Ex Parte Schroff

Patent Trial and Appeal Board

Aug 31, 2018

11569697 (P.T.A.B. Aug. 31, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
11/569,697 12/15/2006
23373 7590 09/05/2018
SUGHRUE MION, PLLC
2100 PENNSYLVANIA A VENUE, N.W.
SUITE 800
WASHINGTON, DC 20037
FIRST NAMED INVENTOR
Matthias Schroff
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.
Q235019 1561
EXAMINER
SHIN,DANAH
ART UNIT PAPER NUMBER
1674
NOTIFICATION DATE DELIVERY MODE
09/05/2018 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
PPROCESSING@SUGHRUE.COM
sughrue@sughrue.com
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MATTHIAS SCHROFF 1
Appeal2016-007660
Application 11/569,697
Technology Center 1600
Before TONI R. SCHEINER, ULRIKE W. JENKS, and
ELIZABETH A. LA VIER, Administrative Patent Judges.
SCHEINER, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) from the final rejection of
claims 16 and 18-31, directed to a DNA construct for specific inhibition of
gene expression by RNA interference. The claims have been rejected on the
grounds of indefiniteness, anticipation, and obviousness.
We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
1 Appellant identifies the Real Party in Interest as Mo lo gen AG of Berlin,
Germany. Br. 2.
Appeal 2016-007 660
Application 11/569,697
BACKGROUND
The Specification is directed to a DNA vector free of plasmid or viral
components, which, when transcribed, results in expression of a small
interference RNA (siRNA) sequence (Spec. 7:8-9), i.e., "a double-stranded
RNA molecule in which the pairing strands are linked on one side by a non-
complementary single strand" (id. at 4:7-9).
[The DNA vector] is capped by hairpin loop-shaped
oligodeoxynucleotides having arranged therebetween a
promoter at the 5' end and a termination signal at the 3' end of a
double DNA strand, said DNA double strand including a
singular copy 19-23 bases in length of a gene sequence, once in
5'-3' direction and once in a 3'-5' direction, a sequence 8-12
bases in length of two single strands being arranged between
each 5'-3' and 3'-5' orientation of the singular copy of the gene
sequence, said single strands being selected such that opposite
bases are by no means complementary to each other and the
flanking double strand regions are thereby linked to each other
by two DNA single strands.
Id. at 6:27-7:4.
"[F]ollowing transfection thereof in eukaryotic cells, [ the vector is]
suitable for targeted inhibition of formation of defined proteins therein by
RNA interference." Id. at 1:9-11.
STATEMENT OF THE CASE
Claims 16 and 18-31 are on appeal. 2 Independent claim 16 is
representative and reads as follows ( emphasis added):
16. A vector which, following transfection thereof into
eukaryotic cells, specifically inhibits formation of defined
proteins therein by RNA interference comprising:
2 Claims 1-15 have been withdrawn from consideration, and claim 1 7 has
been cancelled.
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Appeal 2016-007 660
Application 11/569,697
two hairpin loop-shaped oligodeoxynucleotides having
arranged between said two hairpin loop-shaped
oligodeoxynucleotides a promoter at a 5' end and a termination
signal at a 3' end of a DNA double strand, said DNA
double strand comprising between said promoter and
termination signal, a first gene sequence consisting of 19--23
bases, wherein said first gene sequence forms a first double
stranded region in 5'-3' direction and a second gene sequence
consisting of said 19-23 bases in 3'-5' direction, wherein said
second gene sequence forms a second double stranded region,
wherein the vector further comprises two single DNA strands
linking said first double stranded region with said second
double stranded region comprising 8-12 bases, said two single
DNA strands being not complementary to each other and not
self-complementary and wherein
said first double stranded region and second double
stranded region have short protruding ends of single-stranded
DNA at their ends, and
said hairpin loop-shaped oligodeoxynucleotides have
short protruding ends of single-stranded DNA at their ends, and
said promoter has short protruding ends of single-
stranded DNA,
a single-stranded 5' end of the promoter being capable of
pairing with one of the hairpin loop-shaped
oligodeoxynucleotides, and a single-stranded 3' end of the
promoter being complementary to a single-stranded 5' end of
the first double stranded region, and
a termination signal for RNA polymerases with short
protruding ends of single-stranded DNA,
a 5' protrusion of the termination signal being capable of
specific pairing with a 3' end of the second DNA double
stranded region, and a 3' protrusion of the termination signal
being capable of specific pairing with one of said hairpin loop-
shaped oligodeoxynucleotides.
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Application 11/569,697
The claims stand rejected as follows:
Claims 16 and 18-31 under35 U.S.C. §112, second paragraph, as
indefinite;
Claims 16, 18-29, and 31 under pre-AIA 35 U.S.C. § I02(a) as
anticipated by Taira; 3 and
Claims 16 and 18-31 underpre-AIA35 U.S.C. § I03(a) as
unpatentable over Agami, 4 Blumenfeld, 5 Wittig, 6 Robbins, 7 and Baer. 8
INDEFINITENESS
Claims 16 and 18-31 stand rejected under 35 U.S.C. § 112, second
paragraph, as indefinite.
The Examiner finds that "[t]he term 'short' in 'short protruding ends'
is a relative term which renders the claims indefinite." Final Act. 3.
According to the Examiner, "one of ordinary skill in the art would not be
reasonably apprised of the scope of the invention" because "the specification
does not provide a standard for ascertaining the requisite degree." Id.
3 Taira et al., U.S. Patent Application Publication US 2005/0048647 Al,
published March 3, 2005.
4 Agami et al., U.S. Patent Application Publication US 2003/0144239 Al,
published July 31, 2003.
5 Blumenfeld et al., European Patent Application EP O 572 287 A2,
Published December 1, 1993.
6 Wittig et al, U.S. Patent No. 6,451,563 Bl, issued September 17, 2002.
7 Robbins et al., International Patent Application WO 2004/085623 A2,
published October 7, 2004.
8 Madeline Baer et al., Structure and transcription of a human gene for HJ
RNA, the RNA component of human RNase P, 18 Nucleic Acids Research
97-103 (1989).
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Application 11/569,697
Appellant contends that "the interpretation of the claim term 'short
protruding ends' does not rely on the exercise of subjective judgment
without restriction." Br. 7. Appellant contends, for example, that "the
skilled artisan would understand the 'short protruding ends' to be short
compared to the total length of the components to which they are attached."
Id. Moreover, Appellant contends that the Specification teaches that the
purpose of the short protruding ends is to ligate the various components of
the vector together (e.g., to ligate the promoter to the hairpin-loop shaped
oligo), and "the specification provides concrete examples of the claimed
'short protruding ends,"' e.g., "the protrusions of the constructs shown in
Fig. 1 and 2 are four bases long." Id.; see Spec. 10:31-11 :5; Figs. 1 and 2.
We agree with Appellant that "the skilled artisan would understand
the scope of the claim term 'short protruding ends"' (id. at 8), given the
guidance in the Specification. Accordingly, the rejection of claims 16 and
18-31 as indefinite under 35 U.S.C. § 112, second paragraph is reversed.
ANTICIPATION
Claims 16, 18-29, and 31 stand rejected under 35 U.S.C. § 102(e) as
anticipated by Taira.
Taira
Taira discloses "an intracellular siRNA expression system capable of
producing [RNA interference]" comprising "an antisense code DNA coding
for antisense RNA directed against a region of a target gene mRNA, a sense
code DNA coding for sense RNA directed against the same region of said
target gene mRNA, and one or more promoters." Taira ,r,r 9, 11.
"[T]he antisense and sense code DNAs are arranged in the opposite
orientation on the same DNA strand via a linker" and, once transcribed, "the
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Application 11/569,697
linker portion forms a loop and sense and antisense RNA on its both sides
pair up ( a stem structure)" (id. ,r 83 ), i.e., "a stem-loop structure in which
ends of one side of double-stranded RNA are connected by a [single-
stranded] linker RNA" (id. ,r 69; Fig. 28). Taira teaches that "the length of
the double-stranded RNA region that is a final transcription product of
siRNAs to be expressed is, for example, 15 to 49 bp" and "there is no
particular limitation in the length of the linker as long as it has a length so as
not to hinder the pairing of the stem portion." Id. Finally, Taira discloses at
least one siRNA where the double stranded RNA is 19 base pairs in length,
and the single-stranded linker is 11 bases in length. Id. ,r 179; SEQ ID
N0:21.
Discussion
The Examiner finds that Taira's siRNA expression system meets all
the limitations of claim 16, including the requirement that the vector's first
double stranded DNA region is linked to the second double stranded region
by two 8-12 base single DNA strands, where the two single DNA strands
are neither complementary to each other nor self-complementary.
The Examiner finds that Taira teaches that the "linker sequence [ of its
siRNA] forms a loop of a stem-loop dsRNA" (Final Act. 4 ( citing Taira
,r 83)), and the loop portion of the linker "is neither self-complementary nor
double-stranded" (id. at 6 (citing Taira ,r 179)). The Examiner specifically
identifies the siRNA represented by Taira's SEQ ID N0:21 as anticipating
claim 16, but acknowledges that the linker portion of SEQ ID N0:21 is
single-stranded RNA, rather than double-stranded DNA, as required by the
claim. Nevertheless, the Examiner contends that "it is prima facie apparent
to any ordinarily skilled artisan that SEQ ID N0:21 ... which is referred to
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Application 11/569,697
as the 'sequence of the stem-loop siRNA transcribed', is transcribed from a
DNA sequence." Final Act. 6. Thus, the Examiner contends, "the mere fact
that Taira et al. did not disclose the DNA sequence per se does not fail to
anticipate the DNA sequence limitation." Id.
Appellant contends that claim 16 requires, in relevant part, "two
single DNA strands linking said first double stranded region with said
[second] double stranded region comprising 8-12 bases, said two single
DNA strands being not complementary to each other and not self-
complementary." Br. 8. Appellant contends that "the fact that the siRNA
transcribed from the linker of Taira forms a stem-loop sequence is precisely
because that sequence is self-complementary; if it were not, the transcribed
sequence would not form the 'stem' of the 'stem-loop' sequence." Id. at 9.
Appellant further contends that "Taira's failure to disclose the required DNA
element is precisely why Taira fails to anticipate the rejected claims." Id. at
10.
We find that Appellant has the better position. We agree with the
Examiner that Taira discloses an siRNA with an 11 base single-stranded
non-self-complementary portion (the linking "loop"), and a 19 base pair
double-stranded RNA portion (the sense/antisense "stem") targeting the
gene to be inhibited. Nevertheless, claim 16 is directed to the vector from
which an siRNA is transcribed, and explicitly requires two single DNA
linking strands, wherein the two single DNA strands are not complementary
to each other and not self-complementary. To the extent the Examiner finds
that Taira discloses that its siRNA is transcribed from a double-stranded
DNA expression system we agree, but the Examiner does not point to
anything that indicates that the two DNA strands of the linker in Taira's
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Application 11/569,697
double-stranded DNA expression system are inherently "not complementary
to each other and not self-complementary." It is well settled that
"[i]nherency ... may not be established by probabilities or possibilities. The
mere fact that a certain thing may result from a given set of circumstances is
not sufficient." MEHL/Biophile Int'!. Corp. v. Milgraum, 192 F.3d 1362,
1365 (Fed. Cir. 1999). We agree with Appellant that "Taira's failure to
disclose the required DNA element is precisely why Taira fails to anticipate
the rejected claims." Br. 10.
Accordingly, we reverse the rejection of claim 16 as anticipated by
Taira, as well as the rejection of dependent claims 18-29 and 31.
OBVIOUSNESS
Claims 16 and 18-31 stand rejected under 35 U.S.C. §103 as
unpatentable over Agami, Blumenfeld, Wittig, Robbins, and Baer.
Agami
Agami discloses a "vector for expressing short interfering RNAs
(siRNAs) to inhibit the expression of a target gene." Agami ,r 3. Agami's
vectors "are DNA molecules capable of integrating into the genome of the
target cells allow[ing] for stable, long term expression of the siRNA and
hence long term inhibition of the target gene." Id. ,r 18. Agami teaches that
the DNA vector "transcribed to generate the siRNA may be double or single
stranded nucleic acid" (id. ,r 119), and includes a promoter downstream of
the transcription start site, as well as a transcriptional termination element
(id. ,r,r 89, 94).
Agami further teaches that the siRNA transcribed from the DNA
vector is a short double stranded RNA molecule "compris[ing] a region
identical to a region of the sense strand of the target gene and a second
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Application 11/569,697
region which corresponds to the antisense strand of the target gene." Id.
,r,r 98, 102. "The two complementary regions are usually separated by a
short spacer region such that when the two complementary regions hybridise
a stem loop or hairpin structure is formed with the spacer forming the loop."
Id. ,I 102.
Discussion
The Examiner finds that Agami teaches "a vector comprising H 1
promoter operably linked to a gene sequence in the 5'-3' direction linked via
a li[ n ]ker sequence to another gene sequence in the 3 '-5' direction" (Final
Act. 7) and "a termination signal sequence" (id. at 8), "wherein the vector
produces a hairpin dsRNA" (id. at 7). The Examiner cites Blumenfeld as
teaching "that a closed dumbbell oligonucleotide comprising a double-
stranded DNA is stabilized and 'resistant to degradation"' (id. at 8), and
Wittig as teaching "a closed dumbbell construct 'essentially free from
contamination by genomic DNA"' (id.).
The Examiner concludes that it would have been obvious for one of
ordinary skill in the art "to utilize the closed 'dumbbell' oligonucleotide
design when making the HI promoter-containing shRNA [short hairpin
RNA] vector of Agami" (id. at 9), in order "to make an shRNA vector that is
'resistant to degradation' and 'essentially free from contamination by
genomic DNA"' (id.).
Appellant reiterates that "the rejected claims require, inter alia, 'two
single DNA strands linking said first double stranded region with said
[second] double stranded region comprising 8-12 bases, said two single
DNA strands being not complementary to each other and not self-
complementary. "' Br. 11. Appellant contends that "[ n Jone of the
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Application 11/569,697
publications cited by the Examiner disclose or suggest this limitation of the
present claims," nor has the Examiner "pointed to any disclosure, either in
the cited publications, or elsewhere in the art, that would lead the person of
ordinary skill to modify the teachings of the publications ... in order to
incorporate this limitation." Id.
The Examiner responds that Agami "discloses the coding strand DNA
and template strand DNA sequences in the 5 '-3' direction ... wherein the
linker sequence in each strand is indicated by underlining" (Ans. 9) as
shown below:
S ' 9 ~t::::,:,:c,(;'!~GAGCTC-'1''.:GGCG'!'A::;; H£,~~iSt!:s.~C:!AcC•:;c :AACAGC'!C C:AAC t t t. t t ggau . .3 '
. .
i.~r .. :d
The above sequences are reproduced from Agami's Example 6, with
underlining added by the Examiner. Agami ,r,r 244--250. According to the
Examiner, "Agami's expression system contains two DNA linker sequences
(5'- TTCAAGAGA in the coding strand; 5'- TCTCTTGAA in the template
strand), wherein the two separated strands of each linker are not
complementary." Ans. 10.
According to Agami, however, the two oligonucleotides relied on by
the Examiner "were annealed to generate an insert with compatible ends to a
BgIII and HindIII digested pSUPER vector." Agami ,r 245. That being the
case, one of the two strands should be read in the 3'-5' direction, while the
other maintains the 5'-3' direction. When one of the strands is read in the
3'-5' direction, it is clear that the two linker sequences are perfectly
complementary. Thus, the Examiner has not established that Agami
discloses "two single DNA strands linking said first double stranded region
with said second double stranded region comprising 8-12 bases, said two
10
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Application 11/569,697
single DNA strands being not complementary to each other and not self-
complementary" as required by claim 16. Nor has the Examiner explained
how the remaining references cited teach or suggest this particular
limitation.
Accordingly, we reverse the rejection of claim 16 as unpatentable
over Agami, Blumenfeld, Wittig, Robbins, and Baer, as well as the rejection
of dependent claims 18-31.
SUMMARY
The rejection of claims 16 and 18-31 as indefinite under 35 U.S.C.
§ 112, second paragraph is reversed;
Therejectionofclaims 16, 18-29,and31 under35U.S.C. § 102(e)as
anticipated by Taira is reversed; and
The rejection of claims 16 and 18-31 under 35 U.S.C. § 103(a) as
unpatentable over Agami, Blumenfeld, Wittig, Robbins, and Baer is
reversed.
REVERSED
11