CA S9 EFFECTOR PROTEINS WITH ENHANCED STABILITY

§101 §102 §103 §112 §DP

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 . Claim Status Claims 1-7, 20-23, 60-63, 67-68, 72-73, 76, 116 are pending and examined here. The specification of 07/28/2026 is entered. Priority The claim to benefit to 63/193,620, filed on 05/27/2021, via it’s 371 of PCT/EP2022/064368, filed on 05/26/2022, is recognized. All claims enjoy the filing date of ‘620 filing. Information Disclosure Statement The information disclosure statement (IDS) submitted on 11/07/2024 and 09/01/2026 were filed before the mailing date of this first Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Specification The disclosure is objected to because of the following informalities: Fig. 6 has 5 panels, the Brief Description does not note nor describe the panels. Fig. 8 description appears to be switched for Fig. panel 8A and 8B; panels 8A and 8B in figure is of CD34 and EMX1, respectively; while description (par. 46) indicates “EMX1 site (8A) and the CD34 site (8B)”. Confirmation and correction is required. Appropriate correction is required. Claim Objections Claims 61, 63, 68, and 73 are objected to because of the following informalities: the claims recite “any of claims 23,” deletion of “any of” and singular form of claims is required. Appropriate correction is required. 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 2-7, 21-22, 60, 62, 67, 72 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 60, 62, 67 and 72 recite “any of claims 1 to 22”, claims 8 to 19 are canceled, thus these claims are indefinite because they depend on at least one canceled claim. Claims 2-7 are rejected for indefiniteness because the specification does not clearly define monopartite nuclear localization signal (MP-NLS) and bipartite nuclear localization signal (BP-NLS) (see Tables 1 and 2 for exemplary sequences provided). The specification recognizes SEQ ID NO: 3 (AVKRPAATKKAGQAKKKKLD) as a monopartite nuclear localization signal (MP-NLS, see par. 69 and Table 1). The specification also notes SEQ ID NOs 8 and 9, which have subsequence of SEQ ID NO: 3, as classic bipartite NLS (see Table 2, par. 70). The art does not recognize SEQ ID NO: 3 as a MP-NLS (see Lu et al. (2021, Cell Commun Signal, 19, pg. 1-10: see “the BP [bipartite] NLS at the C-terminus of nucleoplasmin, whose sequence is KRPAATKKAGQAKKKK, can guide the protein into the nucleus”, pg. 3; also see Zhu et al. (2015, J. of Genetics and Genomics, 43, 25-36, in IDS, Fig. 1 legend “C-terminal bipartite nucleoplasmin”)). Since the specification does not clearly define bipartite nuclear localization signal (BP-NLS) but only provides specific sequences as examples (see par. 70 and Table 2), the prior art of Lu indicates that BP-NLS is “characterized by two clusters of 2–3 positively charged amino acids that are separated by a 9–12 amino-acid linker region” (pg. 3). Based on this definition, SEQ ID NO: 4 (MSRRRKANPTKLSENAKKLAKEVEN) also does not appear to be a monopartite NLS. Thus, it is unclear what exactly is MP-NLS or BP-NLS. Although an applicant can be their own lexicographer, the unclear relationship between a structure of a MP-NLS/BP-NLS and its classification as a MP-NLS/BP-NLS does not provide adequate notice regarding the metes and bounds of the claimed NLS to a skilled artisan. In the interest of compact prosecution, for art rejection purposes, each NLS cited will be analyzed based on how it is recognized in the art/reference. Claim 20 recites the language of “with an E-value cut-off of 1E-5.” The E-value cut-off is dependent on many factors, which includes the size of the proteins being compared, databases used, and the algorithm parameters set in the database. E.g., there can be identical proteins that based on parameter setting can still result in varying E-values. Thus, there is uncertainty regarding the scope of the claim due to the E-value language. Claims 72-73 are rejected for indefiniteness since a viral vector cannot comprise “the protein.” The claim is interpreted as “A viral vector encoding the protein of” (for cl. 72) or “A viral vector encoding the Cas9 effector protein and the guide polynucleotide of claim 23” (for cl. 73). 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 60-61 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 60 and 61 recite a eukaryotic cell comprising the protein of any of claims 1 to 22 or of claim 23, respectively. Specification indicates that a eukaryotic cell can be a human cell (par. 189) and therefore encompasses the cells in a human organism and the human organism itself. The specification also mentions diseases used to target liposomes carrying claimed subject matter (par. 153), the diseases noted are human diseases, such as Alzheimer’s and Parkinson’s disease, thus encompasses cells within a human organism. Amending the claim to an isolated, in vitro or ex vivo eukaryotic cell will be remedial. Claim Rejections - 35 USC § 102 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 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 1-7, 23, 60, 61, 62, 63, 67, 68, 72, 73, 76, 116 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wu et al. ( WO2019213273, pub. 11/7/2019, “Wu”, in IDS). The recitation of “Cas9 effector protein” in claim 1 is considered a preamble and is interpreted as not further limiting the body of the claim. Regarding instant cl. 1, 2, 4, 5, Wu discloses CRISPR-Cas9 mediated gene modification utilizing Cas-fusion proteins comprising c-myc or c-myc-like nuclear localization signal (NLS) sequence fused to its amino terminus (i.e. 1st NLS) and an SV40 NLS and nucleoplasmin bipartite NLS fused to its carboxyl terminus (i.e. 2nd NLS) (par. 4, 6, cl. 1, cl. 2, par. 18, see below Fig. 15; relevant to instant cl. 1, 4, 5). As provided by instant specification, c-myc-NLS and SV40 NLS are monopartite NLS (relevant to instant cl. 2). PNG media_image1.png 303 481 media_image1.png Greyscale Regarding instant cl. 3, and 6, Wu discloses that the CRISPR enzyme has one NLS sequence fused at or near its amino terminus and at least one NLS sequences fused at or near its carboxy terminus (par. 7, cl. 1). Wu discloses NLS sequence is selected from SV40 large T-antigen, nucleoplasmin, c-Myc, c-Myc- like, and hRNPA1 (cl. 3). Wu discloses that nucleoplasmin bipartite NLS (BP-NLS) of SEQ ID NO: 2 (KRPAATKKAGQAKKKK, par. 82). Thus, Wu contemplates that a BP-NLS can be fused at or near the amino terminus (relevant to instant cl. 3) or that the amino terminus has a BP-NLS and the carboxy terminus has a MP-NLS (relevant to instant cl. 6) Regarding instant cl. 7, Wu discloses NLS sequence is selected from SV40 large T-antigen, c-Myc, and c-Myc- like, both are considered monopartite NLS (cl. 3). Regarding instant cl. 23, 60, and 61, Wu discloses electroporation of Cas9 and sgRNA RNP (both lentiviral pooled sgRNAs or chemically modified synthetic sgRNAs) complexes enables delivery genome editing material to human cells (par. 134). Wu’s cl. 11 discloses a guide RNA that targets and hybridizes to a target sequence on a DNA molecule (par. 18). Regarding instant cl. 62, 63, 67-68, Wu discloses a pharmaceutical composition refers to active agent with a pharmaceutically acceptable carrier, and carriers disclosed are a nanoparticle and a liposome (par. 49). Regarding instant cl. 72-73, Wu discloses that a vector is a nucleic acid construct designed for delivery to a host cell and the vector can be viral (par. 46). Regarding instant cl. 76, Wu discloses a method of altering of at least one gene product, the method comprising introducing into a cell any of the nucleic acid molecules or vector encoding CRISPR enzyme with NLS at amino and carboxy ends and at least one guide RNA (gRNA) that targets and hybridizes with a target sequence of a DNA molecule (cl. 19). Wu demonstrates following electroporation of Cas9 and sgRNA RNP complexes in healthy donor CD34+ hematopoietic progenitor stem cells (HPSCs), a “dose-dependent relationship was observed between RNP concentration and indel frequency and similar editing efficiency at Cas9:sgRNA molar ratios ranging from 1:1 to 1:2.5 (Fig.5c-5e)” (par. 134). Wu demonstrates that “[e]diting with sgRNA-1617, which cleaves directly within a GATA1 binding motif at the core of the +58 enhancer, gave the highest levels of γ-globin and HbF induction in erythroid progeny (Fig.1a, 1c, and Fig.5f, 5h),” which is a site-specific modification of a target sequence in a eukaryotic cell that resulted in cleavage of genomic DNA that would inherently produce cohesive ends and is followed by modifying the target sequence. Regarding instant cl. 116, Wu discloses the method comprising introducing into a cell any of the nucleic acid molecules or vector encoding CRISPR enzyme with NLS at amino and carboxy ends (cl. 19, see Wu sequences of Fig. 15 above), so the nucleic acid/vector have the sequence encoding the NLS at the appropriate ends of Cas9. Since Wu discloses the active steps of requiring attaching a 1st-NLS to the N-terminus of the Cas9 effector protein and attaching a 2nd-NLS to the C-terminus of the Cas9, as noted above, it would necessarily meet the functional limitation of reducing degradation of Cas9 effector protein in a cell by attaching the NLSes at both ends. 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 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. ( WO2019213273, pub. 11/7/2019, “Wu”) as applied to claims 1-7, 23, 60, 61, 62, 63, 67, 68, 72, 73, 76, 116 above, and further in view of Maresca et al. (WO2019099943, pub. 5/23/2019, in IDS, “Maresca”, shares co-inventor with instant app but is outside the 102(a)(1) grace period). Wu discloses CRISPR-Cas9 mediated gene modification utilizing Cas-fusion proteins comprising c-myc-like nuclear localization signal (NLS) sequence fused to its amino terminus (i.e. 1st NLS) and an SV40 NLS and nucleoplasmin bipartite NLS fused to its carboxyl terminus (i.e. 2nd NLS) (par. 4, 6, cl. 1, cl. 2). Wu does not disclose the “Cas9 effector protein comprises a domain that matches a TIGR03031 protein family with an E-value cut-off of 1E-5” (cl. 20) and at least 90% identical to SEQ ID NO: 98 (cl. 21). Maresca discloses a “stiCas9” (aka “sticky Cas9”), which are Cas9 effector protein capable of generating cohesive ends (par. 9). Maresca points out that DNA fragments with cohesive ends provide advantage over blunt ends in inserting a nucleic acid in between the fragments and re-joining the fragments together since the sticky ends will only pair with a complementary cohesive ends (par. 209). Maresca points out that stiCas9 is derived from a bacterial species having a Type II-B CRISPR system (par. 202) and discloses that StiCas9 comprises a domain that matches a TIGR03031 protein family with an E-value cut-off of 1E-5 (cl. 22; relevant to instant cl. 20). Maresca demonstrates that using a Type II-B Cas9, i.e. MHCas9, results in sticky ends, i.e. a 3-4 nucleotide overhang as opposed to either a blunt end or a single nucleotide overhang as generated by Type II-A Cas9, a canonical Streptococcus pyogenes Cas9, i.e. SpCas9 (par. 456, 452). One of the stiCas9 disclosed by Maresca is SEQ ID NO: 71, which is a polypeptide sequence at least 90% identical to instant SEQ ID NO: 98 (1407 [a.a. match]/1438 [total size of SEQ ID NO: 98] is 97% identity; see alignment section below after the conclusion section, relevant to instant cl. 21). Maresca demonstrates that SEQ ID NO: 71, which is classified as a Cas9 protein from MH0245_GL0161830 (see Fig. 30, pg. 54-55, it is also termed “MH0245” or “MHCas9, see par. 128). Maresca demonstrates that MHCas9’s nuclease activity generates cohesive end with a 5’ overhang (Fig. 35, par. 128). One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have substituted the Cas9 comprising NLS at both terminals of Wu in view of Maresca and arrive at the claimed invention with a reasonable expectation of success. Based on the success of Wu in editing human genome using Cas9 comprising NLS at both terminals, and the success of Maresca generating sticky ends using a stiCas9 enzyme or specifically SEQ ID NO: 71 (i.e. MHCas9) comprising a domain that matches a TIGR03031 protein family with an E-value cut-off of 1E-5 and noting that sticky ends are advantageous of blunt ends of SpCas9, a skilled artisan would reasonably expect success in generating genomic sticky ends greater than 1 nt. by substituting the Cas9 of Wu with a stiCas9, or specifically SEQ ID NO: 71, of Maresca. Thus, cl. 20-21 is obvious. Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. ( WO2019213273, pub. 11/7/2019, “Wu”) and Maresca et al. (WO2019099943, pub. 5/23/2019, in IDS, “Maresca”, shares co-inventor with instant app but is outside the 102(a)(1) grace period) as applied to claims 1-7, 20-21, 23, 60, 61, 62, 63, 67, 68, 72, 73, 76, 116 above, and further in view of Kleinstiver et al. (2016, Nature, 529, 490-495). Disclosure of Wu and Maresca are noted above. Wu and Maresca do not disclose the selected modifications of cl. 22 (one is at position Q661A) Kleinstiver discloses identification of a high-fidelity variant of Streptococcus pyogenes Cas9 (SpCas9-HF1) by mutating various positions that reduce non-specific DNA contacts (abstract). Kleinstiver tested one or all of amino acid positions 497, 661, 695, and 926 that make direct hydrogen bonds with the DNA with the hopes that it would alter the energetics of the SpCas9-gRNA complex so that it might retain enough for robust on-target activity but have a diminished ability to cleave mismatched off-target sites (pg. 490). Here, the authors mutated said positions to alanine (A) and demonstrated that alanine substitutions of one or all of these residues did not reduce on-target cleavage efficiency but “rendered all or nearly all off-target events undetectable” (pg. 490, abstract). One of the KSR’s rationale for supporting conclusion of obviousness is “obvious to try,” requiring the following three findings: (1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success. Here, Kleinstiver discloses that CRISPR-Cas9 based editing results in unwanted mutations and demonstrates that modifying the positions 497, 661, 695, and 926 on a SpCas9 resulted in reduced off-target events, thus providing finite number of mutations a skilled artisan could have pursued with a reasonable expectation of success. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have tried modifying the SEQ ID NO: 71 with NLS at N and C- terminal of Maresca and Wu in view of Kleinstiver to have arrived at the claimed invention with a reasonable expectation of success. Based on the success of Maresca’s SEQ ID NO: 71 ability to edit a genome, and of Kleinstiver demonstrating success of modified SpCas9 at positions 497, 661, 695 and 926, a skilled artisan would reasonably expect success by trying to modify SEQ ID NO: 71 of Maresca at one or all of positions 497, 661, 695, and 926 with alanine for an improved Cas9 protein that results in reduced off-target activity. Thus, cl. 22 would be prima facie obvious. 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 1-7, 21, 62,63, 67, 68, 72, 73, 76, and 116 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 21, 26, 31, 35, 42, 44, 46, of copending Application No. 18/439,897 in view of Wu et al. ( WO2019213273, pub. 11/7/2019, “Wu”, in IDS). Claim 1 of ‘897 teaches a CRISPR-Cas system comprising a) Cas9 effector protein capable of generating cohesive ends (stiCas9) and b) a guide polynucleotide that forms a complex with stiCas9 and comprises a guide sequence capable of hybridizing with a target sequence in a eukaryotic cell. Claim 2 teaches a Cas9 effector protein comprising a NLS. Claim 26 teaches stiCas9 comprising one or more NLS. Thus claims 1, 2 and 26 teach a stiCas9 that comprise one or more NLS (correspond to instant cl. 1, 116). The claims of ‘897 do not teach the 1st NLS, 2nd NLS, monopartite and bipartite NLS. As noted above, briefly, Wu discloses 1st NLS, 2nd NLS, monopartite and bipartite NLS, c-myc monopartite NLS, nucleoplasmin-bipartite NLS, and the locations of NLS at both N- and C- terminals of Cas9 protein, and either end can be monopartite and bipartite NLS (see cite points above, correspond to instant cl. 2-7). Thus, it would be obvious for a skilled artisan to modify stiCas9 comprising NLS of ‘897 with positioning of NLS at N- and C- terminals of stiCas9, including monopartite NLS (c-myc), bipartite NLS (nucleoplasmin) as taught by Wu, corresponding to instant cl. 1-7). Regarding instant cl. 116, the product of ‘897 and Wu and instant method claim of 116 are not patentably distinct from each other, since the product claim of ‘897 and Wu result in the limitation of “reducing degradation of Cas9 effector protein. Claim 21 of ‘897 teaches stiCas9 comprises a domain having at least 95% identity to any of one of SEQ ID NOs:10-97; one is SEQ ID NO: 71, which is 90% identical to SEQ ID NO: 98, corresponding to instant cl. 21. Claim 31 (delivery particle), claim 35 (a vesicle), claim 42 (viral vector) and claim 44 (a eukaryote cell) of ‘897 comprising the CRISPR-Cas system of claim 1, corresponds to instant cl. 62, 63, 67, 68, 72, and 73. Claim 46 of ‘897 corresponds with instant cl. 76. This is a provisional nonstatutory double patenting rejection. Conclusion No claim allowed. Alignment relevant to instant cl. 21: Qy= instant SEQ ID NO: 98; Db=SEQ ID NO: 71 of Maresca Query Match 97.9%; Score 7240; Length 1445; Best Local Similarity 100.0%; Matches 1408; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 22 TVKSTLAVDMGGRYTGIFSYTTDSGFPKAKEARAYVLNMPDNDALTYSMAARTQTRHRIR 81 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 38 TVKSTLAVDMGGRYTGIFSYTTDSGFPKAKEARAYVLNMPDNDALTYSMAARTQTRHRIR 97 Qy 82 SQQRFVLARRLTYILIEGKLKRKLSPREKEAISSLLRRRGYSRLESELDLSVLQGVESGF 141 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 98 SQQRFVLARRLTYILIEGKLKRKLSPREKEAISSLLRRRGYSRLESELDLSVLQGVESGF 157 Qy 142 FKCFLPNFDEDENLLTQWTSLTDGYLQNNSDSRRQIQIFLESSKDSKEFLTVVKSQHQDT 201 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 158 FKCFLPNFDEDENLLTQWTSLTDGYLQNNSDSRRQIQIFLESSKDSKEFLTVVKSQHQDT 217 Qy 202 KEYKNALKVMRDDAESMIEQSMFGHKHRRLYLEAIA QDIPRDSRLKPIIEAFSGVEKFHH 261 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 218 KEYKNALKVMRDDAESMIEQSMFGHKHRRLYLEAIA QDIPRDSRLKPIIEAFSGVEKFHH 277 Qy 262 FIGNLSNLQLRALRWYFNDPSMKNNVFDKERLKSVLVRAYQFFHYPKDLTQQRAEVLNAY 321 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 278 FIGNLSNLQLRALRWYFNDPSMKNNVFDKERLKSVLVRAYQFFHYPKDLTQQRAEVLNAY 337 Qy 322 EGATDILETLQTLNPELTIPPYEDQNNRRPPLDQTLWLSPRLLDQRYGDTWEIWVQNLLR 381 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 338 EGATDILETLQTLNPELTIPPYEDQNNRRPPLDQTLWLSPRLLDQRYGDTWEIWVQNLLR 397 Qy 382 SPLSKGIDENLDTILITTDRKARLLERQSGRLIHYTSQKLYHSYVLQRLLDRTVENDAYL 441 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 398 SPLSKGIDENLDTILITTDRKARLLERQSGRLIHYTSQKLYHSYVLQRLLDRTVENDAYL 457 Qy 442 LKTLVSSNRGNSNEIHQAQERLTRDLGSQHIKKFLDFVRQYYDEVDKAKRGLWFIVEKPL 501 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 458 LKTLVSSNRGNSNEIHQAQERLTRDLGSQHIKKFLDFVRQYYDEVDKAKRGLWFIVEKPL 517 Qy 502 MERADIHPPMKNDSVILRLVGNILCVSDLVDLSFWTRKVKGQSTVRSLCTAIEKTRKEYG 561 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 518 MERADIHPPMKNDSVILRLVGNILCVSDLVDLSFWTRKVKGQSTVRSLCTAIEKTRKEYG 577 Qy 562 NSFNYLYQRALYLQSKGKKLSAEDKDFIKLQSNVLLVSDVIAEALDIKEEQKKKFANPFS 621 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 578 NSFNYLYQRALYLQSKGKKLSAEDKDFIKLQSNVLLVSDVIAEALDIKEEQKKKFANPFS 637 Qy 622 LAQLYNIIETEKSGFISTTLAAVDENAWRNNLQGKARCVQLCADTVRPFDGALRNILDRQ 681 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 638 LAQLYNIIETEKSGFISTTLAAVDENAWRNNLQGKARCVQLCADTVRPFDGALRNILDRQ 697 Qy 682 AYEIAKLKAEELLSTELKNQTIDLVVLLESNQFAFSASLAEVKKSANTAAIRQKVAKAQK 741 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 698 AYEIAKLKAEELLSTELKNQTIDLVVLLESNQFAFSASLAEVKKSANTAAIRQKVAKAQK 757 Qy 742 RQQDRWLSKDERIKSASRGLCPYTGKNLGDKGEVDHIIPRSLSMNYMGSILNSEANLIYC 801 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 758 RQQDRWLSKDERIKSASRGLCPYTGKNLGDKGEVDHIIPRSLSMNYMGSILNSEANLIYC 817 Qy 802 SQEGNQLKLNGRKKLSDLADNYLKVVFGTADRGTICKYIEKSVSELTDAKIVQFELLDRS 861 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 818 SQEGNQLKLNGRKKLSDLADNYLKVVFGTADRGTICKYIEKSVSELTDAKIVQFELLDRS 877 Qy 862 QQDAVRHALFLEDFSEARRRIIRLLGKINTARVNGTQAWFAKSFITKLRELTKEWCANNQ 921 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 878 QQDAVRHALFLEDFSEARRRIIRLLGKINTARVNGTQAWFAKSFITKLRELTKEWCANNQ 937 Qy 922 ITLAFDLYRLDAQTVSQDYRKKFALINKDWAKPDDKKQPIASHAIDAFCVFAAAKDKRNI 981 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 938 ITLAFDLYRLDAQTVSQDYRKKFALINKDWAKPDDKKQPIASHAIDAFCVFAAAKDKRNI 997 Qy 982 ANVLGVFDEVAEEQNLKTIAQLMPSEVNLISPKRKSILDKNEVGSRALMKEGIFAEHFLP 1041 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 998 ANVLGVFDEVAEEQNLKTIAQLMPSEVNLISPKRKSILDKNEVGSRALMKEGIFAEHFLP 1057 Qy 1042 ILVRGDDCRIGFDWSESGSVKVKDADKLFGVLDGLLKQSQKRSVNGFETYTVDRIKAFEL 1101 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1058 ILVRGDDCRIGFDWSESGSVKVKDADKLFGVLDGLLKQSQKRSVNGFETYTVDRIKAFEL 1117 Qy 1102 LHDVFIRPCSQKMLEQAEVLEKLHYITQNISVTSVYDAVNRQFKCREEILKDKDFDIKVD 1161 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1118 LHDVFIRPCSQKMLEQAEVLEKLHYITQNISVTSVYDAVNRQFKCREEILKDKDFDIKVD 1177 Qy 1162 LGNRFGSAKGKITLPAKREWEKLVNRSELKNLIKDKLSDKGSEKTPDGETLIYDIFRSIP 1221 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1178 LGNRFGSAKGKITLPAKREWEKLVNRSELKNLIKDKLSDKGSEKTPDGETLIYDIFRSIP 1237 Qy 1222 VQKLSHKATRRVWSLPKIPSISSGVRIKRKDSNGNDIYQLYMLNDTKCKGFVVNEKGVID 1281 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1238 VQKLSHKATRRVWSLPKIPSISSGVRIKRKDSNGNDIYQLYMLNDTKCKGFVVNEKGVID 1297 Qy 1282 WSSDLVADLYKQPTLTILNGRYLKADQYVRMDQWYEVDCGRDDVIVKMCPGTSGRRYIEI 1341 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1298 WSSDLVADLYKQPTLTILNGRYLKADQYVRMDQWYEVDCGRDDVIVKMCPGTSGRRYIEI 1357 Qy 1342 TQSKKQFEDWTGYISGSFWNYPVTIKLSSQQIANFVKNSQMPLLGKPRSGQITVITLGNT 1401 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1358 TQSKKQFEDWTGYISGSFWNYPVTIKLSSQQIANFVKNSQMPLLGKPRSGQITVITLGNT 1417 Qy 1402 LKYWYCVESKNSMMNEAYQKAYLVHFNQ 1429 |||||||||||||||||||||||||||| Db 1418 LKYWYCVESKNSMMNEAYQKAYLVHFNQ 1445 Closing Paragraph Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEYUR A. VYAS whose telephone number is (571)272-0924. The examiner can normally be reached M-F 9am - 4 pm (EST). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /KEYUR A VYAS/Examiner, Art Unit 1637 /Soren Harward/Primary Examiner, TC 1600