Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Status of Claims
1-3, 6-7, 12, 14, 23, 32, 35-36, 38, 40-41, 44, 54, 67, 73, and 91-93 are pending and under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Specifically, FIG 4B shows 2 nucleotide sequences (41 bases) that do not include SEQ ID NOs and appear to be different from the 22 nucleotide SEQ ID NO. 1 that is indicated at [0012] of the specification. Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 67, 91 and 93 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 67 recited “(e.g. CK8e).” The metes and bounds of this phrase are indefinite since it is unclear how the limitations within parenthesis relate to the scope of the claimed invention. Further the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 91 and 93 recite elements (a), (b), (c). However it is not clear if the claim requires all elements or any one of the claimed elements. Therefore scope of the claim is ambiguous. For the sake of compact prosecution, the claims are interpreted to read (a), (b) or (c).
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 32, 34, 35, 91, and 93 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 32, 34, 35, 91, and 93 require 90% identity to enumerated sgRNAs. Applicant’s claims do not provide support for all nucleic acids comprising 90% identity to claimed sequences. The specification as filed does not provide sufficient evidence that Applicants were in possession of the full scope of the claimed invention at the time of filing of the instant invention. As such, >90% identity to a 22 base pair polynucleotide, encompasses
22
C
2
×
3
2
=
2079
nucleotide molecules. However, the specification only taught thee specifically claimed nucleotides. The specification also does not provide any guidance on how or where the nucleotides need to be changed. It is clear that the vector of the invention was restricted to the claimed sequences. For example, see instant specification at [0008], [0056], [0152].
Thus, Applicants were not in possession of the full scope of the claimed invention at the time of filing of the instant invention.
Claims 2-3, 6-7, 12, 14, 23, 32, 35-36, 38, 40-41, 44, 54, 67, 73, and 91-93 inherit the rejection due to their dependency on rejected claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 6-7, 12, 14, 23, 32, 35, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Lundberg et al (WO2018002812A1; Published Jan 4, 2018; hereinafter “Lundberg;” See PTO-892).
Regarding claims 1, 12 and 14: Lundberg disclosed “28 SaCas9 gRNAs targeting the 3 'UTR of DMPK. These gRNAs were tested for cutting efficiencies using SaCas9” (See Specification [000524]) SEQ ID NO: 5808 of Lundberg of 100% identical to ntd 2-22 of SEQ ID NO: 1 (see alignment below). Additionally, Lundberg taught that “some aspects, the one or more deoxyribonucleic acid (DNA) endonuclease is encoded in an AAV vector particle (claim 12 and 14). In some aspects, the one or more gRNA or one or more sgRNA is encoded in an AAV vector particle. In some aspects, the one or more
deoxyribonucleic acid (DNA) endonuclease is encoded in an AAV vector particle which also encodes the one or more gRNA or one or more sgRNA.” (See Specification [00028]). The AAV vector particle which encoding the one or more gRNA or one or more sgRNA and DNA endonuclease reads on the claimed composition comprising a single nucleic acid molecule encoding one or more guide RNAs and a Cas9, wherein the single nucleic acid molecule comprises a first nucleic acid encoding one or more spacer sequences comprising at least 20, or 21 contiguous nucleotides of a spacer sequence selected from any one of SEQ ID NOs: 1-8, 10-28, and 101-154, and a second nucleic acid encoding a Staphylococcus aureus Cas9 (SaCas9). As such it is submitted that it was well known in the art that AAV vectors are standard vehicles for in vivo gene delivery, at least based on the disclosures of Lundberg. It would have been obvious for a person of ordinary skill in the art to use the specific spacer sequence of SEQ ID NO: 5808, in combination with SaCas9 encoded in an AAV vector as taught by Lundberg in AAV vector, which read on the claimed composition comprising the first and the second nucleic acid of claim 1(b). The person would reasonably expect that a known functional spacer would function similarly when used in a standard CRISPR system such as those disclosed in Lundberg. It would have been obvious for a person of ordinary skill in to art to use the spacer sequence disclosed in Lundberg which is identical to ntd 2-22 of the claimed sequence, in conventional CRISPR/Cas9 system because prior art taught each component and their combination would yield predictable DNA targeting results.
Query 3 CCCGGAGTCGAAGACAGTTC 22
||||||||||||||||||||
Sbjct 1 CCCGGAGTCGAAGACAGTTC 20
Alignment of instant SEQ ID NO: 1 to SEQ ID NO: 5808 of Lundberg
Regarding claim 6: Claim 31 taught sgRNA can be introduced for gene editing.
Regarding claim 7: Claim 37 taught a chemically modified sgRNA.
Regarding claim 23 and 44: Claim 26 taught a DNA endonuclease having SEQ ID NO: 1-620. It is noted that SEQ ID NO: 28 of Lundberg is 100% identical to instant 711. (See alignment below).
Query 1 KRNYILGLDIGITSVGYGIIDYETRDVIDAGVRLFKEANVENNEGRRSKRGARRLKRRRR 60
KRNYILGLDIGITSVGYGIIDYETRDVIDAGVRLFKEANVENNEGRRSKRGARRLKRRRR
Sbjct 2 KRNYILGLDIGITSVGYGIIDYETRDVIDAGVRLFKEANVENNEGRRSKRGARRLKRRRR 61
Query 61 HRIQRVKKLLFDYNLLTDHSELSGINPYEARVKGLSQKLSEEEFSAALLHLAKRRGVHNV 120
HRIQRVKKLLFDYNLLTDHSELSGINPYEARVKGLSQKLSEEEFSAALLHLAKRRGVHNV
Sbjct 62 HRIQRVKKLLFDYNLLTDHSELSGINPYEARVKGLSQKLSEEEFSAALLHLAKRRGVHNV 121
Query 121 NEVEEDTGNELSTKEQISRNSKALEEKYVAELQLERLKKDGEVRGSINRFKTSDYVKEAK 180
NEVEEDTGNELSTKEQISRNSKALEEKYVAELQLERLKKDGEVRGSINRFKTSDYVKEAK
Sbjct 122 NEVEEDTGNELSTKEQISRNSKALEEKYVAELQLERLKKDGEVRGSINRFKTSDYVKEAK 181
Query 181 QLLKVQKAYHQLDQSFIDTYIDLLETRRTYYEGPGEGSPFGWKDIKEWYEMLMGHCTYFP 240
QLLKVQKAYHQLDQSFIDTYIDLLETRRTYYEGPGEGSPFGWKDIKEWYEMLMGHCTYFP
Sbjct 182 QLLKVQKAYHQLDQSFIDTYIDLLETRRTYYEGPGEGSPFGWKDIKEWYEMLMGHCTYFP 241
Query 241 EELRSVKYAYNADLYNALNDLNNLVITRDENEKLEYYEKFQIIENVFKQKKKPTLKQIAK 300
EELRSVKYAYNADLYNALNDLNNLVITRDENEKLEYYEKFQIIENVFKQKKKPTLKQIAK
Sbjct 242 EELRSVKYAYNADLYNALNDLNNLVITRDENEKLEYYEKFQIIENVFKQKKKPTLKQIAK 301
Query 301 EILVNEEDIKGYRVTSTGKPEFTNLKVYHDIKDITARKEIIENAELLDQIAKILTIYQSS 360
EILVNEEDIKGYRVTSTGKPEFTNLKVYHDIKDITARKEIIENAELLDQIAKILTIYQSS
Sbjct 302 EILVNEEDIKGYRVTSTGKPEFTNLKVYHDIKDITARKEIIENAELLDQIAKILTIYQSS 361
Query 361 EDIQEELTNLNSELTQEEIEQISNLKGYTGTHNLSLKAINLILDELWHTNDNQIAIFNRL 420
EDIQEELTNLNSELTQEEIEQISNLKGYTGTHNLSLKAINLILDELWHTNDNQIAIFNRL
Sbjct 362 EDIQEELTNLNSELTQEEIEQISNLKGYTGTHNLSLKAINLILDELWHTNDNQIAIFNRL 421
Query 421 KLVPKKVDLSQQKEIPTTLVDDFILSPVVKRSFIQSIKVINAIIKKYGLPNDIIIELARE 480
KLVPKKVDLSQQKEIPTTLVDDFILSPVVKRSFIQSIKVINAIIKKYGLPNDIIIELARE
Sbjct 422 KLVPKKVDLSQQKEIPTTLVDDFILSPVVKRSFIQSIKVINAIIKKYGLPNDIIIELARE 481
Query 481 KNSKDAQKMINEMQKRNRQTNERIEEIIRTTGKENAKYLIEKIKLHDMQEGKCLYSLEAI 540
KNSKDAQKMINEMQKRNRQTNERIEEIIRTTGKENAKYLIEKIKLHDMQEGKCLYSLEAI
Sbjct 482 KNSKDAQKMINEMQKRNRQTNERIEEIIRTTGKENAKYLIEKIKLHDMQEGKCLYSLEAI 541
Query 541 PLEDLLNNPFNYEVDHIIPRSVSFDNSFNNKVLVKQEENSKKGNRTPFQYLSSSDSKISY 600
PLEDLLNNPFNYEVDHIIPRSVSFDNSFNNKVLVKQEENSKKGNRTPFQYLSSSDSKISY
Sbjct 542 PLEDLLNNPFNYEVDHIIPRSVSFDNSFNNKVLVKQEENSKKGNRTPFQYLSSSDSKISY 601
Query 601 ETFKKHILNLAKGKGRISKTKKEYLLEERDINRFSVQKDFINRNLVDTRYATRGLMNLLR 660
ETFKKHILNLAKGKGRISKTKKEYLLEERDINRFSVQKDFINRNLVDTRYATRGLMNLLR
Sbjct 602 ETFKKHILNLAKGKGRISKTKKEYLLEERDINRFSVQKDFINRNLVDTRYATRGLMNLLR 661
Query 661 SYFRVNNLDVKVKSINGGFTSFLRRKWKFKKERNKGYKHHAEDALIIANADFIFKEWKKL 720
SYFRVNNLDVKVKSINGGFTSFLRRKWKFKKERNKGYKHHAEDALIIANADFIFKEWKKL
Sbjct 662 SYFRVNNLDVKVKSINGGFTSFLRRKWKFKKERNKGYKHHAEDALIIANADFIFKEWKKL 721
Query 721 DKAKKVMENQMFEEKQAESMPEIETEQEYKEIFITPHQIKHIKDFKDYKYSHRVDKKPNR 780
DKAKKVMENQMFEEKQAESMPEIETEQEYKEIFITPHQIKHIKDFKDYKYSHRVDKKPNR
Sbjct 722 DKAKKVMENQMFEEKQAESMPEIETEQEYKEIFITPHQIKHIKDFKDYKYSHRVDKKPNR 781
Query 781 ELINDTLYSTRKDDKGNTLIVNNLNGLYDKDNDKLKKLINKSPEKLLMYHHDPQTYQKLK 840
ELINDTLYSTRKDDKGNTLIVNNLNGLYDKDNDKLKKLINKSPEKLLMYHHDPQTYQKLK
Sbjct 782 ELINDTLYSTRKDDKGNTLIVNNLNGLYDKDNDKLKKLINKSPEKLLMYHHDPQTYQKLK 841
Query 841 LIMEQYGDEKNPLYKYYEETGNYLTKYSKKDNGPVIKKIKYYGNKLNAHLDITDDYPNSR 900
LIMEQYGDEKNPLYKYYEETGNYLTKYSKKDNGPVIKKIKYYGNKLNAHLDITDDYPNSR
Sbjct 842 LIMEQYGDEKNPLYKYYEETGNYLTKYSKKDNGPVIKKIKYYGNKLNAHLDITDDYPNSR 901
Query 901 NKVVKLSLKPYRFDVYLDNGVYKFVTVKNLDVIKKENYYEVNSKCYEEAKKLKKISNQAE 960
NKVVKLSLKPYRFDVYLDNGVYKFVTVKNLDVIKKENYYEVNSKCYEEAKKLKKISNQAE
Sbjct 902 NKVVKLSLKPYRFDVYLDNGVYKFVTVKNLDVIKKENYYEVNSKCYEEAKKLKKISNQAE 961
Query 961 FIASFYNNDLIKINGELYRVIGVNNDLLNRIEVNMIDITYREYLENMNDKRPPRIIKTIA 1020
FIASFYNNDLIKINGELYRVIGVNNDLLNRIEVNMIDITYREYLENMNDKRPPRIIKTIA
Sbjct 962 FIASFYNNDLIKINGELYRVIGVNNDLLNRIEVNMIDITYREYLENMNDKRPPRIIKTIA 1021
Query 1021 SKTQSIKKYSTDILGNLYEVKSKKHPQIIKKG 1052
SKTQSIKKYSTDILGNLYEVKSKKHPQIIKKG
Sbjct 1022 SKTQSIKKYSTDILGNLYEVKSKKHPQIIKKG 1053
Alignment between instant SEQ ID NO: 711 and SEQ ID NO: 28 of Lundberg
Regarding claim 32 and 35: Lundberg taught Myotonic Dystrophy Type I using ntd 2-22 bases of SEQ ID NO: 1. (See claim 1 of Lundberg). Further, Lundberg taught deletion of trinucleotide repeat in DMPK gene associated with myotonic dystrophy. (See claim 1 of Lundberg).
Claims 2-3, and 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Lundberg et al (WO2018002812A1; Published Jan 4, 2018; hereinafter “Lundberg;” See PTO-892) in view of Robert et al (Genome Med. 2015 Aug 27; hereinafter "Robert;" See PTO-892).
Regarding claim 2, 3, and 40-41: The teachings of Lundberg are set forth above. Lundberg did not teach use of DNA-PK inhibitors. Roberts used pharmacological inhibitors of DNA-PKcs, a key player in NHEJ, such as NU7441 (claim 3) and KU-0060648, to ameliorate the rates of HDR repair events and found that they were able to reduce the frequency of NHEJ while increasing the rate of HDR following Cas9-mediated DNA cleavage. (See Roberts Abstract; FIG. 2D). Roberts explained that “Cas9 will generate double-stranded breaks (DSB) at the target site which are repaired by the erroneous non-homologous end-joining (NHEJ) pathway to introduce indels (insertions/deletions) or if an appropriate target-homologous donor template is supplied in trans, by homology directed-repair (HDR),” however, “[i]n general, NHEJ is the more frequently observed repair pathway when using Cas9-mediated genome engineering, even in the presence of a donor HDR template “ (See Robert p. 1, col. 1-2). Roberts indicated that “[i]mproving HDR efficiency would significantly reduce the downstream workload involved in identifying appropriate clones of interest.” (See Roberts, p. 1, col. 2). It would have been obvious for a person of ordinary skill in the art to modify the method taught by Lundberg to include the DNA-PK inhibitor taught by Robert to improve genome editing efficiency and to reduce NHEJ, which was a known drawback of CRISPR technology and enhances Cas9-mediated editing outcomes. The person would have had a reasonable expectation of success at arriving at editing nucleic acids using the methods of Lundberg and Robert.
Claims 36, 38, 73 and 91-93 are rejected under 35 U.S.C. 103 as being unpatentable over Lundberg et al (WO2018002812A1; Published Jan 4, 2018; hereinafter “Lundberg;” See PTO-892) in view of Matson et al (PLoS One. 2019 Dec 10; hereinafter "Matson;" See PTO-892).
Regarding claim 36, 38 and 91-93: The teachings of Lundberg are set forth above. Lundberg did not teach the exact spacer sequences as required by the instant claim, rather, only a SEQ ID NO: 5080 that is 100% identical to ntd 2-22 of the instant SEQ ID NO: 1. It is also noted that Lundberg taught a SEQ ID NO: 11956 that is 100% identical to 1-20 of instant SEQ ID NO: 18. Lundberg also noted that modified polynucleotides can be used in the CRISPR/Cas9 or CRISPR/Cpfl system, in which case the guide RNAs (either single-molecule guides or double- molecule guides) and/or a DNA or an RNA encoding a Cas9 or Cpfl endonuclease introduced into a cell can be modified, as described and illustrated below. (See Lundberg [000167]). As such, as required by claim 91-93, Lundberg further taught use of two nucleic acids for gene editing. It is noted that none of the sequences of Lundberg cover the claimed 22ntd length of each guide. It is however noted that the length of spacer sequences are optimizable. For example, Matson taught that extension of sgRNA length, responsible for recognition of the target DNA sequence for Cas9 cleavage, result in improved specificity for the GGTA1 gene and less off-target DNA cleavage. (See Matson Abstract). Matson developed spacers with 19, 30, 40 and 53 bp spacer lengths and found that longer spacers reduced off target effects. (See Matson Fig. 1, 3). As such one of ordinary skill would have been motivated to optimize sgRNA design parameters, including length. Additionally, as taught by Matson, modifying spacer length is predictable and operable. Accordingly, Matson provided motivation to modify known spacer sequences, including by extending their length, to achieve improved genome editing outcomes. It would have been obvious to a person of ordinary skill in the art to design guide RNA spacer sequences based on the target sequences disclosed in Lundberg as CRISPR guide RNAs are routinely selected to be complementary to target DNA adjacent to PAM sites and to further modify spacer lengths including extending beyond 20 ntd, in view of Matson’s teaching that spacer length is a result-effective variable that can be optimized to improve specificity and reduce off target effects.
Regarding claim 73: Lundberg taught a SEQ ID NO: 15870 which is 100% identical to ntd 1-20 of instant SEQ ID NO: 4 and a SEQ ID NO: 18532 which is 100% identical to ntd 2-20 of instant SEQ ID NO: 12. (See alignment below).
Query 1 CCAGTTCACAACCGCTCCGA 20
||||||||||||||||||||
Sbjct 1 CCAGTTCACAACCGCTCCGA 20
Alignment between Lundberg SEQ ID NO: 15870 and instant SEQ ID NO: 4
Query 1 ACTTTGCGAACCAACGATA 19
|||||||||||||||||||
Sbjct 2 ACTTTGCGAACCAACGATA 20
Alignment between Lundberg SEQ ID NO: 18532 and instant SEQ ID NO: 12
Claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over Lundberg et al (WO2018002812A1; Published Jan 4, 2018; hereinafter “Lundberg;” See PTO-892) in view of CN110835631A (Published Feb 25, 2020; Hereinafter “Beijing Academy;” See PTO-892) as evidenced by Celotti et al (STAR Protoc. 2024 Sep 20; See PTO-892).
Regarding claim 54: The teachings of Lundberg are set forth above. Lundberg did not teach the specific scaffold sequence as required by the claim. Beijing Academy taught a sequence 9, which is described as a backbone sequence and is 100% identical to SEQ ID NO: 910 of instant claims/application. It is pointed out that as evidenced by Celotti et al (See p. 21, #61) scaffold sequence is also called a backbone sequence in the field of gene editing. As such it would have been obvious for a person of ordinary skill in the art to incorporate the SaCas9 sgRNA scaffold sequence of Beijing Academy because scaffold sequences are well-known structural components required for Cas9 function and are used in CRISPR sgRNA designs to enable predictable Cas9 binding and activity.
Query 1 GTTTTAGTACTCTGGAAACAGAATCTACTAAAACAAGGCAAAATGCCGTGTTTATCTCGT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1 GTTTTAGTACTCTGGAAACAGAATCTACTAAAACAAGGCAAAATGCCGTGTTTATCTCGT 60
Query 61 CAACTTGTTGGCGAGAT 77
|||||||||||||||||
Sbjct 61 CAACTTGTTGGCGAGAT 77
Alignment of sequence 9 to Beijing Academy to instant SEQ ID NO: 910
Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Lundberg et al (WO2018002812A1; Published Jan 4, 2018; hereinafter “Lundberg;” See PTO-892) in view of in view of Ran et al (Nat Protoc. 2013 Nov; hereinafter "Ran;" See PTO-892).
Regarding claim 67: The teachings of Lundberg are set forth above. Lundberg did not teach the specific AAV vector architecture as enumerated in the instant claim. Ran taught “a set of tools for Cas9-mediated genome editing via nonhomologous end joining (NHEJ) or homology-directed repair (HDR) in mammalian cells, as well as generation of modified cell lines for downstream functional studies. Ran further taught minimization of off-target cleavage by using a double-nicking strategy using the Cas9 nickase mutant with paired guide RNAs. (See Ran Abstract). Ran’s method taught that “sgRNAs can be delivered as either PCR amplicons containing an expression cassette or sgRNA-expressing plasmids. PCR-based sgRNA delivery appends the custom sgRNA sequence onto the reverse PCR primer used to amplify a U6 promoter template. The resulting amplicon could be co-transfected with a Cas9 expression plasmid pSpCas9. This method is optimal for rapid screening of multiple candidate sgRNAs, as cell transfections for functional testing can be performed shortly after obtaining the sgRNA-encoding primers. Because this simple method obviates the need for plasmid-based cloning and sequence verification, it is well suited for testing or co-transfecting a large number of sgRNAs for generating large knockout libraries or other scale-sensitive applications.” (See Ran Figure 4, p. 5, 4th para). A such Ran taught modular CRISPR-Cas9 system where sgRNAs (guide + scaffold) are easily inserted into standardized vectors and used with Cas9 in a AAV vector and used for rapid, scalable genome editing. It would have been obvious for a person of ordinary skill in the art to modify the CRISPR system of Lundberg in view of Ran in order to simplify the construction of CRISPR vectors using Ran’s single cloning sgRNA insertion strategy as to facilitate efficient delivery and expression of CRISPR components in mammalian cells. Combining these known teachings improves ease of use and scalability of Lundberg’s system.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1-3, 6-7, 12, 14, 23, 32, 35-36, 38, 40-41, 44, 54, 67, and 73, provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 9, 11, 16-18, 23-24, 26, 33, 96, 99, 133, 137, 152, 154, 161, 163, and 178, of copending Application No. US18/035,631 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the reasons indicated below.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 1 and 33: Claim 1 of the reference application is directed to a composition comprising: one or more guide RNAs (gRNAs), or a vector encoding one or more gRNAs, wherein each gRNA comprises: a SEQ ID NO: 56 which is 100% identical to the SEQ ID NO: 1 of the claimed sequence.
Query 1 GCCCCGGAGTCGAAGACAGTTC 22
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Sbjct 1 GCCCCGGAGTCGAAGACAGTTC 22
Alignment between SEQ ID NO: 56 of reference application with SEQ ID NO: 1 of instant application
Regarding claims 6-7: Claim 17-18 of the reference application disclosed that the reference RNA is a sgRNA and wherein the sgRNA is modified.
Regarding claims 12 and 14: Claims 24 and 26 of the reference application disclosed a viral vector and wherein the vector is an adeno-associated vector.
Regarding claim 32: Claim 178 of the reference application taught treatment of a muscular dystrophy using the composition of claim 1
Regarding claim 35: Claim 152 of reference application taught excision of trinucleotide repeats using a first spacer which can be a SEQ ID NO: 56 (which is 100% identical to instant SEQ ID NO: 1).
Claim 91-93 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application No. 18/035,631 in view of Matson et al (PLoS One. 2019 Dec 10; hereinafter "Matson;" See PTO-892).
Regarding claim 91: Claim 1 of the reference application taught a composition comprising a pair of guides comprising a SEQ ID NO: 21 (which is 100% identical to instant SEQ ID NO: 1) and a SEQ ID NO: 19 which is 100% identical to instant SEQ ID NO: 28.
It is recognized that instant SEQ ID NO: 1 has an extra G at the 5’ and SEQ ID NO: 21 has a additional T at the 3’ ends. It is however noted as indicated above, Matson taught optimizing guides are routine in the art of gene editing using CRISPR/Cas9. As such, it would have been obvious for a person of ordinary skill in the art to shift the guide by a nucleotide to optimize editing.
Query 1 CCCCGGAGTCGAAGACAGTTC 21
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Sbjct 2 CCCCGGAGTCGAAGACAGTTC 22
Alignment between SEQ ID NO: 21 of reference application with SEQ ID NO: 1 of instant application
Query 1 AGATGGAGGGCCTTTTATTCGC 22
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Sbjct 1 AGATGGAGGGCCTTTTATTCGC 22
Alignment between SEQ ID NO: 19 of reference application with SEQ ID NO: 28 of instant application
Claims 1-3, 6-7, 12, 14, and 23 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3, 6, 7, 12, 14, 23, 32, 35, 38, 39, 42, 45, 47, 53, and 62-64 of copending Application No. US18/456,288 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the reasons stated below.
Regarding claim 1 and 33: Claim 1 of the reference application is directed to a composition comprising a single nucleic acid molecule encoding one or more guide RNAs and a Cas9, wherein the single nucleic acid molecule comprises: a. a first nucleic acid encoding one or more spacer sequence of a SEQ ID NO: 5 which is 100% identical to the SEQ ID NO: 1 of the claimed sequence.
Regarding claims 2-3: Claims 2 and 3 of reference application require DNA-PK inhibitor wherein the DNA-PK inhibitor is Compounds 1, 2 or 6.
Regarding claims 6-7: Claims 6-7 of reference application require that the gRNA is a sgRNA and that the sgRNA is a modified sgRNA.
Regarding claims 12 and 14: Claims 12 and 14 of the reference application disclosed a viral vector and wherein the vector is an adeno-associated vector.
Query 1 GCCCCGGAGTCGAAGACAGTTC 22
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Sbjct 1 GCCCCGGAGTCGAAGACAGTTC 22
Alignment between SEQ ID NO: 5 of reference application with SEQ ID NO: 1 of instant application
Claims 32, 35-36, 38, 40-41, 44, 54, 67, 73, and 91-93 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 32, 35, 38, 39, 42, 45, 47, 53, and 62-64 of U.S. Application No. 18/456,288 in view of Yin et al (Cell Discov 5, 2019; hereinafter "Yin;" See PTO-892).
Regarding claim 32 and 35: Claim 32 of reference application is directed to a method of treating Myotonic Dystrophy Type 1 (DM1) by delivering to a cell a single nucleic acid molecule comprising a nucleic acid encoding a Staphylococcus lugdunensis Cas9 (SluCas9); and: i) a nucleic acid encoding a guide RNA, wherein the guide RNA comprises a SEQ ID NO: 5. Similarly claim 35 of reference application is directed to a method of excising a CTG repeat in the 3' UTR of the DMPK gene, the method comprising delivering to a cell a single nucleic acid molecule comprising a nucleic acid encoding a Staphylococcus lugdunensis Cas9 (SluCas9); and: i) a SEQ ID NO: 5. It is noted that instant claims require a SaCas9, however, Yin taught optimization of engineered nucleases with high editing and low off target activity for efficient and precise genome editing. (See Yin abstract). Yin taught that high-fidelity Cas9 variants, including both eCas9 and the new FeCas9, could significantly reduce the Cas9 off-target activity with no obvious editing retardation. As such, Yin pointed to the routine practice of optimization of Cas nucleases to achieve the most desirable result in gene editing. As such one of ordinary skill in the art would readily recognize that use of various Cas enzymes is routine in CRISPR systems.
Regarding claims 40-41: Claims 38-39 of reference application taught use of DNA-PK inhibitor wherein the inhibitor of Compounds 1-2 and 6.
Regarding claim 91: Claim 62 of reference application is directed to a composition comprising a first nucleic acid molecule and a second nucleic acid molecule, wherein the first nucleic acid molecule encodes a Staphylococcus lugdunensis Cas9 (SluCas9) and the second nucleic acid molecule encodes one or more guide RNAs comprising: a spacer sequence SEQ ID NO: 5.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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