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 .
Claims 1-2, 8-9, and 11-24 are pending. Claims 15-24 are withdrawn from further
consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being
no allowable generic or linking claim. Claims 3-7 and 10 are canceled. Claims 1-2, 8, 13, 15-16, 21, and 23 are amended. Claims 1-2, 8-9, and 11-14 are under examination.
Response to Amendment
The Amendment filed 3/20/26 has been entered. Claims 1-2, 8-9, and 11-24 are pending. Applicant’s amendment of claims 2 and 13 have overcome the 112(b) rejections previously set forth in the Non-Final Office Action mailed 12/23/25.
Response to Arguments
Applicant's arguments, see pages 6-11, filed 3/20/26, with respect to the rejections of claims 1-2, 8-9, and 11-14 under 35 USC 103 have been fully considered and are found unpersuasive, and the 103 rejections documented in the Non-Final mailed on 12/23/25 have been revised to address amendments filed 3/20/26 in this Final Office Action. More detailed responses to Applicant’s arguments are provided at the end of each maintained rejection.
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.
Claims 1-2, 8-9, and 11-14 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Hirsch et al. 2014; US 2014/0271551 A1; USPGPub citation 1 in IDS filed on 1/17/23.
This rejection is revised/updated in response to amendments filed 3/20/26.
Hirsch et al. teaches “SYNTHETIC ADENO-ASSOCIATED VIRUS INVERTED TERMINAL REPEATS” (Title).
Relevant to claim 1, Hirsch et al. Abstract teaches “This invention relates to synthetic adeno-associated virus (AAV) inverted terminal repeats (ITRs) that exhibit altered activities compared to a naturally occurring AAV ITR and methods of using the same for delivery of nucleic acids to a cell or a subject. The synthetic ITRS provide a larger packaging capacity and the ability to manipulate activities such as transduction efficiency, cellular response to transduction, and transcription.”
Further relevant to claim 1, Hirsch et al. teaches “One aspect of the invention relates to a polynucleotide comprising at least one synthetic AAVITR, wherein one or more CpG motifs in said ITR are deleted and/or substituted, relative to the sequence of a naturally occurring AAV ITR such as ITR2. In some embodiments, it is the minimal functional ITR in which one or more CpG motifs are deleted and/or substituted. The AAV ITR2 contains 16 CpG motifs, TLR-9 directly binds to CpG sequence motifs and results in the activation of cellular innate immunity. It is also well known that methylation of CpG motifs results in transcriptional silencing. Removal of CpG motifs in the ITR is expected to result in decreased TLR-9 recognition and/or decreased methylation and therefore decreased transgene silencing. In some embodiments at least 1 CpG motif is deleted and/or substituted, e.g., at least 4 or more or 8 or more CpG motifs, e.g., at least 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15, or 16 CpG motifs. The phrase ‘deleted and/or substituted’ as used herein means that one or both nucleotides in the CpG motif is deleted, substituted with a different nucleotide, or any combination of deletions and substitutions” (paragraphs 0109-0110).
Further relevant to claim 1, Hirsch et al. teaches “In embodiments of the invention the rAAV vector genome comprises at least one ITR sequence (e.g., AAV ITR sequence), optionally two ITRs (e.g., two AAV ITRs), which typically will be at the 5' and 3' ends of the vector genome and flank the heterologous nucleic acid, but need not be contiguous thereto.” (paragraph 0083).
Although Hirsch et al. does not specify that the above substitutions are guanine to thymine, the skilled artisan would recognize that DNA is a double-stranded molecule that naturally allows for either adenine-thymine or cytosine-guanine pairings. Thus, the skilled artisan would recognize that the Hirsch et al. CpG motif substitutions would obviously include adenine-thymine nucleotides, therefore obviating cytosine or guanine (CpG) substitutions to A or T (the only other possible, naturally occurring nucleotide substitutions). Additionally, Hirsch et al. discloses that all 16/16 CpG motifs within the ITR are substitutable, indicating to the skilled artisan that all possible combinations of substitutions are included within the Hirsch et al. methodology.
Thus, these teachings read on claim 1 limitations.
Relevant to claim 2 (a), Hirsch et al. SEQ ID NO: 8 demonstrates ≥ 70% sequence identity to SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, and SEQ ID NO:12 (see compiled ABSS alignments; NPL citation U in PTO-892 filed 12/23/25). Additionally, the skilled artisan would recognize that the Hirsch et al. teaching of CpG deletions and substitutions would result in higher sequence similarities to the claimed sequences. Relevant to claim 2 (b), Hirsch et al. SEQ ID NO: 8 has 165 nucleic acids, which is within the claimed range.
Relevant to claims 8-9 and 11-12, Hirsch et al. teaches “In embodiments of the invention the rAAV vector genome comprises at least one ITR sequence (e.g., AAV ITR sequence), optionally two ITRs (e.g., two AAV ITRs), which typically will be at the 5' and 3' ends of the vector genome and flank the heterologous nucleic acid, but need not be contiguous thereto.” (paragraph 0083).
Taken with the above CpG motif substitution teachings relevant to claim 1, although Hirsch et al. does not specify that the above substitutions are guanine to adenine, the skilled artisan would recognize that DNA is a double-stranded molecule that naturally allows for either adenine-thymine or cytosine-guanine pairings. Thus, the skilled artisan would recognize that the Hirsch et al. CpG motif substitutions would obviously include adenine-thymine nucleotides. The skilled artisan would further recognize that substitutions with complementary bases would enable proper structural integrity/base pairing and thus find claims 9 and 12 limitations obvious given the above Hirsch et al. teachings.
Thus, these teachings read on claims 8-9 and 11-12 limitations.
Relevant to claim 13, Hirsch et al. SEQ ID NO: 8 would approach ≥ 80% sequence identity to SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, and SEQ ID NO:12 (see compiled ABSS alignments), as the skilled artisan would recognize that the Hirsch et al. teaching of CpG deletions and substitutions would result in higher sequence similarities to the claimed sequences.
Relevant to claim 14, given the above teachings relevant to claims 1, 2(a) and 13, the skilled artisan would find it obvious that the CpG-modified Hirsch et al. SEQ ID NO: 8 would embrace at least one of SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: and 11, SEQ ID NO: 12.
Hirsch et al. does not teach a specific embodiment having all the claimed elements. That being said, however, it must be remembered that "[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious." KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. AG. Pro, 425 U.S. 273, 282 (1976)). "[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious," the relevant question is "whether the improvement is more than the predictable use of prior art elements according to their established functions." (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR at 1741. The Court emphasized that "[a] person of ordinary skill is... a person of ordinary creativity, not an automaton." Id. At 1742.
Consistent with this reasoning, it would have been prima facie obvious to have selected various combinations of various disclosed elements — including nucleic acid substitutions and complementary bases — for an adeno-associated virus inverted terminal repeat (ITR) free of CpG motifs, to arrive at compositions "yielding no more than one would expect from such an arrangement."
Applicant’s Arguments and Response to Applicant’s Arguments
Applicant argues that “one of ordinary skill in the art would not reasonably arrive at the claimed ITR having a guanine to thymine substitution in a first CpG motif in an A segment of the 5’-end ITR or a guanine to thymine substitution in a first CpG motif in an A segment of the 3’-end ITR when Hirsch only provides the general guidance that ‘one or more CpG motifs… are deleted and/or substituted’ when testing more than 32,000 conditions would be required” (Remarks 3/20/26, page 8, paragraph 2).
The Examiner respectfully disagrees. Although there are 16 CpG motifs in the adeno-associated virus ITR, Hirsch et al. discloses to the skilled artisan that all 16 CpG motif nucleotides can be “substituted with a different nucleotide, or any combination of deletions and substitutions” (see Hirsch et al. paragraphs 0109-0110). This broad disclosure of Hirsch et al. teaches the skilled artisan that all possible nucleotide substitutions are possible in order to substitute all CpG motif nucleotides.
Additionally, the Applicant’s unpredictability argument relies on the breadth of possible substitutions across 32 CpG sites. However, claim 1 is limited to an ITR with either a 5’-end ITR comprising the G -> T substitution, or a 3’-end ITR comprising the G -> T substitution, which is supported by dependent claims 8 and 11 later further limiting claim 1 to either be the 5’-end ITR or 3’-end ITR, respectively. Thus, claim 1 scope is only commensurate with 16 CpG sites, which is considerably lower than the argued unpredictable scope. Furthermore, claim 1 requires a G -> T substitution “in a first CpG motif”, which does not require all subsequent CpG motifs to include a G -> T substitution, thus only further limiting the claim scope and purported unpredictability.
Conclusion
THIS ACTION IS MADE FINAL. 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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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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