Christopher E. Bradburne et al.

Patent Trials and Appeals Board

Jan 17, 2020

14768465 - (D) (P.T.A.B. Jan. 17, 2020)

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.
14/768,465 08/18/2015 Christopher E. Bradburne 2974-SPL-US 7381
26085 7590 01/17/2020
THE JOHNS HOPKINS UNIVERSITY APPLIED PHYSICS LAB.
OFFICE OF PATENT COUNSEL
11100 JOHNS HOPKINS ROAD
MAIL STOP 7-127
LAUREL, MD 20723-6099
EXAMINER
ANGELL, JON E
ART UNIT PAPER NUMBER
1635
NOTIFICATION DATE DELIVERY MODE
01/17/2020 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):
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte CHRISTOPHER E. BRADBURNE and LUCY M. CARRUTH
____________

Appeal 2018-004487
Application 14/768,465
Technology Center 1600
____________

Before ULRIKE W. JENKS, TIMOTHY G. MAJORS, and
MICHAEL A. VALEK, Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims as obvious. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.

1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R.
§ 1.42(a). Appellant identifies the real party in interest as The Johns
Hopkins University of Baltimore, Maryland. Appeal Br. 2.
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Application 14/768,465

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STATEMENT OF THE CASE
“All influenzas, and many other (-) strand RNA viruses such as
Hantaviruses, utilize a ‘Cap-Snatching’ mechanism to prime the synthesis of
their own RNA.” Spec. ¶ 7. “During this mechanism, the viral transcriptase
cleaves m7G-capped RNA leader sequences from host mRNAs to prime
transcription of the viral genome.” Id. ¶ 15.
The Influenza A polymerase complex consists of three
viral proteins, PB1, PB2 and PA, which are all required for
viral mRNA synthesis. Whilst the role of PA is still unknown,
PB2 binds to the 5' cap structure of cellular mRNAs . . . , which
activates its endonuclease domain to cleave at a site 10-14
nucleotides downstream the 5' cap structure.
Id. ¶ 17.
RNA interference sequences (RNAi) “inhibit gene expression,
typically by causing the destruction of specific mRNA molecules, or by
binding complementary nucleotide sequences and inhibiting their
transcription or translation by polymerases or ribosomes, respectively.” Id.
¶ 24.
Current RNAi technology involves activating the host
RNAi machinery in both infected and non-infected host cells,
exposing both types to potential toxicity and off-target effects
that are common with RNAi-based therapies. The presently
disclosed methods only allow for activation of RNAi machinery
in infected cells and therefore allow for the treatment,
prevention and/or diagnosis of virally-infected subjects and/or
cells and tissues with minimal effects to the host since
constructs are inactive unless in the presence of Cap-Snatching
virus.
Id. ¶ 18.

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Claims 1, 2, and 6–12 are on appeal,2 and can be found in the Claims
Appendix of the Appeal Brief. Claim 1, reproduced below, is illustrative of
the claimed subject matter:
1. An expression vector comprising a polynucleotide coding
sequence operably linked to a constitutive promoter, wherein
the polynucleotide coding sequence encodes a precursor RNAi
construct, wherein the precursor RNAi construct comprises an
mRNA molecule comprising:
(a) a 5' methylguanosine cap leader;
(b) an 8 to 12 nucleotide sequence immediately downstream
from the methylguanosine cap leader; and
(c) an RNAi sequence immediately downstream from the 8 to
12 nucleotide sequence, the RNAi sequence comprising 20
to 25 nucleotides;
wherein the mRNA molecule does not comprise a
ribosomal binding site, and
wherein in the presence of a Cap-Snatching virus, the
8 to 12 nucleotide sequence is removed and the RNAi sequence
becomes activated.
Appeal Br. 8 (Claims Appendix).
REFERENCES
The prior art relied upon by Examiner is:
Name Reference Date
Chen et al. (“Chen”) US 2006/0160759 Al July 20, 2006
Marisa B. Banasik et al., Development of an Integrase Deficient
Lentiviral Vector for Transient shRNA Expression in Respiratory
Epithelia, 458 Molecular Therapy S385 (2009) (“Banasik”)
Xuezhong Cai et al., Human microRNAs are processed from capped,
polyadenylated transcripts that can also function as mRNAs, 10 RNA
1957–66 (2004) (“Cai”)

2 Claims 3–5 and 13–32 are withdrawn. Appeal Br. 2.
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Alexandre Dias et al., The cap-snatching endonuclease of influenza virus
polymerase resides in the PA subunit, 458 Nature 914–18 (2009) (“Dias”)
KV Morris & JJ Rossi, Lentiviral-mediated delivery of siRNAs for
antiviral therapy, 13 Gene Therapy 553–58 (2006) (“Morris”)
Stephen J. Plotch et al., A unique Cap(m7GpppXm)-Dependent Influenza
Virion Endonuclease Cleaves Capped RNAs to Generate the Primers
That Initiate Viral RNA Transcription, 23 Cell 847–58 (1981) (“Plotch”)
REJECTION
Appellant requests review of the rejection of claims 1, 2, and 6–12
under 35 U.S.C. § 103 over Chen in view of Morris, Banasik, Dias, Plotch,
and Cai.
Analysis
Appellant contends that the element of locating the RNAi sequence
immediately downstream from the 8-12 nucleotide sequence is missing from
the cited references. Appeal Br. 6. We agree with Appellant that Examiner
has not articulated a sufficient rationale to support the conclusion that the
claims are obvious.
“‘[R]ejections on obviousness grounds cannot be sustained by mere
conclusory statements; instead, there must be some articulated reasoning
with some rational underpinning to support the legal conclusion of
obviousness.”’ KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007)
(citing In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006)). “[O]bviousness
requires the additional showing that a person of ordinary skill at the time of
the invention would have selected and combined those prior art elements in
the normal course of research and development to yield the claimed
invention.” Unigene Laboratories, Inc. v. Apotex, Inc., 655 F.3d 1352, 1360
(Fed. Cir. 2011).
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To summarize, Examiner relies on Chen for teaching iRNA sequences
targeting influenza and expressing these sequences using a viral vector.
Ans. 4–5. Chen uses small interfering RNA (siRNA) to suppress influenza
virus replication, and tests various influenza A virus siRNAs. Chen ¶ 345.
Examiner finds that Chen’s SEQ ID NO: 69 has 100% sequence similarity to
claimed SEQ ID NO: 1. Ans. 7. Examiner relies on Morris and Banasik for
teaching additional elements directed to the viral vector expression system.
Ans. 4.
Examiner acknowledges that Chen does not teach “a mRNA
comprising: (a) a 5'methylguanosine cap leader, (b) an 8-12 nucleotide
sequence immediately downstream from the cap leader, and (c) an iRNA
sequence immediately downstream from the 8 to 12 nucleotide sequence,
wherein the mRNA molecule does not comprise a ribosomal binding site” as
required by claim 1. Ans. 4.
Examiner relies on Dias and Plotch for teaching the cap-snatching
mechanism utilized by influenza virus. Ans. 5. Specifically, Dias teaches
that influenza virus polymerase (comprising PA, PB1, and PB2 subunits) is
responsible for replication and transcription of the viral RNA. Dias
Abstract. “The PB2 subunit binds the 5' cap of host pre-mRNAs[], which
are subsequently cleaved after 10-13 nucleotides by the viral endonuclease.”
Id. Plotch teaches these eukaryotic RNA caps with their attached
nucleotides act as primers for the synthesis of influenza viral mRNA and
transfer their 5′-terminal methylated cap structure and short stretch of
nucleotides (about 10-15) to the viral mRNA. Plotch 847. Both Dias and
Plotch suggest that the target for inhibition is the polymerase involved in the
host cap-snatching mechanism. Dias 918 (“These observations will be
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helpful in developing potential new antivirals using a structure-based
approach.”); Plotch 856 (“[If] a cap-recognizing endonuclease is unique to
influenza virions, it might be an ideal target for specific anti-influenza virus
drugs”). Neither Dias, nor Plotch, suggests using the cap-snatching
mechanism itself to activate the therapeutic molecule, i.e., the recited iRNA
sequence. Because mRNA missing the 5' cap is more prone to degradation,
one of ordinary skill in the art would not have recognized that removing
protecting structures from cellular RNA would result in a new beneficial
structure. Indeed the ordinary artisan would have expected the RNA to
degrade and not be further available. Plotch 856 (“[I]nitial removal of the
capped 5′ end of a mRNA by a cap-dependent endonuclease would facilitate
subsequent RNA degradation.”).
Finally, Examiner directs our attention to Cai for teaching
“microRNA molecules [a type of iRNA that] can be derived from
pri-miRNA transcripts that are capped with a 5' 7-methylguanosine (m7G)
cap and a 3' poly(A) tail.” Ans. 5.
Cai teaches that “[a] defining characteristic of almost all eukaryotic
mRNAs is that they are terminally modified by addition of a 5' 7-methyl
guanylate (m7G) cap and a 3' poly(A) tail.” Cai 1958. “MicroRNAs
(miRNAs) are ~22-nt noncoding RNAs expressed in a wide range of
eukaryotic organisms.” Id. 1957. According to Cai, the biological function
of miRNAs in humans is not well known, but in other cell systems they have
been shown to inhibit the expression of mRNAs bearing complementary
sequences. Id. Cai teaches that “miRNAs are initially expressed as part of
one arm of an imperfect ~80-nt RNA hairpin that, in turn, forms part of a
longer transcript termed a primary miRNA (pri-miRNA).” Id. The pri-
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miRNA can serve as a precursor for the embedded mature miRNA. Id. at
1959. Cai explains that the pri-miRNA is processed by two RNase III
enzymes Drosha and Dicer to produce a 20 nucleotide duplex. Id. at 1957.
Cai teaches that the 80 nt structure is first degraded to a 65 nt structure and
ultimately degraded to a 20 nt miRNA structure. Cai, however, does not
disclose limiting the distance between the cap structure and the miRNA
sequence to 8-12 nt.
What is missing from Examiner’s analysis is evidence that an
ordinarily skilled person would have a reason to look to Cai’s miRNA
processing using cellular RNAase enzymes that differ structurally and
functionally from the influenza polymerases to arrive at the mRNA structure
as claimed. See KSR, 550 U.S. at 418 (obviousness rejections require “some
articulated reasoning with some rational underpinning”).
Accordingly, the evidence of record does not support Examiner’s
conclusion that the claimed mRNA structure is obvious.

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 2, 6–12 103 Chen, Morris,
Banasik, Dias,
Plotch, Cai
1, 2, 6–12

REVERSED