DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse in response to an Election of Species Requirement in the reply filed on 09/05/2025 is acknowledged, the elections being: an intron sequence from a gene encoding a COL1A2 protein; intron sequence comprising a sequence having at least 80% or more sequence identity to SEQ ID NO: 2; transgene CDKL5; an AAV Cap coding sequence encoding a capsid protein of serotype AAV9 and SEQ ID NO: 2 inserted at A-5.
Claims 1-2, 5, 8-9, 15, 21-22, 25, 28, 30, 35-36, 38-39, 41, 45-47, and 49 read on the elected invention are examined on the merits herein.
Claim Objections
Claim 25 is objected to because of the following informalities: there is a typographical error in line 3 of claim 25; “…having a exon splice donor…” should read “…having an exon splice donor…”. 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.
Claims 45-47, and 49 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.
Regarding claim 45: The instant claim depend from canceled claim 44. This renders claim 45 indefinite. For the purposes of compact prosecution, claim 45 will be interpreted as depending from claim 41 for the remainder of examination.
Claim 46 depends from claim 45, inherits its deficiencies, and thus is likewise rejected as indefinite.
Regarding claim 47: This instant claim recites terms designated as locations appropriate for intron insertion; e.g., A-5. However, part (ii) of claim 47 is drawn to locations within the AAV9 Cap coding sequence; while the instant disclosure provides guidance regarding the specifics of these locations within the AAV8 Cap coding sequence, it does not do so for AAV9; as such, the exact location designated as appropriate for intron insertion, and therefore necessarily the metes and bounds of the instant claim, would not be immediately understood by a person having ordinary skill in the art. Thus, absent any clear definition or guidance in the instant specification, recitation of the term location A-5 renders the instant claim indefinite.
Claim 49 depends from claim 47, inherits its deficiencies, and thus is likewise rejected as indefinite.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 5, 8-9, 15, 21-22, 28, 30, 39, 41, and 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over Xiao, et al. (U.S. Patent No. 6,329,181) in view of Prockop, et al. (U.S. Patent No. 6,265,157).
Xiao, et al. teaches methods and compositions for preparations of recombinant parvovirus virions with a reduced number of replication competent particles (Abstract).
Prockop, et al. teaches intronic sequences of five human collagen genes, including COL1A2 (Abstract).
Regarding claims 1-2, 9, 15, 21-22, 28, 30, 39:
Xiao, et al. teaches nucleic acid construct pCLV3, wherein the 850 bp human β-globin intron is cloned into the AAV2 genome at position 2916 in the VP3 region (Fig. 3A; col. 19, lines 23-27), followed by subsequent packaging of the recombinant vector by transfection of HEK293 cells (col. 19, lines 49-60). The pCLV3 construct reads on the recombinant nucleic acid construct comprising an AAV Rep coding sequence and an AAV Cap coding sequence, wherein said AAV Cap coding sequence has been modified via the insertion of one or more heterologous excisable intron sequences in the VP3 region of said AAV Cap coding sequence limitation recited in claim 1, the wherein the AAV Cap coding sequence encodes a capsid protein of serotype AAV2 limitation recited in claim 2, and the vector comprising the recombinant nucleic acid construct limitation recited in claim 28. The transfected HEK293 cells reads on the host cell comprising the recombinant nucleic acid construct limitation recited in claim 30 and the wherein said host cell is a HEK293 cell limitation recited in claim 39.
Xiao, et al. does not teach the total length of the one or more heterologous excisable intron sequences as at least 1 kb, as required by the remaining limitation recited in claim 1.
However, Prockop, et al. teaches a COL1A2 intron comprising 2642 bp and encoded by the sequence set forth as SEQ ID NO: 59 (Figs. 5B-3, -4, -5); this reads on the wherein the total length of the one or more heterologous excisable intron sequences is at least 1 kb limitation recited in claim 1, the wherein the total length of the one or more heterologous excisable intron sequences together is at least 1.5 kb limitation recited in claim 9, the wherein the total length of the one or more heterologous excisable intron sequences together is 1.0 kb to 5.0 kb limitation recited in claim 15, as well as the wherein the one or more heterologous excisable intron sequences is an intron sequence from a gene encoding a COL1A2 protein limitation recited in claim 21. Additionally, as SEQ ID NO: 59 shares 98.3% sequence identity to instant SEQ ID NO: 2, the COL1A2 intron taught by Prockop, et al. reads on the wherein the one or more heterologous excisable intron sequences comprise a sequence selected from a sequence which is at least 80% or more identical to SEQ ID NO: 2 limitation recited in claim 22. See sequence alignments at the end of the Office action.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the pCLV3 nucleic acid construct taught by Xiao, et al. by substituting the β-globin intron with the COL1A2 intron of Prockop, et al. This conclusion of obviousness is based on the ‘substitution rationale’. Given that Xiao, et al. teaches intron sequence insertion increases the size of the viral genome (col. 2, lines 47-48), wherein the increase in size prevents packaging of a pseudo wild-type virus into a replication competent particle (col. 2, lines 39-41), the use of a COL1A2 intron in place of the β-globin intron is a predictable use of prior art elements according to their established functions, leading to the predictable result of increased viral genome size and prevention of replication competent particles. Further, as Xiao, et al. teaches the use of a heterologous intron in an rAAV nucleic acid construct, a person having ordinary skill in the art would have a reasonable expectation of success. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results. See MPEP 2143(I)(B).
Therefore, the limitations recited in claim 1 are thus rendered obvious.
Regarding claim 5: Following the above discussion, the pCLV3 construct taught by Xiao, et al. comprises a p40 promoter (Fig. 3A); this reads on the wherein the recombinant nucleic acid construct further comprises one or more nucleic acid sequences selected from a promoter, an AAV intron, and a coding sequence for a selectable marker limitation recited in claim 5.
Regarding claim 8: Following the above discussion, Xiao, et al. teaches the intron insertion maintained the consensus sequences for the splice donor sites and acceptor sites (col. 19, lines 27-29); this reads on the wherein the one or more heterologous excisable intron sequences comprise at least one splice donor and at least one splice acceptor site limitation recited in claim 8.
Regarding claim 41: Following the above discussion, Xiao, et al. teaches introduction of at least one intron sequence to the structural and/or non-structural protein coding regions reduces and/or eliminates the number of contaminated replication competent particles generated during recombinant virion production (col. 2, lines 26-30); thus, the modified method of Xiao, et al. wherein the recombinant vector comprising the intron-containing plasmid is packaged into HEK293 cells (col. 19, lines 49-60) reads on the method of producing a preparation of recombinant AAV (rAAV), said method comprising culturing the host cell of claim 30 under suitable conditions that promote the production of rAAV, wherein the preparation of rAAV contains reduced levels of caр DNA or rep DNA or both cap and rep DNA compared to a corresponding preparation of rAAV produced using an unmodified AAV Cap coding sequence limitation recited in claim 41.
Regarding claim 45: In the interest of compact prosecution, claim 45 is interpreted as depending from claim 41. Therefore, following the above discussion, the modified rAAV of Xiao, et al. reads on the limitations recited in the instant claim.
Regarding claim 46: Following the above discussion, Xiao, et al. teaches an embodiment where the rAAV vector is incorporated into a pharmaceutical composition suitable for administration to a subject, wherein the composition comprises the vector and a pharmaceutically acceptable carrier (col. 19, lines 12-16); this reads on the pharmaceutical composition comprising the rAAV of claim 45 and a pharmaceutically acceptable carrier limitation recited in claim 46.
Claims 1-2, 5, 8-9, 15, 21-22, 28, 30, 35, 39, 41, and 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over Khabou, et al. (Biotechnol Bioeng. 2016) in view of Prockop, et al. (U.S. Patent No. 6,265,157) and Xiao, et al. (U.S. Patent No. 6,329,181); as evidenced by Wilson, et al. (US 2019/0054188), Choi, et al. (Curr Protoc Hum Genet. 2007), and Halbert, et al. (Gene Ther. 2010).
Khabou, et al. teaches the effects of peptide insertion into AAV vectors (Abstract).
The teachings of Prockop, et al. and Xiao, et al. are set forth above.
Regarding claims 1-2, 9, 15, 21-22, 28:
Khabou, et al. teaches the 7m8 peptide inserted into the capsid of AAV9, at residue 588 (Figs. 2A, D); as evidenced by Wilson, et al., the VP3 region of SEQ ID NO: 123 (corresponding to GenBank Accession No. AY530579 for the AAV9 Cap gene; see par. 0070) comprises amino acid residues 203 to 736 (par. 0090). Thus, the AAV9-7m8 vector reads on the recombinant nucleic acid construct comprising an AAV Rep coding sequence and an AAV Cap coding sequence, wherein said AAV Cap coding sequence has been modified via the insertion of one or more heterologous excisable intron sequences in the VP3 region of said AAV Cap coding sequence limitation recited in claim 1, the wherein the AAV Cap coding sequence encodes a capsid protein of serotype AAV9 limitation recited in claim 2, and the vector comprising the recombinant nucleic acid construct limitation recited in claim 28.
Khabou, et al. does not teach the total length of the one or more heterologous excisable intron sequences as at least 1 kb, as required by the remaining limitation recited in claim 1.
However, Prockop, et al. teaches a COL1A2 intron comprising 2642 bp and encoded by the sequence set forth as SEQ ID NO: 59 (Figs. 5B-3, -4, -5); this reads on the wherein the total length of the one or more heterologous excisable intron sequences is at least 1 kb limitation recited in claim 1, the wherein the total length of the one or more heterologous excisable intron sequences together is at least 1.5 kb limitation recited in claim 9, the wherein the total length of the one or more heterologous excisable intron sequences together is 1.0 kb to 5.0 kb limitation recited in claim 15, as well as the wherein the one or more heterologous excisable intron sequences is an intron sequence from a gene encoding a COL1A2 protein limitation recited in claim 21. Additionally, as SEQ ID NO: 59 shares 98.3% sequence identity to instant SEQ ID NO: 2, the COL1A2 intron taught by Prockop, et al. reads on the wherein the one or more heterologous excisable intron sequences comprise a sequence selected from a sequence which is at least 80% or more identical to SEQ ID NO: 2 limitation recited in claim 22. See sequence alignments at the end of the Office action.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the AAV9-7m8 vector taught by Khabou, et al. by substituting the 7m8 peptide with the COL1A2 intron of Prockop, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so because Xiao, et al. teaches intron sequence insertion increases the size of the viral genome (col. 2, lines 47-48), and that the increase in size prevents packaging of a pseudo wild-type virus into a replication competent particle (col. 2, lines 39-41). Further, as Xiao, et al. teaches the use of a heterologous intron in an rAAV nucleic acid construct, a person having ordinary skill in the art would have a reasonable expectation of success.
Therefore, the limitations recited in claim 1 are thus rendered obvious.
Regarding claim 5: Following the above discussion, Khabou, et al. teaches the AAV9-7m8 vector further comprises GFP under the control of a ubiquitous CAG promoter (pg. 2714; col. 2, par. 1); this reads on the wherein the recombinant nucleic acid construct further comprises a promoter and a coding sequence for a selectable marker limitations recited in claim 5.
Regarding claim 8: Following the above discussion, the modified AAV9-7m8 heterologous intron-containing vector of Khabou, et al. implicitly reads on the wherein the one or more heterologous excisable intron sequences comprise at least one splice donor and at least one splice acceptor site limitation recited in claim 8.
Regarding claims 30, 39: Following the above discussion, Khabou, et al. teaches HEK293T cells were transduced with the vector (pg. 2715; col. 1, par. 1); this reads on the host cell comprising the recombinant nucleic acid construct limitation recited in claim 30, as well as the wherein said host cell is a HEK293 cell limitation recited in claim 39.
Regarding claim 35: Following the above discussion, Khabou, et al. does not explicitly teach the limitations recited in the instant claim. However, Khabou, et al. does teach the recombinant AAVs of the disclosure were produced as previously described using the co-transfection method of Choi, et al. (Curr Protoc Hum Genet. 2007). As evidenced by Choi, et al., the production of rAAV particles requires an rAAV vector plasmid containing a transgene flanked by AAV inverted terminal repeats (ITRs), as well as a plasmid supplying adenoviral helper genes (pg. 1, par. 2); this reads on the limitations recited in claim 35.
Regarding claim 41: Following the above discussion, Khabou, et al. does not explicitly teach the limitations recited in the instant claim. However, as evidenced by Halbert, et al., introduction of a large intron in the cap gene (captron) results in undetectable cap expression in cells exposed to vectors comprising the captron plasmid (pg. 412; col. 1, par. 1). Additionally, Xiao, et al. teaches intron sequence insertion increases the size of the viral genome (col. 2, lines 47-48) and prevents packaging of a pseudo wild-type virus into a replication competent particle (col. 2, lines 39-41). Thus, the modified AAV9-7m8 heterologous intron-containing vector of Khabou, et al. reads on the limitations recited in the instant claim.
Regarding claim 45: In the interest of compact prosecution, claim 45 is interpreted as depending from claim 41. Therefore, following the above discussion, the modified rAAV of Khabou, et al. reads on the limitations recited in the instant claim.
Regarding claim 46: Following the above discussion, Khabou, et al. teaches AAV vector stocks were titer adjusted by dilution in PBS containing 0.001% Pluronic (pg. 2722; col. 1, par. 2); this reads on the pharmaceutical composition comprising the rAAV of claim 45 and a pharmaceutically acceptable carrier limitation recited in claim 46.
Claims 25 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Khabou, et al. (Biotechnol Bioeng. 2016) in view of Prockop, et al. (U.S. Patent No. 6,265,157) and Xiao, et al. (U.S. Patent No. 6,329,181), further in view of Russell and Betts, et al. (Dev Dyn. 2008) and Borensztajn, et al. (PLoS Genet. 2006); as evidenced by Wilson, et al. (US 2019/0054188), Choi, et al. (Curr Protoc Hum Genet. 2007), and Halbert, et al. (Gene Ther. 2010).
The teachings of Khabou, et al., Prockop, et al., and Xiao, et al. are set forth above.
Russell and Betts teaches a splice variant of the bovine Dnmt1 with a ubiquitous expression pattern (Abstract).
Borensztajn, et al. teaches splice site selection as a key element of pre-mRNA splicing (Abstract).
Regarding claim 25: It is set forth above the modified nucleic acid construct of Khabou, et al. renders obvious the limitations recited in claim 1. None of the teachings of Khabou, et al., Prockop, et al., or Xiao, et al. disclose the limitations recited in claim 25.
However, Russell and Betts teaches consensus sequence CAG/G for splice sites (pg. 1054; par. 1); this reads on the wherein the one or more heterologous excisable intron sequences is inserted at a location of cap VP3 having a[n] exon splice donor/exon splice acceptor sequence selected from CAG/G (SEQ ID NO: 32) limitation recited in claim 25.
It would have been prima facie obvious to a person having ordinary skill in the art to have used the consensus sequence CAG/G as taught by Russell and Betts for the exon splice donor and splice acceptor sites in the modified nucleic acid construct of Khabou, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so as consensus sequence motifs are necessarily highly conserved, as well as known in the art; thus, one skilled in the art would have more than a reasonable expectation of success in splicing using a consensus sequence. This renders obvious the limitations recited in claim 25.
Regarding claim 47: It is set forth above the term location A-5 lacks a clear definition in the instant specification and renders the instant claim indefinite. In the interest of compact prosecution, however, the limitation recited in claim 47 will be addressed.
Following the above discussion, none of the teachings of Khabou, et al., Prockop, et al., or Xiao, et al. disclose the limitations recited in claim 47.
However, Borensztajn, et al. teaches any abnormality in mammalian pre-mRNA splicing may generate aberrant mRNAs that are either unstable or code for defective and/or deleterious proteins (pg. 1297; col. 1, par. 1).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have used routine optimization for the selection of locations within the AAV9 VP3 region comprising the consensus sequence CAG/G, for the reasons disclosed by Borensztajn, et al.; namely, to ensure the modified nucleic acid construct of Khabou, et al. properly encodes for the production of rAAV. Additionally, “[a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.” See In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); see MPEP § 716.02.
Therefore, the limitations recited in claim 47 are thus rendered obvious.
Claims 36 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Khabou, et al. (Biotechnol Bioeng. 2016) in view of Prockop, et al. (U.S. Patent No. 6,265,157) and Xiao, et al. (U.S. Patent No. 6,329,181), further in view of Gao, et al. (Brain. 2020); as evidenced by Wilson, et al. (US 2019/0054188), Choi, et al. (Curr Protoc Hum Genet. 2007), and Halbert, et al. (Gene Ther. 2010).
The teachings of Khabou, et al., Prockop, et al., and Xiao, et al. are set forth above.
Gao, et al. teaches gene therapy mediated by AAV vectors Cdkl5 knockout mice (Abstract).
Regarding claims 36, 38: It is set forth above the modified nucleic acid construct of Khabou, et al. renders obvious the limitations recited in claim 35. None of the teachings of Khabou, et al., Prockop, et al., or Xiao, et al. disclose the limitations recited in claim 36.
However, Gao, et al. teaches codon-optimized CDKL5 transgene sequences were cloned into AAV plasmids; AAV vectors were subsequently prepared via 3-plasmid co-transfection of HEK293T cells (pg. 814; col. 1, pars. 4-5). The codon-optimized CDKL5 transgene reads on the wherein the transgene coding sequence is a codon-optimized coding sequence limitation recited in claim 36, as well as the wherein the transgene is cyclin-dependent kinase-like 5 (CDKL5) limitation recited in claim 38.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the AAV plasmid comprising the sequence encoding GFP under the ubiquitous CAG promoter taught by Khabou, et al. (pg. 2716; col. 2, par. 2) by substituting the sequence encoding GFP with the codon-optimized CDKL5 transgene sequence taught by Gao, et al. (pg. 814; col. 1, par. 4). This conclusion of obviousness is based on the ‘substitution rationale’. The use of the sequence encoding CDKL5 in place of the sequence encoding GFP is a predictable use of prior art elements according to their established functions of encoding a gene product, leading to the predictable result of the expression of said gene product. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results; see MPEP 2143(I)(B). Further, a person having ordinary skill in the art would be additionally motivated to make such a modification, as Gao, et al. teaches mutations in the CDKL5 gene cause the severe neurodevelopmental disorder, cyclin-dependent kinase-like 5 disorder (Abstract).
Therefore, the limitations recited in claims 36 and 38 are thus rendered obvious.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Khabou, et al. (Biotechnol Bioeng. 2016) in view of Prockop, et al. (U.S. Patent No. 6,265,157) and Xiao, et al. (U.S. Patent No. 6,329,181); further in view of Russell and Betts, et al. (Dev Dyn. 2008), Borensztajn, et al. (PLoS Genet. 2006), and Pekrun, et al. (U.S. Patent No. 11,608,510); as evidenced by Wilson, et al. (US 2019/0054188), Choi, et al. (Curr Protoc Hum Genet. 2007), and Halbert, et al. (Gene Ther. 2010).
The teachings of Khabou, et al., Prockop, et al., Xiao, et al., Russell and Betts, and Borensztajn, et al. are set forth above.
Pekrun, et al. teaches variant AAV capsid polypeptides (Abstract).
Regarding claim 49: It is set forth above the modified nucleic acid construct of Khabou, et al. renders obvious the limitations recited in claim 47. Khabou, et al., nor the previously cited references teach the limitations recited in the instant claim.
However, Pekrun, et al. teaches AAV capsid nucleic acid sequence SEQ ID NO: 51, encoding AAV9hu14 (Table 5; cols. 59-60). As SEQ ID NO: 51 shares 99.9% sequence identity to instant SEQ ID NO: 42, this reads on the wherein the AAV Cap coding sequence before modification comprises a nucleotide sequence that is at least 99% identical to the nucleotide sequence of SEQ ID NO: 42 limitation recited in the instant claim. See sequence alignments at the end of the Office action.
It would have been prima facie obvious to a person having ordinary skill in the art to have further the modified nucleic acid construct of Khabou, et al. by substituting the nucleic acid sequence encoding the AAV9 Cap gene with SEQ ID NO: 51, as taught by Pekrun, et al. This conclusion of obviousness is based on the ‘substitution rationale’. The use of the nucleic acid sequence taught by Pekrun, et al. in place of the sequence used in the nucleic acid construct of Khabou, et al. is a predictable use of prior art elements according to their established functions of encoding an AAV9 capsid, leading to the predictable result of expression of an AAV9 capsid. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results; see MPEP 2143(I)(B).
This renders obvious the limitations of claim 49.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GINA PRONZATI whose telephone number is (571)270-5725. The examiner can normally be reached Monday - Friday 9:00a - 5:00p ET.
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
SEQUENCE ALIGNMENTS
Query, “Qy” (instant SEQ ID NO: 2) vs. Database, “Db” (U.S. Patent No. 6,265,157; SEQ ID NO: 59)
PNG
media_image1.png
279
714
media_image1.png
Greyscale
Query, “Qy” (instant SEQ ID NO: 42) vs. Database, “Db” (U.S. Patent No. 11,608,510; SEQ ID NO: 51)
PNG
media_image2.png
552
694
media_image2.png
Greyscale