Ex Parte Simon

Board of Patent Appeals and Interferences

Sep 1, 2010

11126551 (B.P.A.I. Sep. 1, 2010)

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.
11/126,551 05/11/2005 Michael R. Simon SMR-10103/38 4073
25006 7590 09/01/2010
GIFFORD, KRASS, SPRINKLE,ANDERSON & CITKOWSKI, P.C
PO BOX 7021
TROY, MI 48007-7021
EXAMINER
CHONG, KIMBERLY
ART UNIT PAPER NUMBER
1635
MAIL DATE DELIVERY MODE
09/01/2010 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MICHAEL R. SIMON
__________

Appeal 2010-003299
Application 11/126,551
Technology Center 1600
__________

Before ERIC GRIMES, LORA M. GREEN, and JEFFREY N. FREDMAN,
Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to a
composition comprising an antibody to a cell surface receptor linked to an

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.
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Application 11/126,551

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RNA that comprises a small interfering RNA. The Examiner has rejected
the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We
affirm.
STATEMENT OF THE CASE
Claims 1-20 are on appeal. The claims have not been argued
separately and therefore stand or fall together. 37 C.F.R. § 41.37(c)(1)(vii).
Claim 1 is representative and reads as follows:
1. A composition comprising: a cell surface receptor specific
immunoglobulin or immunoglobulin component ligand specific to a cell
surface receptor of a cell and having a bond to a small hairpin RNA or a
double-stranded RNA, said small hairpin RNA or said double-stranded RNA
comprising a small interfering RNA sequence complementary to a
nucleotide sequence of a target gene in the cell wherein the immunoglobulin
or the immunoglobulin component ligand contains a cell surface receptor
specific antigen binding site complementary to the cell surface receptor and
wherein said ligand bonded to said small hairpin RNA or said double-
stranded RNA induces internalization into said cell by action of said ligand
specific to a cell surface receptor.

Issue
The Examiner has rejected claims 1-20 under 35 U.S.C. §103(a) as
being obvious in view of Lust,2 Hammond,3 Tuschl,4 Kozlov,5 Yura,6 and
Junghans.7

2 Lust et al., US 2004/0141982 A1, July 22, 2004
3 Scott M. Hammond et al., Post-Transcriptional Gene Silencing By Double-
Stranded RNA, 2 NATURE REVIEWS GENETICS 110-119 (2001)
4 Tuschl et al., US 2004/0259247 A1, Dec. 23, 2004
5 Igor A. Kozlov et al., Efficient Strategies for Conjugation of
Oligonucleotides to Antibodies Enabling Highly Sensitive Protein Detection,
73 BIOPOLYMERS 621-630 (2004)
6 Kei Yura et al, Putative Mechanism of Natural Transformation as Deduced
from Genome Data, 6 DNA RESEARCH 75-82 (1999)
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The Examiner finds that Lust discloses “an immunotoxin wherein an
anti-CD38 antibody is fused to a DNA encoding a cytotoxic agent such as an
antisense or a ribozyme in the treatment of malignant myeloma” (Ans. 4).
The Examiner finds that Hammond discloses “two methods for silencing
specific genes: antisense and RNA interference” (id. at 5). The Examiner
finds that Tuschl discloses the use of small interfering RNA, or siRNA,
“molecules to silence target gene expression … and teach [that] said siRNA
are sequence specific, exhibit high in vivo stability and can be used to target
many types of cells, such as tumor cells” (id.). The Examiner finds that
Kozlov discloses that “a hydrazone bond between the amino terminus of a
protein and the end of an oligonucleotide produces an oligonucleotide
conjugate that is very stable” (id.).8
The Examiner concludes that it would have been obvious to one of
ordinary skill in the art to replace Lust’s antisense compound with an siRNA
“to target multiple myeloma cells … because it was well known … that
siRNA molecules are efficient molecules to target and decrease expression
of a target gene” (id. at 6). The Examiner further concludes that it would
have been “obvious to one of skill in the art to use a hydrazone bond as
taught by Kozlov et al. and attach the ligand to the nucleic acid” (id. at 6)
because Kozlov discloses that “hydrazone bonds produce nucleic acid
conjugates having increased stability over long periods of time under
physiological conditions” (id. at 7).

7 Monika Junghans et al., Antisense delivery using protamine-
oligonucleotide particles, 28 NUCLEIC ACIDS RESEARCH, e45i-viii (2000)
8 The Examiner relies on Yura and Junghans for the disclosure of dependent
claim limitations.
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Appellant contends that one of skill in the art would not have a reason,
and would not have had a reasonable expectation of success, to form the
claimed composition for the treatment of myeloma because Hammond
teaches that RNA interference (RNAi) only works in mammalian embryos
(Appeal Br. 12-13) and RNAi cannot be directed to specific cell types (id. at
15-16). Appellant also contends that the cited references do not suggest a
bond between a cell surface receptor specific ligand and an RNA (id. at 18-
20).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s conclusion that one of skill in
the art would have considered it obvious to combine the teachings of the
cited references, with a reasonable expectation of successfully forming the
composition of claim 1?
Findings of Fact
1. Lust discloses a “fusion polypeptide comprising … a polypeptide
that specifically binds [the] CD38 antigen that is linked to … a DNA binding
protein” (Lust 1, ¶ 0006).
2. “CD38 is a cell surface antigen that is known to be expressed in
high density on virtually all malignant plasma cells from the majority of
myeloma patients” (id. at 1, ¶ 0007).
3. Lust discloses that “[p]referably, the CD38 binding polypeptide is
an antibody [or] a fragment or a variant thereof” (id. at 1, ¶ 0008).
4. Lust discloses
a therapeutic composition which comprises a fusion
polypeptide of the invention and a DNA molecule encoding a
cytotoxic agent. Thus, the fusion polypeptide functions as a
carrier to introduce a therapeutic gene encoding a cytotoxic
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agent, e.g., toxin genes …; cell suicide genes …; proteins that
activate chemotherapeutic genes …; a ribozyme, RNase, or an
antisense sequence …; into CD38+ cells such as myeloma cells.
(Id. at 1-2, ¶ 0011.)
5. Lust discloses that the “complexes are internalized into antigen
expressing cells, e.g., multiple myeloma cells, by receptor mediated
endocytosis” (id. at 13, ¶ 0125).
6. Hammond discloses that “[i]n diverse organisms, double-stranded
(ds)RNAs have been shown to inhibit gene expression in a sequence-specific
manner. This biological process, [is] termed RNA interference, or RNAi.”
(Hammond 110.)
7. Tuschl discloses the use of a “Drosophila in vitro system … to
further explore the mechanism of RNAi. We demonstrate that short 21 and
22 nt RNAs, when base-paired with 3' overhanging ends, act as the guide
RNAs for sequence-specific mRNA degradation.” (Tuschl 1, ¶ 0006.)
8. Tuschl discloses that “experiments in human in vivo cell culture
systems (HeLa cells) show that double-stranded RNA molecules having a
length of preferably from 19-25 nucleotides have RNAi activity” (id. at 1,
¶ 0007).
9. Tuschl discloses that RNAi “may be used for determining the
function of a gene in a cell or an organism or even for modulating the
function of a gene in a cell or an organism, being capable of mediating RNA
interference. The cell is preferably a eukaryotic cell or a cell line, e.g. a
plant cell or an animal cell, such as a mammalian cell.” (Id. at 3, ¶ 0029).
10. Kozlov discloses “methods for the conjugation of
oligonucleotides to antibodies.… Conjugation between the modified
oligonucleotide and antibody resulted in the formation of a hydrazone bond
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that proved to be stable over long periods of time under physiological
conditions.” (Kozlov, abstract.)
Analysis
Claim 1 is directed to a composition comprising an immunoglobulin
ligand specific to a cell-surface receptor, bound to a small interfering RNA
(e.g., a double-stranded RNA) having a sequence complementary to a target
gene in the cell, where the immunoglobulin ligand induces internalization of
the complex into the cell after binding to a cell-surface receptor.
Lust discloses a fusion polypeptide comprising an antibody to the
CD38 cell-surface antigen linked to a DNA binding protein, where the
fusion polypeptide functions as a carrier to introduce a therapeutic DNA
(e.g., a ribozyme or an antisense sequence) into a myeloma cell by receptor-
mediated endocytosis. Hammond discloses that RNA interference (RNAi)
results in sequence-specific inhibition of gene expression. Tuschl discloses
that double-stranded RNA molecules having a length of preferably from 19-
25 nucleotides have RNAi activity in human cells. Kozlov discloses a
method of stably linking oligonucleotides to antibodies.
In view of these disclosures, it would have been obvious to one of
skill in the art to modify Lust’s fusion protein/DNA complex by replacing
Lust’s therapeutic DNA with Tuschl’s double-stranded RNA molecule
having RNAi activity, because Hammond discloses that RNAi is a method
for sequence-specific inhibition of gene expression. A person of ordinary
skill in the art therefore would have recognized that RNAi is an art-
recognized alternative to the antisense approach suggested by Lust and,
based on Tuschl’s teachings, would have reasonably expected double-
stranded RNAs to inhibit gene expression in human cells. In addition, it
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would have been obvious to link Tuschl’s double-stranded RNA molecule
directly to the anti-CD38 antibody in Lust’s compound, rather than via a
DNA-binding protein, because Kozlov teaches a method of stably forming
an antibody/oligonucleotide conjugate. The cited references therefore would
have made obvious the product defined by claim 1.
Appellant argues that the cited references do not provide a reasonable
expectation that RNAi could successfully be used as the therapeutic agent in
Lust’s treatment of myeloma because “Hammond et al. and Tuschl et al.
teach that RNAi methods are not operable in vertebrate organisms beyond
the embryonic stage” (Appeal Br. 15). Appellant cites Hammond’s
disclosure that although dsRNA induces sequence-specific gene silencing in
early mouse embryos, “the use of this approach is … limited [] to a narrow
developmental window, and effects provoked in early embryos do not persist
after implantation” (id. at 14; citing Hammond at 117). Appellant argues
that Tuschl “teach[es] that cultured human derived cells (HeLa) may be
susceptible to RNAi processes by 20-25 nucleotide long dsRNA molecules
…, but a person having ordinary skill in the art recognizes that this does not
teach or suggest treatment of multiple myeloma specifically as desired in
Lust et al. - particularly in an organism where multiple cell types are
present” (id. at 15).
This argument is not persuasive. The cited references provide a
reasonable expectation of using dsRNA to inhibit a target gene in a
vertebrate organism since Tuschl discloses that dsRNA have RNAi activity
in human cancer cells (HeLa cells) in vivo and Lust discloses a method of
targeting a therapeutic agent specifically to CD38+ cancer (i.e., myeloma)
cells. Hammond’s statement that RNAi is “limited to a narrow
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developmental window” in mice (Hammond 117) is contradicted by
Tuschl’s later statement that dsRNA in fact has RNAi activity in HeLa cells.
Hammond’s statement therefore would not have discouraged a skilled
worker from combining the teachings of the cited references. In any event,
claim 1 is drawn to a composition useful for any purpose, and the
combination of the cited references suggests the claimed composition at
least for the purpose of in vitro cancer therapy research (FF 9).
Appellant argues that a “person of ordinary skill in the art has no
reasonable expectation of success in using RNAi for cell specific targeting
as the cited prior art teach that RNAi knock-down is not restrictable to cell
type” (Appeal Br. 15) because Hammond “teach[es] that RNAi is entirely
nonspecific for cell type” (id. at 16) and Tuschl does not teach restricting
siRNA to a specific cell type (id. at 17).
This argument is not persuasive because it does not address the
combined teachings of the references; specifically, Lust’s teaching of
directing therapeutic agents specifically to CD38+ cells using an antibody
that binds CD38. Appellant has pointed to no evidence showing that a
dsRNA agent attached to an anti-CD38 antibody would have effects on cells
that do not express CD38.
Finally, Appellant argues that the cited art does not suggest “a bond
between a cell surface receptor specific ligand and a siRNA or dsRNA”
(Appeal Br. 17) because Lust discloses using a DNA binding polypeptide to
associate an antibody fragment with a DNA molecule (id. at 18) and Kozlov
teaches forming a covalent bond between a protein and a DNA, not RNA,
molecule (id. at 20).
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This argument is not persuasive. Kozlov discloses attaching DNA
molecules directly to antibodies. A person of ordinary skill in the art would
reasonably expect that the disclosed technique would also successfully
attach RNA molecules directly to antibodies, in view of the very close
chemical similarity of DNA and RNA. Appellant has pointed to no evidence
to the contrary. And, for the reasons discussed above, a skilled worker
would have considered it obvious to use Kozlov’s technique to attach a
dsRNA to Lust’s anti-CD38 antibody.
Conclusion of Law
The preponderance of evidence of record supports the Examiner’s
conclusion that one of ordinary skill in the art would have considered it
obvious to combine the teachings of the cited references, with a reasonable
expectation of successfully forming the composition of claim 1.
SUMMARY
We affirm the rejection of claims 1-20 under 35 U.S.C. §103(a).
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

Appeal 2010-003299
Application 11/126,551

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lp

GIFFORD, KRASS, SPRINKLE,ANDERSON & CITKOWSKI, P.C
PO BOX 7021
TROY MI 48007-7021