Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/10/2023 and 7/18/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of Claims
Claims 1-16, 25-28, 31-35 and 36-38 are pending and under exam. Claims 17-24 and 29-30 are cancelled.
WITHDRAWN REJECTIONS
Claim Rejections - 35 USC § 112
Claims 1-16, and 25-28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The rejection as applied in the non-final office action of 12/16/2025 is withdrawn but is adapted for the instant claims as enumerated below.
Claim Rejections - 35 USC § 103
Claims 1-3, 5-8, 12-13, 15-16 and 25-28 are rejected under 35 U.S.C. 103 as being unpatentable over Kirin et al (U.S. Patent No. 11802278 as supported by 63/016,207 filed 04/27/2020; hereinafter "Kirin;" See PTO-892) in view of Do et al (US20200147241A1; published 05/14/2020; hereinafter "Do;" See IDS of 07/18/2023).
Claims 4, 9 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Kirin et al (U.S. Patent No. 11802278 as supported by 63/016,207 filed 04/27/2020; hereinafter "Kirin;" See PTO-892) in view of Do et al (US20200147241A1; published 05/14/2020; hereinafter "Do;" See IDS of 07/18/2023) and Yasuda et al (Mol Ther Methods Clin Dev. 2020 Jul 9; hereinafter “Yasuda;” See IDS of 07/18/2023).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Kirin et al (U.S. Patent No. 11802278 as supported by 63/016,207 filed 04/27/2020; hereinafter "Kirin;" See PTO-892) in view of Do et al (US20200147241A1; published 05/14/2020; hereinafter "Do;" See IDS of 07/18/2023) and Hordeux et al (WO2020132455 Jun 25, 2020; hereinafter “Hordeux;” See IDS of 07/18/2023).
The rejection as applied in the non-final office action of 12/16/2025 is withdrawn but is adapted for the instant claims as enumerated below.
MAINTAINED REJECTIONS
Claims 5, 7, 10, 12-16 and 25-28 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
Claim 12 covers all coding sequences coding sequence comprises nucleotides 94 to 1287 of SEQ ID NO: 4, or a sequence at least 85% identical thereto. Even if only substitution mutations were considered, >85% identity to a 1014 base pair polynucleotide encompasses
1014
C
79
×
3
79
=
m
o
r
e
t
h
a
n
7.3
×
10
156
nucleotide molecules. This amounts to enormous number of polynucleotides which do not have support in the specification. The specification provides no description of these variants or that the Applicants had possession of such an expansive genus at the time of filing. It is also noted that the specification provided no evidence that variants differing by 15% from the claimed nucleotides retain any therapeutic or enzymatic function.
The disclosure contains no examples of variant sequences, no mutational analysis, no conservative substitution tables, no structural or functional domains identified, and no guidance whatsoever regarding which residues may be altered. As such, the specification does not provide any indication that the inventors had possession of the exceedingly broad genus of “85% identity” variants.
Because the specification provides only a single sequence (SEQ ID NO: 4) and no guidance regarding permissible substitutions, structural domains, functional requirements, or mutation-tolerant regions, it fails to demonstrate possession of the vast genus of polynucleotides now claimed.
Regarding claims 5: The claim requires a heterologous signal peptide. The specification at [0073] provided support for the heterologous signaling peptide that “such a heterologous signal peptide is preferably of human origin and may include, e.g., an IL-2 signal peptide. Particular heterologous signal peptides workable in the certain embodiments include amino acids 1-20 from chymotrypsinogen B2, the signal peptide of human alpha-1-antitrypsin, amino acids 1-25 from iduronate-2-sulphatase, and amino acids 1-23 from protease CI inhibitor. See, e.g., WO2018046774. Other signal/leader peptides may be natively found in an immunoglobulin (e.g., IgG), a cytokine (e.g., IL-2, IL12, IL18, or the like), insulin, albumin, β-glucuronidase, alkaline protease or the fibronectin secretory signal peptides, amongst others. See, also, e.g., signalpeptide.de/index.php?m=listspdb_mammalia. Such a chimeric hGLA may have the heterologous leader in the place of the entire 31 amino acid native signal peptide.” It is however noted that “a “laundry list” disclosure of every possible moiety for every possible position does not constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species” (See MPEP 2163.05 B. II). As such, generic references to categories of signal peptides or to external databases do not demonstrate possession of the particular chimeric polypeptides encompassed by the claim.
The specification provides no representative species and no structural guidance regarding which signal peptides are compatible with alpha-galactosidase, the application as filed does not reasonably convey to those of ordinary skill in the art that the inventors had possession of the full scope of the claimed constructs.
Regarding claim 7: The claim requires a tissue specific promoter. The specification indicates at [0099] that “Examples of promoters that are tissue-specific are well known for liver and other tissues,” and further incorporates some scientific papers by reference. As indicated above, a laundry list disclosure does not constitute written description. Because the claims encompass unidentified tissue specific promoters and the specification provides no representative species and no structural guidance regarding which tissue specific promoters are compatible with alpha-galactosidase, the application as filed does not reasonably convey to those of ordinary skill in the art that the inventors had possession of the full scope of the claimed constructs.
Regarding claim 10: The claim requires one or more miRNA target sequences. The breadth of the claim encompasses any and all miRNA sequences. The specification at [0103] states that “The miRNA target sequences are designed to be specifically recognized by miRNA present in cells in which transgene expression is undesirable and/or reduced levels of transgene expression are desired.” Further in [0104] and [105], the specification taught miR-182 and miR-183 sequences. The specification does not provide structural requirements, or any other guidance for a person of ordinary skill in the art to select miRNA targets, to support broader claim scope. As such specification describes a desired result and does not provide any structure for the miRNA sequences. As such the specification fails to demonstrate possession of the claimed scope of the claim.
Response to Applicant’s Arguments:
Applicant argued that one of ordinary skill in the art would understand, based on codon degeneracy of the genetic code, how to generate nucleotide sequences encoding the recited amino acid sequences. However, the argument addresses whether variant sequences could be generated, rather than whether the specification reasonably conveys possession of the full scope of the claimed genus as required by 35 U.S.C. §112(a)
The claims are directed to coding sequences having at least 85% identity to SEQ ID NO: 4 that encode a functional human alpha galactosidase A. The specification provides the disclosed hGLA sequence but does not identify which nucleotide or amino acid substitutions may be made while retaining the functional hGLA activity. Nor does the specification identify mutation-tolerant regions, conserved residues, or representative functional variants, or any structural features common to the claimed genus that would allow one or ordinary skill in the art to recognize the members of the claimed genus that retain the required functionality.
Accordingly, the specification does not reasonably convey possession of the full scope of the claimed genus of functional hGLA variants encompassed by the claims.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENTS
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-10, 12-16, and 25-28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 1: Claims 1 and 12 cover all coding sequences coding sequence comprises nucleotides 94 to 1287 of SEQ ID NO: 4, or a sequence at least 95% identical thereto comprising amino acids 32 to 427 of SEQ ID NOs: 2, 7 or 17. It is noted that the specification did not provide support for a functional hGLA having at least amino acids amino acids 32-427 of SEQ ID NO: 2, 7 or 17. It is noted that the claim encompasses that the examples only demonstrated that the application has possession for a functional hGLA comprising SEQ ID NO: 7. (See Specification [0224]). As such the claimed percent identity amounts to enormous number of polynucleotides which do not have support in the specification. The specification provides no description of any of the encompassed variants. It is also noted that the specification provided no evidence that variants differing by 5% from the claimed nucleotides retain any therapeutic or enzymatic function.
Because the specification provides only a single sequence (SEQ ID NO: 4) and no guidance regarding permissible substitutions, structural domains, functional requirements, or mutation-tolerant regions, it fails to demonstrate possession of the genus of polynucleotides now claimed.
Accordingly, claims 2-10, 13-16, and 25-28 are rejected under 35 U.S.C. §112(a) for lack of written description in view of their dependency.
Similar rejection applies to claim 16.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5-8, 12-13, 15-16 and 25-28 are rejected under 35 U.S.C. 103 as being unpatentable over Kirin et al (U.S. Patent No. 11802278 as supported by 63/016,207 filed 04/27/2020; hereinafter "Kirn;" See PTO-892) in view of Do et al (US20200147241A1; published 05/14/2020; hereinafter "Do;" See IDS of 07/18/2023).
Regarding claims 1 and 12: Claim 23 of 63/016/207 (Kirn) and claim 1 of the patent taught an rAAV comprising a capsid, and SEQ ID NO: 1 which is 96% identical to claimed nucleotides 94-1286 of instant SEQ ID NO: 4 linked to a CAG promoter. (See alignment below). Also claim 1 of Kirin taught Claim 23 of 63/016/207 (Kirn) taught an rAAV comprising a capsid, and SEQ ID NO: 1 which is 96% identical to claimed nucleotides 94-1286 of instant SEQ ID NO: 4 linked to a CAG promoter. The CAG promoter reads on the claimed regulatory sequences which direct expression of the hGLA in a target cell. Kirn did not teach a hGLA having a cysteine residue at position 233 and/or position 359 based on the amino acid residue numbering of SEQ ID NO: 2. Do taught a viral vector comprising a stabilized form of h-alpha galactosidase comprising D233C and I359C mutations. Do taught that the modified human α-GAL polypeptide forms a homodimer which is stabilized by a disulfide bond and shows increased half-life at pH 7.4 compared with a wild type α-GAL polypeptide. (See Do [0027]). It is also noted that Do expressly taught administration of hGLA in mice using AAVhu68. (See Do [0159]). As such one of ordinary skill in the art at the time of invention would have been motivated to express the stabilized hGLA variants of Do in the AAV gene therapy vectors of Kirn. It is noted that Do expressly taught that the D233C/I359C variants increase enzyme stability and therapeutic potential. (Do Abstract). Further Kirn taught hGLA expression AAV based hGLA cassettes using sequences 96% identical to instant SEQ ID NO: 4. It is also noted that amino acid encoding sequence of the SEQ ID NO: 1 disclosed by Kirin comprises amino acids 32 to 427 of SEQ ID NO: 2. It would have been obvious to substitute the hGLA of Kirn with the stability enhanced hGLA variant for the purpose of enhanced hGLA stability and therapeutic potential. Therefore the combination yields composition with predictable results.
Query Match 96.4%; Score 1151.4; Length 1290;
Best Local Similarity 97.8%;
Matches 1167; Conservative 0; Mismatches 26; Indels 0; Gaps 0;
Qy 1 CTGGATAACGGCCTGGCCAGAACACCTACAATGGGCTGGCTGCACTGGGAGAGATTCATG 60
|||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||
Db 94 CTGGATAATGGCCTGGCCAGAACACCTACAATGGGCTGGCTGCACTGGGAGAGATTCATG 153
Qy 61 TGCAACCTGGACTGCCAAGAGGAACCCGACAGCTGCATCAGCGAGAAGCTGTTCATGGAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 154 TGCAACCTGGACTGCCAAGAGGAACCCGACAGCTGCATCAGCGAGAAGCTGTTCATGGAA 213
Qy 121 ATGGCCGAGCTGATGGTGTCCGAAGGCTGGAAGGACGCCGGCTACGAGTACCTGTGCATC 180
||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||
Db 214 ATGGCCGAGCTGATGGTGTCCGAAGGCTGGAAGGATGCCGGCTACGAGTACCTGTGCATC 273
Qy 181 GACGACTGTTGGATGGCCCCTCAGAGAGACTCTGAGGGCAGACTGCAGGCCGATCCTCAG 240
||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||
Db 274 GACGACTGTTGGATGGCCCCTCAGAGAGACTCTGAGGGCAGACTGCAAGCCGATCCTCAG 333
Qy 241 AGATTTCCCCACGGCATTAGACAGCTGGCCAACTACGTGCACAGCAAGGGCCTGAAGCTG 300
||||| || |||||||| ||||||||||||||||||||||||||||||||||||||||||
Db 334 AGATTCCCTCACGGCATCAGACAGCTGGCCAACTACGTGCACAGCAAGGGCCTGAAGCTG 393
Qy 301 GGCATCTACGCCGACGTGGGCAACAAGACCTGTGCCGGCTTTCCTGGCAGCTTCGGCTAC 360
|||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||
Db 394 GGCATCTATGCCGACGTGGGCAACAAGACCTGTGCCGGCTTTCCTGGCAGCTTCGGCTAC 453
Qy 361 TACGATATCGACGCCCAGACCTTCGCCGATTGGGGAGTCGATCTGCTGAAGTTCGACGGC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 454 TACGATATCGACGCCCAGACCTTCGCCGATTGGGGAGTCGATCTGCTGAAGTTCGACGGC 513
Qy 421 TGCTACTGCGACAGCCTGGAAAATCTGGCCGACGGCTACAAGCACATGTCTCTGGCCCTG 480
|||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||
Db 514 TGCTACTGCGACAGCCTGGAAAATCTGGCCGACGGCTACAAGCACATGTCACTGGCCCTG 573
Qy 481 AATCGGACCGGCAGATCCATCGTGTACAGCTGCGAGTGGCCCCTGTACATGTGGCCCTTC 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 574 AATCGGACCGGCAGATCCATCGTGTACAGCTGCGAGTGGCCCCTGTACATGTGGCCCTTC 633
Qy 541 CAGAAGCCTAACTACACCGAGATCAGACAGTACTGCAACCACTGGCGGAACTTCGCCGAC 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 634 CAGAAGCCTAACTACACCGAGATCAGACAGTACTGCAACCACTGGCGGAACTTCGCCGAC 693
Qy 601 ATCTGCGATAGCTGGAAGTCCATCAAGAGCATCCTGGACTGGACCAGCTTCAATCAAGAG 660
||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 694 ATCGACGATAGCTGGAAGTCCATCAAGAGCATCCTGGACTGGACCAGCTTCAATCAAGAG 753
Qy 661 CGGATCGTGGACGTGGCAGGACCTGGCGGATGGAACGATCCTGACATGCTGGTCATCGGC 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 754 CGGATCGTGGACGTGGCAGGACCTGGCGGATGGAACGATCCTGACATGCTGGTCATCGGC 813
Qy 721 AACTTCGGCCTGAGCTGGAACCAGCAAGTGACCCAGATGGCCCTGTGGGCCATTATGGCC 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 814 AACTTCGGCCTGAGCTGGAACCAGCAAGTGACCCAGATGGCCCTGTGGGCCATTATGGCC 873
Qy 781 GCTCCTCTGTTCATGAGCAACGACCTGAGACACATCAGCCCTCAGGCCAAGGCTCTGCTG 840
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 874 GCTCCTCTGTTCATGAGCAACGACCTGAGACACATCAGCCCTCAGGCCAAGGCTCTGCTC 933
Qy 841 CAGGACAAGGATGTGATCGCTATCAACCAGGATCCTCTGGGCAAGCAGGGCTACCAGCTG 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 934 CAGGACAAGGATGTGATCGCTATCAACCAGGATCCTCTGGGCAAGCAGGGCTACCAGCTG 993
Qy 901 AGACAGGGCGACAATTTCGAAGTGTGGGAAAGACCCCTGAGCGGACTGGCTTGGGCCGTC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 994 AGACAGGGCGACAATTTCGAAGTGTGGGAAAGACCCCTGAGCGGACTGGCTTGGGCCGTC 1053
Qy 961 GCCATGATCAACCGGCAAGAGTGCGGCGGCCCCAGATCCTACACAATCGCCGTGGCCAGT 1020
|||||||||||| | |||||| |||||| ||| | ||||||||||| |||||||| |
Db 1054 GCCATGATCAACAGACAAGAGATCGGCGGACCCCGGTCCTACACAATTGCCGTGGCTTCT 1113
Qy 1021 CTCGGCAAAGGCGTGGCATGTAATCCCGCCTGCTTCATCACACAGCTGCTGCCCGTGAAG 1080
||||||||||||||||| ||||||||||||||||| ||||||||||||||||||||||||
Db 1114 CTCGGCAAAGGCGTGGCCTGTAATCCCGCCTGCTTTATCACACAGCTGCTGCCCGTGAAG 1173
Qy 1081 AGAAAGCTGGGCTTTTACGAGTGGACCAGCAGACTGCGGAGCCACATCAATCCTACCGGC 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1174 AGAAAGCTGGGCTTTTACGAGTGGACCAGCAGACTGCGGAGCCACATCAATCCTACCGGC 1233
Qy 1141 ACAGTGCTGCTGCAGCTGGAAAACACCATGCAGATGAGCCTGAAGGACCTGCT 1193
|||||||||||||| ||||||||||| ||||||||||||||||||||||||||
Db 1234 ACAGTGCTGCTGCAACTGGAAAACACAATGCAGATGAGCCTGAAGGACCTGCT 1286
Alignment of SEQ ID NO: 1 of 63/016,207 with SEQ ID NO: 4 (position 94-1287)
Regarding claim 2: It is noted that the SEQ ID NO: 1 of Kirn translates to a polypeptide with 100% identity to instant SEQ ID NO: 2. (See alignment below)
Query 1 MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFMCNLDCQEEP 60
MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFMCNLDCQEEP
Sbjct 1 MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFMCNLDCQEEP 60
Query 61 DSCISEKLFMEMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQL 120
DSCISEKLFMEMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQL
Sbjct 61 DSCISEKLFMEMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQL 120
Query 121 ANYVHSKGLKLGIYADVGNKTCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENL 180
ANYVHSKGLKLGIYADVGNKTCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENL
Sbjct 121 ANYVHSKGLKLGIYADVGNKTCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENL 180
Query 181 ADGYKHMSLALNRTGRSIVYSCEWPLYMWPFQKPNYTEIRQYCNHWRNFADIDDSWKSIK 240
ADGYKHMSLALNRTGRSIVYSCEWPLYMWPFQKPNYTEIRQYCNHWRNFADIDDSWKSIK
Sbjct 181 ADGYKHMSLALNRTGRSIVYSCEWPLYMWPFQKPNYTEIRQYCNHWRNFADIDDSWKSIK 240
Query 241 SILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQVTQMALWAIMAAPLFMSNDL 300
SILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQVTQMALWAIMAAPLFMSNDL
Sbjct 241 SILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQVTQMALWAIMAAPLFMSNDL 300
Query 301 RHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWAVAMINRQEIG 360
RHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWAVAMINRQEIG
Sbjct 301 RHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWAVAMINRQEIG 360
Query 361 GPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT 420
GPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT
Sbjct 361 GPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT 420
Query 421 MQMSLKDLL 429
MQMSLKDLL
Sbjct 421 MQMSLKDLL 429
Translated SEQ ID NO: 1 of 63/016,207 with SEQ ID NO: 2 (even 32-429)
Regarding claims 3, 13 and 16: Do taught a SEQ ID NO: 5 which is 100% identical to instant SEQ ID NO: 7.
Query 1 MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFMCNLDCQEEP 60
MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFMCNLDCQEEP
Sbjct 1 MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFMCNLDCQEEP 60
Query 61 DSCISEKLFMEMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQL 120
DSCISEKLFMEMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQL
Sbjct 61 DSCISEKLFMEMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQL 120
Query 121 ANYVHSKGLKLGIYADVGNKTCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENL 180
ANYVHSKGLKLGIYADVGNKTCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENL
Sbjct 121 ANYVHSKGLKLGIYADVGNKTCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENL 180
Query 181 ADGYKHMSLALNRTGRSIVYSCEWPLYMWPFQKPNYTEIRQYCNHWRNFADICDSWKSIK 240
ADGYKHMSLALNRTGRSIVYSCEWPLYMWPFQKPNYTEIRQYCNHWRNFADICDSWKSIK
Sbjct 181 ADGYKHMSLALNRTGRSIVYSCEWPLYMWPFQKPNYTEIRQYCNHWRNFADICDSWKSIK 240
Query 241 SILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQVTQMALWAIMAAPLFMSNDL 300
SILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQVTQMALWAIMAAPLFMSNDL
Sbjct 241 SILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQVTQMALWAIMAAPLFMSNDL 300
Query 301 RHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWAVAMINRQECG 360
RHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWAVAMINRQECG
Sbjct 301 RHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWAVAMINRQECG 360
Query 361 GPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT 420
GPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT
Sbjct 361 GPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT 420
Query 421 MQMSLKDLL 429
MQMSLKDLL
Sbjct 421 MQMSLKDLL 429
Alignment between SEQ ID NO: 5 of Do to SEQ ID NO: 7 of instant application.
Regarding claims 5 and 15: Do taught use of a signal sequence. Further [004] taught a binding immunoglobulin protein (Bip) signal sequence.
Regarding claim 6: SEQ ID : 1 of Kirn yields a protein that is 99% identical to claimed SEQ ID NO: 17. (see alignment below).
Query 1 MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFCCNLDCQEEP 60
MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERF CNLDCQEEP
Sbjct 1 MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFMCNLDCQEEP 60
Query 61 DSCISEKLFMEMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQL 120
DSCISEKLFMEMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQL
Sbjct 61 DSCISEKLFMEMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQL 120
Query 121 ANYVHSKGLKLGIYADVGNKTCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENL 180
ANYVHSKGLKLGIYADVGNKTCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENL
Sbjct 121 ANYVHSKGLKLGIYADVGNKTCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENL 180
Query 181 ADGYKHMSLALNRTGRSIVYSCEWPLYMWPFQKPNYTEIRQYCNHWRNFADIDDSWKSIK 240
ADGYKHMSLALNRTGRSIVYSCEWPLYMWPFQKPNYTEIRQYCNHWRNFADIDDSWKSIK
Sbjct 181 ADGYKHMSLALNRTGRSIVYSCEWPLYMWPFQKPNYTEIRQYCNHWRNFADIDDSWKSIK 240
Query 241 SILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQVTQMALWAIMAAPLFMSNDL 300
SILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQVTQMALWAIMAAPLFMSNDL
Sbjct 241 SILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQVTQMALWAIMAAPLFMSNDL 300
Query 301 RHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWAVAMINRQEIC 360
RHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWAVAMINRQEI
Sbjct 301 RHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWAVAMINRQEIG 360
Query 361 GPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT 420
GPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT
Sbjct 361 GPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT 420
Query 421 MQMSLKDLL 429
MQMSLKDLL
Sbjct 421 MQMSLKDLL 429
Translated SEQ ID NO: 1 of 63/016,207 with SEQ ID NO: 17
Regarding claim 7: Col 9, line 62 to Col 10, line 18 of patent of Kirn taught a tissue specific promoter.
Regarding claim 8: Col 9, lines 27-38 of patent of Kirn taught that regulatory regions can include “promoters, translation leader sequences, introns, polyadenylation recognition sequences, RNA processing sites, effector binding sites and stem-loop structures. If a coding region is intended for expression in a eukaryotic cell, a polyadenylation signal and transcription termination sequence will usually be located 3' to the coding sequence.” Further, Col 3, lines 20-25 of patent of Kirn explicitly stated that “[i]n preferred embodiments, the transcription control sequence comprises a CAG promoter comprising (i) the cytomegalovirus (CMV) early enhancer element, (ii) the promoter, first exon and first intron of chicken beta-actin gene and (iii) the splice acceptor of the rabbit beta-globin gene.” As such one of ordinary skill in the art would have applied all the routinely used elements taught by Kirin in the rAAV.
Regarding claim 25: Kirn taught “[n]on-viral vectors include plasmids, liposomes, electrically charged lipids (cytofectins), DNA-protein complexes, and biopolymers.” (See Kirin Col 11, lines 1-4 of patent).
Regarding claim 26: Kirn taught a method of introducing “nucleotide sequence carrying the viral vector functions into a cellular host for replication and packaging may be employed, including but not limited to, electroporation, calcium phosphate precipitation, microinjection, cationic or anionic liposomes, and liposomes in combination with a nuclear localization signal.” (See Kirin Col 18, lines 26-34 of patent). It is clear that Kirin anticipated a composition of a host cell comprising a plasmid comprising an expression cassette of alpha gal as taught by Kirin and Do.
Regarding claim 27-28: In Col 20, Lines 40-48 of patent, Kirn taught “a nucleotide sequence at least 90%, at least 95%, at least 98% identical, or 100% identical to the nucleotide sequence of SEQ ID NO: 1 or a pharmaceutical composition comprising such a nucleic acid and at least one pharmaceutically acceptable excipient.” Additionally, Col 20, Lines 52-55 of patent taught treatment of Fabry disease using the nucleic acid.
Claims 4, 9 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Kirin et al (U.S. Patent No. 11802278 as supported by 63/016,207 filed 04/27/2020; hereinafter "Kirn;" See PTO-892) in view of Do et al (US20200147241A1; published 05/14/2020; hereinafter "Do;" See IDS of 07/18/2023) and Yasuda et al (Mol Ther Methods Clin Dev. 2020 Jul 9; hereinafter “Yasuda;” See IDS of 07/18/2023).
Regarding claim 4 and 14: Teachings of Kirn in view of Do are set forth above. The prior did not teach use of native signal peptide for expression of hGLA. However, Yasuda taught AAV2/6-hGLA vectors had a transgene expression cassette comprising “codon-optimized full-length hGLA cDNA, including the native GLA signal peptide (amino acids 1–31).” Yasuda also demonstrated production of GLA in mice transduced with the AAV (See Yasuda Figure 2). As such one of ordinary skill in the art before the filing date of the instant invention would have been motivated to express the stabilized hGLA variants of Do in the AAV gene therapy vectors of Kirn using a native signal peptide. The person would have expected predictable results in view of teachings of Yasuda.
Regarding claim 9: Figure 1 of Yasuda taught the use of WPRE element in AAV2/6 expression construct.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Kirn et al (U.S. Patent No. 11802278 as supported by 63/016,207 filed 04/27/2020; hereinafter "Kirn;" See PTO-892) in view of Do et al (US20200147241A1; published 05/14/2020; hereinafter "Do;" See IDS of 07/18/2023) and Hordeux et al (WO2020132455 Jun 25, 2020; hereinafter “Hordeux;” See IDS of 07/18/2023).
Regarding claim 10: Teachings of Kirn in view of Do are set forth above. The prior did not teach use of miRNA in the vector genome. Hordeux taught use of miRNA 183 and 182 for repression of a gene product expression in dorsal root ganglion (DRG). (See Hordeux claim 1).
As such, insertion of miRNA target sites was broadly understood to provide predictable, sequence-dependent silencing of transgene expression. It is submitted that the claimed method is modular, does not require modification of the encoded GLA protein, and was widely used across different AAV constructs. Accordingly, a skilled artisan would expect success in applying miRNA detargeting to an AAV-GLA construct.
It is also submitted that the claim merely recites “one or more miRNA sequences,” without identifying any specific miRNA, sequence context, copy number, or unique function. Nothing in the record demonstrates criticality of a particular miRNA or that adding miRNA sequences to an AAV-GLA construct yields unexpected results.
Thus, the full breadth of the claim is an obvious design choice.
Response to Arguments
Applicants argued that Kirin did not teach or suggest a AAVhu68 capsid, having a cysteine at 233 and/or 359 or coding sequence encoding such a protein, coding sequence of SEQ ID NO: 4 or a sequence 95% identical hereto and Do only recited a laundry list of proteins, signal peptides, vectors and capsids. Applicants’ arguments have been fully considered but are not persuasive.
It is submitted that obviousness cannot the argued by attacking references individually. Kirin is relied upon for teaching AAV-mediated hGLA expression platform and the claimed coding sequence while Do is relied upon for teaching D233C and I359C substitutions that improve stability. The rejection does not rely on Do to teach Kirin’s coding sequence, nor does it rely on Kirin alone to disclose AAVhu68 capsid and stabilized hGLA variants comprising D233C and I359C substitutions that improve enzyme stability. One of ordinary skill in the art would have been motivated to incorporate the stabilized hGLA variants taught by Do into AAV mediated hGLA delivery system taught by Kirin to improve enzyme stability with a reasonable expectation of success. Accordingly, the rejection is maintained.
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 1-10, 12-16, and 25-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8-10, 12-16, 20, 25-29, 32 of copending Application No. 18/712,323 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the reasons stated below.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Following claims are anticipated by the reference application.
Instant application
18/712,323 (reference application)
1
1, 3
3
2
8
4
9
5
27
25
It is noted that SEQ ID NOs: 2, 4 and 7 of reference application are 100% identical to SEQ ID NOs: 2, 4 and 7 of instant application.
Response to Arguments
Applicants argued that the claims of the reference application recite additional limitations, including a specific dosing regimen and biomarkers, that are not required by the instant claims. This argument is not persuasive. The issue under the judicially created doctrine of non-statutory double patenting is whether the instant claims are patentably distinct from the claims of the reference application, not whether the reference claims include additional limitations. The presence of additional limitations in the reference claims does not render the instant claims patentably distinct where the instant claims merely encompass an obvious variation or broader version of the same invention. Accordingly, the rejection is maintained. Also, the reference claims are directed to a narrower embodiment requiring specific dosing and biomarker limitations, whereas the instant claims broadly encompass the same composition without those additional limitations. Omitting limitations from otherwise overlapping claimed invention does not establish patentable distinctness for purposes of obviousness-type double patenting.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: It is submitted that from the sequence search results, SEQ ID NO: 4 or a sequence 99% identical to SEQ ID NO: 4 are novel. The prior art fails to teach or suggest an rAAV comprising an AAVhy68 capsid packaged with the particular hGLA coding sequence recited in the allowed claims, wherein the GLA comprises the specifically recited amino acid substitutions while retaining functional alpha galactosidase activity.
Claim Objections
Claim 11 is objected to as it depends from a rejected base claim and will be allowable if written in an independent form.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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