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 amendment submitted on 11/5/2025 is acknowledged.
Applicant’s election without traverse of Group I, Claims 1-18 and 22-23, drawn to a nucleic acid construct or a cell comprising one or more nucleic acid constructs, in the reply filed on 7/4/2025 is acknowledged.
Claims 19-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 7/4/2025.
Claims 1-18 and 22-23 are under examination on the merits.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) submitted on 11/5/2025 are in compliance with 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
Objections Removed
The previous objection to claims 15, 18, and 23 are hereby withdrawn due to amendment.
Objections Maintained
Specification
(Previous Objection Maintained) The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 25 (“www.kazusa.or.jp/codon”). 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. The examiner suggests changing all “.” In the hyperlinks to “_” to render them non-browser executable.
New Objections
Claim 1 is objected to because of the following informalities: it contains a typographical mistake on line 14, where “first and second expression cassette” should instead be “first and second expression cassettes”. Appropriate correction is required.
Claim 23 is objected to because of the following informalities: it contains a typographical mistake on line 3, where it is missing a period to end the sentence. Appropriate correction is required.
Claim 18 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Withdrawn Rejections
Claim Rejections - 35 USC § 112
The previous rejection of claims 10, 13-16, 18, and 22 under 35 U.S.C. §112(b) is hereby withdrawn due to amendment of the claims.
New Rejections
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
(New Rejection Necessitated by Amendment) Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 2 requires “the cell according to claim 1, wherein the nucleotide sequence comprising the transgene flanked by the parvoviral inverted terminal repeat sequence is present on a second nucleic acid construct. However, claim 1, from which claim 2 depends, already indicates “wherein the nucleotide sequence comprising the transgene flanked by the parvoviral inverted terminal repeat sequence is present on a second nucleic acid construct. Therefore, claim 2 does not further limit claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Maintained Rejections
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Previous Rejection Maintained) Claims 1-17 and 22-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bakker et al. (PGPub US 20100261254 A1, published 10/14/2010; hereinafter referred to as “Bakker”) as evidenced by Beaton et al. (J Virol. 1989 Oct;63(10):4450-4. doi: 10.1128/JVI.63.10.4450-4454.1989. PMID: 2550677; hereinafter referred to as “Beaton”).
The claimed invention encompasses a cell comprising one or more nucleic acid constructs comprising: i) a first expression cassette comprising a first promoter operably linked to a nucleotide sequence encoding an mRNA, translation of which in the cell produces at least one of parvoviral Rep 78 and 68 proteins; ii) a second expression cassette comprising a second promoter operably linked to a nucleotide sequence encoding an mRNA, translation of which in the cell produces at least one of parvoviral Rep 52 and 40 proteins; iii) a third expression cassette comprising a third promoter operably linked to a nucleotide sequence encoding parvoviral VP1, VP2, and VP3 capsid proteins; and, iv) a nucleotide sequence comprising a transgene that is flanked by at least one parvoviral inverted terminal repeat sequence, wherein the nucleotide sequence comprising the transgene flanked by the parvoviral inverted terminal repeat sequence is present on a second nucleic acid construct, wherein, the first and second expression cassette are present on a first nucleic acid construct with the third expression cassette, and wherein, upon transfection of the cell with the nucleic acid constructs, the first promoter is active before the second and third promoters, as recited in claim 1. In another embodiment, the nucleotide sequence comprising the transgene flanked by the parvoviral inverted terminal repeat sequence is present on a second nucleic acid construct, as recited in claim 2. In a more specific embodiment, the second nucleic acid construct further comprises a fourth expression cassette comprising a fourth promoter operably linked to a nucleotide sequence encoding parvoviral VP1, VP2, and VP3 capsid proteins, wherein the first promoter is active before the second, third, and fourth promoters, wherein optionally, the third and fourth promoters are identical, and wherein optionally, the parvoviral VP1, VP2, and VP3 capsid proteins encoded by the nucleotide sequences in the third and fourth expression cassettes are identical, as recited in claim 3. In a more specific embodiment, the at least one parvoviral Rep 78 and 68 proteins and the at least one of parvoviral Rep 52 and 40 proteins comprise a common amino acid sequence comprising the amino acid sequence from the second amino acid to the most C-terminal amino acid of the at least one of the parvoviral Rep 52 and 40 proteins, wherein the common amino acid sequence of the at least one of parvoviral Rep 78 and 68 proteins and the at least one of parvoviral Rep 52 and 40 proteins are at least 90% identical, and wherein the nucleotide sequence encoding the common amino acid sequence of the at least one of parvoviral Rep 78 and 68 proteins and the nucleotide sequence encoding the common amino acid sequences of the at least one of parvoviral Rep 52 and 40 proteins are less than 90% identical, as recited in claim 4. In a more specific embodiment, the common amino acid sequences of the at least one of parvoviral Rep 78 and 68 proteins and the at least one of parvoviral Rep 52 and 40 proteins are at least 99% identical, as recited in claim 5. Alternatively, the nucleotide sequence encoding the common amino acid sequence of the at least one of parvoviral Rep 78 and 68 proteins, or nucleotide sequence encoding the common amino acid sequence of the at least one of parvoviral Rep 52 and 40 proteins, has an improved codon usage bias for the cell as compared to the other, as recited in claim 6, or wherein the difference in codon adaptation index between the nucleotide sequences is at least 0.2, as recited in claim 7.
In other embodiments of the claimed invention, the first promoter is a constitutive promoter, as recited in claim 8. Alternatively, at least one of the second, third, and fourth promoters is an inducible promoter, as recited in claim 9, or more specifically, the inducible promoter is a viral promoter that is induced at a later stage in the virus’ infection cycle, as recited in claim 10.
In another embodiment, at least one of the first and second nucleic acid construct is stably integrated in the genome of the cell, as recited in claim 11. Alternatively, the cell is an insect cell, and wherein at least one of the first and second nucleic acid construct is an insect cell-compatible vector, as recited in claim 12. In a particular embodiment, the insect cell-compatible vector is a baculoviral vector, as recited in claim 13. In a more specific embodiment, a) the first promoter is selected from a deltaEI promoter and an EI promoter; and b) the second, third, and fourth promoters are selected from a polH promoter and a p10 promoter, as recited in claim 14. Alternatively, at least one expression cassette comprises at least one baculovirus enhancer element and/or at least one ecdysone responsive element, as recited in claim 15.
In another embodiment, the nucleotide sequence encoding an mRNA, translation of which in the cell produces at least one of parvoviral Rep78 and 68 proteins, comprises an intact parvoviral p19 promoter, as recited in claim 16. Alternatively, the at least one of parvoviral Rep 78 and 68 proteins, the at least one of parvoviral Rep52 and 40 proteins, the parvoviral VP1, VP2, and VP3 capsid proteins and the at least one parvoviral inverted terminal repeat sequence are from an adeno associated virus (AAV), as recited in claim 17.
Another embodiment of the claimed invention encompasses a nucleic acid construct, comprising i) a first expression cassette comprising a first promoter operably linked to a nucleotide sequence encoding an mRNA, translation of which in a cell produces at least one of parvoviral Rep 78 and 68 proteins; ii) a second expression cassette comprising a second promoter operably linked to a nucleotide sequence encoding an mRNA, translation of which in a cell produces at least one of parvoviral Rep 52 and 40 proteins; and iii) a third expression cassette comprising a third promoter operably linked to a nucleotide sequence encoding parvoviral VP1, VP2, and VP3 capsid proteins, as recited in claim 22. A different embodiment is a nucleic acid construct comprising a nucleotide sequence comprising a transgene that is flanked by at least one parvoviral inverted terminal repeat sequence, as recited in claim 23.
The Prior Art
Bakker teaches parvoviral vectors and methods of their production (Abstract), with the object to provide for means and methods that allow for stable and high yield (large scale) production of heterologous proteins and parvoviral vectors (para. [0009]). Bakker discloses an insect cell comprising a first nucleotide sequence encoding a first amino acid sequence of a parvoviral Rep52 or Rep40 protein and a second nucleotide sequence coding for a second amino acid sequence of a parvoviral Rep78 or Rep68 protein, wherein the first and second amino acid sequences comprise a common amino acid sequence, wherein the nucleotide sequence that encode the common amino acid sequence are less than 90% identical, wherein the common amino acid sequences comprise the amino acid sequences from the second amino acid to the most C-terminal amino acid of the parvoviral Rep 52 or Rep40 protein (claim 1). The amino acid sequences may share at least 99% sequence identity (claim 2). The nucleotide sequences are part of a nucleic acid construct and are each operably linked to expression control sequences for expression in an insect cell (claim 8). Bakker further teaches the insect cell further comprising a third nucleotide sequence comprising at least one parvoviral inverted terminal repeat (ITR) sequence encoding a “gene product of interest”, and a fourth nucleotide sequence comprising parvoviral capsid protein-coding sequences (VP1, VP2, and VP3; para. [0004]) operably linked to expression control sequences (claim 13; paras. [0049-54] and [0004]). Additionally, any one of, or all four, nucleotide sequences may be part of a nucleic acid construct that is an insect cell-compatible vector (claims 14-17), or specifically a baculoviral vector (claim 28), additionally any, or all, of the nucleotide sequences may be integrated into the genome of the insect cell. Bakker further describes a recombinant baculovirus construct harboring two independent Rep expression units (one for Rep78 and one for Rep52), each under the control of a separate insect cell promoter, the ΔIE1 and PolH promoters, respectively (para. [0005]). The first promoter or second promoter may be an inducible promoter (paras. [0084-0085]). The promoters may be any late or very late baculovirus gene promoter (para. [0084]). The promoters may also specifically be deltaE1, E1, polH, or p10 promoters (para. [0084]). Additionally, Bakker discloses that following AAV infection in mammalian cells, the Rep genes are expressed from the p5 and p19 promoters (para. [0017]). Beaton demonstrates that the AAV p5 and p19 promoters are constitutive (Abstract; p. 4450, col. 1, para. 2).
Bakker also teaches that the nucleotide sequence coding for Rep 52 or Rep 40 has an improved codon usage bias as compared to the nucleotide sequence coding for the common amino acid sequence in the second nucleotide sequence or vice versa, or more specifically wherein the difference in codon adaptation index is at least 0.2 (claims 3-4).
Bakker further discloses enhancer elements are used to enhance the expression of parvoviral Rep protein, therefore the first expression cassette comprises at least one baculovirus enhancer element and/or ecdysone responsive element, wherein the enhancer element can be hr1, hr2, hr3, hr4, or hr5 (paras. [0085-86]).
Bakker also describes that the genome of AAV comprises ITRs that flank the non-structural Rep proteins and the structural (VP1, VP2, and VP3) proteins that form the capsid, and a splicing event in the rep ORF results in the expression of four Rep proteins (i.e., Rep78, Rep68, Rep52, and Rep40; para. [0017]).
Therefore, Bakker anticipates claims 1-17 and 22-23.
Response to Arguments
Applicant's arguments filed 11/5/2025 have been fully considered but they are not persuasive.
Applicant presents the following arguments:
Claim 1 has been amended, it has been specified that the cell comprises the first and second expression cassette on a first nucleic acid construct and the nucleotide sequence comprising the transgene flanked by the parvoviral inverted terminal repeat sequence is present on a second nucleic acid construct.
Bakker discloses various configurations of nucleic acid constructs but does not disclose the specific two-construct system now claimed. While Bakker states that “[t]he number of nucleic acid constructs employed in the insect cell for the production of the recombinant parvoviral (rAAV) vector is not limiting in the invention” and mentions that “one, two, three, four, five, or more separate constructs can be employed,” Bakker does not disclose or suggest the specific arrangement required by amended claim 1. For at least these reasons, claim 1 is allowable over Bakker and the dependent claims are allowable therewith.
Applicant’s arguments have been carefully considered but are not persuasive:
Applicant recognizes that Bakker discloses a construct system, and Bakker makes it clear that the constructs can be manipulated as necessary to facilitate expression of the disclosed genes, but also for expressing a gene encoding a product of interest, such as a therapeutic protein. The options for configuring the nucleic acid sequences within a cell disclosed by Bakker, which overlap with those of the instant claims, encompass the configuration of nucleic acid constructs of the instant claims. Bakker discloses that the rep, VP, and product of interest encoding sequences may be on 1, 2, 3, 4, or 5 or more constructs, and provides examples of those sequences being together on constructs or present on distinct constructs, with examples of each (Bakker, paras. [0049-55] and claims 14-17). Bakker also specifically indicates that if fewer than five constructs are used, the constructs can comprise various combinations of the at least one AAV ITR, and the VP1, VP2, VP3, and the Rep protein coding sequences (para. [0049]), and indicates that the AAV ITR may be encoded by another construct than the ones that encode AAV VP1, VP2, VP3, and Rep proteins (paras. [0049]-[0050]).
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.
(Previous Rejection Maintained) Claims 1-17 and 22-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 8,697,417. Although the claims at issue are not identical, they are not patentably distinct from each other because each set of claims is drawn to a cell comprising nucleic acid constructs comprising one or more expression cassettes with promoters operably linked to nucleotide sequence encoding mRNAs, translation of which produces parvoviral Rep 78 and 68, Rep 52 and 40, capsid proteins (VP1-VP3), and/or a nucleotide sequence comprising a transgene flanked by at least one parvoviral ITR. Each set of claims also covers similar orientation of the expression cassettes and constructs, such as where they are integrated into the genome; or on single or multiple constructs, such as insect cell-compatible vectors like baculoviral vectors. Additionally, each set of claims encompasses identity requirements of the nucleotide sequences and amino acid sequences, codon adaptation index indices, promoter types, enhancer elements, and the source of the components being AAV.
(Previous Rejection Maintained) Claims 1-17 and 22-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 17/948,862 in view of Bakker (PGPub US 20100261254 A1, published 10/14/2010; hereinafter referred to as “Bakker”; supra). Both the instant and copending claims are drawn to a cell comprising a nucleotide sequence encoding an mRNA, translation of which in the cell produces at least one of parvoviral Rep 78 and 68 proteins; a second nucleotide sequence encoding an mRNA, translation of which in the cell produces at least one of parvoviral Rep 52 and 40 proteins; a nucleotide sequence comprising parvoviral capsid protein coding sequences; and a nucleotide sequence comprising a transgene that is flanked by at least one parvoviral inverted terminal repeat sequence, promoters operably linked to said nucleotide sequences, wherein at least some of the nucleotide sequences are integrated into the cell genome (copending claims 1 and 12). The copending claims also encompass promoters, enhancers, and sequence identity requirements, the sequences originating from AAV, codon usage optimization, and promoter activation requirements present in the instant claims (copending claims 2-9 and 14-15). Bakker, which anticipates the instant claims 1-17 and 22-23 (as described above), renders obvious any minor differences in instant and copending claims. For instance, although the copending claims do not mention a codon adaptation index of 0.2, as required by the instant claims, that would be obvious from Bakker, which teaches such a requirement in related constructs and cells (see rejection above).
This is a provisional nonstatutory double patenting rejection.
Allowable Subject Matter
SEQ ID NO: 10 and SEQ ID NO: 12 are free of the prior art of record.
Conclusion
No claim is 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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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671