DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Application Status
This action is written in response to applicant’s correspondence received on 07/29/2026. Claims 3-4, 7, 14, 16, 21, 25-28, 32-36, 39, and 52-58 are currently pending.
Election/Restrictions
Applicant’s election without traverse of Group 2 in the reply filed on 07/29/2026 is acknowledged. The Restriction Requirement mailed on 04/29/2026 is still proper. Claims 3-4, 7, 14, 16, 21, 25-28, 32-36, 39, and 52-58 are examined on the merit accordingly.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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. This application is a 371 of PCT/US2022/075869 filed on 09/01/2022 and claims priority to PRO 63/342,128 filed on 05/15/2022, PRO 63/331,868 filed on 04/17/2022, PRO 63/331,870 filed on 04/17/2022, and PRO 63/239,650 filed on 09/01/2021.
Based on the disclosure of the provisional applications, the following priority dates are assigned to each claim:
09/01/2021, claims 3, 21, 25-28, 32-35, 52, 53;
04/17/2022, claims 4, 7, 14, 16, 36, 39, 54-58.
Specification
5. The use of the terms GenBank, Unigene, Entrez, Elsevier, PubMed, BioRad, ddPCR, IDEXX, American Type Culture Collection, Transnetyx, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 102. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
7. Claims 3, 21, 25-28, 52, 53 are objected to because of the following informalities:
The recitation “SEQ ID NO.:” is inconsistent with the rest of the disclosure for including a period “.” Before “:”. Editing to “SEQ ID NO:” is recommended.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 54 is 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.
The recitation “young pediatric subject” is considered indefinite. To one with ordinary skill in the art, it is unclear whether the relative term “young” shares the same scope with “pediatric” or limits a subset of “pediatric subject”. One would not be appraised of the metes and bounds of the limitation.
Claim Rejections - 35 USC § 102
10. 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.
11. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 3, 4, 7, 14, 16, 21, 32, 34-36, 39, 54, 56, 57, 58 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Loiler (WO2020047472A1, published on 03/05/2020, listed on IDS 03/01/2024), claim 16 is evidenced by Demirbas (Metabolism. 2018;83:188-196), claim 57 is evidenced by Dutta (Life Sci. 2016;152:244-8).
Regarding claim 3, Loiler (2020) teaches A method for treating galactosemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a polynucleotide or composition or a viral particle, i.e. virion, of a recombinant adeno-associated virus (AAV) vector comprising an expression cassette (FIGs. 1A-1C), which comprises a nucleotide sequence encoding human galactose-1-phosphate uridylyl transferase (hGALT; FIGs. 1A-1C). Loiler further teaches recombinant AAV virions comprising: 1) an AAV capsid; and 2) the recombinant AAV vector encompassed by the instant claim 1; and the AAV capsid protein encapsulating the recombinant AAV vector (Page 19, ¶[0085]).
Loiler teaches that the sequence encoding hGALT is operably linked to one or more regulatory elements comprising a promoter that promotes expression of the hGALT coding sequence and a polyadenylation (poly(A)) tail signal. Loiler teaches that the promoter may comprise a cytomegalovirus early enhancer, chicken ß-actin, rabbit ß-globin splice acceptor (CAG) promoter, or an elongation factor-1 (EF-1) promoter (Page 3, ¶[0009] lines 6 and 9). Loiler teaches that the poly(A) tail signal may comprise a bovine growth hormone (bGH) poly(A) tail signal or a simian virus 40 (SV40) poly(A) tail signal (FIGs. 1A-1C; Page 29, ¶[0117] line 8; Page 46, lines 6). Finally, Loiler teaches that the AAV vector includes flanking inverted terminal repeat (ITR) nucleotide sequences (FIGs. 1A-1C; Page 2, ¶[0007]). Loiler further teaches that the hGALT protein encoded by the recombinant AAV vector comprises the amino acid sequence in SEQ ID NO: 4, which is a 100% perfect match with the claimed amino acid sequence of instant SEQ ID NO: 1, see alignment below: Query: Loiler (2020) SEQ ID NO: 4, Sbjct: SEQ ID NO: 1 of the instant application.
379/379(100%)
Query 1 MSRSGTDPQQRQQASEADAAAATFRANDHQHIRYNPLQDEWVLVSAHRMKRPWQGQVEPQ 60
MSRSGTDPQQRQQASEADAAAATFRANDHQHIRYNPLQDEWVLVSAHRMKRPWQGQVEPQ
Sbjct 1 MSRSGTDPQQRQQASEADAAAATFRANDHQHIRYNPLQDEWVLVSAHRMKRPWQGQVEPQ 60
Query 61 LLKTVPRHDPLNPLCPGAIRANGEVNPQYDSTFLFDNDFPALQPDAPSPGPSDHPLFQAK 120
LLKTVPRHDPLNPLCPGAIRANGEVNPQYDSTFLFDNDFPALQPDAPSPGPSDHPLFQAK
Sbjct 61 LLKTVPRHDPLNPLCPGAIRANGEVNPQYDSTFLFDNDFPALQPDAPSPGPSDHPLFQAK 120
Query 121 SARGVCKVMCFHPWSDVTLPLMSVPEIRAVVDAWASVTEELGAQYPWVQIFENKGAMMGC 180
SARGVCKVMCFHPWSDVTLPLMSVPEIRAVVDAWASVTEELGAQYPWVQIFENKGAMMGC
Sbjct 121 SARGVCKVMCFHPWSDVTLPLMSVPEIRAVVDAWASVTEELGAQYPWVQIFENKGAMMGC 180
Query 181 SNPHPHCQVWASSFLPDIAQREERSQQAYKSQHGEPLLMEYSRQELLRKERLVLTSEHWL 240
SNPHPHCQVWASSFLPDIAQREERSQQAYKSQHGEPLLMEYSRQELLRKERLVLTSEHWL
Sbjct 181 SNPHPHCQVWASSFLPDIAQREERSQQAYKSQHGEPLLMEYSRQELLRKERLVLTSEHWL 240
Query 241 VLVPFWATWPYQTLLLPRRHVRRLPELTPAERDDLASIMKKLLTKYDNLFETSFPYSMGW 300
VLVPFWATWPYQTLLLPRRHVRRLPELTPAERDDLASIMKKLLTKYDNLFETSFPYSMGW
Sbjct 241 VLVPFWATWPYQTLLLPRRHVRRLPELTPAERDDLASIMKKLLTKYDNLFETSFPYSMGW 300
Query 301 HGAPTGSEAGANWNHWQLHAHYYPPLLRSATVRKFMVGYEMLAQAQRDLTPEQAAERLRA 360
HGAPTGSEAGANWNHWQLHAHYYPPLLRSATVRKFMVGYEMLAQAQRDLTPEQAAERLRA
Sbjct 301 HGAPTGSEAGANWNHWQLHAHYYPPLLRSATVRKFMVGYEMLAQAQRDLTPEQAAERLRA 360
Query 361 LPEVHYHLGQKDRETATIA 379
LPEVHYHLGQKDRETATIA
Sbjct 361 LPEVHYHLGQKDRETATIA 379
Regarding claim 4, Loiler further teaches a method of increasing galactose metabolism in a subject suffering from galactosemia (Claim 38), comprising administering the claimed polynucleotide, composition, or viral particles to a subject in need thereof, the recitation “results in a reduction in the subject’s galactose, galactitol, and/or galactose-1-phosphate (Gal-1P) levels in comparison to pre-administration levels” is merely intended outcome, patently indistinct from the prior art’s method with identical steps applying the same therapeutic polynucleotide or composition.
Regarding claim 7, Loiler further teaches a method for introducing a functional GALT enzyme into a cell (Claim 35) comprising contacting the cell with the claimed polynucleotide, composition, or viral particles. The recitation of the instant claim 7 “results in an increase in the subject’s hGALT protein expression and/or hGALT enzyme activity in comparison to pre-administration’s GALT protein expression and/or hGALT enzyme activity” is merely intended outcome, patently indistinct from the prior art’s method with identical steps applying the same therapeutic polynucleotide or composition.
Regarding claim 14, Loiler further teaches a method of reducing a disease condition in a subject suffering from galactosemia comprising administering to the subject in need thereof the claimed polynucleotide, composition, or viral particles. The recitation “inhibits cataract formation or promotes cataract resorption or limits the severity of cataract formation in the subject” is merely intended outcome, patently indistinct from the prior art’s method with identical steps applying the same therapeutic polynucleotide or composition.
Regarding claim 16, Loiler further teaches the method of treating a subject suffering from galactosemia by reducing a disease condition or symptom involving “growth restrictions” (Page 4, ¶[0017], line 8). As evidenced by Demirbas’s teachings on how classic galactosemia impedes growth in childhood and early adolescence (Page 191, left col, last ¶, first 4 lines, under 3.1.1.4. Effect of Classic Galactosemia on Body Composition and Growth), at least some embodiments of Loiler’s method is applied to reduce a pre-pubertal growth delay.
Regarding claim 21, Loiler further teaches recombinant AAV vectors comprises the nucleotide sequence that encodes hGALT comprises a nucleic acid SEQ ID NO: 1 having 100% identity to the nucleotide sequence of the instant SEQ ID NO: 2. See alignment below between Query, SEQ ID NO: 1 of Loiler (2020) and Sbjct, SEQ ID NO: 2 of the instant application:
1140/1140(100%)
Query 1 ATGAGCAGAAGCGGCACCGACCCTCAGCAGAGACAGCAGGCCTCTGAAGCCGATGCCGCC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1 ATGAGCAGAAGCGGCACCGACCCTCAGCAGAGACAGCAGGCCTCTGAAGCCGATGCCGCC 60
Query 61 GCTGCCACCTTCAGAGCCAATGACCACCAGCACATCCGGTACAACCCCCTGCAGGACGAG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 61 GCTGCCACCTTCAGAGCCAATGACCACCAGCACATCCGGTACAACCCCCTGCAGGACGAG 120
Query 121 TGGGTGCTGGTGTCCGCCCACAGAATGAAGAGGCCTTGGCAGGGCCAGGTGGAACCCCAG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 121 TGGGTGCTGGTGTCCGCCCACAGAATGAAGAGGCCTTGGCAGGGCCAGGTGGAACCCCAG 180
Query 181 CTGCTGAAAACCGTGCCCAGACACGACCCCCTGAACCCTCTGTGTCCTGGCGCCATTAGA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 181 CTGCTGAAAACCGTGCCCAGACACGACCCCCTGAACCCTCTGTGTCCTGGCGCCATTAGA 240
Query 241 GCCAACGGCGAAGTGAACCCCCAGTACGACAGCACCTTCCTGTTCGACAACGACTTCCCC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 241 GCCAACGGCGAAGTGAACCCCCAGTACGACAGCACCTTCCTGTTCGACAACGACTTCCCC 300
Query 301 GCCCTGCAGCCTGATGCCCCATCTCCTGGACCTAGCGACCACCCTCTGTTCCAGGCCAAG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 301 GCCCTGCAGCCTGATGCCCCATCTCCTGGACCTAGCGACCACCCTCTGTTCCAGGCCAAG 360
Query 361 TCTGCCAGAGGCGTGTGCAAAGTGATGTGCTTCCACCCTTGGAGCGACGTGACCCTGCCC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 361 TCTGCCAGAGGCGTGTGCAAAGTGATGTGCTTCCACCCTTGGAGCGACGTGACCCTGCCC 420
Query 421 CTGATGAGCGTGCCAGAGATCAGAGCCGTGGTGGATGCCTGGGCCAGCGTGACAGAAGAA 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 421 CTGATGAGCGTGCCAGAGATCAGAGCCGTGGTGGATGCCTGGGCCAGCGTGACAGAAGAA 480
Query 481 CTGGGAGCCCAGTACCCCTGGGTGCAGATCTTCGAGAACAAGGGCGCCATGATGGGCTGC 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 481 CTGGGAGCCCAGTACCCCTGGGTGCAGATCTTCGAGAACAAGGGCGCCATGATGGGCTGC 540
Query 541 AGCAACCCCCACCCTCACTGTCAAGTGTGGGCCAGCAGCTTCCTGCCCGATATCGCCCAG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 541 AGCAACCCCCACCCTCACTGTCAAGTGTGGGCCAGCAGCTTCCTGCCCGATATCGCCCAG 600
Query 601 CGGGAAGAGAGAAGCCAGCAGGCTTACAAGAGCCAGCACGGCGAGCCCCTGCTGATGGAA 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 601 CGGGAAGAGAGAAGCCAGCAGGCTTACAAGAGCCAGCACGGCGAGCCCCTGCTGATGGAA 660
Query 661 TACTCCAGACAGGAACTGCTGCGGAAAGAACGGCTGGTGCTGACCAGCGAGCACTGGCTG 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 661 TACTCCAGACAGGAACTGCTGCGGAAAGAACGGCTGGTGCTGACCAGCGAGCACTGGCTG 720
Query 721 GTGCTGGTGCCTTTTTGGGCCACATGGCCCTACCAGACCCTGCTGCTGCCTAGAAGGCAC 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 721 GTGCTGGTGCCTTTTTGGGCCACATGGCCCTACCAGACCCTGCTGCTGCCTAGAAGGCAC 780
Query 781 GTGCGGAGACTGCCTGAGCTGACACCCGCCGAGAGAGATGACCTGGCCAGCATCATGAAG 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 781 GTGCGGAGACTGCCTGAGCTGACACCCGCCGAGAGAGATGACCTGGCCAGCATCATGAAG 840
Query 841 AAACTGCTGACCAAATACGACAACCTGTTCGAGACCAGCTTCCCCTACAGCATGGGCTGG 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 841 AAACTGCTGACCAAATACGACAACCTGTTCGAGACCAGCTTCCCCTACAGCATGGGCTGG 900
Query 901 CACGGCGCTCCTACAGGATCTGAGGCTGGCGCCAACTGGAACCACTGGCAGCTGCACGCC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 901 CACGGCGCTCCTACAGGATCTGAGGCTGGCGCCAACTGGAACCACTGGCAGCTGCACGCC 960
Query 961 CACTACTACCCCCCACTGCTGAGATCTGCCACCGTGCGGAAGTTCATGGTGGGATACGAG 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 961 CACTACTACCCCCCACTGCTGAGATCTGCCACCGTGCGGAAGTTCATGGTGGGATACGAG 1020
Query 1021 ATGCTGGCTCAGGCCCAGAGAGATCTGACCCCTGAACAGGCCGCCGAACGGCTGAGAGCA 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1021 ATGCTGGCTCAGGCCCAGAGAGATCTGACCCCTGAACAGGCCGCCGAACGGCTGAGAGCA 1080
Query 1081 CTGCCCGAAGTGCACTACCACCTGGGACAGAAGGACAGAGAGACAGCCACAATCGCCTGA 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1081 CTGCCCGAAGTGCACTACCACCTGGGACAGAAGGACAGAGAGACAGCCACAATCGCCTGA 1140
Loiler further teaches that “…a recombinant adeno- associated viral ("AAV") vector comprising… the polynucleotide sequence encoding GALT comprises…the nucleotide sequence set forth in SEQ ID NO: 1” (Page 1, ¶[0005]; FIGs 1A-1C). Since SEQ ID NO: 1 disclosed by Loiler is 100% match with the instant SEQ ID NO: 2, as shown above, the nucleic acid that encodes hGALT in the AAV vectors disclosed by Loiler comprises the sequence set forth in the instant SEQ ID NO: 2.
Regarding claim 32, Loiler further teaches recombinant AAV virions, wherein the AAV capsid has an amino acid sequence (SEQ ID NO: 10) which is 85.5% identical to the instant SEQ ID NO: 18 (AAV9 capsid), see alignment below: Query=Loiler SEQ ID NO: 10 Sbjct=Instant SEQ ID NO: 18.
Query 1 MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDNGRGLVLPGYKYLGPFNGLD 60
MAADGYLPDWLEDNLSEGIREWW LKPGAP+PKANQQ QDN RGLVLPGYKYLGP NGLD
Sbjct 1 MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLD 60
Query 61 KGEPVNAADAAALEHDKAYDQQLQAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQ 120
KGEPVNAADAAALEHDKAYDQQL+AGDNPYL+YNHADAEFQERL+EDTSFGGNLGRAVFQ
Sbjct 61 KGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQ 120
Query 121 AKKRVLEPLGLVESPVKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQPAKKRLNFGQTGDS 180
AKKR+LEPLGLVE KTAPGKKRPVE SPQ PDSS GIGK G QPAKKRLNFGQTGD+
Sbjct 121 AKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQE-PDSSAGIGKSGAQPAKKRLNFGQTGDT 179
Query 181 ESVPDPQPIGEPPAGPSGLGSGTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRV 240
ESVPDPQPIGEPPA PSG+GS TMA+GGGAP+ADNNEGADGVGSSSGNWHCDS WLGDRV
Sbjct 180 ESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRV 239
Query 241 ITTSTRTWALPTYNNHLYKQISNGTSGGSTNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQ 300
ITTSTRTWALPTYNNHLYKQISN TSGGS+NDN YFGYSTPWGYFDFNRFHCHFSPRDWQ
Sbjct 240 ITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQ 299
Query 301 RLINNNWGFRPKRLNFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSA 360
RLINNNWGFRPKRLNFKLFNIQVKEVT N G KTIANNLTST+QVFTDS+YQLPYVLGSA
Sbjct 300 RLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSA 359
Query 361 HQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFEFSYNFED 420
H+GCLPPFPADVFMIPQYGYLTLN+GSQAVGRSSFYCLEYFPSQMLRTGNNF+FSY FE+
Sbjct 360 HEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFEN 419
Query 421 VPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQSTGGTAGTQQLLFSQAGPNNMSAQAKNW 480
VPFHSSYAHSQSLDRLMNPLIDQYLYYLS+T + G Q L FS AGP+NM+ Q +N+
Sbjct 420 VPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQ-NQQTLKFSVAGPSNMAVQGRNY 478
Query 481 LPGPCYRQQRVSTTLSQNNNSNFAWTGATKYHLNGRDSLVNPGVAMATHKDDEERFFPSS 540
+PGP YRQQRVSTT++QNNNS FAW GA+ + LNGR+SL+NPG AMA+HK+ E+RFFP S
Sbjct 479 IPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLS 538
Query 541 GVLMFGKQGAGKDNVDYSSVMLTSEEEIKTTNPVATEQYGVVADNLQQQNAAPIVGAVNS 600
G L+FGKQG G+DNVD VM+T+EEEIKTTNPVATE YG VA N Q A G V +
Sbjct 539 GSLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQN 598
Query 601 QGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADP 660
QG LPGMVWQ+RDVYLQGPIWAKIPHTDGNFHPSPLMGGFG+KHPPPQILIKNTPVPADP
Sbjct 599 QGILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADP 658
Query 661 PTTFNQAKLASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTNVDFAVNTE 720
PT FN+ KL SFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKS NV+FAVNTE
Sbjct 659 PTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE 718
Query 721 GTYSEPRPIGTRYLTRNL 738
G YSEPRPIGTRYLTRNL
Sbjct 719 GVYSEPRPIGTRYLTRNL 736
Regarding claim 34, Loiler further teaches “Non-limiting examples of route of administration include intravenous, intra-arterial, intramuscular, intracardiac, intrathecal, subventricular, epidural, intracerebral, intracerebroventricular, sub-retinal, intravitreal, intraarticular, intraocular, intraperitoneal, intrauterine, intradermal, subcutaneous, transdermal, transmuccosal, and inhalation” when discussion examples of administration routes for the claimed recombinant AAV virion (Page 26, ¶[0105]).
Regarding claim 35, Loiler further teaches “intravenous,… intrathecal, …” when discussion examples of administration routes for the recombinant AAV virion (Page 26, ¶[0105]).
Regarding claim 36, Loiler further teaches biodistribution to various organs in FIG. 2 and FIG. 5. Using cells, the vectors are shown to be effective in transducing the expression of hGALT proteins in FIG. 6. The recitation “wherein galactose levels, galactitol levels and/or Gal-1P levels are reduced in liver, muscle, brain, eye, ovary, red blood cells and/or blood plasma” is merely intended outcome and is patently indistinct from the prior art with identical steps and the claimed virions or vectors.
Regarding claim 39, Loiler further teaches biodistribution to various organs in FIG. 2 and FIG. 5. Using cells, the vectors are shown to be effective in transducing the expression of hGALT proteins in FIG. 6. The recitation “wherein hGALT protein expression and/or hGALT enzyme activity is increased in the subject’s liver, muscle, brain, eye, red blood cells and/or blood plasma” merely intended outcome and is patently indistinct from the prior art with identical steps and the claimed virions or vectors.
Regarding claim 54, the limitation “young pediatric subject” is interpreted to encompass any subject with an equivalent pediatric life stage. Loiler further teaches treating mice at 4 weeks of age (Page 41, ¶[0157]), although this is for biodistribution study, it is a necessary pre-evaluation experiment before treatments in the same subject cohort, thus Loiler teaches “young pediatric subject”.
Regarding claim 56, Loiler further teaches “efficacious doses range in the 1012 to 1014 Vg/kg if given intravenously based on similar disease models and serotypes” (Page 40, ¶[0152], lines 5-6).
Regarding claim 57, as evidenced by Dutta (2016; Full citation see above in §112a above), mice at P42 day of age are at prepubertal phase (Page 247, right col, 2nd ¶, last line), hence 4 weeks old mice, used by Loiler are prior to the age of puberty.
Regarding claim 58, which depends from claim 57, Loiler further teaches that “efficacious doses range in the 1012 to 1014 Vg/kg if given intravenously based on similar disease models and serotypes” (Page 40, ¶[0152], lines 5-6).
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 25 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Loiler (2020) in view of Hou (US20200377887A1, published on 12/03/2020), further in view of Sahenk (US20200339960 A1, published on 10/29/2020).
The teachings of Loiler (2020) have been discussed above as applied to claims 3, 4, 7, 14, 16, 21, 32, 34-36, 39. Loiler further teaches that the rAAV vector is a self-complementary vector (scAAV) or a single stranded DNA vector (ssAAV) (Page 27, ¶[0107] & [0108]). Loiler teaches that while ssAAVs require second strand synthesis, which limits transfection efficiency, scAAVs show increased and prolonged transgene expression in vitro and in vivo (Page 2, ¶[0007]). Hou further teaches that scAAV viral genomes contain DNA strands which anneal together to form double stranded DNA. By skipping second strand synthesis, scAAVs allow for rapid expression in the cell (Page 8, ¶[0050]). However, the self-anneal requirement for scAAV genomes indicates that the capacity of the scAAV is effectively halved compared with the capacity of ssAAV counterparts. Loiler further teaches good in vivo expression profiles (Loiler, Pages 52-53, Examples 3-5, FIGs. 16-28).
Regarding claim 25, Loiler does not teach any embodiment of the claimed recombinant AAV, wherein the inverted terminal repeat (ITR) nucleotide sequences comprise a 5’ AAV2 ITR having a nucleotide sequence of the instant SEQ ID NO: 11 and a 3’ AAV2 ITR having a nucleotide sequence of the instant SEQ ID NO: 12, or the reverse complement thereof.
However, Hou (2020) teaches at least one embodiment of recombinant AAV vectors, set forth in SEQ ID NO: 45, that meet the above claimed limitations and comprise a 5’ AAV2 ITR having a nucleotide sequence of the instant SEQ ID NO: 11 and a 3’ AAV2 ITR having a nucleotide sequence of the instant SEQ ID NO: 12, or the reverse complement thereof. See alignments below. Hou further teaches good in vivo expression profile (Page 134, Example 4).
Query = The instant SEQ ID NO: 11, Sbjct = Hou SEQ ID NO: 45
Query 1 TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1 TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGG 60
Query 61 CGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 61 CGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTG 120
Query 121 GCCAACTCCATCACTAGGGGTTCCT 145
|||||||||||||||||||||||||
Sbjct 121 GCCAACTCCATCACTAGGGGTTCCT 145
Query = The instant SEQ ID NO: 12, Sbjct = Hou SEQ ID NO: 45
Query 1 AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 4460 AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGG 4519
Query 61 CCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 4520 CCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGC 4579
Query 121 GAGCGCGCAGAGAGGGAGTGGCCAA 145
|||||||||||||||||||||||||
Sbjct 4580 GAGCGCGCAGAGAGGGAGTGGCCAA 4604
Regarding claim 26, Loiler does not teach any embodiment of the claimed recombinant AAV, wherein the ITR nucleotide sequences comprise a 5’ AAV2 ITR having a nucleotide sequence of the instant SEQ ID NO: 11 and a 3’ AAV2 ITR having a nucleotide sequence of the instant SEQ ID NO: 13, or the reverse complement thereof.
However, Sahenk (2020) teaches at least one embodiment of recombinant AAV vectors, set forth in SEQ ID NO: 11, that meet the above claimed limitations and comprises a 5’ AAV2 ITR having a nucleotide sequence of the instant SEQ ID NO: 11 and a 3’ AAV2 ITR having a nucleotide sequence of the instant SEQ ID NO: 13, or the reverse complement thereof. See alignments below. Sahenk further teaches good in vivo tolerance (Page 96, ¶[0305]) and expression of scAAV vectors (Page 96, ¶[0305]).
Query = The instant SEQ ID NO: 11, Sbjct = Sahenk SEQ ID NO: 11
Query 18 GCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGG 77
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2248 GCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGG 2189
Query 78 TCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAG 137
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 2188 TCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAG 2129
Query 138 GGGTTCCT 145
||||||||
Sbjct 2128 GGGTTCCT 2121
Query = The instant SEQ ID NO: 13, Sbjct = Sahenk SEQ ID NO: 11
Query 1 CCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGAC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 112 CCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGAC 53
Query 61 GCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAG 106
||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 52 GCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAG 7
It would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have modified the recombinant AAV vector embodiments taught by Loiler via simple substitution of the ITR sequences and would have experimented with different AAV genome types, such as ssAAV and scAAV vectors, to have weighed the pros and cons of each format using the known ITR sequence pairing, involving the claimed SEQ ID NOs: 11, 12, 13, so that optimal transgene expression can be achieved through proven vector structural element arrangements in the art. It would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results because success demonstrated by prior arts. One would have been motivated to do so because the recombinant AAV vectors comprising the claimed ITR pairings show good in vivo gene expression and toxicology profiles. The larger cargo capacity but less efficient ssAAV would have been weighed against the faster and more durable gene expression of scAAVs with smaller cargo capacity, and PHOSITAs would have arrived at the claimed inventions simply by testing and comparing the known formats.
Claims 52 and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Loiler (2020) in view of Wilson (US20230270884A1, published on 08/31/2023, claims priority to 07/13/2020 in PRO 63/051,336), further in view of Chatterjee (US20190134118A1, published on 05/09/2019).
The teachings of Loiler (2020) have been discussed above as applied to claims 3, 4, 7, 14, 16, 21, 25, 26, 32, 34-36, 39. Loiler does not teach the CAG promoter has a nucleotide sequence of SEQ ID NO: 9 or the SV40 poly(A) tail signal comprises the nucleotide sequence of SEQ ID NO: 16.
However, Wilson (2020) teaches an 841nt promoter sequence in SEQ ID NO: 87 (SEQ listing indicates it is a CAG promoter on Page 116), which comprises the claimed instant SEQ ID NO: 9 in its first 670 nucleotide, see alignment below. Wilson further demonstrates that the CAG promoter or its equivalent CB7 promoter with a CMV early enhancer (SEQ ID NO: 86, sharing the same sequence) has been consistently effective for both in vitro and in vivo applications (¶[0025]-[0031]; FIGs 8-12, 14).
Query=instant SEQ ID NO: 9, Sbjct=SEQ ID NO: 87 of Wilson
Query 1 CCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1 CCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGA 60
Query 61 CGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCAT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 61 CGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCAT 120
Query 121 ATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 121 ATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCC 180
Query 181 CAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 181 CAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCT 240
Query 241 ATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTccccatctcccccccctcc 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 241 ATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCC 300
Query 301 ccacccccAattttgtatttatttattttttaattattttGTGCAGCGATgggggcgggg 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 301 CCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGG 360
Query 361 ggggggggggggcgcgcgccaggcggggcggggcggggcgaggggcggggcggggcgagg 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 361 GGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGG 420
Query 421 cggagaggtgcggcggcagccaatcagagcggcgcgCTCCGAAAGTTTCCTTTTATggcg 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 421 CGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCG 480
Query 481 aggcggcggcggcggcggccctataaaaagcgaagcgcgcggcgggcgggagtcgctgcg 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 481 AGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCGGGAGTCGCTGCG 540
Query 541 cgctgccttcgccccgtgccccgctccgccgccgcctcgcgccgcccgccccgGCTCTGA 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 541 CGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTCGCGCCGCCCGCCCCGGCTCTGA 600
Query 601 CTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAAT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 601 CTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAAT 660
Query 661 TAGCGCTTGG 670
||||||||||
Sbjct 661 TAGCGCTTGG 670
Wilson does not teach the SV40 poly(A) tail signal nucleotide sequence of SEQ ID NO: 16.
However, Chatterjee (2019) teaches an SV40 poly(A) tail signal comprising a nucleotide sequence with 100% sequence identity to SEQ ID NO: 16, see alignment below:
Query: Instant SEQ ID NO: 16; Sbjct: Chatterjee SEQ ID NO: 78, SV40 PolyA Tail
PNG
media_image1.png
280
846
media_image1.png
Greyscale
Regarding claims 52 and 53, it would have been obvious to persons having ordinary skills in the art (PHOSITAs) before the effective filing date of the claimed invention to have modified the AAV vector embodiments taught by Loiler via simple substitution of the CAG promoter sequences with a different sequence design that resulted in different length, taught by Wilson (2020) as one of the preferred embodiments (Page 11, ¶[0074]). The same modification logic applies to replacing the SV40 poly(A) tail signal of Loiler with the SV40 polyA tail signal sequence of Chatterjee, set forth in SEQ ID NO: 78. It would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to do so because Wilson (2020) teaches that the recombinant AAV vectors comprising the claimed promoter show robust in vitro (FIGs. 8-12) and in vivo gene expression and toxicology profiles in mice (FIG. 14) mediated by a CAG or CB7 promoter with identical sequences (SEQ ID NOs: 86 and 87; ¶[0025]-[0031]). One would have been further motivated to adopt the SV40 polyA tail signal sequences from Chatterjee (2019), because it teaches that when used for gene replacement purpose, the exogenous transgene “coding sequence or portion thereof is followed by an SV 40 polyadenylation sequence, which is strong enough to support proper expression and significantly reduce further transcription of the rest of the endogenous” gene (Page 25, ¶[0190], lines 3-7”. One would have reasonable expectations of success because these are known functional elements with the same functions. Testing one against the other is part of a routine laboratory optimization process known in the art and to PHOSITA.
Claims 27 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Loiler (2020) in view of Hou (2020), further in view of Sahenk (2020), Wilson (2020), and Chatterjee (2019).
The teachings of Loiler (2020), Hou (2020), Sahenk (2020), Wilson (2020), and Chatterjee (2019) have been discussed above as applied to claims 3, 4, 7, 14, 16, 21, 25, 26, 32, 34-36, 39, 52, 53.
Loiler does not teach a rAAV vector, wherein the expression cassette comprises a nucleotide sequence that has at least 85% identity to the nucleotide sequence of SEQ ID NO: 3. Nor does Loiler teach a rAAV vector, wherein the expression cassette comprises a nucleotide sequence that has at least 85% identity to the nucleotide sequence of SEQ ID NO: 19.
However, Hou (2020), Sahenk (2020), Wilson (2020), and Chatterjee (2019) each teaches different claimed AAV vector elemental sequences based on sequence alignment below (details see the NCBI_Sequence_Alignment_SEQ ID NOs 9, 2, 16, 19.pdf listed in PTO-892):
-Hou teaches a sequence set forth in SEQ ID NO: 45 that comprises the instant SEQ ID NOs: 11 & 12.
-Loiler teaches a sequence set forth in SEQ ID NO: 1 that comprises 100% sequence identity of the instant SEQ ID NO: 2, encoding hGALT.
-Wilson teaches a CAG promoter sequence set forth in SEQ ID NO: 87 that matches the instant SEQ ID NO: 9.
-Sahenk teaches a sequence set forth in SEQ ID NO: 11 that comprises the instant SEQ ID NO: 13.
-Chatterjee teaches a sequence set forth in SEQ ID NO: 78 that comprises an SV40 polyA tail sequence in the claimed instant SEQ ID NO: 16.
The following schema show the arrangements with claimed elements within SEQ ID NOs: 9, 19, 3:
SEQ ID NO: 19 1931/1964x100%=98.3% 1931nt are known elements in the art.
[CAG promoter]----[ hGALT ]----[SV40 poly(A) tail signal]
[SEQ ID NO: 9]----[ SEQ ID NO: 2 ]----[ SEQ ID NO: 16 ]
[ Wilson ]----[ Loiler ]----[ Chatterjee ]
[ 1-670 ]-12-[ 683-1822 ]-21-[ 1844-1964 ]
SEQ ID NO: 3 2217/2292x100%=96.7% 2217nt are known elements in the art.
[ 5'ITR ]-[ Expression Cassette ]-[ 3' ITR ]
[SEQ ID NO: 11]-[ SEQ ID NO: 19 ]-[SEQ ID NO: 13]
[ Hou ]-[ Wilson, Loiler, Chatterjee ]-[ Sahenk ]
[ 1-145 ]-49-[ 195-2159 ]-26-[ 2187-2292 ]
As over 95% of the sequence of each of the claimed SEQ ID NOs: 9, 19, and 3 comprises known sequences for functional AAV vector elements in the art with only a small fraction (<5%) of the sequences being generic spacers or linkers that function as “glue” resulting from routine laboratory optimization. The prior arts, Loiler, Hou, Wilson, Sahenk, and Chatterjee, each teaches various modular element(s) essential for the claimed inventions.
It would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have modified the recombinant AAV vector embodiments taught by Loiler via simple substitution of the known AAV regulatory element sequences, and would have experimented with different AAV vector elemental architecture known in the art based on the teachings and examples of Hou, Wilson, Sahenk, Loiler, and Chatterjee, such that optimal transgene expression can be achieved. It would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to do so because the recombinant AAV vectors comprising the claimed vector elements show good in vivo gene expression and toxicology profiles (Loiler, Pages 52-53, Examples 3-5, FIGs. 16-28; Hou, Page 134, Example 4). PHOSITAs would have arrived as the claimed inventions through routine optimizations and explorations with reasonable expectation of success because these elements are known to have the same, interchangeable functions.
Regarding claim 27, PHOSITAs would have generated a rAAV vector wherein the expression cassette and flanking ITR nucleotide sequences comprise a nucleic acid that has at least 85% identity to the nucleotide sequence of SEQ ID NO: 3, and would have tested it with reasonable expectation of success based on the prior arts shown in the vector arrangements above.
Regarding claim 28, PHOSITAs would have generated a rAAV vector wherein the vector comprises a nucleotide sequence that has at least 85% identity to the nucleotide sequence of SEQ ID NO: 19, and would have tested it with reasonable expectation of success based on the prior arts shown in the vector arrangements above.
Claim 55 is rejected under 35 U.S.C. 103 as being unpatentable over Loiler (2020) in view of Demirbas (2018). The teachings of Loiler have been discussed above. Loiler further teaches that “In the context of therapeutic or prophylactic applications, the effective amount will depend on … age, …” (Page 25, ¶[0103]) and that “Methods of determining the most effective means and dosage of administration are known to those of skill in the art and will vary with … age, … of the subject being treated” (Page 26, ¶[0105]). Loiler does not specifically teach the age range of type 1 galactosemia suitable for the AAV-based GALT replacement gene therapy.
However, Demirbas teaches that it is known in the art that at least some human subjects between the ages of 4 month to 4 years suffer from certain symptoms of Classic Galactosemia (Page 190, last 2 lines-page 191, first line).
It would have been obvious to persons having ordinary skills in the art (PHOSITAs) before the effective filing date of the claimed invention to have applied the AAV-based GALT replacement gene therapy taught by Loiler (2020) to human subjects suffering from symptoms of Classic Galatosemia, between the ages of 4 months and 4 years, based on teachings by Demirbas (2018), and at least some embodiments of the method of treating would have involved young pediatric subjects that are about 4 years old, about 3.5 years old, about 3 years old, about 2.5 years old, about 2 years old, about 1.5 years old, about 1 year old, or about 6 months old. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. One would have been motivated to do so because Loiler (2020) teaches that an AAV-based hGALT gene therapy method of treating galactosemia would treat and alleviate a variety of symptoms (Claim 39) that cover those described by Demirbas, impacting human subjects from 4 month old to 4 year old. One would have reasonable expectations of success because Loiler describes robust transduction of GALT expression in cell models using the claimed AAV GALT vectors (Page 41, ¶[0156], FIG. 6).
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.
US Application 18/687,808
Claims 1, 3-4, 7, 9, 12, 14, 16, 18, 20-21, 23-28, 31-36 and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24, 27-29 of copending Application 18/687,808. Although the claims at issue are not identical, they are not patentably distinct from each other.
US Application 18/687,808 teaches a composition of AAV capsid and recombinant AAV vectors comprising regulatory elements and a nucleic acid sequence encoding the human GALT gene and methods of treating galactosemia using the claimed composition with a plurality of intended outcomes.
Regarding claims 3, claims 1 & 2 of US Application 18/687,808 teache all limitations.
Regarding claims 21, claim 3 of US Application 18/687,808 teaches all sequence limitations for the hGALT transgene encoded by the rAAV vectors.
Regarding claim 25, claim 7 of US Application 18/687,808 teaches all sequence limitations.
Regarding claim 26, claim 8 of US Application 18/687,808 teaches the same ITR limitation.
Regarding claims 27, claim 9 of US Application 18/687,808 teaches the same expression cassette sequences of the instant claims.
Regarding claims 28, claim 10 of US Application 18/687,808 teaches the same sequence.
Regarding claim 32, claim 15 of US Application 18/687,808 teaches the same capsid sequence.
Regarding claim 33, claim 16 of US Application 18/687,808 teaches the same AAV types.
Regarding claim 34, claim 20 of US Application 18/687,808 teaches the same delivery routes.
Regarding claim 35, claim 21 of US Application 18/687,808 teaches the same routes of delivery for AAV-based method of treating galactosemia.
Regarding claims 52 & 53, claim 5 of US Application 18/687,808 teaches the sequences.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
US Application 18/715,015
Claims 1, 3-4, 7, 9, 12, 14, 16, 18, 20-21, 23-28, 31-36 and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-9, 11-12, 14-17, 19-20, 23-24, 26 and 28 of copending Application 18/715,015 in view of Loiler (2020) see full citation above. Although the claims at issue are not identical, they are not patentably distinct from each other.
US Application 18/715,015 teaches a recombinant AAV vector encoding a hPax4 gene and methods for treating diabetes mellitus in a subject in need thereof or methods for reducing the risk of developing diabetes in a subject positive for anti-islet auto-antibodies, methods comprising administering a therapeutically effective amount of AAV virions to the subject in need thereof, and involve rAAV vectors, expression cassettes, and plasmids comprising modular regulatory elements, along with a method of producing rAAV virions.
US Application 18/715,015 does not teach a rAAV encoding hGALT gene for treating galactosemia.
However, Loiler (2020) teaches using a rAAV vector comprising nucleic acid sequences encoding the same human GALT and an AAV capsid to treat galactosemia.
It would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have modified the recombinant AAV virion embodiments taught by Loiler via simple substitution of the known AAV capsid sequences disclosed in US Application 18/715,015, and would have experimented with different AAV vector designs, regulatory element or capsid variants to identify the optimal variant for optimal vector performance and therapeutic outcomes based on the teachings and examples of the US Application 18/715,015. It would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to do so because of the in vivo impact of the rAAV vectors demonstrated by US Application 18/715,015 (Page 12, ¶[0069] & [0070]; FIG. 5 & FIG. 6). PHOSITAs would have arrived at the claimed inventions through the explorations with reasonable expectation for success.
Claims 1, 7-9, 11-12, 24 of 18/715,015 correspond to the instant claims 3, 25-28, 32, 33.
Claims 14-17, 19-20, 23 of 18/715,015 correspond to the instant claims 34, 35.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
41. No claims are allowable.
42. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
