Ex Parte Simon

Board of Patent Appeals and Interferences

Sep 7, 2010

11186609 (B.P.A.I. Sep. 7, 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.
11/186,609 07/21/2005 Michael R. Simon SMR-10104/38 6405
25006 7590 09/07/2010
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
09/07/2010 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 2010-003312
Application 11/186,609
Technology Center 1600
__________

Before ERIC GRIMES, CAROL A. SPIEGEL, and MELANIE L.
McCOLLUM, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to an
antibody to a cell surface receptor bound via an RNA binding protein to a

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.
Appeal 2010-003312
Application 11/186,609

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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, 2, 4-13, 15-25, 27, 28, 30, 31, and 35 are on appeal. Claims
1 and 10 are representative and reads as follows:
1. A composition comprising:
a cell surface receptor specific immunoglobulin or immunoglobulin
fragment ligand specific to a cell surface receptor of a cell and having a cell
surface receptor specific binding site, said immunoglobulin or
immunoglobulin fragment ligand having a first bond to an RNA binding
protein, said RNA binding protein adsorbed to a double-stranded RNA or to
a small hairpin RNA sequence complementary to a nucleotide sequence of a
target gene in the cell and comprising a small interfering RNA operative to
suppress production of a cellular protein, wherein said immunoglobulin or
immunoglobulin fragment ligand induces internalization into said cell of the
composition subsequent to the binding of said immunoglobulin or
immunoglobulin fragment ligand to a cell surface receptor of a target cell.

10. The composition of claim 1 further comprising said
immunogloblin or immunoglobulin fragment ligand having a second bond to
an internalization moiety.

Issue
The Examiner has rejected claims 1, 2, 4-13, 15-25, 27, 28, 30, 31,
and 35 under 35 U.S.C. §103(a) as being obvious in view of Lust,2
Hammond,3 Tuschl,4 Kozlov,5 Yura,6 Junghans,7 and Muratovska.8 The

2 Lust et al., US 2004/0141982, 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, Dec. 23, 2004
5 Igor A. Kozlov et al., Efficient Strategies for the Conjugation of
Oligonucleotides to Antibodies Enabling Highly Sensitive Protein Detection,
73 BIOPOLYMERS 621-630 (2004)
Appeal 2010-003312
Application 11/186,609

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claims have been argued in two groups: claims 2, 4-9, 13, 15, and 16 stand
or fall with claim 1; claims 11, 12, 17-25, 27, 28, 30, 31 and 35 stand or fall
with claim 10. 37 C.F.R. § 41.37(c)(1)(vii).
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. 5).
The Examiner finds that Hammond discloses “two methods for silencing
specific genes: antisense and RNA interference” with RNA interference
providing some advantages (id.). The Examiner finds that Tuschl teaches
the use of small interfering RNA, or siRNA, “molecules to silence target
gene expression … and teach said siRNA are sequence specific, exhibit high
in vivo stability and can be used to target many types of cells, such as tumor
cells.… Further, Tuschl et al. teach that … siRNAs represent a new
alternative to antisense or ribozyme therapeutics” (id. at 6). The Examiner
finds that Junghans discloses “using a DNA binding molecule, such as
protamine, to deliver antisense compounds efficiently to cells” (id.).
The Examiner concludes that it would have been obvious to one of
ordinary skill in the art to replace Lust’s antisense or ribozyme with an
“siRNA for conjugating to a fab’ fragment to target multiple myeloma cells”
because of the disclosed efficiency and specificity of siRNAs. The

6 Kei Yura et al, Putative Mechanism of Natural Transformation as Deduced
from Genome Data, 6 DNA RESEARCH 75-82 (1999)
7 Monika Junghans et al., Antisense delivery using protamine-
oligonucleotide particles, 28 NUCLEIC ACIDS RESEARCH, e45i-viii (2000
8 Alexandra Muratovska et al., Conjugate for efficient delivery of short
interfering RNA (siRNA) into mammalian cells, 558 FEBS Letters 63-68
(2004)
Appeal 2010-003312
Application 11/186,609

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Examiner further concludes that it would have been obvious to one of skill
in the art to adsorb a protamine molecule to a nucleic acid molecule “to
increase delivery of said composition because Junghans et al. teach nucleic
acid molecules are highly susceptible to nuclease degradation” (id.).9
Appellant contends that one of skill in the art would not have been
motivated, with a reasonable expectation of success, to form the claimed
composition for the treatment of multiple myeloma because Hammond
teaches that RNA interference (RNAi) only works in mammalian embryos
(Appeal Br. 15-16) and RNAi cannot be confined to specific cell types (id. at
18-19). Appellant also contends, with relevance to claim 10, that the cited
references do not suggest an internalization moiety bound to a cell surface
receptor specific ligand (id. at 21-23).
The issue with respect to this rejection is: Does the evidence of
record support 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
compositions of claims 1 and 10?
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).

9 The Examiner relies on Kozlov and Yura to supply limitations of
dependent claims that were not argued separately.
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Application 11/186,609

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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 that a “preferred DNA binding polypeptide of the
invention includes, but is not limited to, protamine, histone or polylysine”
(id. at ¶ 0010).
5. The Specification discloses that “RNA binding proteins
illustratively include histone (Jacobs and Imani 1988) … and protamine
(Warrant and Kim 1978)” (Spec. 9: 18-20).
6. 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
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.)
7. Lust discloses that the “complexes are internalized into antigen
expressing cells, e.g., multiple myeloma cells, by receptor mediated
endocytosis” (id. at 13, ¶ 0125).
8. 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).
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Application 11/186,609

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9. 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).
10. 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).
11. Tuschl discloses that small interfering RNA “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).
12. Junghans discloses that
[p]rotamine, a polycationic peptide (mol. wt 4000-4500), was
evaluated as a potential penetration enhancer for phosphodiester
antisense oligonucleotides (ODNs). Unique complexes in the
form of nanoparticles were spontaneously formed, which we
call ‘proticles’. … FITC-labelled ODNs bound to protamine
showed an increased cellular uptake into human histiocytic
lymphoma U 937 cells compared to free ODNs. Proticles
significantly decreased cellular growth in a cell proliferation
assay using ODNs against the c-myc proto-oncogene.
(Junghans, abstract.)
13. Muratovska discloses that “[m]embrane permeant peptides
(MPPs) are suitable candidates for the delivery of relatively large molecules,
such as nucleic acids, peptides, proteins … to cells” (Muratovska 63, right
col.).
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14. Muratovska discloses that “[s]iRNAs … coupled to the
membrane permeant peptides (MPPs) penetratin and transportan …
efficiently reduced transient and stable expression of reporter transgenes in
several mammalian cell types in a high proportion of cells, and demonstrated
equivalent or better delivery characteristics than cationic liposomes with
fewer manipulations.” (id. at abstract).
Analysis
Claim 1 is directed to a composition comprising an immunoglobulin
ligand specific to a cell surface receptor, bound to an RNA binding protein,
which is adsorbed to a small interfering RNA (e.g., a double-stranded RNA)
having a sequence complementary to 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 cellular antigen linked a DNA binding protein, where the fusion
polypeptide functions as carrier to introduce a therapeutic oligonucleotide
(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 preferably of 19-25
nucleotides have RNAi activity in human cells. Junghans discloses that
antisense oligonucleotides bound to protamine showed an increased cellular
uptake compared to control oligonucleotides.
In view of these disclosures, it would have been obvious to one of
ordinary skill in the art to modify Lust’s fusion protein/DNA complex by
replacing Lust’s therapeutic DNA with Tuschl’s double-stranded RNA
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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 was an
art-recognized alternative to Lust’s antisense approach and, based on
Tuschl’s teachings, would have reasonably expected double-stranded RNAs
to inhibit gene expression in human cells. A skilled worker would also
reasonably expect that Lust’s protamine or histone DNA-binding protein
would also bind Tuschl’s double-stranded RNA, since protamine and histone
were known RNA-binding proteins (FF 5). 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. teach that siRNA
does not work in vertebrate organisms beyond the embryonic stage – long
before multiple myeloma is relevant” (Appeal Br. 15). Appellant cites
Hammond’s disclosure that although dsRNA was shown to induce 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.; citing Hammond at
117). Appellant argues that Tuschl presents no evidence that RNAi methods
will work in vivo in vertebrate organisms because Tuschl’s treatment of
human cells are limited to cultured cells in vitro (id. at 17).
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 (FF 10) and Lust discloses a
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method of targeting a therapeutic agent specifically to CD38+ cancer (i.e.,
myeloma) cells. Hammond’s statement that RNAi is “limited to a narrow
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 suggest the claimed composition at least
for the purpose of in vitro cancer therapy research (FF 11), even assuming
that a skilled worker would have considered the line of research unlikely to
yield a clinically effective treatment of cancer.
Appellant argues that a “person of ordinary skill in the art has no
reasonable expectation of success using RNAi for cell specific targeting as
the cited prior art teach that RNAi knock-down is not restrictable to cell
type” (Appeal Br. 18) because Hammond “teach[es] that RNAi is entirely
nonspecific for cell type” (id. at 19) and Tuschl does not teach restricting
siRNA to a specific cell type (id. at 21).
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.
Claim 10 adds to claim 1 the limitation that the immunoglobulin
ligand has a second bond to an internalization moiety. The Examiner
concludes that one of skill in the art would have been motivated “to
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Application 11/186,609

10
specifically incorporate an internalization moiety such as a transportan
peptide[ ] because Muratovska et al. teach oligonucleotides, such as siRNA,
cannot always be efficiently transfected into cells and have a biological
effect and the use of an internalization moiety such as transportan, increases
the activity of a siRNA” (Ans. 8). We agree with the Examiner’s reasoning
and conclusion.
Appellant argues that the prior art does not suggest “an internalization
moiety bound to a cell surface receptor specific ligand” (Appeal Br. 21).
Appellant argues that Lust discloses that its complexes are internalized by
receptor mediated endocytosis, without the need for an internalization
moiety (id.), and that Muratovska only discloses that “membrane permeant
peptide (MPP) may serve as a suitable substitute for Lipofectamine in cells
not amenable to transfection with the aid of Lipofectamine- not that siRNA
is more efficiently transported by the use of MPP or that transportan
increases the activity of a siRNA” (Appeal Br. 23).
This argument is not persuasive. Muratovska discloses that siRNAs
were efficiently delivered to mammalian cells when conjugated to the
membrane permeant peptides (MPPs) penetratin and transportan.
Muratovska also suggests using MPPs to transport other large molecules,
including proteins, into cells. Although Lust discloses that its complexes
deliver oligonucleotides via receptor-mediated endocytosis, a person of
ordinary skill in the art would reasonably expect that the addition of an MPP
to the complex suggested by Muratovska would increase the efficiency with
which the complex is transported into the target cell.
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Conclusion of Law
The 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 compositions of claims 1 and 10.
SUMMARY
We affirm the rejection of claims 1, 2, 4-13, 15-25, 27, 28, 30, 31, and
35 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

lp

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