus on the lack of a
teaching of one claimed step in a prior art reference, where the step is taught
in a different reference and the Examiner concludes it would have been
obvious to those of ordinary skill in the art to have combined the teachings
to arrive at the claimed method. (See App. Br. 17-18; see Reply Br. 3-7.)
For example, Appellants argue that some of the cited references relate
to different technology or include aspects that are incompatible with or
different from the claimed method. (App. Br. 17-18.) Specifically,
Appellants argue that some of the cited references refer to the selection of
proteins, not oligonucleotides, that some of the references refer to only
positive selection, and that some of the references refer only to surface-
bound aptamers, not internalized ones. (Id.)
We are not persuaded by these arguments because the teachings of the
cited references are not considered separately in an obviousness rejection.
The test for obviousness is not whether the features of a
secondary reference may be bodily incorporated into the
structure of the primary reference; nor is it that the claimed
invention must be expressly suggested in any one or all of the
references. Rather, the test is what the combined teachings of
the references would have suggested to those of ordinary skill
in the art.
In re Keller, 642 F.2d 413, 425 (C.C.P.A. 1981). (See Ans. 2-7.) The
Examiner has provided sufficient evidence and explanation to show that one
of ordinary skill in the art would have had reason to combine the elements of
the cited prior art, in order to improve the existing selection schemes. (See
Final Act. 8.) The Examiner has also provided sufficient evidence to show
that there would have had a reasonable expectation of the success in doing
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so because each step had been performed successfully in the prior art in
different combinations with other steps. (See Non-Final Act. 10-11.)
Contrary to Appellants' argument (see App. Br. 2-3; see Reply Br.
12-13), we agree with the Examiner that one of ordinary skill in the art
would have had a reason to combine the elements of the prior art because the
art demonstrates iterative selection schemes were known to be modifiable,
and had been used in many different ways to successfully select the desired
aptamer. (See Non-Final Act. 9; see Ans. 16-17.) Each prior art reference
cited by the Examiner uses a slightly different combination of elements, to
achieve selection of the desired molecules. These references show that
positive and negative selection schemes were known to be able to
successfully select aptamers using different cells types, and to successfully
select internalized peptides.
Appellants argue that "once the method of each of the references is
deconstructed, one of skill in the art is left with a large collection of
individual steps that can be recombined in many different ways to achieve
many different results," indicating that the claimed method was obtained
only by impermissible hindsight. (See App. Br. 17.) To the contrary, we
find that because the cited art shows different aspects of known selection
methods being used in different combinations to tailor a selection method to
particular needs and outcomes, the claimed methods would have been
obvious. "[I]f a technique has been used to improve one device, and a
person of ordinary skill in the art would recognize that it would improve
similar devices in the same way, using the technique is obvious unless its
actual application is beyond his or her skill." KSR, 550 U.S. at 417 (2007).
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Appellants also argue that the claimed method requires a comparison
between the internalization of oligonucleotide aptamers in different cell
types. (See App. Br. 14.) This argument does not persuade us that the
Examiner erred because claim 1 does not recite steps for an actual
comparison. Instead, claim 1 recites two contacting steps: one with non-
target cells and one with target cells. (See App. Br. 35, Claims App'x.)
Because Shadidi and Diener teach contacting either peptides or RNA
aptamers with non-target and target cells types, we are not persuaded that
Appellants' claims require steps not taught in the prior art.
Appellants argue further that one of ordinary skill in the art would not
have had a reasonable expectation of success that the aptamer would
internalize in different cell types after targeting a receptor. (App. Br. 24--
31.) According to Appellants, Ohuchi teaches selecting aptamers that bind
the receptor TBRII at the surface of the cell, not after the aptamer-receptor
complex has been internalized. (See App. Br. 24--25.) Appellants argue that
Diener teaches performing selection at 4 ° C, a temperature Appellants assert
is incompatible with endocytosis, presumed to be necessary for
internalization. (See App. Br. 24, citing Tomoda 17; see also Reply Br. 8-9.)
Appellants argue further that even if an aptamer demonstrates binding to a
receptor, it does not necessarily internalize efficiently. (See App. Br. 26-28,
17 Tomoda, et al., "Temperature Effect on Endocytosis and Exocytosis by
Rabbit Alveolar Macrophages," J. Biol. Chem. 15445-15450 (1989).
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citing Rockey 18, Fan 19, N aranda 20, Zaki 21 .) According to Appellants, the
evidence they cite shows that merely binding to a cell surface receptor does
not mean the aptamer will predictably internalize.
Despite Appellants' arguments that Ohuchi and Diener fail to teach
selection of internalized aptamers, we are persuaded that one of ordinary
skill in the art would have been motivated and had a reasonable expectation
of success in doing so because Farokhzad teaches selection of nanoparticle-
aptamer bioconjugates that target prostate cancer cells. (See Ans. 3--4.)
Specifically, Farokhzad teaches:
We next examined if the binding ofbioconjugates to LNCaP cells
results in particle uptake. Using z-axis fluorescent microscopy and
three-dimensional image reconstruction, we studied the localization of
the nanoparticle-aptamer bioconjugates after incubation with LNCaP
cells. The data demonstrate that even at 2 hours. the particles were
largely internalized into cells (Fig. 4B). This differential uptake of
bioconjugates by LNCaP versus PC3 cells was reproducibly observed
with different passages of cells and nanoparticle-aptamer bioconjugate
preparations.
18 Rockey et al., "Rational Truncation of an RNA Aptamer to Prostate-
Specific Membrane Antigen Using Computational Structural Modeling," 21
Nucleic Acid Therap. 299-314 (2011 ).
19 Fan et al., "Down-Regulation Does Not Mediate Natriuretic
PeptideDependent Desensitization ofNatriuretic Peptide Receptor (N PR)-A
or N PR-B: Guanylyl Cyclase-Linked Natriuretic Peptide Receptors Do Not
Internalize," 67 Mol. Pharmacol., 174--183 (2005).
20 Naranda et al., "A peptide derived from an extracellular domain
selectively inhibits receptor internalization: Target sequences on insulin and
insulin-like growth factor 1 receptors," 94 Proc. Nat'l Acad. Sci. 11692-97
(1997).
21 Zaki et al., "Ligand-Induced Changes in Surface µ-Opioid Receptor
Number: Relationship to G Protein Activation?" 292 J. Pharmacol. Exp.
Therapeutics 1127-34 (2000).
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(Farokhzad 7671.) Because Farokhzad teaches that under the correct
conditions, aptamers internalize into certain cell types, we are persuaded that
those of ordinary skill would have had a reasonable expectation of success in
combining the steps of the prior art methods to select internalized aptamers.
Appellants cite to Win 22 to argue that the nanoparticle portion of the
aptamer conjugates of Farokhzad could have influenced internalization.
(See App. Br. 29-31.) According to Appellants, the influence of the
nanoparticle indicates one of ordinary skill in the art would not have
reasonably expected success from the claimed method of isolating
internalizing oligonucleotides that bind to different cell types with different
efficiencies. (See id.) We are not persuaded by Appellants' arguments
because, as Appellants acknowledge, Farokhzad describes "significantly
enhanced" binding of nanoparticle-aptamer conjugates as compared to
nanoparticles alone. (See Farokhzad 7670, Fig. 4A; see App. Br. 30.) Thus,
we are persuaded that the oligonucleotide aptamer contributes to
internalization at least to some extent. We need not be persuaded that the
nanoparticle has no contribution to internalization, as Appellants argue, as
long as it was known in the art that the aptamer contributes to internalization
at least to some extent because Appellants' claims do not include any
limitations on the efficiency of the selection method.
Farokhzad concludes: "In this article, we have developed controlled
release polymer drug delivery vehicles suitable for conjugation to aptamers
22 Win et al., "Effects of particle size and surface coating on cellular uptake
of polymeric nan op articles for oral delivery of anticancer drugs," 26
Biomaterials 2713-22 (2005).
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and developed, as proof of concept, nanoparticle-aptamer bioconjugates,
which target and are taken up by prostate cancer epithelial cells." (Id.)
Because the studies of Farokhzad were described as "proof of concept" that
oligonucleotide ligand aptamers could contribute to selective internalization
of nanoparticle conjugates, we are persuaded that one of ordinary skill in the
art would have reasonably expected the claimed selection methods would be
successful. 23
We note, too, that Appellants do not claim an oligonucleotide aptamer
that can internalize or that can deliver a drug to a cell but, instead, a method
of selecting oligonucleotides that are selectively internalized by targeted
cells. Thus, the expectation of success necessary is that the method would
work given the presence of internalizing oligonucleotides.
Appellants also argue that selection of peptides as in Shadidi and
selection of nucleic acids as in Wu are non-analogous arts and that their
combination would not have provided one of ordinary skill with a reasonable
expectation of success. (See App. Br. 32-33; see Reply Br. 9-12.) We are
not persuaded by Appellants' argument because both Wu and Shadidi teach
selection of molecules (Wu teaches selection of oligonucleotides and
Shadidi teaches selection of peptides) for delivery of therapeutic
oligonucleotides to target cells. (Ans. 16-17 .) Thus, despite the differences
23 Appellants argue that the working examples provided in their
Specification demonstrate favorable results in selecting and testing
internalized aptamers using the claimed method. (See App. Br. 18-19.)
Because there is no requirement under 35 U.S.C. § 103 that a Specification
demonstrate favorable results with a claimed method, we do not opine on the
merits of the results shown.
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between oligonucleotides and peptides (see App. Br. 32), Wu and Shadidi
both relate to selecting small molecules for targeting purposes, the same goal
as Appellants' claimed methods. See In re Clay, 966 F.2d 656, 659
(Fed.Cir.1992) ("If a reference disclosure has the same purpose as the
claimed invention, the reference relates to the same problem, and that fact
supports use of that reference in an obviousness rejection."); See In re Klein,
647 F.3d 1343, 1348 (Fed. Cir. 2011).
Appellants argue further that the claimed method would be obvious
only by impermissibly applying an "obvious to try" rationale. (App. Br. 15-
16, citing In re Kubin, 561F.3d1351, 1359 (Fed. Cir. 2009) andin re
O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988).) According to Appellants,
the cited prior art provides no direction in the many possible choices and the
Examiner used hindsight to "cherry-pick" the claimed method steps. (See
also App. Br. 21-22.) We are not persuaded by this argument because
Ohuchi provides guidance for selecting molecules with negative-positive
selection schemes, Shadidi provides guidance on selecting internalized
molecules using different cell types, and Wu provides guidance on selecting
internalized oligonucleotides. The teachings of each of these references is
directed to towards a goal of Appellants' claimed method - selecting
internalized oligonucleotide aptamers using different cell types. The
Examiner's rejection is based on the modification of these known
techniques.
Appellants also argue that Wu teaches away from the disclosures of
Ohuchi, Diener, and Shadidi, as well as from the claimed methods. (App.
Br. 21-23.) Appellants argue that Wu teaches that selected aptamers are
internalized more efficiently than random aptamers in the same cell type,
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thus teaching away from selective internalization in different cell types.
(See App. Br. 22.) Appellants argue that because Wu uses a positive
selection step only, combining it's teachings with the teachings of Ohuchi,
Diener, and Shadidi, which use both negative and positive selection steps,
would change the principle of operation used in those references. (See App.
Br. 22-23.)
We are not persuaded by these arguments because Wu does not
discourage either the use of different cells or negative selection steps. In re
Gurley, 27 F3d 551, 553 (Fed. Cir. 1994) ("A reference may be said to teach
away when a person of ordinary skill, upon reading the reference, would be
discouraged from following the path set out in the reference, or would be led
in a direction divergent from the path that was taken by the applicant.") (See
Ans. 10-12.) Appellants do not direct us to a teaching in Wu that indicates
its methods could not be combined with additional selection steps using
different cells or negative strategies.
Secondary Indicia of Non-obviousness
Appellants argue that a manuscript by Xiao et al., is "based on the
selection process disclosed in the above-referenced application" and
demonstrates that identifying aptamers that selectively internalize into target
cells was an unmet need in the art. (App. Br. 20-21.) According to
Appellants, Xiao demonstrates that "identifying aptamers that selectively
internalize into target cells was an unmet need and [that Xiao] is an excellent
summary of the problem appellants were addressing." (App. Br. 20.)
Specifically, Appellants argue that Xiao reports a high percentage of false
positives from the SELEX method of Diener, which is solved by the claimed
method. (See App. Br. 20, citing Xiao 697, left col., second paragraph.)
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Appellants have not persuaded us that Xiao provides evidence of non-
obviousness that outweighs the evidence of obviousness on this record.
First, Appellants compare Xiao to the selection process disclosed in
Appellants' application, but do not analyze Xiao in light of the elements of
Appellants' claim I. See In re Grasselli, 713 F.2d 731, 743 (Fed. Cir. 1983)
("[i]t is well settled 'that objective evidence or non-obviousness must be
commensurate in scope with the claims which the evidence is offered to
support."' (quoting Jn re Tiffin, 448 F.2d 791(CCPA1971)).
Furthermore, Xiao does not actually cite Diener as Appellants assert.
(See App. Br. 20.) Thus, although Xiao reports a selection method different
from SELEX, we are not persuaded that the results reported in Xiao
necessarily resolved an unmet need in light of the prior art cited by the
Examiner. Xiao indicates that the reported results were achieved by
selecting aptamers at 37° C, instead of 4° C. (See Xiao 697, left col., second
paragraph.) Even though Diener does not address the temperature needed
for internalization, Appellants do not address why the teaching of
Farokhazad to selectively internalize RNA aptamers into prostate cancer
cells at 37° C would not have been considered by those of ordinary skill in
the art. Thus, we are not persuaded that Xiao demonstrates the solution to
an unmet need.
In general, even though Xiao may report a useful selection method,
Appellants do not persuade us that it represents the end of a long-felt and
unmet need in the art. Appellants fail to direct us to other mention in the
prior art, by those not named as inventors on the instant application, of the
problem solved by Appellants' claimed method. See In re Gershon, 3 72
F.2d 535, 538 (C.C.P.A. 1967) ("Since the alleged problem in this case was
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Application 12/376,005
first recognized by appellants, and others apparently have not yet become
aware of its existence, it goes without saying that there could not possibly be
any evidence of either a long-felt need in the dentifrice art for a solution to a
problem of dubious existence or failure of others skilled in the art who
unsuccessfully attempted to solve a problem of which they were not
aware.").
Appellants do not persuade us that the Examiner erred in rejecting
claim 1 or the claims that depend on it as being obvious over the cited the
prior art.
Conclusion
Upon consideration of the record and for the reasons given, the
rejections of Appellants' claims 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
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