DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 23 July 2026 have been entered. Claims 1-56 were previously pending in the application. Claims 2, 4-8, 12-30, 35, 37, and 39-56 have been cancelled, and new claims 57-61 have been added by Applicant.
Claims 1, 3, 9-11, 31-34, 36, 38, and 57-61 are currently pending in the application. Claims 1, 31, 33, 34, and 36 are independent claims.
The election of Group I, drawn to a first nucleic acid comprising a sequence encoding an ORF for a functional dependoparvovirus B MAAP polypeptide; a first dependoparvovirus B particle; a first vector; a cell, cell-free system, or other translation system; and a first dependoparvovirus B MAAP polypeptide, remains in effect in the instant application.
The following election of species remains in effect in the instant application:
Position of the first nucleotide of the exogenous start codon: Position 74;
Nucleic acid sequences encoding MAAP: SEQ ID NO: 4;
MAAP polypeptide amino acid sequence: SEQ ID NO: 3;
Nucleic acid sequences encoding VP1: SEQ ID NO: 2;
VP1 polypeptide sequences: SEQ ID NO: 1;
Rep polypeptide sequences: SEQ ID NO: 333.
New claim 59 is newly withdrawn from consideration as being directed to a nonelected species due to the elected sequence of SEQ ID NO: 4 comprising an exogenous ATG start codon and not an exogenous CTG start codon, there being no allowable generic or linking claim.
Claims 1, 3, 9-11, 31-34, 36, 38, 57-58, and 60-61 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2021/047700, filed 26 August 2021, which claims priority to U.S. Provisional Application No. 63/070,763, filed 26 August 2020.
Thus, the earliest possible priority for the instant application is 26 August 2020.
Specification
The objection to the specification of the disclosure for containing an embedded hyperlink and/or other form of browser-executable code on page 193 line 27 is withdrawn in view of the amendment to the specification. The amendment to the specification of the disclosure filed 23 July 2026 has been entered.
Claim Objections
The objection to amended and cancelled claims 1-4, 6-8, 10-16, 22-25, 27, 29-30, 36-37, and 39 for multiple informalities is withdrawn in view of the amendment to the claims.
Claim Rejections - 35 USC § 112(b)
The rejection of amended and cancelled claims 2, 7, 11, 14, 16, 18, 21, 23, 25, 27-29, 34, and 39 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for multiple issues of indefiniteness is withdrawn in view of Applicant’s amendments to the claims.
*The following new rejection is necessitated by Applicant’s amendments to the claims.
Amended, previously presented, original, and new claims 1, 3, 9-11, 31-34, 36, 38, 57-58, and 60-61 are newly 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. Claims 9-11, 31-34, 36, 38, 57-58, and 60-61 are included in this rejection due to their dependence on and/or encompassing of amended independent claim 1.
Amended independent claim 1 newly recites, “polypeptide comprising an amino acid sequence that differs by no more than 2 amino acids from the amino acid sequence of any one of SEQ ID NOs: 3, …, and 319”, which is indefinite because it is unclear whether the group of SEQ ID NOs recited is an open or a closed group. As such, the metes and bounds of the claims cannot be determined.
Amended claim 3 recites the limitation “the sequence” in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 3 is dependent on amended independent claim 1. Claim 1 recite “a sequence” in line 1 and additionally newly recites “an amino acid sequence” in line 3 and “the amino acid sequence of any one of SEQ ID NOs:” in line 4. As such, it is unclear to which sequence “the sequence” of claim 3 line 1 is referring. Therefore, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 112(a)- Written Description
The rejection of amended and cancelled 1, 7-8, 11, 14-16, 18-19, 21-22, and 39 under 35 U.S.C. 112(a) for three written description issues regarding each of 1) the MAAP polypeptide sequence; 2) the VP1/Cap polypeptide sequence; and 3) the Rep polypeptide sequence is withdrawn in view of Applicant’s amendments to the claims such that independent claim 1 now requires that the sequence of the MAAP polypeptide differ by no more than 2 amino acids from the amino acid sequence of any one of the recited SEQ ID NOs, including the elected SEQ ID NO: 3. Additionally, the claims no longer recite sequences for the VP1 polypeptide nor the Rep polypeptide other than specifying a range of positions within the VP1 encoding sequence SEQ ID NO: 327 which correspond to the position of the mutations creating the exogenous start codons according to the sequences recited in independent claim 1.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, original, and cancelled claims 1-25, 27-34, and 36-39 under 35 U.S.C. 103 as being unpatentable over Asokan [US20240294576A1, published 5 September 2024, filed 5 May 2021, with priority to 05 May 2020]; in view of Galibert et al. [US20230374540A1, published 23 November 2023, filed 25 June 2021, with priority to 25 June 2020]; Peabody [1989, The Journal of Biological Chemistry, 264(9), 5031-5035]; NCBI NC_006152.1 [2018, Adeno-associated virus 5, complete genome, retrieved on 19 February 2026 from: <https://www.ncbi.nlm.nih.gov/nucleotide/NC_006152.1?report=genbank&log$=nuclalign&blast_rank=1&RID=TEJ71783014>, published 13 August 2018]; and Bahou et al. [US20140155469A1, published 05 June 2014]; is withdrawn over cancelled claims 2, 4-8, 12-30, 35, 37, and 39-56, maintained over amended, previously presented, and original claims 1, 3, 9-11, 31-34, 36, and 38, and newly applied to new claims 57 and 60-61. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 1 to recite a MAAP polypeptide comprising an amino acid sequences that differs by no more than 2 amino acids from the amino acid sequence of SEQ ID NOs: 3 (as elected). Note that the cancelled claim 39 previously recited wherein the MAAP polypeptide comprises an amino acid sequence with at least 80% identity to SEQ ID NOs: 3 (as elected).
Asokan was cited for teaching an AAV5 MAAP polypeptide comprising an amino acid sequence with 97.7% identity to the sequence of elected SEQ ID NO: 3 (e.g., Asokan SEQ ID NO: 5):
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Note that the sequence of Asokan SEQ ID NO: 5 differs from the sequence of instantly elected SEQ ID NO: 3 by only 1 amino acid in addition to lacking the exogenous ATG-encoded methionine. As such, the sequence of Asokan SEQ ID NO: 5 differs by only 2 amino acids from the sequence of instant SEQ ID NO: 3.
Regarding the exogenous start codon, as described in the prior action, Galibert and Peabody were cited for teaching the motivation to substitute a non-canonical start codon with a canonical ATG start codon to increase the expression of the resultant polypeptide to thereby increase the expression of the AAV5 MAAP and likewise increase the packaging, production, and secretion of rAAV particles compared to an rAAV particle comprising the endogenous non-canonical start codon.
Additionally, Galibert was also cited for teaching the motivation to mutate any one of the potential non-canonical start sites in the +1 reading frame of the VP1 protein, within the vicinity of the estimated CGG start site, to a canonical ATG start site to assess the MAAP protein production from the modified nucleic acid, including the AAG immediately upstream of the CGG corresponding to VP1 nt position 77-79, thereby mutating the A at position 75 to T.
In modifying the AAG codon at 74-76 to ATG for the nucleic acid sequence encoding a MAAP polypeptide having an amino acid sequence according to Asokan SEQ ID NO: 5, the ordinary artisan would produce a MAAP polypeptide comprising an additional MET amino acid at the N-terminus such that the amino acid sequence generated would comprise a single amino acid difference from the amino acid sequence of instant SEQ ID NO: 3.
Regarding new claim 57, as described above, Asokan, Galibert, and Peabody provide the motivation for a MAAP polypeptide which comprises an amino acid sequence that differs by no more than 1 amino acid from the amino acid sequence of instant SEQ ID NO: 3.
Regarding new claims 60-61, Asokan was cited for teaching wherein the ORF encoding MAAP comprises a nucleic acid sequence with at least 80% identity to the sequence according to elected SEQ ID NO: 4 (e.g., SEQ ID NO: 20):
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Note that the sequence of Asokan SEQ ID NO: 20 has 98.3% identity to instant SEQ ID NO 4, and so has at least 90% identity and at least 95% identity to the elected sequence of SEQ ID NO: 4.
Given the teachings and motivation of Galibert and Peabody to modify an MAAP encoding sequence to comprise a canonical ATG start codon and the motivation taught by Galibert to mutate any one of the potential non-canonical start sites in the +1 reading frame of the VP1 protein, within the vicinity of the estimated CGG start site, to a canonical ATG start site to assess the MAAP protein production from the modified nucleic acid, including the AAG immediately upstream of the CGG corresponding to VP1 nt position 77-79, thereby mutating the A at position 75 to T, it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the nucleic acid comprising an ORF encoding an AAV5 MAAP polypeptide of Asokan to comprise an exogenous ATG start codon at position 74-76 relative to a VP1 encoding sequence of instant SEQ IS NO: 327 such that the encoded MAAP polypeptide has an amino acid sequence that differs by no more than 1 or 2 amino acids from the amino acid sequence of instant SEQ ID NO: 3 with a reasonable expectation of success.
Applicant argues that:
Asokan is not prior art in that the Asokan provisional application 63/020,051 does not disclose [350] and SEQ ID NO: 20 cited in the prior action;
Galibert is not prior art in that Galibert provisional application 63/043,837 provides no teaching of an AAV5 MAAP ORF having an exogenous start codon; and
Galibert teaches away from the instantly claimed invention by teaching that it is advantageous to inactivate translation of MAAP.
However, this is not agreed.
In response to Applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Specifically, regarding Applicant’s argument 1), although Asokan provisional application 63/020,051 does not disclose [350] and SEQ ID NO: 20 cited in the prior action, the ‘051 provision application still discloses relevant teachings, such as the AAV5 MAAP amino acid sequence according to SEQ ID NO: 5 (which matches SEQ ID NO: 5 of the non-provisional Asokan reference cited) and an AAV MAAP encoding sequence according SEQ ID NO. 18 (which is distinct from SEQ ID NO: 18 of the non-provisional Asokan reference cited).
Additionally, as discussed above, Galibert and Peabody provide teachings and motivations for substituting the AAG codon at positions 74-76 relative to a VP1 encoding sequence of SEQ ID NO: 327 to an exogenous ATG start codon. As such, it would have been obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the MAAP encoding sequence of Asokan to arrive at the instantly claimed invention.
Regarding Applicant’s argument 2), note that the Galibert provision application 63/043,837 does in fact teach an AAV5 MAAP ORFs having exogenous start codons. Specifically, the “Plasmids Used” table on page 13 discloses the vectors p0280-MAAP, p0283-MAAP-GFP, and p0326-MAAP start 2 which each provide for expression of MAAP driven by an exogenous ATG codon [pg 19 lines 375-379].
Although the ‘837 Galibert provisional application does not teach that the specific MAAP sequence used with the exogenous start codon constructs were AAV5 MAAP proteins, Galibert teaches AAV5 MAAP polypeptide (SEQ ID NO: 5) [pg 8 line 234]. Nothing in the teachings of Galibert suggest that the motivation provided for mutating the MAAP start codon should be limited to only a particular AAV serotype. As such, applying the teachings and motivation of Galibert to the teachings of Asokan would result in a nucleic acid sequence encoding an AAV5 MAAP polypeptide as instantly claimed.
Regarding Applicant’s argument 3), note that in considering the reference as a whole, teachings which would lead towards the claimed invention are not to be ignored merely because the reference also includes teachings which do not direct a skilled artisan towards the claimed invention.
Galibert was cited for teaching that modification of an AAV2 MAAP CTG start codon to a CGG start codon reduces the expression of the AAV2 MAAP, decreases the titers of AAV2 particles produced, decreases the specificity of packaging viral genomes vs contaminant genomes, and reduces the percentage of capsids which contain an AAV genome, as demonstrated in Figure 1, 3, 4, 7, 8, 11, 12, 14.
Applicant asserts that Galibert concludes that MAAP expression should be decreased rather than increased, thereby teaching away from the claimed subject matter. However, Galibert teaches also motivation for expressing MAAP proteins independent of the VP1 protein construct and AAV packaging, such as when using the constructs having MAAP driven by ATG start codons (e.g., p0280-MAAP, p0283-MAAP-GFP, and p0326-MAAP-start2) to compare with the WT sequence to determine the primary start site used for translation of WT MAAP by Western blot [0229-0231, Table 1].
Additionally, Asokan teaches complementation in trans with VP/AAP-null AAV plasmids to provide endogenous levels of MAAP protein, wherein certain AAV serotypes with mutated MAAP are secreted more slowly than others, and that extracellular secretion kinetics of such AAV particles can be enhanced by complementation in trans of an MAAP from an AAV serotype displaying rapid extracellular secretion kinetics [0082-0083, 0088-0096, 0377-0384, 0385-0386, Figure 3D-E, J, 4A-H, also see ‘051 provisional pg 10 ¶ 3]. Asokan specifically teaches that overexpression of MAAP was associated with a notable increase in spherical vesicles with a diameter ranging from about 20-50 nm, indicating that MAAP can promote secretion of a specific type of extracellular vesicle [0385]. As such, Asokan teaches the necessity of expressing MAAP protein for AAV packaging. Also, by teaching the motivation to provide MAAP proteins via complementation in trans for AAV packaging, Asokan is teaching to provide a nucleic acid encoding MAAP protein wherein the MAAP protein expression is independent from an overlapping VP1 protein expression. Given the teachings of Galibert to specifically express MAAP from a construct lacking VP1 expression and comprising an exogenous ATG codon, and the teachings of Asokan to overexpress MAAP polypeptides independent of VP1 expression, an ordinarily skilled artisan at the time of filing would have been motivated to provide MAAP expression via a construct which comprises a canonical ATG start codon.
Therefore, Applicant’s arguments do not overcome a finding of obviousness under 35 U.S.C. 103 over Asokan, Galibert, Peabody, NCBI, and Bahou, and the rejection is maintained.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
