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 .
DETAILED ACTION
Claim Status
Claims 4-6, 8-9, and 11-13 are currently pending in this application.
Election/Restriction
Election was made without traverse of Group I, claims 4-6, 9, and 11-12, in the reply filed Aug. 7, 2026. Claims 8 and 13 are withdrawn from further consideration as being drawn to a non-elected invention(s), and claims 4-6, 9, and 11-12 have been considered on the merits.
Claim Interpretation
In claim 4, the term “coding” gene is interpreted as meaning a nucleic acid gene sequence encoding the gene product named recombinant coagulation factor VIII, such as resulting in expression of a coagulation factor VIII protein whenever the vector is inside a cell activating transcription from said tissue-specific promoter.
In claims 4-6, 9, and 11-12, the term “recombinant” with regard to the expression vector is interpreted as ordinarily understood to one of skill in the art as the vector comprises two or more functional biological sequences not naturally found together as constructed in the vector. This preamble limitation is deemed met by the requisite “recombinant” coding gene required in all claims. Similarly in claims 5 and 6, the term “recombinant” with regard to said lentivirus or cell is deemed met by the requisite “recombinant” expression vector.
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 9 and 12 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 pre-AIA the applicant regards as the invention.
Claim 9 recites the phrase “preferably, the pharmaceutical composition further comprises any one or a combination of at least two of a pharmaceutically acceptable carrier, excipient or diluent,” which is ambiguous and unclear as to whether the language after “preferably” is a limitation or optional feature.
Also, claim 12 recites the term “pEGWI.” This term does not appear to be commonly used in the art and is not defined in the claim or the specification. If this is an abbreviation, then the abbreviation needs to be spelled out at least once in the claim set. A person of ordinary skill in the art reading the claim would not understand the metes and bounds of pEGWI. Furthermore in view of the instant specification (pg. 5-6), a “pEGWI” may or may not have a mutated 5’ splice donor site, a U3 region enhancer, and/or any insulator element (e.g., cHS4) as well as variants with different safety profiles. Thus, pEGWI appears to represent a genus of lentiviral vectors.
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.
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 4-6, 9, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Guo (WO2019228527A1) in view of Olgasi (Olgasi et al., Stem Cell Reports 11: 1391-1406 (2018); IDS ref.) and Benmohamed (WO2021211760A1, published 2021-10-21).
Regarding claims 4 and 11, Guo teaches a recombinant expression lentiviral vector comprising a coagulation factor VIII transgene (FVIII or FVIII-BDD gene) operably linked to a promoter capable of initiating gene expression (e.g., EF1α or CM), such as for uses in recombinant protein expression in mammalian host cell or in gene delivery to treat hemophilia A via replacement therapy (Abstract, pg. 1, pg. 14-15, Fig. 4, pg. 16-19; claims 6 and 15). Guo teaches (SEQ ID NO: 2) wherein the FVIII transgene comprises the coding sequence of instant SEQ ID NO: 5 (pg. 12-14; Example 1, pg. 26), as shown below.
Sequence 4374 BP; 1252 A; 996 C; 983 G; 1143 T; 0 U; 0 Other;
Query Match 100.0%; Score 4374; Length 4374;
Best Local Similarity 100.0%;
Matches 4374; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ATGCAGATCGAACTGAGCACCTGCTTCTTCCTGTGTCTCCTGAGATTCTGCTTTAGTGCT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ATGCAGATCGAACTGAGCACCTGCTTCTTCCTGTGTCTCCTGAGATTCTGCTTTAGTGCT 60
Qy 61 ACCAGACGGTATTACCTGGGAGCCGTCGAGCTGAGTTGGGATTACATGCAGTCCGACCTC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ACCAGACGGTATTACCTGGGAGCCGTCGAGCTGAGTTGGGATTACATGCAGTCCGACCTC 120
Qy 121 GGAGAACTGCCTGTGGATGCACGCTTTCCACCAAGAGTGCCTAAGTCATTCCCATTCAAC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GGAGAACTGCCTGTGGATGCACGCTTTCCACCAAGAGTGCCTAAGTCATTCCCATTCAAC 180
Qy 181 ACCTCAGTCGTGTATAAGAAGACTCTGTTCGTCGAGTTTACTGATCACCTGTTCAATATC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ACCTCAGTCGTGTATAAGAAGACTCTGTTCGTCGAGTTTACTGATCACCTGTTCAATATC 240
Qy 241 GCTAAACCTAGACCACCCTGGATGGGACTGCTGGGTCCTACAATCCAGGCAGAGGTCTAT 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GCTAAACCTAGACCACCCTGGATGGGACTGCTGGGTCCTACAATCCAGGCAGAGGTCTAT 300
Qy 301 GACACTGTGGTGATTACACTTAAGAACATGGCTTCCCATCCTGTCAGTCTTCATGCTGTT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GACACTGTGGTGATTACACTTAAGAACATGGCTTCCCATCCTGTCAGTCTTCATGCTGTT 360
Qy 361 GGTGTATCCTACTGGAAAGCTTCTGAGGGAGCTGAATATGATGATCAGACCAGTCAAAGG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GGTGTATCCTACTGGAAAGCTTCTGAGGGAGCTGAATATGATGATCAGACCAGTCAAAGG 420
Qy 421 GAGAAAGAAGATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGGCAGGTCCTG 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GAGAAAGAAGATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGGCAGGTCCTG 480
Qy 481 AAAGAGAATGGTCCAATGGCCTCTGACCCACTGTGCCTTACCTACTCATATCTTTCTCAT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 AAAGAGAATGGTCCAATGGCCTCTGACCCACTGTGCCTTACCTACTCATATCTTTCTCAT 540
Qy 541 GTGGACCTGGTAAAAGACTTGAATTCAGGCCTCATTGGAGCCCTACTAGTATGTAGAGAA 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 GTGGACCTGGTAAAAGACTTGAATTCAGGCCTCATTGGAGCCCTACTAGTATGTAGAGAA 600
Qy 601 GGGAGTCTGGCCAAGGAAAAGACACAGACCTTGCACAAATTTATACTACTTTTTGCTGTA 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 GGGAGTCTGGCCAAGGAAAAGACACAGACCTTGCACAAATTTATACTACTTTTTGCTGTA 660
Qy 661 TTTGATGAAGGGAAAAGTTGGCACTCAGAAACAAAGAACTCCTTGATGCAGGATAGGGAT 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 TTTGATGAAGGGAAAAGTTGGCACTCAGAAACAAAGAACTCCTTGATGCAGGATAGGGAT 720
Qy 721 GCTGCATCTGCTCGGGCCTGGCCTAAAATGCACACAGTCAATGGTTATGTAAACAGGTCT 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 GCTGCATCTGCTCGGGCCTGGCCTAAAATGCACACAGTCAATGGTTATGTAAACAGGTCT 780
Qy 781 CTGCCAGGTCTGATTGGATGCCACAGGAAATCAGTCTATTGGCATGTGATTGGAATGGGC 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 CTGCCAGGTCTGATTGGATGCCACAGGAAATCAGTCTATTGGCATGTGATTGGAATGGGC 840
Qy 841 ACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATTTCTTGTGAGGAACCAT 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 ACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATTTCTTGTGAGGAACCAT 900
Qy 901 CGCCAGGCGTCCTTGGAAATCTCGCCAATAACTTTCCTTACTGCTCAAACACTCTTGATG 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 CGCCAGGCGTCCTTGGAAATCTCGCCAATAACTTTCCTTACTGCTCAAACACTCTTGATG 960
Qy 961 GACCTTGGACAGTTTCTACTGTTTTGTCATATCTCTTCCCACCAACATGATGGCATGGAA 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 GACCTTGGACAGTTTCTACTGTTTTGTCATATCTCTTCCCACCAACATGATGGCATGGAA 1020
Qy 1021 GCTTATGTCAAAGTAGACAGCTGTCCAGAGGAACCCCAACTACGAATGAAAAATAATGAA 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 GCTTATGTCAAAGTAGACAGCTGTCCAGAGGAACCCCAACTACGAATGAAAAATAATGAA 1080
Qy 1081 GAAGCGGAAGACTATGATGATGATCTTACTGATTCTGAAATGGATGTGGTCAGGTTTGAT 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 GAAGCGGAAGACTATGATGATGATCTTACTGATTCTGAAATGGATGTGGTCAGGTTTGAT 1140
Qy 1141 GATGACAACTCTCCTTCCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTAAAACT 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 GATGACAACTCTCCTTCCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTAAAACT 1200
Qy 1201 TGGGTACATTACATTGCTGCTGAAGAGGAGGACTGGGACTATGCTCCCTTAGTCCTCGCC 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 TGGGTACATTACATTGCTGCTGAAGAGGAGGACTGGGACTATGCTCCCTTAGTCCTCGCC 1260
Qy 1261 CCCGATGACAGAAGTTATAAAAGTCAATATTTGAACAATGGCCCTCAGCGGATTGGTAGG 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 CCCGATGACAGAAGTTATAAAAGTCAATATTTGAACAATGGCCCTCAGCGGATTGGTAGG 1320
Qy 1321 AAGTACAAAAAAGTCCGATTTATGGCATACACAGATGAAACCTTTAAGACTCGTGAAGCT 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1321 AAGTACAAAAAAGTCCGATTTATGGCATACACAGATGAAACCTTTAAGACTCGTGAAGCT 1380
Qy 1381 ATTCAGCATGAATCAGGAATCTTGGGACCTTTACTTTATGGGGAAGTTGGAGACACACTG 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1381 ATTCAGCATGAATCAGGAATCTTGGGACCTTTACTTTATGGGGAAGTTGGAGACACACTG 1440
Qy 1441 TTGATTATATTTAAGAATCAAGCAAGCAGACCATATAACATCTACCCTCACGGAATCACT 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1441 TTGATTATATTTAAGAATCAAGCAAGCAGACCATATAACATCTACCCTCACGGAATCACT 1500
Qy 1501 GATGTCCGTCCTTTGTATTCAAGGAGATTACCAAAAGGTGTAAAACATTTGAAGGATTTT 1560
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1501 GATGTCCGTCCTTTGTATTCAAGGAGATTACCAAAAGGTGTAAAACATTTGAAGGATTTT 1560
Qy 1561 CCAATTCTGCCAGGAGAAATATTCAAATATAAATGGACAGTGACTGTAGAAGATGGGCCA 1620
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1561 CCAATTCTGCCAGGAGAAATATTCAAATATAAATGGACAGTGACTGTAGAAGATGGGCCA 1620
Qy 1621 ACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTAGTTTCGTTAATATGGAGAGA 1680
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1621 ACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTAGTTTCGTTAATATGGAGAGA 1680
Qy 1681 GATCTAGCTTCAGGACTCATTGGCCCTCTCCTCATCTGCTACAAAGAATCTGTAGATCAA 1740
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1681 GATCTAGCTTCAGGACTCATTGGCCCTCTCCTCATCTGCTACAAAGAATCTGTAGATCAA 1740
Qy 1741 AGAGGAAACCAGATAATGTCAGACAAGAGGAATGTCATCCTGTTTTCTGTATTTGATGAG 1800
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1741 AGAGGAAACCAGATAATGTCAGACAAGAGGAATGTCATCCTGTTTTCTGTATTTGATGAG 1800
Qy 1801 AACCGAAGCTGGTACCTCACAGAGAATATACAACGCTTTCTCCCCAATCCAGCTGGAGTG 1860
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1801 AACCGAAGCTGGTACCTCACAGAGAATATACAACGCTTTCTCCCCAATCCAGCTGGAGTG 1860
Qy 1861 CAGCTTGAGGATCCAGAGTTCCAAGCCTCCAACATCATGCACAGCATCAATGGCTATGTT 1920
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1861 CAGCTTGAGGATCCAGAGTTCCAAGCCTCCAACATCATGCACAGCATCAATGGCTATGTT 1920
Qy 1921 TTTGATAGTTTGCAGTTGTCAGTTTGTTTGCATGAGGTGGCATACTGGTACATTCTAAGC 1980
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1921 TTTGATAGTTTGCAGTTGTCAGTTTGTTTGCATGAGGTGGCATACTGGTACATTCTAAGC 1980
Qy 1981 ATTGGAGCACAGACTGACTTCCTTTCTGTCTTCTTCTCTGGATATACCTTCAAACACAAA 2040
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1981 ATTGGAGCACAGACTGACTTCCTTTCTGTCTTCTTCTCTGGATATACCTTCAAACACAAA 2040
Qy 2041 ATGGTCTATGAAGACACACTCACCCTATTCCCATTCTCAGGAGAAACTGTCTTCATGTCG 2100
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2041 ATGGTCTATGAAGACACACTCACCCTATTCCCATTCTCAGGAGAAACTGTCTTCATGTCG 2100
Qy 2101 ATGGAAAACCCAGGTCTATGGATTCTGGGGTGCCACAACTCAGACTTTCGGAACAGAGGC 2160
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2101 ATGGAAAACCCAGGTCTATGGATTCTGGGGTGCCACAACTCAGACTTTCGGAACAGAGGC 2160
Qy 2161 ATGACCGCCTTACTGAAGGTTTCTAGTTGTGACAAGAACACTGGTGATTATTACGAGGAC 2220
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2161 ATGACCGCCTTACTGAAGGTTTCTAGTTGTGACAAGAACACTGGTGATTATTACGAGGAC 2220
Qy 2221 AGTTATGAAGATATTTCAGCATACTTGCTGAGTAAAAACAATGCCATTGAACCAAGAAGC 2280
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2221 AGTTATGAAGATATTTCAGCATACTTGCTGAGTAAAAACAATGCCATTGAACCAAGAAGC 2280
Qy 2281 TTTTCTCAGAATCCTCCTGTCCTCAAACGCCATCAACGGGAGATTACACGGACCACACTC 2340
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2281 TTTTCTCAGAATCCTCCTGTCCTCAAACGCCATCAACGGGAGATTACACGGACCACACTC 2340
Qy 2341 CAAAGCGATCAGGAGGAGATCGACTATGACGATACCATATCTGTGGAAATGAAGAAAGAG 2400
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2341 CAAAGCGATCAGGAGGAGATCGACTATGACGATACCATATCTGTGGAAATGAAGAAAGAG 2400
Qy 2401 GACTTCGACATCTACGACGAAGATGAGAACCAAAGTCCAAGATCCTTCCAGAAGAAGACT 2460
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2401 GACTTCGACATCTACGACGAAGATGAGAACCAAAGTCCAAGATCCTTCCAGAAGAAGACT 2460
Qy 2461 AGGCACTACTTCATCGCTGCCGTGGAACGCCTCTGGGATTACGGAATGTCCAGTTCTCCA 2520
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2461 AGGCACTACTTCATCGCTGCCGTGGAACGCCTCTGGGATTACGGAATGTCCAGTTCTCCA 2520
Qy 2521 CATGTCCTCAGGAATAGGGCACAGTCTGGCTCTGTTCCACAGTTTAAGAAAGTTGTCTTT 2580
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2521 CATGTCCTCAGGAATAGGGCACAGTCTGGCTCTGTTCCACAGTTTAAGAAAGTTGTCTTT 2580
Qy 2581 CAGGAGTTCACAGATGGCTCATTCACTCAACCACTGTATAGAGGCGAACTGAATGAGCAC 2640
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2581 CAGGAGTTCACAGATGGCTCATTCACTCAACCACTGTATAGAGGCGAACTGAATGAGCAC 2640
Qy 2641 CTGGGACTGCTGGGTCCCTACATCAGAGCCGAAGTGGAGGATAACATTATGGTCACCTTT 2700
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2641 CTGGGACTGCTGGGTCCCTACATCAGAGCCGAAGTGGAGGATAACATTATGGTCACCTTT 2700
Qy 2701 CGGAACCAAGCCTCCAGGCCATACAGTTTCTACAGTTCTCTGATCTCATACGAGGAAGAT 2760
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2701 CGGAACCAAGCCTCCAGGCCATACAGTTTCTACAGTTCTCTGATCTCATACGAGGAAGAT 2760
Qy 2761 CAGAGGCAAGGAGCAGAACCAAGGAAGAACTTCGTGAAACCAAACGAGACAAAGACCTAT 2820
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2761 CAGAGGCAAGGAGCAGAACCAAGGAAGAACTTCGTGAAACCAAACGAGACAAAGACCTAT 2820
Qy 2821 TTCTGGAAAGTTCAGCATCATATGGCACCCACTAAAGATGAGTTTGACTGCAAAGCCTGG 2880
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2821 TTCTGGAAAGTTCAGCATCATATGGCACCCACTAAAGATGAGTTTGACTGCAAAGCCTGG 2880
Qy 2881 GCTTATTTCTCTGATGTTGACCTGGAAAAAGATGTGCACTCAGGCCTGATTGGACCCCTT 2940
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2881 GCTTATTTCTCTGATGTTGACCTGGAAAAAGATGTGCACTCAGGCCTGATTGGACCCCTT 2940
Qy 2941 CTGGTCTGCCACACTAACACACTGAACCCTGCTCATGGGAGACAAGTGACAGTACAGGAA 3000
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2941 CTGGTCTGCCACACTAACACACTGAACCCTGCTCATGGGAGACAAGTGACAGTACAGGAA 3000
Qy 3001 TTTGCTCTGTTTTTCACCATCTTTGATGAGACCAAAAGCTGGTACTTCACTGAAAATATG 3060
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3001 TTTGCTCTGTTTTTCACCATCTTTGATGAGACCAAAAGCTGGTACTTCACTGAAAATATG 3060
Qy 3061 GAAAGAAACTGCAGGGCTCCCTGCAATATCCAGATGGAAGATCCCACTTTTAAAGAGAAT 3120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3061 GAAAGAAACTGCAGGGCTCCCTGCAATATCCAGATGGAAGATCCCACTTTTAAAGAGAAT 3120
Qy 3121 TATCGCTTCCATGCAATCAATGGCTACATAATGGATACACTACCTGGCTTAGTAATGGCT 3180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3121 TATCGCTTCCATGCAATCAATGGCTACATAATGGATACACTACCTGGCTTAGTAATGGCT 3180
Qy 3181 CAGGATCAAAGGATTCGATGGTATCTGCTCAGCATGGGCAGCAATGAAAACATCCATTCT 3240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3181 CAGGATCAAAGGATTCGATGGTATCTGCTCAGCATGGGCAGCAATGAAAACATCCATTCT 3240
Qy 3241 ATTCATTTCAGTGGACATGTGTTCACTGTACGAAAAAAAGAGGAGTATAAAATGGCACTG 3300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3241 ATTCATTTCAGTGGACATGTGTTCACTGTACGAAAAAAAGAGGAGTATAAAATGGCACTG 3300
Qy 3301 TACAATCTCTATCCAGGTGTTTTTGAGACAGTGGAAATGTTACCATCCAAAGCTGGAATT 3360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3301 TACAATCTCTATCCAGGTGTTTTTGAGACAGTGGAAATGTTACCATCCAAAGCTGGAATT 3360
Qy 3361 TGGCGGGTGGAATGCCTTATTGGCGAGCATCTACATGCTGGGATGAGCACACTTTTTCTG 3420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3361 TGGCGGGTGGAATGCCTTATTGGCGAGCATCTACATGCTGGGATGAGCACACTTTTTCTG 3420
Qy 3421 GTGTACAGCAATAAGTGTCAGACTCCCCTGGGAATGGCTTCTGGACACATTAGAGATTTT 3480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3421 GTGTACAGCAATAAGTGTCAGACTCCCCTGGGAATGGCTTCTGGACACATTAGAGATTTT 3480
Qy 3481 CAGATTACAGCTTCAGGACAATATGGACAGTGGGCCCCAAAGCTGGCCAGACTTCATTAT 3540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3481 CAGATTACAGCTTCAGGACAATATGGACAGTGGGCCCCAAAGCTGGCCAGACTTCATTAT 3540
Qy 3541 TCCGGATCAATCAATGCCTGGAGCACCAAGGAGCCCTTTTCTTGGATCAAGGTGGATCTG 3600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3541 TCCGGATCAATCAATGCCTGGAGCACCAAGGAGCCCTTTTCTTGGATCAAGGTGGATCTG 3600
Qy 3601 TTGGCACCAATGATTATTCACGGCATCAAGACCCAGGGTGCCCGTCAGAAGTTCTCCAGC 3660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3601 TTGGCACCAATGATTATTCACGGCATCAAGACCCAGGGTGCCCGTCAGAAGTTCTCCAGC 3660
Qy 3661 CTCTACATCTCTCAGTTTATCATCATGTATAGTCTTGATGGGAAGAAGTGGCAGACTTAT 3720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3661 CTCTACATCTCTCAGTTTATCATCATGTATAGTCTTGATGGGAAGAAGTGGCAGACTTAT 3720
Qy 3721 CGAGGAAATTCCACTGGAACCTTAATGGTCTTCTTTGGCAATGTGGATTCATCTGGGATA 3780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3721 CGAGGAAATTCCACTGGAACCTTAATGGTCTTCTTTGGCAATGTGGATTCATCTGGGATA 3780
Qy 3781 AAACACAATATTTTTAACCCTCCAATTATTGCTCGATACATCCGTTTGCACCCAACTCAT 3840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3781 AAACACAATATTTTTAACCCTCCAATTATTGCTCGATACATCCGTTTGCACCCAACTCAT 3840
Qy 3841 TATAGCATTCGCAGCACTCTTCGCATGGAGTTGATGGGCTGTGATTTAAATAGTTGCAGC 3900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3841 TATAGCATTCGCAGCACTCTTCGCATGGAGTTGATGGGCTGTGATTTAAATAGTTGCAGC 3900
Qy 3901 ATGCCATTGGGAATGGAGAGTAAAGCAATATCAGATGCACAGATTACTGCTTCATCCTAC 3960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3901 ATGCCATTGGGAATGGAGAGTAAAGCAATATCAGATGCACAGATTACTGCTTCATCCTAC 3960
Qy 3961 TTTACCAATATGTTTGCCACCTGGTCTCCTTCAAAAGCTCGACTTCACCTCCAAGGGAGG 4020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3961 TTTACCAATATGTTTGCCACCTGGTCTCCTTCAAAAGCTCGACTTCACCTCCAAGGGAGG 4020
Qy 4021 AGTAATGCCTGGAGACCTCAGGTGAATAATCCAAAAGAGTGGCTGCAAGTGGACTTCCAG 4080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4021 AGTAATGCCTGGAGACCTCAGGTGAATAATCCAAAAGAGTGGCTGCAAGTGGACTTCCAG 4080
Qy 4081 AAGACAATGAAAGTCACAGGAGTAACTACTCAGGGAGTAAAATCTCTGCTTACCAGCATG 4140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4081 AAGACAATGAAAGTCACAGGAGTAACTACTCAGGGAGTAAAATCTCTGCTTACCAGCATG 4140
Qy 4141 TATGTGAAGGAGTTCCTCATCTCCAGCAGTCAAGATGGCCATCAGTGGACTCTCTTTTTT 4200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4141 TATGTGAAGGAGTTCCTCATCTCCAGCAGTCAAGATGGCCATCAGTGGACTCTCTTTTTT 4200
Qy 4201 CAGAATGGCAAAGTAAAGGTTTTTCAGGGAAATCAAGACTCCTTCACACCTGTGGTGAAC 4260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4201 CAGAATGGCAAAGTAAAGGTTTTTCAGGGAAATCAAGACTCCTTCACACCTGTGGTGAAC 4260
Qy 4261 TCTCTAGACCCACCGTTACTGACTCGCTACCTTCGAATTCACCCCCAGAGTTGGGTGCAC 4320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4261 TCTCTAGACCCACCGTTACTGACTCGCTACCTTCGAATTCACCCCCAGAGTTGGGTGCAC 4320
Qy 4321 CAGATTGCCCTGAGGATGGAGGTTCTGGGCTGCGAGGCACAGGACCTCTACTGA 4374
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 4321 CAGATTGCCCTGAGGATGGAGGTTCTGGGCTGCGAGGCACAGGACCTCTACTGA 4374
Guo does not teach wherein the promoter is expressly tissue-specific nor consisting of instant SEQ ID NO: 1.
However Olgasi teaches coagulation factor FVIII (FVIII) is normally expressed in endothelial cells and forced expression via a lentiviral vector (e.g., LV.VEC.hBDDFVIII (Fig. S1)) using an endothelial specific promoter can restore FVIII protein levels in a mouse model (pg. 1391, right col.) and, more specifically, that by expressing FVIII using the endothelial specific promoter VEC (cadherin 5) and can be used to complement FVIII genetic defects in human hemophilic cells (Fig. 4) and treat hemophilic mice (pg. 1402; 1403, left col., para. 4; pg. 1399, right col., Fig. 5). Although Olgasi does not teach the sequence of the VEC promoter used, VEC promoter sequences were known in the prior art, such as disclosed by Benmohamed (SEQ ID NO: 174), as shown below, as a known recombinant tool for expression vectors known to achieve transgene expression.
# Query: SEQ ID NO: 1
# Length: 1218
# Identity: 1209/1218 (99.3%)
SEQ ID NO 1 2 cggccg-ctccaaaaatatccttccatcacactccccatcttgtgctctg 50
|..||. |||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 164 cctcctcctccaaaaatatccttccatcacactccccatcttgtgctctg 213
SEQ ID NO 1 51 atttactaaacggccctgggccctctctttctcagggtctctgcttgccc 100
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 214 atttactaaacggccctgggccctctctttctcagggtctctgcttgccc 263
SEQ ID NO 1 101 agctatataataaaacaagtttgggacttcccaaccattcacccatggaa 150
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 264 agctatataataaaacaagtttgggacttcccaaccattcacccatggaa 313
SEQ ID NO 1 151 aaacagaagcaactcttcaaaggacagattcccaggatctgccctgggag 200
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 314 aaacagaagcaactcttcaaaggacagattcccaggatctgccctgggag 363
SEQ ID NO 1 201 attccaaatcagttgatctggggtgagcccagtcctctgtagtttttaga 250
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 364 attccaaatcagttgatctggggtgagcccagtcctctgtagtttttaga 413
SEQ ID NO 1 251 agctcctcctatgtctctcctggtcagcagaatcttggcccctcccttcc 300
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 414 agctcctcctatgtctctcctggtcagcagaatcttggcccctcccttcc 463
SEQ ID NO 1 301 ccccagcctcttggttcttctgggctctgatccagcctcagcgtcactgt 350
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 464 ccccagcctcttggttcttctgggctctgatccagcctcagcgtcactgt 513
SEQ ID NO 1 351 cttccacgcccctctttgattctcgtttatgtcaaaagccttgtgaggat 400
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 514 cttccacgcccctctttgattctcgtttatgtcaaaagccttgtgaggat 563
SEQ ID NO 1 401 gaggctgtgattatccccattttacagatgaggaaactgtggctccagga 450
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 564 gaggctgtgattatccccattttacagatgaggaaactgtggctccagga 613
SEQ ID NO 1 451 tgacacaactggccagaggtcacatcagaagcagagctgggtcacttgac 500
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 614 tgacacaactggccagaggtcacatcagaagcagagctgggtcacttgac 663
SEQ ID NO 1 501 tccacccaatatccctaaatgcaaacatcccctacagaccgaggctggca 550
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 664 tccacccaatatccctaaatgcaaacatcccctacagaccgaggctggca 713
SEQ ID NO 1 551 ccttagagctggagtccatgcccgctctgaccaggagaagccaacctggt 600
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 714 ccttagagctggagtccatgcccgctctgaccaggagaagccaacctggt 763
SEQ ID NO 1 601 cctccagagccaagagcttctgtccctttcccatctcctgaagcctccct 650
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 764 cctccagagccaagagcttctgtccctttcccatctcctgaagcctccct 813
SEQ ID NO 1 651 gtcacctttaaagtccattcccacaaagacatcatgggatcaccacagaa 700
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 814 gtcacctttaaagtccattcccacaaagacatcatgggatcaccacagaa 863
SEQ ID NO 1 701 aatcaagctctggggctaggctgaccccagctagatttttggctctttta 750
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 864 aatcaagctctggggctaggctgaccccagctagatttttggctctttta 913
SEQ ID NO 1 751 taccccagctgggtggacaagcaccttaaacccgctgagcctcagcttcc 800
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 914 taccccagctgggtggacaagcaccttaaacccgctgagcctcagcttcc 963
SEQ ID NO 1 801 cgggctataaaatgggggtgatgacacctgcctgtagcattccaaggagg 850
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 964 cgggctataaaatgggggtgatgacacctgcctgtagcattccaaggagg 1013
SEQ ID NO 1 851 gttaaatgtgatgctgcagccaagggtccccacagccaggctctttgcag 900
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 1014 gttaaatgtgatgctgcagccaagggtccccacagccaggctctttgcag 1063
SEQ ID NO 1 901 gtgctgggttcagagtcccagagctgaggccgggagtaggggttcaagtg 950
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 1064 gtgctgggttcagagtcccagagctgaggccgggagtaggggttcaagtg 1113
SEQ ID NO 1 951 gggtgccccaggcagggtccagtgccagccctctgtggagacagccatcc 1000
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 1114 gggtgccccaggcagggtccagtgccagccctctgtggagacagccatcc 1163
SEQ ID NO 1 1001 ggggccgaggcagccgcccaccgcagggcctgcctatctgcagccagccc 1050
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 1164 ggggccgaggcagccgcccaccgcagggcctgcctatctgcagccagccc 1213
SEQ ID NO 1 1051 agccctcacaaaggaacaataacaggaaaccatcccagggggaagtgggc 1100
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 1214 agccctcacaaaggaacaataacaggaaaccatcccagggggaagtgggc 1263
SEQ ID NO 1 1101 cagggccagctggaaaacctgaaggggaggcagccaggcctccctcgcca 1150
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 1264 cagggccagctggaaaacctgaaggggaggcagccaggcctccctcgcca 1313
SEQ ID NO 1 1151 gcggggtgtggctcccctccaaagacggtcggctgacaggctccacagag 1200
||||||||||||||||||||||||||||||||||||||||||||||||||
SEQ ID 174 1314 gcggggtgtggctcccctccaaagacggtcggctgacaggctccacagag 1363
SEQ ID NO 1 1201 ctccactcccggggatcc 1218
||||||||.||...|.||
SEQ ID 174 1364 ctccactcacgctcagcc 1381
The skilled artisan with the goal of replacement FVIII expression in a cell or a subject having mutated VIII (such as a hemophilia A patient) would be motivated to target the replacement VIII expression to an endogenous tissue and Olgasi teaches a prior art promoter in a lentiviral vector already used for the same purpose. Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to design the viral vector taught by Guo to comprise a VEC promoter driving the FVIII transgene wherein the promoter comprises instant SEQ ID NO: 1 in view of Benmohamed. One of ordinary skill in the art would be motivated by Olgasi demonstrating the VEC promoter works for the same purpose and Benmohamed disclosing an exemplary VEC promoter sequence. The record is silent as to any critical function to the exact first and last 8 nucleotides of the tissue specific promoter. Thus, although the sequence taught by Benmohamed is only 99.3% identical to SEQ ID NO: 1, this 0.7% difference is deemed as insignificant absent evidence to the contrary and is within the skills of the ordinary person of skill in the art to arrive at with a reasonable expectation of success when implementing the combination taught by the art detailed above, such as due to restriction site engineering the human VEC promoter for ligation into the vector.
Regarding claim 5, Guo teaches a recombinant lentivirus comprising the recombinant expression vector (pg. 5, 16-17; claim 7).
Regarding claim 6, Guo teaches a recombinant cell containing the recombinant expression vector (pg. 17; claims 11, 7-10 and 12).
Regarding claim 9, Guo teaches a pharmaceutical composition comprising the recombinant expression vector and another component such as an excipient, diluent carrier, or adjuvant (pg. 18, claim 13).
Claims 4-6, 9, and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Guo in view of Olgasi and Benmohamed as applied above, and further in view of Iwakuma (Iwakuma et al., Virology 261: 120-32 (1999)).
Regarding claim 12, Guo, Olgasi, and Benmohamed does not teach wherein the lentiviral vector is or comprises pEGWI. However Iwakuma teaches an HIV-derived lentiviral vector having modified 3’ U3 and/or U5 region sequences to confer improved safety and efficacy for transgene expression (Abstract, pg. 125-127, Fig. 7-8). Iwakuma teaches U3 region alterations which render this vector self-inactivating (SIN) to improve safety and titers (Fig. 4, 7). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to design the lentiviral vector taught by the combination of Guo, Olgasi, and Benmohamed to have a SIN backbone with such a U3 region deletion, interpreted as meeting the “pEGWI” limitation in view of the instant specification at instant pg. 5 (e.g., [0020]). One of ordinary skill in the art would be motivated by the higher titers achieved with the “pEGWI” vector feature. Also, one of ordinary skill in the art with the goal of using the expression vector for gene therapy in a hemophilic subject as taught by Guo and Olgasi would be motivated by Iwakuma teaching this lentivirus vector feature’s improved safety due to engineered self-inactivation to prevent spread of replicating lentivirus and oncogene genotoxicity in the subject.
Conclusion
No claim is allowed.
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/ERIC J ROGERS/
Examiner, Art Unit 1638
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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