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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-3, 5-7, 9-11, 13-17, 52-53, 55, 57-58, 60, 70-71, 74, 76 and 88) in the reply filed on 4/2/2026 is acknowledged. Applicant’s election of SA1 (SEQ ID NO:60), SEQ ID NO:6 for modified HS4-650, and SEQ ID NO:84 for the sequence of lentiviral vector is also acknowledged. Upon the election of SEQ ID NO:6, and SEQ ID NO:84, claims 5, 9, 53, 57 and 60 are withdrawn.
Claims 4, 8, 12, 19-34, 36-51, 54, 56, 59, 61-69, 72-73, 75, 77-82, 84-87 have been canceled, claims 5-7, 9-11, 13, 18, 35, 53, 57, 60 and 83 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1-3, 14-17, 52, 55, 58, 70-71, 74, 76 and 88 have been considered on the merits.
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.
Claim(s) 1-3, 52, 55, 58, 70-71, 74, 76 and 88 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. (WO2020/139796A1; IDS ref.) in view of Cavazzana-Calvo et al. (2010, Nature), Richmond (2000, BioMed Central; IDS ref.) and Havens et al. (2013, Wiley Interdiscip. Rev. RNA) and as evidenced by NetGene Server splicing site prediction on SEQ ID NO:38 of Yan et al. (2026).
Regarding claims 1-3, Yan et al. teach a method of hematopoietic stem cell-gene therapy for Wiskott-Aldrich Syndrome using a lentiviral vector comprising a promoter operably linked to WASP (i.e. the first nucleic acid) and insulators including cHS4 such as 650cHS4 (i.e. the second nucleic acid) (para. 164, 170, 184). The 650cHS4 is considered identical to the claimed HS4-650 insulator. Yan et al. teach the insulator has SEQ ID NO: 38 or at least 95% sequence identity thereof (para. 14).
Yan et al. do not teach that the HS4-650 being modified to inactivate splice acceptor site.
Cavazzana-Calvo et al. teach that b-globin-expressing lentiviral vector comprises cHS4 encodes a mutated adult b-globin and b-globin allele bears a point mutation that causes alternative splicing (Abstract). Cavazzana-Calvo et al. teach that the predominant HMGA2 mRNA species expressed in the patient’s cells was sequenced. It is truncated by alternative splicing of the third intron with a cryptic 39 splice signal (GTAT(C)6AG) located within the cHS4 insulator core and cleavage/polyadenylation within the adjacent R region of the left long-terminal-repeat (Fig. 3d).
Thus, it would have been obvious to a person skilled in the art that the lentiviral vector of Yan et al. would inherently contain aberrant splice sites in the cHS4 insulator.
Regarding the SEQ ID NO: 60 (elected species; SA1), Yan et al. in view of Cavazzana-Calvo et al. do not particularly teach the limitation. However, based on Cavazzana-Calvo et al., one skilled in the art would predict splice sites of b-globin gene, i.e. cHS4 or HS4-650 of Yan et al. At the time of invention was filed, it is known in the art that splice sites can be predicted by using the NetGene2 server according to Richmond (p.2). Thus, it would have been obvious to a person skilled in the art to search splice sites of HS4-650 using the NetGene2 server with a reasonable expectation of success. The prediction using the NetGene2 server of SEQ ID NO:38 disclosed in Yan et al. (para. 14) resulted in the splice acceptor sites as shown below.
PNG
media_image1.png
246
820
media_image1.png
Greyscale
The acceptor splice site shown above identifies the claimed SA1 sequence (i.e. SEQ ID NO:60 of claim 1) (circled). Thus, it would have been obvious to a person skilled in the art that the claimed SA1 site in the HS4-650 would be readily identified by using the NetGene2 server. As these cryptic splice sites would produce aberrant splicing of the b-globin as taught by Cavazzana-Calvo et al. causing unwanted outcome of expressing a transgene using the lentiviral vector comprising HS4-650, ones killed in the art would understand that the aberrant splicing would be silenced by known means in the art.
Havens et al. teach that the silencing the aberrant splicing sites can be carried out various means including splice site mutations (p.6, Correction of Aberrant Splicing). Havens et al. teach that 5’ splice site (ss) and/or 3’ ss mutation (Fig. 2) would be one of several ways to silence aberrant splicing.
It would have been obvious to a person skilled in the art to mutate the dinucleotide (i.e. AG) in order to silence the acceptor splice sites identified by the prediction using the NetGene2 server with a reasonable expectation of success. One skilled in the art would recognize that the AG dinucleotide signal sequence (3’ss) can be mutated into the limited number of possibilities including mutation of A and/or G to any other nucleotides.
Regarding claim 52, the lentiviral vector of Yan et al. has HS4-650 downstream of the WASP expressing cassette (see Fig.1F-1I).
Regarding claim 55, the lentiviral vector of Yan et al. contains WPRE between hWASp gene and Ins650 (see Fig. 1F-1l). Thus, it would have been obvious to a person skilled in the art that the lentiviral vector of Yan et al. in view of Cavazzana-Calvo et al., Richmond and Havens et al. would contain WPRE between hWASp gene and Ins650 having mutations silencing aberrant splicing.
Regarding claim 70 directed to the polyadenylation signal downstream of the first nucleic acid (i.e. WAS gene) and the modified HS4-650, the lentiviral vector of Yan et al. contains rbGpA (rabbit beta-globin polyA signal) downstream of these genes (Fig. 1F-1l). Thus, it would have been obvious to a person skilled in the art that the lentiviral vector of Yan et al. in view of Cavazzana-Calvo et al., Richmond and Havens et al. would have the polyA signal downstream of the WAS gene and HS4-650 insulator having mutations silencing aberrant splicing.
Regarding claim 71, Yan et al. teach that the lentiviral vector is a plasmid (see Fig.22) or packaged into viral particles (para. 117). Thus, it would have been obvious to a person skilled in the art that the lentiviral vector of Yan et al. in view of Cavazzana-Calvo et al., Richmond and Havens et al. would be a plasmid or packaged into viral particles.
Regarding claim 74, Yan et al. teach a host cell including the lentiviral vector (para. 249). Thus, the lentiviral vector of Yan et al. in view of Cavazzana-Calvo et al., Richmond and Havens et al. having the mutated HS4-650 insulator gene for silencing aberrant splicing would be expressed in the host cell based on the teaching of Yan et al. with a reasonable expectation of success.
Regarding claim 76, Yan et al. teach HSCs are transduced with an expression vector (para. 250). Thus, it would have been obvious that the lentiviral vector of Yan et al. in view of Cavazzana-Calvo et al., Richmond and Havens et al. having the mutated HS4-650 insulator gene for silencing aberrant splicing would be expressed in the HSCs with a reasonable expectation of success.
Regarding claim 88 directed to the lentiviral vector comprising the sequence having at least 90% identity to SEQ ID NO:84, Yan et al. teach that SEQ ID NO: 52 (pBRNGTR22_pTL20c_SK734rev_MND_WAS_650; para. 242, Table 4) has 96% identity to SEQ ID NO: 84 (see alignment below). It is noted that upon the modification to silence the aberrant splicing, i.e. point mutation on dinucleotide splice site (i.e. AG^), the identity would be still within the claimed at least 90%.
RESULT 12
BHY59536
ID BHY59536 standard; DNA; 9642 BP.
AC BHY59536;
DT 20-AUG-2020 (first entry)
DE Vector pBRNGTR22_pTL20c_SK734rev_MND_WAS_650 DNA, SEQ 52.
CC PN WO2020139796-A1
CC PD 02-JUL-2020.
CC PF 23-DEC-2019; 2019WO-US068233.
PR 23-DEC-2018; 2018US-0784508P.
CC PA (CSLC ) CSL BEHRING LLC.
CC PI Yan M, Vonarburg CP, Lee C, Guan CC, Aza W;
XX
DR WPI; 2020-594233/057.
Query Match 96.0%; Score 8975.4; Length 9642;
Best Local Similarity 96.6%;
Matches 9328; Conservative 0; Mismatches 6; Indels 319; Gaps 3;
Qy 1 GGCCGCCTCGGCCAAACAGCCCTTGAGTTTACCACTCCCTATCAGTGATAGAGAAAAGTG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GGCCGCCTCGGCCAAACAGCCCTTGAGTTTACCACTCCCTATCAGTGATAGAGAAAAGTG 60
Qy 61 AAAGTCGAGTTTACCACTCCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGTTTACCACT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AAAGTCGAGTTTACCACTCCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGTTTACCACT 120
Qy 121 CCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGTTTACCACTCCCTATCAGTGATAGAGA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 CCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGTTTACCACTCCCTATCAGTGATAGAGA 180
Qy 181 AAAGTGAAAGTCGAGTTTACCAGTCCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGTTT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 AAAGTGAAAGTCGAGTTTACCAGTCCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGTTT 240
Qy 241 ACCACTCCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGTTTACCACTCCCTATCAGTGA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 ACCACTCCCTATCAGTGATAGAGAAAAGTGAAAGTCGAGTTTACCACTCCCTATCAGTGA 300
Qy 301 TAGAGAAAAGTGAAAGTCGAGCTCGCCATGGGAGGCGTGGCCTGGGCGGGACTGGGGAGT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 TAGAGAAAAGTGAAAGTCGAGCTCGCCATGGGAGGCGTGGCCTGGGCGGGACTGGGGAGT 360
Qy 361 GGCGAGCCCTCAGATCCTGCATATAAGCAGCTGCTTTTTGCCTGTACTGGGTCTCTCTGG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GGCGAGCCCTCAGATCCTGCATATAAGCAGCTGCTTTTTGCCTGTACTGGGTCTCTCTGG 420
Qy 421 TTAGACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCT 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 TTAGACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCT 480
Qy 481 CAATAAAGCTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 CAATAAAGCTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGT 540
Qy 541 AACTAGAGATCCCTCAGACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGTGGCGCCCGA 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 AACTAGAGATCCCTCAGACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGTGGCGCCCGA 600
Qy 601 ACAGGGACTTGAAAGCGAAAGGGAAACCAGAGGAGCTCTCTCGACGCAGGACTCGGCTTG 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 ACAGGGACTTGAAAGCGAAAGGGAAACCAGAGGAGCTCTCTCGACGCAGGACTCGGCTTG 660
Qy 661 CTGAAGCGCGCACGGCAAGAGGCGAGGGGCGGCGACTGGTGAGTACGCCAAAAATTTTGA 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 CTGAAGCGCGCACGGCAAGAGGCGAGGGGCGGCGACTGGTGAGTACGCCAAAAATTTTGA 720
Qy 721 CTAGCGGAGGCTAGAAGGAGAGAGATGGGTGCGAGAGCGTCAGTATTAAGCGGGGGAGAA 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 CTAGCGGAGGCTAGAAGGAGAGAGATGGGTGCGAGAGCGTCAGTATTAAGCGGGGGAGAA 780
Qy 781 TTAGATCGCGATGGGAAAAAATTCGGTTAAGGCCAGGGGGAAAGAAAAAATATAAATTAA 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 TTAGATCGCGATGGGAAAAAATTCGGTTAAGGCCAGGGGGAAAGAAAAAATATAAATTAA 840
Qy 841 AACATATAGTATGGGCAAGCAGGGAGCTAGAACGATTCGCAGTTAATACTGGCCTGTTAG 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 AACATATAGTATGGGCAAGCAGGGAGCTAGAACGATTCGCAGTTAATACTGGCCTGTTAG 900
Qy 901 AAACATCAGAAGGCTGTAGACAAATACTGGGACAGCTACAACCATCCCTTCAGACAGGAT 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 AAACATCAGAAGGCTGTAGACAAATACTGGGACAGCTACAACCATCCCTTCAGACAGGAT 960
Qy 961 CAGAAGAACTTAGATCATTATATAATACAGTAGCAACCCTCTATTGTGTGCATCAAAGGA 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 CAGAAGAACTTAGATCATTATATAATACAGTAGCAACCCTCTATTGTGTGCATCAAAGGA 1020
Qy 1021 TAGAGATAAAAGACACCAAGGAAGCTTTAGACAAGATAGAGGAAGAGCAAAACAAAAGTA 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 TAGAGATAAAAGACACCAAGGAAGCTTTAGACAAGATAGAGGAAGAGCAAAACAAAAGTA 1080
Qy 1081 AGAAAAAAGCACAGCAAGCAGCAGGATCTTCAGACCTGGAAATTCCCTACAATCCCCAAA 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 AGAAAAAAGCACAGCAAGCAGCAGGATCTTCAGACCTGGAAATTCCCTACAATCCCCAAA 1140
Qy 1141 GTCAAGGAGTAGTAGAATCTATGAATAAAGAATTAAAGAAAATTATAGGACAGGTAAGAG 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 GTCAAGGAGTAGTAGAATCTATGAATAAAGAATTAAAGAAAATTATAGGACAGGTAAGAG 1200
Qy 1201 ATCAGGCTGAACATCTTAAGACAGCAGTACAAATGGCAGTATTCATCCACAATTTTAAAA 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 ATCAGGCTGAACATCTTAAGACAGCAGTACAAATGGCAGTATTCATCCACAATTTTAAAA 1260
Qy 1261 GAAAAGGGGGGATTGGGGGGTACAGTGCAGGGGAAAGAATAGTAGACATAATAGCAACAG 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 GAAAAGGGGGGATTGGGGGGTACAGTGCAGGGGAAAGAATAGTAGACATAATAGCAACAG 1320
Qy 1321 ACATACAAACTAAAGAATTACAAAAACAAATTACAAAAATTCAAAATTTTCGGGTTTATT 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1321 ACATACAAACTAAAGAATTACAAAAACAAATTACAAAAATTCAAAATTTTCGGGTTTATT 1380
Qy 1381 ACAGGGACAGCAGAAATCCACTTTGGAAAGGACCAGCAAAGCTCCTCTGGAAAGGTGAAG 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1381 ACAGGGACAGCAGAAATCCACTTTGGAAAGGACCAGCAAAGCTCCTCTGGAAAGGTGAAG 1440
Qy 1441 GGGCAGTAGTAATACAAGATAATAGTGACATAAAAGTAGTGCCAAGAAGAAAAGCAAAGA 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1441 GGGCAGTAGTAATACAAGATAATAGTGACATAAAAGTAGTGCCAAGAAGAAAAGCAAAGA 1500
Qy 1501 TCATTAGGGATTATGGAAAACAGATGGCAGGTGATGATTGTGTGGCAAGTAGACAGGATG 1560
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1501 TCATTAGGGATTATGGAAAACAGATGGCAGGTGATGATTGTGTGGCAAGTAGACAGGATG 1560
Qy 1561 AGGATTAGAACATGGAAAAGTTTAGTAAAACACCATAAGGAGGAGATATGAGGGACAATT 1620
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1561 AGGATTAGAACATGGAAAAGTTTAGTAAAACACCATAAGGAGGAGATATGAGGGACAATT 1620
Qy 1621 GGAGAAGTGAATTATATAAATATAAAGTAGTAAAAATTGAACCATTAGGAGTAGCACCCA 1680
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1621 GGAGAAGTGAATTATATAAATATAAAGTAGTAAAAATTGAACCATTAGGAGTAGCACCCA 1680
Qy 1681 CCAAGGCAAAGAGAAGAGTGGTGCAGAGAGAAAAAAGAGCAGTGGGAATAGGAGCTTTGT 1740
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1681 CCAAGGCAAAGAGAAGAGTGGTGCAGAGAGAAAAAAGAGCAGTGGGAATAGGAGCTTTGT 1740
Qy 1741 TCCTTGGGTTCTTGGGAGCAGCAGGAAGCACTATGGGCGCAGCGTCAATGACGCTGACGG 1800
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1741 TCCTTGGGTTCTTGGGAGCAGCAGGAAGCACTATGGGCGCAGCGTCAATGACGCTGACGG 1800
Qy 1801 TACAGGCCAGACAATTATTGTCTGGTATAGTGCAGCAGCAGAACAATTTGCTGAGGGCTA 1860
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1801 TACAGGCCAGACAATTATTGTCTGGTATAGTGCAGCAGCAGAACAATTTGCTGAGGGCTA 1860
Qy 1861 TTGAGGCGCAACAGCATCTGTTGCAACTCACAGTCTGGGGCATCAAGCAGCTCCAGGCAA 1920
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1861 TTGAGGCGCAACAGCATCTGTTGCAACTCACAGTCTGGGGCATCAAGCAGCTCCAGGCAA 1920
Qy 1921 GAATCCTGGCTGTGGAAAGATACCTAAAGGATCAACAGCTCCTGGGGATTTGGGGTTGCT 1980
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1921 GAATCCTGGCTGTGGAAAGATACCTAAAGGATCAACAGCTCCTGGGGATTTGGGGTTGCT 1980
Qy 1981 CTGGAAAACTCATTTGCACCACTGCTGTGCCTTGGAATGCTAGTTGGAGTAATAAATCTC 2040
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1981 CTGGAAAACTCATTTGCACCACTGCTGTGCCTTGGAATGCTAGTTGGAGTAATAAATCTC 2040
Qy 2041 TGGAACAGATTTGGAATCACACGACCTGGATGGAGTGGGACAGAGAAATTAACAATTACA 2100
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2041 TGGAACAGATTTGGAATCACACGACCTGGATGGAGTGGGACAGAGAAATTAACAATTACA 2100
Qy 2101 CAAGCTTAATACACTCCTTAATTGAAGAATCGCAAAACCAGCAAGAAAAGAATGAACAAG 2160
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2101 CAAGCTTAATACACTCCTTAATTGAAGAATCGCAAAACCAGCAAGAAAAGAATGAACAAG 2160
Qy 2161 AATTATTGGAATTAGATAAATGGGCAAGTTTGTGGAATTGGTTTAACATAACAAATTGGC 2220
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2161 AATTATTGGAATTAGATAAATGGGCAAGTTTGTGGAATTGGTTTAACATAACAAATTGGC 2220
Qy 2221 TGTGGTATATAAAATTATTCATAATGATAGTAGGAGGCTTGGTAGGTTTAAGAATAGTTT 2280
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2221 TGTGGTATATAAAATTATTCATAATGATAGTAGGAGGCTTGGTAGGTTTAAGAATAGTTT 2280
Qy 2281 TTGCTGTACTTTCTATAGTGAATAGAGTTAGGCAGGGATATTCACCATTATCGTTTCAGA 2340
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2281 TTGCTGTACTTTCTATAGTGAATAGAGTTAGGCAGGGATATTCACCATTATCGTTTCAGA 2340
Qy 2341 CCCACCTCCCAACCCCGAGGGGACCGAGCTCAAGCTTCGAAGCGATCGC----------- 2389
|||||||||||||||||||||||||||||||||||||||||||||||||
Db 2341 CCCACCTCCCAACCCCGAGGGGACCGAGCTCAAGCTTCGAAGCGATCGCACGCGTCAAAA 2400
Qy 2390 ------------------------------------------------------------ 2389
Db 2401 AAGGATATGCCCTTGACTATGTCGGACAAATAGTCAAGGGCATATCCTGAGGTACCCAGG 2460
Qy 2390 ------------------------------------------------------------ 2389
Db 2461 CGGCGCACAAGCTATATAAACCTGAAGGAAATCTCAACTTTACACTTAGGTCAAGTTACT 2520
Qy 2390 ------------------------------------------------------------ 2389
Db 2521 TATCGTACTAGAGCTTCAGCAGGAAATTTAACTAAAATCTAATTTAACCAGCATAGCAAA 2580
Qy 2390 ------------------------------------------------------------ 2389
Db 2581 TATCATTTATTCCCAAAATGCTAAAGTTTGAGATAAACGGACTTGATTTCCGGCTGTTTT 2640
Qy 2390 ---------------------------------------------------------ACG 2392
|||
Db 2641 GACACTATCCAGAATGCCTTGCAGATGGGTGGGGCATGCTAAATACTGCACGTCGATACG 2700
Qy 2393 CGTGGATCCGAACAGAGAGACAGCAGAATATGGGCCAAACAGGATATCTGTGGTAAGCAG 2452
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2701 CGTGGATCCGAACAGAGAGACAGCAGAATATGGGCCAAACAGGATATCTGTGGTAAGCAG 2760
Qy 2453 TTCCTGCCCCGGCTCAGGGCCAAGAACAGTTGGAACAGCAGAATATGGGCCAAACAGGAT 2512
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2761 TTCCTGCCCCGGCTCAGGGCCAAGAACAGTTGGAACAGCAGAATATGGGCCAAACAGGAT 2820
Qy 2513 ATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAACAGATGGTCCCCAGATGCG 2572
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2821 ATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAACAGATGGTCCCCAGATGCG 2880
Qy 2573 GTCCCGCCCTCAGCAGTTTCTAGAGAACCATCAGATGTTTCCAGGGTGCCCCAAGGACCT 2632
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2881 GTCCCGCCCTCAGCAGTTTCTAGAGAACCATCAGATGTTTCCAGGGTGCCCCAAGGACCT 2940
Qy 2633 GAAATGACCCTGTGCCTTATTTGAACTAACCAATCAGTTCGCTTCTCGCTTCTGTTCGCG 2692
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2941 GAAATGACCCTGTGCCTTATTTGAACTAACCAATCAGTTCGCTTCTCGCTTCTGTTCGCG 3000
Qy 2693 CGCTTCTGCTCCCCGAGCTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGGCG 2752
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3001 CGCTTCTGCTCCCCGAGCTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGGCG 3060
Qy 2753 CGCCAATTCAAGCGAGAAGACAAGGGCAGCCGCCACCATGAGTGGGGGCCCAATGGGAGG 2812
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3061 CGCCAATTCAAGCGAGAAGACAAGGGCAGCCGCCACCATGAGTGGGGGCCCAATGGGAGG 3120
Qy 2813 AAGGCCCGGGGGCCGAGGAGCACCAGCGGTTCAGCAGAACATACCCTCCACCCTCCTCCA 2872
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3121 AAGGCCCGGGGGCCGAGGAGCACCAGCGGTTCAGCAGAACATACCCTCCACCCTCCTCCA 3180
Qy 2873 GGACCACGAGAACCAGCGACTCTTTGAGATGCTTGGACGAAAATGCTTGACGCTGGCCAC 2932
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3181 GGACCACGAGAACCAGCGACTCTTTGAGATGCTTGGACGAAAATGCTTGACGCTGGCCAC 3240
Qy 2933 TGCAGTTGTTCAGCTGTACCTGGCGCTGCCCCCTGGAGCTGAGCACTGGACCAAGGAGCA 2992
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3241 TGCAGTTGTTCAGCTGTACCTGGCGCTGCCCCCTGGAGCTGAGCACTGGACCAAGGAGCA 3300
Qy 2993 TTGTGGGGCTGTGTGCTTCGTGAAGGATAACCCCCAGAAGTCCTACTTCATCCGCCTTTA 3052
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3301 TTGTGGGGCTGTGTGCTTCGTGAAGGATAACCCCCAGAAGTCCTACTTCATCCGCCTTTA 3360
Qy 3053 CGGCCTTCAGGCTGGTCGGCTGCTCTGGGAACAGGAGCTGTACTCACAGCTTGTCTACTC 3112
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3361 CGGCCTTCAGGCTGGTCGGCTGCTCTGGGAACAGGAGCTGTACTCACAGCTTGTCTACTC 3420
Qy 3113 CACCCCCACCCCCTTCTTCCACACCTTCGCTGGAGATGACTGCCAAGCGGGGCTGAACTT 3172
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3421 CACCCCCACCCCCTTCTTCCACACCTTCGCTGGAGATGACTGCCAAGCGGGGCTGAACTT 3480
Qy 3173 TGCAGACGAGGACGAGGCCCAGGCCTTCCGGGCACTCGTGCAGGAGAAGATACAAAAAAG 3232
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3481 TGCAGACGAGGACGAGGCCCAGGCCTTCCGGGCACTCGTGCAGGAGAAGATACAAAAAAG 3540
Qy 3233 GAATCAGAGGCAAAGTGGAGACAGACGCCAGCTACCCCCACCACCAACACCAGCCAATGA 3292
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3541 GAATCAGAGGCAAAGTGGAGACAGACGCCAGCTACCCCCACCACCAACACCAGCCAATGA 3600
Qy 3293 AGAGAGAAGAGGAGGGCTCCCACCCCTGCCCCTGCATCCAGGTGGAGACCAAGGAGGCCC 3352
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3601 AGAGAGAAGAGGAGGGCTCCCACCCCTGCCCCTGCATCCAGGTGGAGACCAAGGAGGCCC 3660
Qy 3353 TCCAGTGGGTCCGCTCTCCCTGGGGCTGGCGACAGTGGACATCCAGAACCCTGACATCAC 3412
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3661 TCCAGTGGGTCCGCTCTCCCTGGGGCTGGCGACAGTGGACATCCAGAACCCTGACATCAC 3720
Qy 3413 GAGTTCACGATACCGTGGGCTCCCAGCACCTGGACCTAGCCCAGCTGATAAGAAACGCTC 3472
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3721 GAGTTCACGATACCGTGGGCTCCCAGCACCTGGACCTAGCCCAGCTGATAAGAAACGCTC 3780
Qy 3473 AGGGAAGAAGAAGATCAGCAAAGCTGATATTGGTGCACCCAGTGGATTCAAGCATGTCAG 3532
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3781 AGGGAAGAAGAAGATCAGCAAAGCTGATATTGGTGCACCCAGTGGATTCAAGCATGTCAG 3840
Qy 3533 CCACGTGGGGTGGGACCCCCAGAATGGATTTGACGTGAACAACCTCGACCCAGATCTGCG 3592
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3841 CCACGTGGGGTGGGACCCCCAGAATGGATTTGACGTGAACAACCTCGACCCAGATCTGCG 3900
Qy 3593 GAGTCTGTTCTCCAGGGCAGGAATCAGCGAGGCCCAGCTCACCGACGCCGAGACCTCTAA 3652
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3901 GAGTCTGTTCTCCAGGGCAGGAATCAGCGAGGCCCAGCTCACCGACGCCGAGACCTCTAA 3960
Qy 3653 ACTTATCTACGACTTCATTGAGGACCAGGGTGGGCTGGAGGCTGTGCGGCAGGAGATGAG 3712
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3961 ACTTATCTACGACTTCATTGAGGACCAGGGTGGGCTGGAGGCTGTGCGGCAGGAGATGAG 4020
Qy 3713 GCGCCAGGAGCCACTTCCGCCGCCCCCACCGCCATCTCGAGGAGGGAACCAGCTCCCCCG 3772
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4021 GCGCCAGGAGCCACTTCCGCCGCCCCCACCGCCATCTCGAGGAGGGAACCAGCTCCCCCG 4080
Qy 3773 GCCCCCTATTGTGGGGGGTAACAAGGGTCGTTCTGGTCCACTGCCCCCTGTACCTTTGGG 3832
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4081 GCCCCCTATTGTGGGGGGTAACAAGGGTCGTTCTGGTCCACTGCCCCCTGTACCTTTGGG 4140
Qy 3833 GATTGCCCCACCCCCACCAACACCCCGGGGACCCCCACCCCCAGGCCGAGGGGGTCCTCC 3892
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4141 GATTGCCCCACCCCCACCAACACCCCGGGGACCCCCACCCCCAGGCCGAGGGGGTCCTCC 4200
Qy 3893 ACCACCACCCCCTCCAGCTACTGGACGTTCTGGACCACTGCCCCCTCCACCCCCTGGAGC 3952
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4201 ACCACCACCCCCTCCAGCTACTGGACGTTCTGGACCACTGCCCCCTCCACCCCCTGGAGC 4260
Qy 3953 TGGTGGGCCACCCATGCCACCACCACCGCCACCACCGCCACCGCCGCCCAGCTCCGGGAA 4012
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4261 TGGTGGGCCACCCATGCCACCACCACCGCCACCACCGCCACCGCCGCCCAGCTCCGGGAA 4320
Qy 4013 TGGACCAGCCCCTCCCCCACTCCCTCCTGCTCTGGTGCCTGCCGGGGGCCTGGCCCCTGG 4072
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4321 TGGACCAGCCCCTCCCCCACTCCCTCCTGCTCTGGTGCCTGCCGGGGGCCTGGCCCCTGG 4380
Qy 4073 TGGGGGTCGGGGAGCGCTTTTGGATCAAATCCGGCAGGGAATTCAGCTGAACAAGACCCC 4132
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4381 TGGGGGTCGGGGAGCGCTTTTGGATCAAATCCGGCAGGGAATTCAGCTGAACAAGACCCC 4440
Qy 4133 TGGGGCCCCAGAGAGCTCAGCGCTGCAGCCACCACCTCAGAGCTCAGAGGGACTGGTGGG 4192
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4441 TGGGGCCCCAGAGAGCTCAGCGCTGCAGCCACCACCTCAGAGCTCAGAGGGACTGGTGGG 4500
Qy 4193 GGCCCTGATGCACGTGATGCAGAAGAGAAGCAGAGCCATCCACTCCTCCGACGAAGGGGA 4252
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4501 GGCCCTGATGCACGTGATGCAGAAGAGAAGCAGAGCCATCCACTCCTCCGACGAAGGGGA 4560
Qy 4253 GGACCAGGCTGGCGATGAAGATGAAGATGATGAATGGGATGACTGATAACTAGTAATCAA 4312
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4561 GGACCAGGCTGGCGATGAAGATGAAGATGATGAATGGGATGACTGATAACTAGTAATCAA 4620
Qy 4313 CCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTT 4372
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4621 CCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTT 4680
Qy 4373 ACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCT 4432
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4681 ACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCT 4740
Qy 4433 TTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCC 4492
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4741 TTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCC 4800
Qy 4493 GTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGG 4552
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4801 GTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGG 4860
Qy 4553 GGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCC 4612
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4861 GGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCC 4920
Qy 4613 ACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGC 4672
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4921 ACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGC 4980
Qy 4673 ACTGACAATTCCGTGGTGTTGTCGGGGAAATCATCGTCCTTTCCTTGGCTGCTCGCCTGT 4732
||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||
Db 4981 ACTGACAATTCCGTGGTGTTGTCGGGGAAATCATCGTCCTTTCCTTGGCTGTTCGCCTGT 5040
Qy 4733 GTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCA 4792
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5041 GTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCA 5100
Qy 4793 GCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTT 4852
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5101 GCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTT 5160
Qy 4853 CGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCACGTACGACCGGTGCGG 4912
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5161 CGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCACGTACGACCGGTGCGG 5220
Qy 4913 CCGCATCGATGCCGTAGTACCTTTAAGACCAATGACTTACAAGGCAGCTGTAGATCTTAG 4972
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5221 CCGCATCGATGCCGTAGTACCTTTAAGACCAATGACTTACAAGGCAGCTGTAGATCTTAG 5280
Qy 4973 CCACTTTTTAAAAGAAAAGGGGGGACTGGAAGGGCTAATTCACTCCCAAAGAAGACAAGA 5032
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5281 CCACTTTTTAAAAGAAAAGGGGGGACTGGAAGGGCTAATTCACTCCCAAAGAAGACAAG- 5339
Qy 5033 TAGCCCCATCCTCACTGACTCCGTCCTGGAGTTGGATGAGAGATAATGGCCTTACGTTGT 5092
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5340 --GCCCCATCCTCACTGACTCCGTCCTGGAGTTGGATGAGAGATAATGGCCTTACGTTGT 5397
Qy 5093 GCCAGGGGAGGGTCGGGCTGGATTTAGCAAGATTTACCTTCTCCAAAGAGCGGTGCTGCA 5152
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5398 GCCAGGGGAGGGTCGGGCTGGATTTAGCAAGATTTACCTTCTCCAAAGAGCGGTGCTGCA 5457
Qy 5153 GTGGCACAGCTGCCCACGGAGGTGGGGGGGTCACCGTCCCTGGAGGTGATGAAGAACTGT 5212
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5458 GTGGCACAGCTGCCCACGGAGGTGGGGGGGTCACCGTCCCTGGAGGTGATGAAGAACTGT 5517
Qy 5213 GGGGATGTGGCACTGAGGGACATGGCCAGTGGGCACGGTGGGTGGGTTGGGGTTGGTCTT 5272
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5518 GGGGATGTGGCACTGAGGGACATGGCCAGTGGGCACGGTGGGTGGGTTGGGGTTGGTCTT 5577
Qy 5273 GGGGATCTTGGAGGGCTTTTCCAGCCTTCATGATTTGACGATTGTATGAACATCTACATG 5332
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5578 GGGGATCTTGGAGGGCTTTTCCAGCCTTCATGATTTGACGATTGTATGAACATCTACATG 5637
Qy 5333 GCAATTCTCCAGCTGCCTGTCCCAGTCCTACTGACCCAGCTGTATCTCTCCAGGCAAGCT 5392
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5638 GCAATTCTCCAGCTGCCTGTCCCAGTCCTACTGACCCAGCTGTATCTCTCCAGGCAAGCT 5697
Qy 5393 CTTCCACCCCTTCTGCTTGCATCCTGACACCATCAAACATGCAGGCTCAGACACATGATA 5452
|||||||||||||||||||||||| ||||||||||||||||||||||||| |
Db 5698 CTTCCACCCCTTCTGCTTGCATCCAGACACCATCAAACATGCAGGCTCAGCC-------- 5749
Qy 5453 TCAAGCTTTTTCCCCGTATCCCCCCTGGTGTCTGCTGGCTCAAAGAGCAGCGAGAAGCGT 5512
| ||||||||||||||||||||||| ||||||||| ||||||||||||||||||||||||
Db 5750 TAAAGCTTTTTCCCCGTATCCCCCCAGGTGTCTGCAGGCTCAAAGAGCAGCGAGAAGCGT 5809
Qy 5513 TCAGAGGAAAGCGATCCCGTGCCACCTTCCCCGTGCCCGGGCTGTCCCCGCACGCTGCCG 5572
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5810 TCAGAGGAAAGCGATCCCGTGCCACCTTCCCCGTGCCCGGGCTGTCCCCGCACGCTGCCG 5869
Qy 5573 GCTCGGGGATGCGGGGGGAGCGCCGGACCGGAGCGGAGCCCCGGGCGGCTCGCTGCTGCC 5632
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5870 GCTCGGGGATGCGGGGGGAGCGCCGGACCGGAGCGGAGCCCCGGGCGGCTCGCTGCTGCC 5929
Qy 5633 CCCTAGCGGGGGAGGGACGTAATTACATCCCTGGGGGCTTTGGGGGGGGGCTGTCCCCGT 5692
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5930 CCCTAGCGGGGGAGGGACGTAATTACATCCCTGGGGGCTTTGGGGGGGGGCTGTCCCCGT 5989
Qy 5693 GAGCTCCCCAGATCTGCTTTTTGCCTGTACTGGGTCTCTCTGGTTAGACCAGATCTGAGC 5752
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 5990 GAGCTCCCCAGATCTGCTTTTTGCCTGTACTGGGTCTCTCTGGTTAGACCAGATCTGAGC 6049
Qy 5753 CTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCTTCAGCTG 5812
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6050 CTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCTTCAGCTG 6109
Qy 5813 CTCGAGCTAGCAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTT 5872
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6110 CTCGAGCTAGCAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTT 6169
Qy 5873 GAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAAT 5932
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6170 GAGCATCTGACTTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAAT 6229
Qy 5933 TTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAAT 5992
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6230 TTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTAAAACATCAGAAT 6289
Qy 5993 GAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGT 6052
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6290 GAGTATTTGGTTTAGAGTTTGGCAACATATGCCCATATGCTGGCTGCCATGAACAAAGGT 6349
Qy 6053 TGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCAT 6112
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6350 TGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCTGTCCATTCCTTATTCCAT 6409
Qy 6113 AGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCT 6172
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6410 AGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATTTTTTTCT 6469
Qy 6173 TTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGA 6232
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6470 TTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGA 6529
Qy 6233 CTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACCTGCAGCCCAAG 6292
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6530 CTACTCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATCCCTCGACCTGCAGCCCAAG 6589
Qy 6293 CTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCC 6352
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6590 CTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCC 6649
Qy 6353 ACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTA 6412
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6650 ACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTA 6709
Qy 6413 ACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCA 6472
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6710 ACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCA 6769
Qy 6473 GCGGATCCGCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCG 6532
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6770 GCGGATCCGCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCG 6829
Qy 6533 CCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTTTTATT 6592
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6830 CCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTTTTATT 6889
Qy 6593 TATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTT 6652
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6890 TATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTT 6949
Qy 6653 TTTGGAGGCCTAGGCTTTTGCAAAAAGCTGTCGACTGCAGAGGCCTGCATGCAAGCTTGG 6712
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 6950 TTTGGAGGCCTAGGCTTTTGCAAAAAGCTGTCGACTGCAGAGGCCTGCATGCAAGCTTGG 7009
Qy 6713 CGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACA 6772
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7010 CGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACA 7069
Qy 6773 ACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCA 6832
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7070 ACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCA 7129
Qy 6833 CATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGC 6892
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7130 CATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGC 7189
Qy 6893 ATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTT 6952
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7190 ATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTT 7249
Qy 6953 CCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACT 7012
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7250 CCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACT 7309
Qy 7013 CAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAG 7072
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7310 CAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAG 7369
Qy 7073 CAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATA 7132
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7370 CAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATA 7429
Qy 7133 GGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACC 7192
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7430 GGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACC 7489
Qy 7193 CGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTG 7252
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7490 CGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTG 7549
Qy 7253 TTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGC 7312
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7550 TTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGC 7609
Qy 7313 TTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGG 7372
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7610 TTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGG 7669
Qy 7373 GCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTC 7432
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7670 GCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTC 7729
Qy 7433 TTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGA 7492
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7730 TTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGA 7789
Qy 7493 TTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACG 7552
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7790 TTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACG 7849
Qy 7553 GCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAA 7612
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7850 GCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAA 7909
Qy 7613 AAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTG 7672
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7910 AAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTG 7969
Qy 7673 TTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTT 7732
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7970 TTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTT 8029
Qy 7733 CTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGAT 7792
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8030 CTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGAT 8089
Qy 7793 TATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCT 7852
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8090 TATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCT 8149
Qy 7853 AAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTA 7912
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8150 AAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTA 8209
Qy 7913 TCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAA 7972
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8210 TCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAA 8269
Qy 7973 CTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCAC 8032
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8270 CTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCAC 8329
Qy 8033 GCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAA 8092
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8330 GCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAA 8389
Qy 8093 GTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAG 8152
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8390 GTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAG 8449
Qy 8153 TAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGG 8212
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8450 TAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGG 8509
Qy 8213 TGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAG 8272
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8510 TGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAG 8569
Qy 8273 TTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTG 8332
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8570 TTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTG 8629
Qy 8333 TCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTC 8392
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8630 TCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTC 8689
Qy 8393 TTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCAT 8452
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8690 TTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCAT 8749
Qy 8453 TCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATA 8512
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8750 TCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATA 8809
Qy 8513 CCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAA 8572
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8810 CCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAA 8869
Qy 8573 AACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCA 8632
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8870 AACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCA 8929
Qy 8633 ACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGC 8692
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8930 ACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGC 8989
Qy 8693 AAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCC 8752
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8990 AAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCC 9049
Qy 8753 TTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTG 8812
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 9050 TTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTG 9109
Qy 8813 AATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCAC 8872
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 9110 AATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCAC 9169
Qy 8873 CTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGA 8932
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 9170 CTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGA 9229
Qy 8933 GGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCC 8992
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 9230 GGCCCTTTCGTCTCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTCC 9289
Qy 8993 CGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCG 9052
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 9290 CGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGGGAGCAGACAAGCCCGTCAGGGCG 9349
Qy 9053 CGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTG 9112
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 9350 CGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTG 9409
Qy 9113 TACTGAGAGTGCACCATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACC 9172
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 9410 TACTGAGAGTGCACCATATGCGGTGTGAAATACCGCACAGATGCGTAAGGAGAAAATACC 9469
Qy 9173 GCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGG 9232
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 9470 GCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGG 9529
Qy 9233 CCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGG 9292
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 9530 CCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTTGGG 9589
Qy 9293 TAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTC 9345
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 9590 TAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTC 9642
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 14-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. in view of Cavazzana-Calvo et al., Richmond and Havens et al. as applied to claim 1 above, and further in view of Hanawa et al. (2007, Molecular Therapy; IDS ref.).
Regarding claims 14-17, while Yan et al. teach that the first nucleic acid encodes a shRNA to knockdown HPRT, and the second nucleic acid encodes WASP, and these two expression cassettes can be arranged in various combination in terms of directions and orders (para. 15, 30-31; p.102, claims 22-23; p.107, claims 75-76), however, Yan et al. do not teach the orientation/direction of the nucleic acid encoding WASP and the nucleic acid encoding CH4-650 disclosed in claims 14-17.
Hanawa et al. teach lentiviral vectors having various configurations with regard to the transgene expressing cassette (i.e. a gene encoding EGFP) and the cHS4 insulator (chicken b-globin gene) expressing cassette (Abstract; Fig.1a). According to the configuration shown in Fig. 1a, cHS4 insulator can be in the same or opposite directions (INS1(+) or INS(-)) with regard to the EGFP expression cassette. Hanawa et al. teach that by modifying the orientation of the HS4 insulator, gene expression levels of the lentiviral vector was changed differently based on the cell types.
It would have been obvious to a person skilled in the art to modify the orientation of cHS4 insulator of the lentiviral vector taught by Yan et al. in order to optimize the expression of WASP from the lentiviral vector of Yan et al. with a reasonable expectation of success.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Conclusion
No claims are allowed.
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/TAEYOON KIM/ Primary Examiner, Art Unit 1631
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