DETAILED ACTION
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 .
Application Status and Election
Applicant’s amendment filed February 12, 2026 amending claims 45 and 86 is acknowledged. Claims 1-2, 4-6, 8, 10, 12, 14, 17-18, 20-21, 42-48, 86-88 are pending.
Applicant’s election without traverse of (A) a guide RNA with SEQ ID NO 2678 having direct repeat of SEQ ID NO 10, (B) a second guide RNA having sequence that is 90% identical to SEQ ID NO 2677, and (C) a Cas12i polypeptide with SEQ ID NO 2642 in the reply filed on February 12, 1026 is acknowledged. Claims 8, 10 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Claims 8, 10 and 12 recite sequences for the direct repeat that do not encompass the direct repeat sequence of SEQ ID NO 2678.
A Cas12i polypeptide with 100% identity to SEQ ID NO 2642 (elected Cas12i polypeptide species) is free of the prior art. The search was widened to include Cas12i polypeptides with 100% identity to SEQ ID NO 2634.
Claims 1-2, 4-6, 14, 17-18, 20-21, 42-48, 86-88 are under examination.
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of 35 U.S.C. 112 (pre-AlA). See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application Nos. 63/108110 fail(s) to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) for one or more claims of this application. The applications fail to provide support for the claims under examination, since there is no disclosure therein of Cas12i2 proteins with SEQ ID NO 2641, 2642, 2643, 2644 or 2645. The first evidence of support for Cas12i2 polypeptides with 100% identity to the above SEQ ID NOs is the provisional application 63/252832 (filed October 6, 2021). As such, the effective filing date for claim 18 is October 6, 2021. The effective filing date for the remaining examined claims is October 30, 2020.
Drawings
The drawings are objected to because: the figures are referred to as “Figure” in the drawings. MPEP §608.02.V states that according to 37 C.F.R. 1.84(u)(1) “View numbers must be preceded by the abbreviation "FIG.".
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term Qubit and NextSeq, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
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 1-2, 4, 6, 14, 17-18, 20-21, 42-48, 86-87 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.
Claims 1 recites “(i) a spacer sequence that is substantially complementary to a target sequence within a BCL11A gene…” Use of “substantially” renders the claim indefinite because it relative term. “Substantially complementary” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The Specification states “the term "substantially complementary" refers to a polynucleotide (e.g., a spacer sequence of an RNA guide) that has a certain level of complementarity to a target sequence” (page 21, ¶1). However, “certain level of complementarity” is also a relative term. So, the “definition” in the Spec does not actually define the term. The Specification states that “in some embodiments” “substantially complementary” to a target has at least about 80%-99% complementarity”. However, this is not a definition and “at least about” is also indefinite because it is not clear if 79% complementarity is included. Therefore, it is not clear how complementary to the BCL11A gene the spacer sequence must be to be considered “substantially complementary” and thus included in the claim.
Claims 2, 4, 6, 14, 17-18, 20-21, 42-48, 86-87 are rejected for depending from claim 1 and not remedying the indefiniteness. Additionally, claim 14 recites “wherein (a) the spacer sequence is substantially complementary to the complementary of a sequence of any of SEQ ID NOs 11-1321.” For the same reasons, it is not clear how complementary the spacer sequence must be to the recited target sequences to be considered “substantially complementary” to be included in the claim.
To overcome this rejection, it is suggested to recite a minimum specific percentage of identity or complementarity to the BCL11A gene or the recited SEQ ID NOs.
It is noted that claims 5 and 88 are not included in this rejection because the RNA guide sequence is clearly defined.
Claim 2 recites where (b) the BCL11A gene comprises… a variant of SEQ ID NO: 2635 or the reverse complement of a variant of SEQ ID NO: 2635.” Claim 2 is indefinite because it is not clear how similar a sequence needs to be to be considered “a variant” of a SEQ ID NO. The Specification does not indicate a minimum level of similarity. It is not clear if a variant must be 95% identical, 80% identical or even have no percent identity to the sequence to be considered “a variant.” This uncertainly renders the structure of the RNA guide indefinite.
To overcome this rejection, it is suggested to delete “a variant of SEQ ID NO: 2635 or the reverse complement of a variant of SEQ ID NO: 2635”.
Claims 4 and 6 recite “wherein the spacer [or direct repeat] comprises (a) nucleotide 1 through nucleotide 16 of a sequence that is at least 90% identical to a sequence of any one of SEQ ID NOs: 1322-2632 [SEQ ID NOs 1-8]…” The recited SEQ ID NOs are 29-30-mers. 90% identical allows 3 nucleotide changes from each of the sequences. Although some of the sequences overlap, many of them have no identity to each other. Additionally, “a sequence” is interpreted as requiring two or more adjacent nucleotides. Using two “a sequence” recitations in the claim together with requiring 90% identity to over 1300 sequences, which have no identity to each other makes it unclear as to exactly what sequences are required in the guide RNA.
Because “comprises” is open language allowing additional nucleotides to be included in the spacer sequence, it is suggested that claim 4 recite: The composition of claim 1, wherein the spacer sequence comprises at least nucleotides 1-16 of any one of SEQ ID NOs 1322-2632 or at least nucleotides 1-16 of a sequence that is 90% identical to any one of SEQ ID NOs 1322-2632.
Likewise it is suggested that claim 6 recite: The composition of claim 1, wherein the direct repeat comprises (a) at least nucleotides 14-36 of any one of SEQ ID NOs 1-8 or at least nucleotides 14-36 of a sequence that is 90% identical to any one of SEQ ID NOs 1-8, (b) at least nucleotides 12-34 of SEQ ID NO 9 or at least nucleotides 12-34 of a sequence that is 90% identical to SEQ ID NO 9, or (c) a sequence that is at least 90% identical to SEQ ID NO 10 or a portion thereof.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 45-46 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claims 45-46 are drawn to a “cell.” The specification does not provide a limiting definition of a cell, and does not expressly exclude cells within a human organism (pages 96-97). Furthermore, claim 46 explicitly recites “a human cell”. Thus, the term “cell” could reasonably be interpreted as encompassing cells within a human organism, which is non-statutory subject matter. The rejection may be obviated by requiring that the cell be an isolated cell, an in vitro human cell, or a non-human cell.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 4-5, 14, 42-43, 45-47 and 86 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Cowan (US 20200330609 A1, published October 22, 2020, filed October 17, 2018) and evidenced by Chang (Chang et al., Molecular Therapy (2017), 4: 137-148) and Zetsche (Zetsche et al., Cell (2015), 163: 759-771).
Regarding claim 1, Cowan teaches “SEQ ID NOs: 36,732-71,947 are 22 bp spacer sequences for targeting within or near a BCL11A gene or other DNA sequence that encodes a regulatory element of the BCL11A gene with an Acidominococcus, a Lachnospiraceae, and a Franciscella Novicida Cpf1 endonuclease” ([0157]). Cowan teaches SEQ ID NO 44,195 has the sequence ctggagcctgtgataaaagcaa (see sequence listing incorporated by reference [0003]). Cowan teaches Cpf1 is a type V CRISPR system that uses crRNAs (i.e., RNA guides) that start with 19 nucleotides of a direct repeat followed by nucleotides of a spacer sequence ([0256]). Therefore, Cowan teaches an RNA guide that comprises (i) a spacer sequence that targets a BCL11A gene and (ii) a direct repeat sequence. Cowan is silent as to the target sequence of SEQ ID NO 44195 and whether the sequence is “substantially complementary” and whether the target sequence is adjacent to a PAM sequence with 5’NTTN-3’.
Zetsche teaches FnCpf1 complexed with a crRNA hybridized to a target sequence (Graphical Abstract). Zetsche teaches the PAM sequence is three nucleotides 5’ of the “target” sequence which is on the non-hybridized strand (i.e., the spacer sequence is the same as the “target” sequence”) (Graphical Abstract). Zetsche teaches the PAM sequence is 5’-TTN (Graphical Abstract).
Chang teaches the sequence of a GATAA enhancer region in the third intron of the BCL11A gene (Figure 1). Chang teaches the sequence of the region comprises the sequence:
AAACCCTTCCTGGAGCCTGTGATAAAAGCAACTGTTAGCTTGCACTAGA
TTTGGGAAGGACCTCGGACACTATTTTCGTTGACAATCGAACGTGATCT (Figure 1C).
The target sequence corresponding to Cowan’s crRNA with SEQ ID NO 44195 is underlined. The PAM sequence that Zetsche teaches is the three nucleotides 5’ of the target sequence is bolded. Because the first nucleotide in the claimed PAM sequence “NTTN” is 5’ of the targeted sequence, any nucleotide reads on the first PAM nucleotide. Thus, the BCL11A target site targeted by an RNA guide with a direct repeat and a spacer sequence with SEQ ID NO 44195 taught in Cowan is inherently 1) complementary to the bottom strand of the BCL11A enhancer region and 2) targets a sequence that is adjacent to a PAM sequence with 5’-NTTN.
Regarding claim 2, as evidenced by Chang (Figure 1), the targeted sequence of Cowan’s RNA guide with a direct repeat and a spacer sequence with SEQ ID NO 44195 inherently targets a sequence in an enhancer region.
Regarding claims 4-5, Cowan’s spacer sequence with SEQ ID NO 44195 comprises a sequence that is 100% identical to nucleotides 1-22 of SEQ ID NO 1332 as shown below:
SEQ ID NO 1332: cuggagccugugauaaaagcaacuguuagc
Cowan’s SEQ 44195: ctggagcctgtgataaaagcaa
Regarding claim 14, as indicated above for claim 1, Cowan’s RNA guide with a direct repeat and a spacer sequence with SEQ ID NO 44195 inherently targets a sequence that is adjacent to (b) a PAM sequence of 5’-CTTC and is immediately adjacent to the PAM sequence.
Regarding claims 42 and 43, Cowan teaches delivering RNA guides as a nucleic acid encoding the guide RNA, wherein the nucleic acid is in a plasmid (i.e., a vector) (Fig 1, [0422]-[0425]).
Regarding claims 45-46, Cowan teaches delivering nucleic acids encoding the RNA guides to cells for expression in cells and for methods of editing the BCL11A gene in human cells ([0434]-[0437], [0531]).
Regarding claim 47, the specification does not provide a special definition for the term "kit”, thus "kit" is interpreted as merely the sum of its contents. The teachings of Cowan, as evidenced by Chang and Zetsche, are recited above a for claim 1.
Regarding claim 86, as indicated above for claim 1, Cowan’s crRNA with FnCpf1 direct repeat and spacer with SEQ ID NO 44195 targets a GATAA motif of an enhancer region of the BCL11A gene. Cowan also teaches that Cpf1 is an RNA-guided endonuclease that efficiently cleaves the target DNA ([0256]). Thus, Cowan as evidenced by Chang, teaches that the crRNA with spacer having SEQ ID NO 44195 would cleave (i.e., disrupt) the GATAA motif.
Regarding claim 87, Cowan teaches a kit having two or more RNA guides ([0495]).
Claim Rejections - 35 USC § 103
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.
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 6, 17-18, 20-21, 44 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Cowan (US 20200330609 A1, published October 22, 2020, filed October 17, 2018) as evidenced by Chang (Chang et al., Molecular Therapy (2017), 4: 137-148) and Zetsche (Zetsche et al., Cell (2015), 163: 759-771), as applied to claims 1, 2, 4-5, 14, 42-43, 45-47 and 86 above, and in view of Cheng (US 20200063126 A1, published February 27, 2020). This rejection is also directed to the elected species of crRNA having SEQ ID NO 2678.
The teachings of Cowan, as evidenced by Zetsche and Chang, are recited above as for claims 1, 2, 4-5, 14, 42-43, 45-47 and 86 and are incorporated here.
Cowan does not teach type V CRISPR systems that comprise Cas12i or their guide RNAs with the direct repeat sequences.
Cheng teaches Cas12i CRISPR systems comprising Cas12i polypeptides and crRNAs comprising direct repeats (FIGs 1-3 and 11). Regarding claim 6, Cheng teaches a Cas12i2 crRNA sequence having a direct repeat sequence of AGAAAUCCGUCUUUCAUUGACGG (i.e., 100% identical to SEQ ID NO 10). Cheng teaches the PAM requirement for Cas12i2 is 5’-TTN (FIG. 41B). Regarding claim 17, Cheng teaches combining a Cas12i2 polypeptide and the crRNA having the direct repeat and spacers with lengths or 17, 20, 23 and 31 nucleotides (FIG 41A, [0169], [0343]). Regarding claim 18, Cheng teaches the amino acid sequence of Cas12i2 is SEQ ID NO 5 ([0016], page 60), which is 100% identical to SEQ ID NO 2624, and 99.74% identical to SEQ ID NO 2642 of the examined application (see OA Appendix). Regarding claim 20, Cheng teaches the Cas12i forms a ribonucleoprotein complex with its crRNA, which then binds to the target sequence ([0040]). Regarding claim 21, Cheng teaches Cas12i2 and guide RNAs delivered to 293T cells targeted to the VEGFA locus resulting in indel formation (i.e., the Cas12i2/crRNA forming an RNP in a cell) ([0169]; FIG 41A). Regarding claim 44, Cheng teaches delivery methods for CRISPR systems are well known in the art and include delivering the Cas effector and the crRNA to cells encoded as a plasmid or a viral vector (i.e., a vector system comprising one or more vectors encoding the crRNA and Cas12i2) ([0045]-[0046], [0311]). Regarding claim 48, Cheng teaches optimizing the coding sequence of Cas12i2 for use in mammalian cells (Table 10). Cheng teaches therapeutic applications of the Cas12i technology ([0304]-[0306]), including editing cells ex vivo for treating sickle cell disease by disruption of the BCL11A erythroid enhancer ([0306]).
Regarding claims 6, 17-18, 20-21, 44 and 48, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have designed the Cas12i2 crRNA with the BCL11A spacer sequence taught in Cowan and combined with the Cas12i2 effector taught in Cheng for the purpose of editing the GATAA motif in the erythroid enhancer sequence of the BCL11A gene. It would have amounted to the simple combination of known prior art elements by known means to yield predictable results. The skilled artisan would have predicted that the Cas12i2 crRNA with direct repeat of SEQ ID NO 10 could be designed to target the BCL11A gene because Cowan teaches using type V CRISPR effectors for editing and Cheng teaches the Cas12i2 technology can be used to edit the BCL11A enhancer. The skilled artisan would have been motivated to have done so for the purpose of treating sickle cell disease as suggested by Cheng.
Claims 87-88 are rejected under 35 U.S.C. 103 as being unpatentable over Cowan (US 20200330609 A1, published October 22, 2020, filed October 17, 2018) as evidenced by Chang (Chang et al., Molecular Therapy (2017), 4: 137-148) and Zetsche (Zetsche et al., Cell (2015), 163: 759-771) and in view of Cheng (US 20200063126 A1, published February 27, 2020), as applied to claims 1, 2, 4-6, 14, 17-18, 20-21, 42-48 and 86 above, further in view of Genbank (NG_011968.1, Homo sapiens BAF chromatin remodeling complex subunit BCL11A (BCL11A), RefSeqGene on chromosome 2, https://www.ncbi.nlm.nih.gov/nuccore/228008311, available October 1, 2019, [retrieved April 13, 2016]). This rejection is also directed to the elected species of two crRNA having SEQ ID NO 2678 and 2677.
The teachings of Cowan, Zetsche, Chang and Cheng, are recited above as for claims 1, 2, 4-6, 14, 17-18, 20-21, 42-48 and 86 and are incorporated here. Cheng also teaches using genome editing to generate two double strand breaks (DSBs) within 50 bases of each other that results in indel formation at both sites and/or a deletion between the DSBs ([0093], [0266]). As indicated above for claim 1, Cowan teaches SEQ ID NOs: 36,732-71,947 sequences for targeting within or near a BCL11A gene with a Type V CRISPR endonuclease ([0157]). Cowan teaches SEQ ID NO 64021 is gaagcuagucuagugcaagcua, which comprises the spacer sequence of SEQ ID NO: 2677 as follows:
SEQ ID NO 2677: agaaauccgucuuucauugacgggaagcuagucuagugcaagc
Cowan SEQ 64021: gaagcuagucuagugcaagcua
Cowan also teaches editing the BCL11A gene, including in a regulatory element, that results in a permanent deletion of a transcription control sequence of the BCL11A gene, including in the +58 DNA hypersensitive site ([0010]). Cowan also teaches that using a Cas nickase (i.e., only cleaving one strand of the DNA) and two separate guides RNAs, one for each nickase, to enable a DSB to form in the target, which reduces the likelihood of DSB occurring at off-target locations ([0275]).
Cowan, Zetsche, Chang and Cheng do not teach the entire sequence of the BCL11A erythroid enhancer sequence.
Genbank teaches the sequence of the BCL11A gene. Genbank teaches the sequence that flanks the sequence taught in Cheng as the BCL11A enhancer as follows. The underlined sequence is Cheng’s enhancer sequence. Bolded nucleotides are spacer sequences, SEQ ID NOs 44195 and 64021 taught in Cowan. Capitalized nucleotides are known 5’-TTN Cpf1 and Cas12i2 PAMs. The vertical lines indicate the position of cleavage by Cas12i2 taught in Cheng.
5’-aaaccCTTCctggagcctgtgataaaagcaact|gttagcttgcactagactagcttcaaagttg
Tttgggaaggtcctcggacactattttcgttga|caatcgaacgtgatctgatcgaagTTTCaac -5’
It would have been obvious to one skilled in the art to have combined the crRNA comprising SEQ ID NO 2378 rendered obvious above with a crRNA comprising the Cas12i2 direct repeat taught in Cheng and a spacer sequence targeted BCL11A taught in Cowan to arrive at a crRNA comprising SEQ ID NO 2677. It would have amounted to the simple combination of prior art elements by known means to yield predictable results. Regarding a crRNA comprising SEQ ID NO 2677, the skilled artisan would have predicted that the Cas12i2 crRNA with direct repeat of SEQ ID NO 10 could be designed to target the BCL11A gene because Cowan teaches using type V CRISPR effectors for editing and Cheng teaches the Cas12i2 technology can be used to edit the BCL11A enhancer, which is targeted Cowan’s spacer with SEQ ID NO 64021 as evidenced by Genbank. It was also predictable that the obvious crRNA could be used to target the specific BCL11A sequence because GenBank teaches the spacer sequence of Cowan is adjacent to a 5’ TTN PAM sequence, which Cheng teaches is also the PAM requirement of Cas12i2. Regarding combining two BCL11A enhancer-targeting crRNAs, the skilled artisan would have predicted the two obvious crRNAs could be combined because 1) Cheng teaches combining two crRNAs for the purpose of creating two single-strand breaks with a nickase or two DSBs with nucleases for creating indels or deletions at the targeted site, and 2) Cowan teaches using two guide RNAs to create a single DSB to reduce off-target editing. The skilled artisan would have been motivated to have done so for the purpose of treating sickle cell disease as suggested by Cheng.
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.
Claims 1-2, 4-6, 14, 17-18, 20-21, 42-48, 86-88 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 8-9, 11, 13-14, 16-18, 35, 164, 233 and 409-418 of copending Application No. 17916270 in view of Cowan (US 20200330609 A1, published October 22, 2020, filed October 17, 2018), Chang (Chang et al., Molecular Therapy (2017), 4: 137-148), Cheng (US 20200063126 A1, published February 27, 2020) and of Genbank (NG_011968.1, Homo sapiens BAF chromatin remodeling complex subunit BCL11A (BCL11A), RefSeqGene on chromosome 2, https://www.ncbi.nlm.nih.gov/nuccore/228008311, available October 1, 2019, [retrieved April 13, 2016]).
Copending claim 1 recites A variant Cas12i2 polypeptide comprising a sequence having at least 95% identity to a sequence set forth in SEQ ID NO: 4, which is over 99% identical to SEQ ID NOs 2634, 2641-2645 of the examined application. Copending claim 8 recites A composition comprising a variant Casl2i2 polypeptide of or a nucleic acid molecule encoding the variant Cas12i2 polypeptide, wherein the composition further comprises an RNA guide or a nucleic acid encoding the RNA guide, wherein the RNA guide comprises a direct repeat sequence and a spacer sequence. Copending claim 9 recites wherein the direct repeat sequence comprises a nucleotide sequence with at least 95% identity to SEQ ID NO 492, which is 100% identical to SEQ ID NO 10 of the examined application and is the direct repeat sequence in SEQ ID NOs 2677 and 2678. Copending claim 13 recites wherein the spacer sequence binds to a target nucleic acid sequence, and wherein the target nucleic acid sequence is adjacent to a 5'- NTTN-3' sequence. Copending claim 17 recites A nucleic acid molecule encoding a variant Cas12i2 polypeptide of claim 1. Copending claim 18 recites A cell comprising the variant Cas12i2 polypeptide of claim 1. Copending claim 233 recite a method of obtaining a deletion in a cell (i.e., editing a genomic sequence), wherein the method comprising contacting the Cas12i2 polypeptide of claim 1 or a nucleic acid encoding the variant Cas12i2 polypeptide with DNA in the cell.
The copending claims do not recite a specific spacer sequence for the guide RNA.
The teachings of Cowan, Chang, Cheng are recited above in paragraphs 29, 31-37, 39-40, 46 and 51 and incorporated here. Briefly, Cowan teaches type V CRISPR crRNA spacer sequences for targeting the enhancer region of BCL11A region include crRNAs comprising the spacer sequences of SEQ ID NOs 2678 and 2677. Chang and GenBank teach the nucleotide sequence of the BCL11A enhancer region. Cheng teaches Cas12i2 polypeptides use crRNAs with direct repeats have SEQ ID NO 10 (i.e., the same as the DR repeat in the copending claims) and that Cas12i2 requires a 5’-TTN PAM, which is the same as a 5’-NTTN PAM.
It would have been obvious to one skilled in the art to have used the copending Cas12i2 polypeptide and crRNA with direct repeat of SEQ ID NO 10 to target the BCL11A enhancer by designing the crRNA with a spacer sequence to arrive at crRNAs with SEQ ID NO 2677 and 2678. It would have amounted to the simple combination of prior art elements by known means to yield predictable results. Regarding a crRNA comprising SEQ ID NO 2677 and 2678, the skilled artisan would have predicted that the Cas12i2 crRNA with direct repeat of SEQ ID NO 10 could be designed to target the BCL11A gene because Cowan teaches using type V CRISPR effectors for editing and Cheng teaches the Cas12i2 technology can be used to edit the BCL11A enhancer, which is targeted Cowan’s spacer with SEQ ID NO 44195 and 64021 as evidenced by Genbank. It was also predictable that the obvious crRNA could be used to target the specific BCL11A sequence because GenBank teaches the spacer sequence of Cowan is adjacent to a 5’ TTN PAM sequence, which Cheng teaches is also the PAM requirement of Cas12i2. Regarding combining two BCL11A enhancer-targeting crRNAs, the skilled artisan would have predicted the two obvious variants of the copending crRNAs could be combined because 1) Cheng teaches combining two crRNAs for the purpose of creating two single-strand breaks with a nickase or two DSBs with nucleases for creating indels or deletions at the targeted site, and 2) Cowan teaches using two guide RNAs to create a single DSB to reduce off-target editing. The skilled artisan would have been motivated to have done so for the purpose of treating sickle cell disease as suggested by Cheng.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 4-6, 14, 17-18, 20-21, 42-48, 86-88 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 7, 9, 12, 18, 23, 26-29, 34-37, 39-43 and 47 of copending Application No. 18000218 in view of Cowan (US 20200330609 A1, published October 22, 2020, filed October 17, 2018), Chang (Chang et al., Molecular Therapy (2017), 4: 137-148), Cheng (US 20200063126 A1, published February 27, 2020) and of Genbank (NG_011968.1, Homo sapiens BAF chromatin remodeling complex subunit BCL11A (BCL11A), RefSeqGene on chromosome 2, https://www.ncbi.nlm.nih.gov/nuccore/228008311, available October 1, 2019, [retrieved April 13, 2016]).
Copending claim 1 recites A composition comprising:(a) an RNA guide or a nucleic acid encoding the RNA guide, wherein the RNA guide comprises a direct repeat sequence and a spacer sequence; and(b) a Cas12i2 polypeptide or a nucleic acid encoding the Casl2i2 polypeptide, wherein the RNA guide forms a complex with the Cas 12i2 polypeptide, and wherein the spacer sequence is capable of hybridizing to a target nucleic acid in a eukaryotic cell that is adjacent to a protospacer adjacent motif (PAM) sequence comprising 4 nucleotides. Copending claim 2 recites wherein the PAM sequence comprises the sequence:(a) 5'-NTTN-3', wherein N is any nucleotide, including 5’-CTTT. Copending claim 5 recites wherein the spacer sequence comprises between 10 and 50 nucleotides in length. Copending claim 12 recites wherein the direct repeat sequence comprises SEQ ID NO: 17, which is 100% identical to SEQ ID NO 10 and the direct repeat portion of SEQ ID NOs 2677 and 2678. Copending claim 23 recites wherein the Cas12i2 polypeptide comprises:(a) an amino acid sequence with at least 95% identity to SEQ ID NO: 2, which is 100% identical to SEQ ID NO 2634 of the examined application. Copending claim 26 recites wherein the target sequence is present in a cell. Copending claim 28 recites wherein the Cas12i2 polypeptide and the RNA guide are encoded in a vector or one or more expression vectors. Copending claim 36 recites A vector comprising a sequence encoding the Cas12i2 polypeptide and RNA guide of the composition of claim 1. Copending claim 37 recites A cell comprising the composition of claim 1. Copending claim 42 recite A method of targeting a sequence adjacent to a PAM sequence comprising four nucleotides, the method comprising contacting the sequence with a composition of claim 1. Copending claim 47 recites A kit or system comprising a composition of claim 1,a cell comprising the composition, or a vector encoding the Cas12i2 polypeptide and RNA guide of the composition.
The copending claims do not recite a specific spacer sequence for the guide RNA.
The teachings of Cowan, Chang, Cheng are recited above in paragraphs 29, 31-37, 39-40, 46 and 51 and incorporated here. Briefly, Cowan teaches type V CRISPR crRNA spacer sequences for targeting the enhancer region of BCL11A region include crRNAs comprising the spacer sequences of SEQ ID NOs 2678 and 2677. Chang and GenBank teach the nucleotide sequence of the BCL11A enhancer region. Cheng teaches Cas12i2 polypeptides use crRNAs with direct repeats have SEQ ID NO 10 (i.e., the same as the DR repeat in the copending claims) and that Cas12i2 requires a 5’-TTN PAM, which is the same as a 5’-NTTN PAM.
The obviousness of having used the copending Cas12i2 polypeptide and crRNA with direct repeat of SEQ ID NO 10 to target the BCL11A enhancer by designing the crRNA with a spacer sequence to arrive at crRNAs with SEQ ID NO 2677 and 2678 is recite above in paragraph 61 and incorporated here.
This is a provisional nonstatutory double patenting rejection
Claims 1-2, 4-6, 14, 17-18, 20-21, 42-48, 86-88 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of copending Application No. 18063607 in view of Cowan (US 20200330609 A1, published October 22, 2020, filed October 17, 2018), Chang (Chang et al., Molecular Therapy (2017), 4: 137-148), Cheng (US 20200063126 A1, published February 27, 2020) and of Genbank (NG_011968.1, Homo sapiens BAF chromatin remodeling complex subunit BCL11A (BCL11A), RefSeqGene on chromosome 2, https://www.ncbi.nlm.nih.gov/nuccore/228008311, available October 1, 2019, [retrieved April 13, 2016]).
Copending claim 1 recites variant Cas12i2 polypeptide comprising the sequence set forth in SEQ ID NO: 4, which is at least 99% identical to SEQ ID NOs 2634 and 2642-2645. Copending claim 3 recites A composition comprising a variant Cas12i2 polypeptide of claim 1, wherein the composition further comprises an RNA guide or a nucleic acid encoding the RNA guide, wherein the RNA guide comprises a direct repeat sequence and a spacer sequence. Copending claim 4 recites wherein the direct repeat sequence comprises a nucleotide sequence with at least 95% sequence identity to any one of SEQ ID NO: 492, with is 100% identical to SEQ ID NO 10 and the direct repeat portion of SEQ ID NOs 2677 and 2678 of the examined application. Copending claim 7 recites A nucleic acid molecule encoding a variant Cas12i2 polypeptide of claim 1. Copending claims 9-10 recite A cell comprising the variant Cas12i2 polypeptide of claim 1, including a human cell. Copending claim 11 recites A method of complexing a variant Cas12i2 polypeptide with an RNA guide (i.e., forming a ribonucleocomplex) wherein the variant Cas12i2 polypeptide comprises a variant Cas12i2 polypeptide of claim 1 and the RNA guide comprises a direct repeat sequence and a spacer sequence. Copending claim 14 recites A method of introducing a deletion or insertion in a cell (i.e., editing a genomic sequence), wherein the method comprises contacting the cell with a composition of claim 3.
The copending claims do not recite a specific spacer sequence for the guide RNA.
The teachings of Cowan, Chang, Cheng are recited above in paragraphs 29, 31-37, 39-40, 46 and 51 and incorporated here. Briefly, Cowan teaches type V CRISPR crRNA spacer sequences for targeting the enhancer region of BCL11A region include crRNAs comprising the spacer sequences of SEQ ID NOs 2678 and 2677. Chang and GenBank teach the nucleotide sequence of the BCL11A enhancer region. Cheng teaches Cas12i2 polypeptides use crRNAs with direct repeats have SEQ ID NO 10 (i.e., the same as the DR repeat in the copending claims) and that Cas12i2 requires a 5’-TTN PAM, which is the same as a 5’-NTTN PAM.
The obviousness of having used the copending Cas12i2 polypeptide and crRNA with direct repeat of SEQ ID NO 10 to target the BCL11A enhancer by designing the crRNA with a spacer sequence to arrive at crRNAs with SEQ ID NO 2677 and 2678 is recite above in paragraph 61 and incorporated here.
This is a provisional nonstatutory double patenting rejection
Conclusion
No claims are allowable.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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