DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendments to the claims and arguments filed on February 10, 2026 have been received and entered. Claims 2, 6-13, 19-20, 24-26, 28 33, 36, 40, 44, 46, 49 and 50 are canceled , while Claims 51-64 are added. Applicants’ cancellation of claims 25-26 renders their objection moot. The Azzouz’s declaration under 37 CFR 1.132 filed February 10, 2026 is insufficient to overcome the rejection of claims based upon Behne et al (Human Molecular Genetics, 2020, Vol. 29, No. 2, 320-324)/ Scarrott et al (Human Gene Therapy, (August 2019) Vol. 30, No. 8, pp. A18. Abstract Number: P03, June 21, 2019) as set forth in the last Office action. The declaration will be discussed below as it pertains to the rejection.
Claims 27, 29, 45, 47-48, 51-64 are pending in the instant application.
Election/Restrictions
Applicant’s election of claims 2, 6-13, 19-20, 24-26, 33, 36, 40, 44-50 (group I) in the reply filed on July 23, 2025 was acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 27, 29 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 23, 2025.
Priority
This application is a 371 of PCT/EP2021/059354 filed on 04/09/2021, which claims priority from foreign application 2005321.1 filed on 04/09/2020 and PCTEP2021057996 filed on 03/26/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/10/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 45, 47-48, 51-64 are under consideration.
Maintained & New-Claim Rejections - 35 USC § 112-written description -in modified form
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 45, 47-48, 51-57, 59-63 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.
In analyzing whether the written description requirement is met for the genus claim, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics, specific features and functional attributes that would distinguish different members of the claimed genus.
The claims embrace a genus of
a nucleic acid molecule comprising a nucleotide sequence that encodesencoding adaptor protein complex 4 subunit bl (AP4B 1), wherein the nucleotide sequence is selected from the group consisting of:
a nucleotide sequence comprising the nucleic acid sequence as set forth in SEQ ID NO:1
a nucleotide sequence degenerate as a result of the genetic code to the nucleotide sequence defined in i)
a nucleotide sequence comprising at least 90% sequence identity with a nucleotide sequence selected from the group to the nucleic acid sequence as set forth in SEQ ID NO: 1, wherein said nucleic acid molecule encodes a polypeptide that forms a complex with polypeptides comprising the AP-4 complex;
a nucleotide sequence that encoding a polypeptide comprising an the amino acid sequence as set forth in SEQ ID NO: 2 (AP4B1); and
a nucleotide sequence that encoding a polypeptide comprising an amino acid sequence wherein said amino acid sequence comprising at least 90% identical sequence identity to the full length amino acid sequence set forth in SEQ ID NO: 2, wherein said polypeptide forms a complex with polypeptides comprising the AP-4 complex..
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that ''applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1 117. The specification does not ''clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1116.
The specification describes expression vectors that are generated containing weaker promoters that are hypothesized to express the hAP4B1 transgene at a level closer to that found endogenously. The promoters are MeP229 (derived from a core fragment of the endogenous Mecp2 gene promoter, amplified by PCR from the pSJG-MeP229-GFP plasmid), hSyn (neuronal cell-specific human synapsin 1 gene promoter) and AP4B1endo (a putative endogenous promoter containing the region ~600bp upstream of the hAP4B1 gene transcription start site. This region is identified in silico as a potential promoter region due its genomic location, and presence of a CpG island and presence of a CCCTC-binding factor (CTCF) binding region- a known transcriptional activator) (see page 20, para. 2 of the specification).
Claims 45 and 52 embrace a genus comprising any nucleotide sequence, or polymorphic sequence variant, as set forth in SEQ ID NO:1 (AP4B1), wherein said nucleic acid molecule encodes a polypeptide that forms a complex with polypeptides comprising the AP-4 complex. As stated supra, the specification discloses an actual reduction to practice and the complete chemical structure of only one species of the claimed genus of nucleic acids that is set forth in SEQ ID NO: 1 encoding amino acid sequence of SEQ ID NO: 2 showing contemplated biological activity.
However, without a recognized correlation between structure and function, those of ordinary skill in the art would not be able to identify without further testing which of those nucleic acids that hybridize to nucleotide sequence encoding amino acid set forth in SEQ ID NO: 2 would also forms a complex with polypeptides comprising the AP-4 complex. The art teaches AP-4-HSP is caused by bi-allelic loss-of-function variants in any of the four AP-4 subunits (ε, β4, μ4, σ4), leading to impaired AP-4 assembly and function (Saffari et al Nat Commun, 2024; 15: 584. 1-22).
Thus, those of ordinary skill in the art would not consider the applicant to have been in possession of the claimed genus of nucleic acid based on the single species disclosed. It is further noted that specification describes that invention may contain conservative substitutions of one or more amino acids in the amino acid sequence represented by SEQ ID NO:2 or substitutions, insertions or deletions of non-essential amino acids. Accordingly, a non-essential amino acid is a residue that may be altered in the amino acid sequences shown in SEQ ID NO:2 without substantially altering the biological function. The specification does not provide guidance to one of skill in art to structurally predict or recognize plurality of different structures of mutants or variants of SEQ ID NO: 2 that result in forming a complex with polypeptides comprising the AP-4 complex It is emphasized that biological activity of a protein is highly dependent on the overall structure of the protein itself and the primary amino acid sequence determines the conformation of the protein (Skolnick et al. (TIBTECH 18:34-39, 2000). Thus, it is apparent that a minor structural difference in factor could result in substantially different activities. The specification does not teach any sequence other than SEQ ID NO: 1 or a nucleic acid encoding SEQ ID NO: 2 that would also show contemplated biological activity. The specification does not provide any guidance on what sequence regions or functional domains must be conserved amongst any of the claimed polynucleotide in order for the resulting polypeptide to function in forming a complex with polypeptides comprising the AP-4 complex. The specification does not provide any disclosure as to what would have been the required structure for other fragments and variants of SEQ IDNO: 1 or nucleic acid encoding SEQ ID: 2. As such, the Artisan of skill could not predict that Applicant possessed any species, except for the SEQ ID NO: 1 and nucleic acid encoding SEQ ID NO: 2 that is capable of forming a complex with polypeptides comprising the AP-4 complex. There is no evidence on record that sequence that has 90-95% sequence identity would have contemplated biological activity. Hence, only the nucleotide sequence as set forth in SEQ ID NO: 1 or nucleic acid encoding amino acid sequence as set forth in SEQ ID: 2 could be demonstrated as possessed for forming a complex with polypeptides comprising the AP-4 complex.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641, 1646 (1998). In the instant case, the claimed embodiments of any nucleotide sequence as set forth in SEQ ID NO: 27 or a polymorphic sequence variant of SEQ ID NO: 27, other than the nucleotide sequence as set forth in SEQ ID NO: 27 encompassed within the genus of endogenous AP4B1 promoter lack a written description. The specification fails to describe what DNA molecules fall into this genus.
The skilled artisan cannot envision the detailed chemical structure of the sequence of any variants showing contemplated biological activity, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
In conclusion, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that Applicant is in possession of genus of isolated nucleic acid or nucleic acid encoding AP4B1 or any nucleotide that complementary strand of which hybridizes under highly stringent condition as set forth in claims that retain the biological activity for forming a complex with polypeptides comprising the AP-4 complex. at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Response to arguments
Applicant disagree with the rejection arguing a person of skill in the art is more than capable of identifying and generating all nucleic acid sequences having at least 90% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 1 and all nucleotide sequences encoding a polypeptide comprising an amino acid sequence comprising at least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 2, such as with the aid of a computer. Applicant assert that AP4B1 variants that cause disease were known (see Ruan et al , 2020). One skilled in the at the time of the invention would understand to avoid these mutations in nucleic acid molecule-based therapeutics to treat disease (that is, where changes should be avoided in AP4B1 to retain activity). he claims recite that the variant peptide has a particular function, namely it forms a complex with polypeptides comprising the AP-4 complex. Thus, non-functional variants are excluded. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is noted that the claim embraces any sequence comprising at least 90% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 1 and all nucleotide sequences encoding a polypeptide comprising an amino acid sequence comprising at least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 2. The DNA sequences of all the variant sequences, other than the SEQ ID NO: 1, encompassed within the genus of AP4B 1 sequence have not been disclosed. Based upon the prior art there is expected to be sequence variation among the species of DNA sequences of AP4B 1 as suggested by Ruan et al , 2020) It should be noted that Runo explicitly states that” the vast majority of pathogenic variants identified so far are truncating variants (allele counts ratio is 52/60) which can often be assumed to disrupt gene function by leading to a complete absence of the gene product by nonsense-mediated decay of an altered transcript or lack of transcription (e.g. nonsense, frameshift, canonical splice site) (see page 5, col. 1). In fact, there is no evidence on the record of a relationship between the structures of the DNA molecules of SEQ ID NO: 1 that would provide any reliable information about the structure of DNA molecules of other variant containing known mutation or yet to be identified variant within the genus. Further there is no evidence on the record that embraced SEQ ID NO: 1 had known structural relationships with any of the truncating variants. The specification has provided the description of SEQ ID NO: 2. However, specification fails to provide any specific guidance which portion amino acid could be added or deleted. It is emphasized that a deleted from critical region of SEQ ID NO: 2 may not show contemplated biological activity as protein is highly dependent on the overall structure of the protein itself and the primary amino acid sequence determines the conformation of the protein. The art of record teaches addition or deletion, which are critical to maintain the protein structure/function, will require guidance. Further, it is known that a minor structural difference in protein structure could result in substantially different activities unless claims necessarily require critical elements in at least 90% sequence. The specification however has not disclosed the critical region or motifs are required for contemplated biological activity. The specification does not teach any sequence that has deletion in critical regions of SEQ ID NO: 2 and also show contemplated biological activity. Further, the specification fails to describe what polypeptides fall into the genus of any sequence comprising at least 90% sequence identity and still has contemplated biological activity. The skilled artisan cannot envision the detailed chemical structure of the all the sequences with at least 90-95 % sequence identity to SEQ ID NO: 1 or 2 showing contemplated biological activity.
Withdrawn-Claim Rejections - 35 USC § 112
Claims 2, 6-13, 19-20, 24-26, 33, 36, 40, 44-50 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Applicants’ cancellation of claims 2, 6-13, 19-20, 24-26, 33, 36, 40, 44 renders their rejections moot. Applicant’s amendment to the claims obviates the basis of the rejection.
Withdrawn-Claim Rejections - 35 USC § 101
Claim 2 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e nature-based product) without significantly more. Applicants’ cancellation of claim 2 renders their rejections moot.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 2, 6, 9, 10, 12 and 24 wererejected under 35 U.S.C. 102(a) (1) as being anticipated by Behne et al (Human Molecular Genetics, 2020, Vol. 29, No. 2 , 320-324) as evidenced by NCBI accession no NM_001253852.1, dated 3/15/2015. Applicants’ cancellation of claims 2, 6, 9, 10, 12 and 24 renders their rejections moot.
Claim 2 is rejected under 35 U.S.C. 102(a) (1) as being anticipated by NCBI accession no NM_001253852.1., dated 3/15/2015. Applicants’ cancellation of claim 2renders their rejections moot.
Claims 2, 9, 10, 11 and 24 were rejected under 35 U.S.C. 102(a) (1) as being anticipated by Scarrott et al (Human Gene Therapy, (August 2019) Vol. 30, No. 8, pp. A18. Abstract Number: P03, June 21, 2019) as evidenced by NCBI accession no NM_001253852.1, dated 3/15/2015. 2, Applicants’ cancellation of claims 2, 9, 10, 11 and 24 renders their rejections moot.
Claims 33 and 40 were rejected under 35 U.S.C. 102(a) (1) as being anticipated by Aldred et al (WO2008073303, dated 06/19/2008). Applicants’ cancellation of claims 33 and 40 renders their rejections moot.
Maintained & New -Claim Rejections - 35 USC § 103-in modified form
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.
Claims 45, 51, 53-58 rejected under 35 U.S.C. 103 as being unpatentable over Behne et al (Human Molecular Genetics, 2020, Vol. 29, No. 2, 320-324)/ Scarrott et al (Human Gene Therapy, (August 2019) Vol. 30, No. 8, pp. A18. Abstract Number: P03, June 21, 2019) as evidenced by NCBI accession no NM_001253852.1., and further in view of Lukashchuk et al ((Molecular Therapy, 2016, 3, 1-10). Please note instant rejection is modified that is necessitated by the amendments to the claims.
With respect to claims 45, 51, 59-64, Behne teaches a lentiviral vector comprising a transcription cassette comprising a ubiquitous promoter (PGK) that is adapted for expression ubiquitously, wherein said cassette further comprising a nucleic acid molecule comprising a nucleotide sequence NM_001253852.1 that encodes AP4B1 (see fig. 3, table 1and page 331, col. 1, para 3). AP4B1 (see fig. 3, table 1and page 331, col. 1, para 3). The accession number for AP4B1 disclosed in Behne has 100% sequence identity to SEQ ID NO: 1 and encodes amino acid as set forth in SEQ IDNO: 2 (see below).
Query Match 100.0%; Score 2220; DB 1; Length 2723;
Best Local Similarity 100.0%;
Matches 2220; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ATGCCGTACCTTGGCTCCGAGGACGTGGTGAAGGAGCTGAAGAAGGCTCTGTGCAATCCT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 187 ATGCCGTACCTTGGCTCCGAGGACGTGGTGAAGGAGCTGAAGAAGGCTCTGTGCAATCCT 246
Qy 61 CACATTCAAGCTGATAGGCTGCGCTACCGGAATGTCATCCAGCGAGTGATTAGGTACATG 120 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 247 CACATTCAAGCTGATAGGCTGCGCTACCGGAATGTCATCCAGCGAGTGATTAGGTACATG 306
Qy 121 ACTCAAGGCTTGGACATGTCTGGTGTTTTTATGGAAATGGTGAAGGCCAGTGCCACTGTA 180 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 307 ACTCAAGGCTTGGACATGTCTGGTGTTTTTATGGAAATGGTGAAGGCCAGTGCCACTGTA 366
Qy 181 GATATTGTCCAGAAGAAGTTGGTTTATCTGTACATGTGCACATATGCTCCCCTGAAACCA 240 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 367 GATATTGTCCAGAAGAAGTTGGTTTATCTGTACATGTGCACATATGCTCCCCTGAAACCA 426
Qy 241 GATCTGGCTCTCCTGGCCATCAATACGCTGTGCAAAGACTGCTCAGACCCCAATCCAATG 300 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 427 GATCTGGCTCTCCTGGCCATCAATACGCTGTGCAAAGACTGCTCAGACCCCAATCCAATG 486
Qy 301 GTGCGAGGGCTGGCGTTACGGAGCATGTGTAGCCTCAGGATGCCTGGTGTGCAGGAGTAT 360 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 487 GTGCGAGGGCTGGCGTTACGGAGCATGTGTAGCCTCAGGATGCCTGGTGTGCAGGAGTAT 546
Qy 361 ATACAACAGCCTATTCTCAATGGTCTGCGGGATAAGGCTTCATATGTCAGGAGAGTGGCA 420 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 547 ATACAACAGCCTATTCTCAATGGTCTGCGGGATAAGGCTTCATATGTCAGGAGAGTGGCA 606
Qy 421 GTCCTTGGATGTGCCAAGATGCATAATCTTCATGGAGACTCTGAAGTAGATGGTGCCCTG 480 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 607 GTCCTTGGATGTGCCAAGATGCATAATCTTCATGGAGACTCTGAAGTAGATGGTGCCCTG 666
Qy 481 GTAAATGAATTATACAGTTTGCTGCGTGACCAGGATCCAATTGTAGTTGTGAACTGCTTG 540 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 667 GTAAATGAATTATACAGTTTGCTGCGTGACCAGGATCCAATTGTAGTTGTGAACTGCTTG 726
Qy 541 AGGTCTCTAGAGGAAATTCTGAAACAGGAAGGAGGCGTTGTCATCAATAAGCCCATTGCT 600 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 727 AGGTCTCTAGAGGAAATTCTGAAACAGGAAGGAGGCGTTGTCATCAATAAGCCCATTGCT 786
Qy 601 CACCATCTCTTAAATCGAATGTCAAAACTGGACCAATGGGGCCAGGCTGAAGTATTGAAC 660 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 787 CACCATCTCTTAAATCGAATGTCAAAACTGGACCAATGGGGCCAGGCTGAAGTATTGAAC 846
Qy 661 TTTCTGCTACGCTACCAACCCCGCAGTGAGGAAGAACTATTTGACATTCTCAATCTGTTG 720 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 847 TTTCTGCTACGCTACCAACCCCGCAGTGAGGAAGAACTATTTGACATTCTCAATCTGTTG 906
Qy 721 GATAGTTTCCTCAAGAGCAGTAGCCCAGGTGTGGTGATGGGAGCTACCAAACTTTTTCTG 780 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 907 GATAGTTTCCTCAAGAGCAGTAGCCCAGGTGTGGTGATGGGAGCTACCAAACTTTTTCTG 966
Qy 781 ATCTTGGCAAAAATGTTTCCCCACGTACAAACTGATGTCCTTGTGCGGGTCAAGGGACCT 840 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 967 ATCTTGGCAAAAATGTTTCCCCACGTACAAACTGATGTCCTTGTGCGGGTCAAGGGACCT 1026
Qy 841 TTGCTAGCTGCCTGTTCTTCAGAGAGCCGTGAGCTCTGTTTTGTTGCTCTTTGTCATGTA 900 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1027 TTGCTAGCTGCCTGTTCTTCAGAGAGCCGTGAGCTCTGTTTTGTTGCTCTTTGTCATGTA 1086
Qy 901 CGCCAGATCTTGCATAGTTTACCAGGTCACTTTAGCAGCCACTACAAAAAGTTTTTTTGC 960 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1087 CGCCAGATCTTGCATAGTTTACCAGGTCACTTTAGCAGCCACTACAAAAAGTTTTTTTGC 1146
Qy 961 TCCTACTCGGAGCCCCACTACATCAAACTACAGAAAGTGGAGGTGCTGTGTGAACTGGTG 1020 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1147 TCCTACTCGGAGCCCCACTACATCAAACTACAGAAAGTGGAGGTGCTGTGTGAACTGGTG 1206
Qy 1021 AACGATGAGAATGTGCAGCAGGTGCTAGAGGAGCTTCGAGGGTACTGCACGGATGTGTCT 1080 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1207 AACGATGAGAATGTGCAGCAGGTGCTAGAGGAGCTTCGAGGGTACTGCACGGATGTGTCT 1266
Qy 1081 GCGGACTTTGCACAGGCTGCCATCTTTGCCATAGGTGGCATTGCCAGGACTTACACAGAT 1140 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1267 GCGGACTTTGCACAGGCTGCCATCTTTGCCATAGGTGGCATTGCCAGGACTTACACAGAT 1326
Qy 1141 CAATGTGTTCAGATTTTAACAGAGTTGCTGGGTCTTCGACAAGAGCACATTACCACAGTG 1200 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1327 CAATGTGTTCAGATTTTAACAGAGTTGCTGGGTCTTCGACAAGAGCACATTACCACAGTG 1386
Qy 1201 GTGGTGCAGACTTTCCGAGACCTGGTTTGGTTGTGTCCTCAGTGTACTGAAGCTGTATGT 1260 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1387 GTGGTGCAGACTTTCCGAGACCTGGTTTGGTTGTGTCCTCAGTGTACTGAAGCTGTATGT 1446
Qy 1261 CAGGCCCTGCCCGGCTGTGAAGAGAACATTCAAGATAGTGAGGGGAAGCAAGCACTTATT 1320 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1447 CAGGCCCTGCCCGGCTGTGAAGAGAACATTCAAGATAGTGAGGGGAAGCAAGCACTTATT 1506
Qy 1321 TGGCTACTTGGTGTCCATGGGGAAAGAATTCCTAATGCTCCTTATGTGTTAGAGGACTTT 1380 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1507 TGGCTACTTGGTGTCCATGGGGAAAGAATTCCTAATGCTCCTTATGTGTTAGAGGACTTT 1566
Qy 1381 GTTGAGAATGTGAAGTCGGAAACATTTCCAGCTGTTAAGATGGAGCTGCTCACTGCTTTG 1440 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1567 GTTGAGAATGTGAAGTCGGAAACATTTCCAGCTGTTAAGATGGAGCTGCTCACTGCTTTG 1626
Qy 1441 CTGCGCCTTTTCCTCTCCCGACCTGCTGAGTGCCAGGACATGCTAGGACGTTTGTTGTAT 1500 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1627 CTGCGCCTTTTCCTCTCCCGACCTGCTGAGTGCCAGGACATGCTAGGACGTTTGTTGTAT 1686
Qy 1501 TACTGCATAGAGGAAGAAAAAGATATGGCTGTACGGGACCGAGGTCTCTTCTATTATCGC 1560 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1687 TACTGCATAGAGGAAGAAAAAGATATGGCTGTACGGGACCGAGGTCTCTTCTATTATCGC 1746
Qy 1561 CTCCTCTTAGTTGGCATTGATGAAGTTAAGCGGATTCTGTGTAGCCCTAAATCTGACCCT 1620 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1747 CTCCTCTTAGTTGGCATTGATGAAGTTAAGCGGATTCTGTGTAGCCCTAAATCTGACCCT 1806
Qy 1621 ACTCTTGGACTTTTGGAGGATCCGGCAGAAAGACCTGTGAATAGCTGGGCCTCAGACTTC 1680 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1807 ACTCTTGGACTTTTGGAGGATCCGGCAGAAAGACCTGTGAATAGCTGGGCCTCAGACTTC 1866
Qy 1681 AACACACTGGTGCCAGTGTATGGCAAAGCCCACTGGGCAACTATCTCTAAATGCCAGGGG 1740 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1867 AACACACTGGTGCCAGTGTATGGCAAAGCCCACTGGGCAACTATCTCTAAATGCCAGGGG 1926
Qy 1741 GCAGAGCGTTGTGACCCAGAGCTTCCTAAAACTTCATCCTTTGCCGCATCAGGACCCTTG 1800 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1927 GCAGAGCGTTGTGACCCAGAGCTTCCTAAAACTTCATCCTTTGCCGCATCAGGACCCTTG 1986
Qy 1801 ATTCCTGAAGAGAACAAGGAGAGGGTACAAGAACTCCCTGATTCTGGAGCCCTCATGCTA 1860 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1987 ATTCCTGAAGAGAACAAGGAGAGGGTACAAGAACTCCCTGATTCTGGAGCCCTCATGCTA 2046
Qy 1861 GTCCCCAATCGCCAGCTTACTGCTGATTATTTTGAGAAAACTTGGCTTAGCCTTAAAGTT 1920 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2047 GTCCCCAATCGCCAGCTTACTGCTGATTATTTTGAGAAAACTTGGCTTAGCCTTAAAGTT 2106
Qy 1921 GCTCATCAGCAAGTGTTGCCTTGGCGGGGAGAATTCCATCCTGACACCCTCCAGATGGCT 1980 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2107 GCTCATCAGCAAGTGTTGCCTTGGCGGGGAGAATTCCATCCTGACACCCTCCAGATGGCT 2166
Qy 1981 CTTCAAGTAGTGAACATCCAGACCATCGCAATGAGTAGGGCTGGGTCTCGGCCATGGAAA 2040 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2167 CTTCAAGTAGTGAACATCCAGACCATCGCAATGAGTAGGGCTGGGTCTCGGCCATGGAAA 2226
Qy 2041 GCATACCTCAGTGCTCAGGATGATACTGGCTGTCTGTTCTTAACAGAACTGCTATTGGAG 2100 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2227 GCATACCTCAGTGCTCAGGATGATACTGGCTGTCTGTTCTTAACAGAACTGCTATTGGAG 2286
Qy 2101 CCTGGAAACTCAGAAATGCAGATCTCTGTGAAACAAAATGAAGCAAGAACGGAGACGCTG 2160 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2287 CCTGGAAACTCAGAAATGCAGATCTCTGTGAAACAAAATGAAGCAAGAACGGAGACGCTG 2346
Qy 2161 AATAGTTTTATTTCTGTATTAGAAACTGTGATTGGAACAATTGAAGAAATAAAATCATAA 2220 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2347 AATAGTTTTATTTCTGTATTAGAAACTGTGATTGGAACAATTGAAGAAATAAAATCATAA 2406
Query Match 100.0%; Score 3836; DB 1; Length 739;
Best Local Similarity 100.0%;
Matches 739; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MPYLGSEDVVKELKKALCNPHIQADRLRYRNVIQRVIRYMTQGLDMSGVFMEMVKASATV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MPYLGSEDVVKELKKALCNPHIQADRLRYRNVIQRVIRYMTQGLDMSGVFMEMVKASATV 60
Qy 61 DIVQKKLVYLYMCTYAPLKPDLALLAINTLCKDCSDPNPMVRGLALRSMCSLRMPGVQEY 120 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DIVQKKLVYLYMCTYAPLKPDLALLAINTLCKDCSDPNPMVRGLALRSMCSLRMPGVQEY 120
Qy 121 IQQPILNGLRDKASYVRRVAVLGCAKMHNLHGDSEVDGALVNELYSLLRDQDPIVVVNCL 180 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 IQQPILNGLRDKASYVRRVAVLGCAKMHNLHGDSEVDGALVNELYSLLRDQDPIVVVNCL 180
Qy 181 RSLEEILKQEGGVVINKPIAHHLLNRMSKLDQWGQAEVLNFLLRYQPRSEEELFDILNLL 240 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 RSLEEILKQEGGVVINKPIAHHLLNRMSKLDQWGQAEVLNFLLRYQPRSEEELFDILNLL 240
Qy 241 DSFLKSSSPGVVMGATKLFLILAKMFPHVQTDVLVRVKGPLLAACSSESRELCFVALCHV 300 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 DSFLKSSSPGVVMGATKLFLILAKMFPHVQTDVLVRVKGPLLAACSSESRELCFVALCHV 300
Qy 301 RQILHSLPGHFSSHYKKFFCSYSEPHYIKLQKVEVLCELVNDENVQQVLEELRGYCTDVS 360 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 RQILHSLPGHFSSHYKKFFCSYSEPHYIKLQKVEVLCELVNDENVQQVLEELRGYCTDVS 360
Qy 361 ADFAQAAIFAIGGIARTYTDQCVQILTELLGLRQEHITTVVVQTFRDLVWLCPQCTEAVC 420 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 ADFAQAAIFAIGGIARTYTDQCVQILTELLGLRQEHITTVVVQTFRDLVWLCPQCTEAVC 420
Qy 421 QALPGCEENIQDSEGKQALIWLLGVHGERIPNAPYVLEDFVENVKSETFPAVKMELLTAL 480 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 QALPGCEENIQDSEGKQALIWLLGVHGERIPNAPYVLEDFVENVKSETFPAVKMELLTAL 480
Qy 481 LRLFLSRPAECQDMLGRLLYYCIEEEKDMAVRDRGLFYYRLLLVGIDEVKRILCSPKSDP 540 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 LRLFLSRPAECQDMLGRLLYYCIEEEKDMAVRDRGLFYYRLLLVGIDEVKRILCSPKSDP 540
Qy 541 TLGLLEDPAERPVNSWASDFNTLVPVYGKAHWATISKCQGAERCDPELPKTSSFAASGPL 600 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 TLGLLEDPAERPVNSWASDFNTLVPVYGKAHWATISKCQGAERCDPELPKTSSFAASGPL 600
Qy 601 IPEENKERVQELPDSGALMLVPNRQLTADYFEKTWLSLKVAHQQVLPWRGEFHPDTLQMA 660 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 IPEENKERVQELPDSGALMLVPNRQLTADYFEKTWLSLKVAHQQVLPWRGEFHPDTLQMA 660
Qy 661 LQVVNIQTIAMSRAGSRPWKAYLSAQDDTGCLFLTELLLEPGNSEMQISVKQNEARTETL 720 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 LQVVNIQTIAMSRAGSRPWKAYLSAQDDTGCLFLTELLLEPGNSEMQISVKQNEARTETL 720
Qy 721 NSFISVLETVIGTIEEIKS 739
|||||||||||||||||||
Db 721 NSFISVLETVIGTIEEIKS 739
Scarrott teaches an AAV9 vector comprising a nucleic acid encoding AP4B1 protein for expression in both in vitro and in vivo models (abstract). The nucleotide sequence as set forth in NM_001253852.1 that encodes AP4B was known in accession no that has 100% sequence identity to SEQ ID NO: 1 and encodes amino acid as set forth in SEQ IDNO: 2.
Behne/ Scarrott differs from claimed invention by not disclosing the ubiquitous promoter selected from CAG promoter or AP-4 subunit specific promoter of AP$B1 as in SEQ ID NO: 27.
Lukashchuk cure the deficiency by a disclosing such promoters that were known before the effective filing date in the context of CNS gene therapy. Lukashchuk teaches transcription cassette comprising a CAG or neuron specific promoter (Syn1 or Hb9) and a transgene that is regulated by said promoter (see fig. 1) (limitation of claims 6-7). It is further disclosed that the vector comprising a nucleic acid encoding reporter protein under the control of these promoters are capable of expressing heterologous gene into motor neuron (see fig. 4). Lukashchuk teaches cells containing motor neurons and interneurons as well as glia were transduced AA encoding GFP under the control of CMV and CAG resulted in the majority of the cells expressing GFP (see fig. 2, page 2, col. 1, para. 2) (limitation of claims 25-26).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to substitute PGK promoter as disclosed in Behne /Scarrott with functionally equivalent ubiquitous or tissue specific promoter as suggested in Lukashchuk, in order to express AP4B1 in neural cell, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification choice amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to use CAG promoter or neuron specific promoter depending upon non-neuronal cell or neuron specific expression required for different disease model (see page 7, col. 1). One of skill in the art would have been expected to have a reasonable expectation of success in substituting one promoter with another know regulatory sequence because the art teaches the successful substitution of ubiquitous promoter with another ubiquitous promoter as evident from the teaching of Lukashchuk (see fig. 1). It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 45 , 47-48, 52, 59-64 are rejected under 35 U.S.C. 103 as being unpatentable over Lukashchuk et al ((Molecular Therapy, 2016, 3, 1-10), Behne et al (Human Molecular Genetics, 2020, Vol. 29, No. 2, 320-324)/ Scarrott et al (Human Gene Therapy, (August 2019) Vol. 30, No. 8, pp. A18. Abstract Number: P03, June 21, 2019) as evidenced by NCBI accession no NM_001253852.and Aldred et al (WO2008073303, dated 06/19/2008 art of record). Please note instant rejection is modified that is necessitated by the amendments to the claims.
With respect to claims 45, 47-48, 52, Lukashchuk teaches an AAV 9 vector comprising r a transcription cassette comprising a neuronal promoter synapsin1 (SYN1) promoter or chicken beta actin hybrid and a gene of interest (GFP). Lukashchuk differs from claimed invention by not disclosing gene of interest is adaptor protein complex 4 subunit bl (AP4B1) and promoter as set forth in SEQ ID NO: 27.
Behne cures the deficiency by disclosing vector comprising a transcription cassette comprising a ubiquitous promoter (PGK) that is operably linked to a nucleic acid molecule comprising a nucleotide sequence NM_001253852.1 that encodes AP4B1 (see fig. 3, table 1and page 331, col. 1, para 3). The accession number for AP4B1 disclosed in Behne has 100% sequence identity to SEQ ID NO: 1 and encodes amino acid as set forth in SEQ IDNO: 2 (see above) (limitation of claims 53-58). Behne teaches deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47) (abstract). (AP4B1), It is disclosed that re-expression of AP4B1 in fibroblasts from patients with AP4B1-associated HSP leads to a reduction of total ATG9A levels and redistribution from the trans-Golgi network to the cell periphery (see Fig. 3). The combination of references differ from claimed invention by not disclosing promoter comprises SEQ ID NO: 27.
Aldred teaches discloses a transcription regulatory sequence operably linked with a heterologous sequence in an expression vector such that expression of the heterologous sequence is under transcriptional control of the transcription regulatory sequences, wherein the regulatory sequence is SEQ ID NO: 2673 (claim, 1 and 10 of ‘303) that has 100% sequence identity to SEQ ID NO: 27 (see sequence search result) (limitation of claims 8 and 33).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the construct of Lukashchuk by replacing the gene of interest with AP4B1 as disclosed in Behne, in order to express AP4B1 in neural cell using neuron specific promoter by substituting one disclosed in Lukashchuk with another functionally equivalent promoter as disclosed in Aldred , with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification choice amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to study the over expression of AP4B1 because prior art recognized that deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia. One of skill in the art would have been expected to have a reasonable expectation of success because substituting a coding sequence and neuron specific promoter with another or using an ubiquitous promoter in a viral vector was routine and prior art successfully reported use of AAV9- vector delivery in targeting neurons throughout the brain (see fig. 1). It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Response to arguments
Applicant disagrees with the rejection by providing a Declaration removing Behne et al. as prior art under 35 U.S.C. § 102(b)(1)(A). In view of this, the rejection is moot. The remaining references do not teach or suggest all of the recited claim elements. Applicant argues that Lukashuchuk suggest using the Hb1 promoter and discourage using the chicken beta actin hybrid promoter. Applicant in part rely on Figure 5 illustrates that a transcription cassette encoding AP4-B1 under the control of the chicken beta actin hybrid promoter in a single delivery of adeno-associated virus serotype 9 expressing hAP4B1 (AAV9/hAP4B1) into the cisterna magna leads to widespread gene transfer and restoration of various hallmarks of disease, including AP-4 cargo (ATG9A) mislocalisation, calbindin- positive spheroids in the deep cerebellar nuclei, anatomical brain defects and motor dysfunction, in an SPG47 mouse model. Furthermore, AAV9/ hAP4-B1-basec gene therapy demonstrated a restoration of plasma neurofilament light (NfL) levels of treated mice when expressed from a chicken beta actin promoter. Applicants’ arguments have been fully considered, but are not found persuasive.
In response , it should be noted that that Dr. Azzouz’s declaration under 37 CFR 1.130 filed February 10, 2026 is insufficient to overcome the rejection of claims based upon Behne et al as set forth in the last Office action. This is because declaration fails to show that: (1) the disclosure was made by the inventor or a joint inventor; and (2) the subject matter disclosed was obtained directly or indirectly from the inventor or a joint inventor (see MPEP 717.01(a)(1). Applicant’s statement (see para. 4) that remaining co-authors on the Behne publications are not inventors of the present application does not clarify contribution of co-authors in Behne publications. It is unclear if disclosure of the publication is made by the inventor or a joint inventor and not by others. The declaration is silent on contribution of twenty-six other co-authors in the Behne publication.
In response to applicant's argument that Lukashuchuk suggest using the Hb1 promoter and discourage using the chicken beta promoter, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, it is Behne who teaches use of a weak ubiquitous PGK promoter and it would have been obvious for one of ordinary skill in the art to substitute ubiquitous PGK promoter with functionally equivalent another ubiquitous CAG promoter as suggested in Lukashuchuk . In fact, instant specification (see page 20 of the specification) and prior of Lukashuchuk both recognizes that these ubiquitous promoters are-recognized or obvious equivalent. It is relevant to note that claims are drawn to AAV and as such do not require any specific resulting outcome and therefore, it would be obvious for one of ordinary skill in the art to try using any ubiquitous or neuron specific promoter known in prior art that function in neuron and/or non-neuronal cells depending on desired intended use, with reasonable expectation of success.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., [ a single delivery of adeno-associated virus serotype 9 expressing hAP4B1 (AAV9/hAP4B1) into the cisterna magna leads to widespread gene transfer and restoration of various hallmarks of disease, including AP-4 cargo (ATG9A) mislocalisation, calbindin- positive spheroids in the deep cerebellar nuclei) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
On page 12 of the applicant’s argument, applicant assert that new claim 52 uses a minimal SPG47 promoter (SEQ ID NO:27). This sequence is not disclosed in the prior art and there is no teaching or suggestion in the cited art to identify as a DNA sequence that has the control elements to regulate expression of APB4-B1. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is noted that new claim 52 is rejected with new combination of prior art reference of record. In the instant case, Aldred teaches the regulatory sequence of SEQ ID NO: 2673 (claim, 1 and 10 of ‘303) that has 100% sequence identity to SEQ ID NO: 27. It should be noted that claim 52 is not limited to a minimal promoter consisting of SEQ ID NO: 27. The term “comprising SEQ ID NO: 27” in the claim is synonymous with "including," "containing," is inclusive or open-ended and does not exclude additional sequence (See MPEP 2111.03).
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants' arguments are not compelling and do not overcome the rejection of record.
Conclusion
No claims allowed.
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.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632