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 .
DETAILED ACTION
Status of Application/Amendment/Claims
Applicant's response filed 10/16/2025 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 06/16/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
With entry of the amendment filed on 10/16/2025, new claims 65, 68-71 and 73-75 are pending in the application.
SEQ ID Nos. 163 and 136 are free of the prior art searched.
New Claim Rejections – necessitated by claim amendments
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 65, 68-71 and 73-75 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 pre-AIA the applicant regards as the invention.
Claim 65 has been amended to recite the ASO modulates expression of one or more isoforms of synaptic GTPase-activating protein (SynGAP1) a1 isoform. Claims 65 and 73 are drawn to ASO sequences having SEQ ID Nos. 82 and 163 wherein SEQ ID No. 82 is defined as targeting SynGAP1 a2 (Table 2) and SEQ ID No. 163 is defined in the specification as targeting SynGAP1 b (Table 4). It is unclear how the sequences can modulate expression of SynGAP1 a1 but are described as modulating different SYNGAP isoforms in the specification. Thus the claims are indefinite.
Claims 74 and 75 are drawn to SEQ ID Nos. 32 and 136 wherein the sequences are recited in the claim as a target region and are indefinite because it is unclear how these sequence modulate SynGAP1 a1 isoform in the claim but in the instant specification they are defined as SynGAP1 a2 (Table 2) and SynGAP1 b (Table 4) modulators, respectively. Thus the claims are indefinite. Claims 68-71 and 73 are rejected as they depend from the rejected claims.
Claim Rejections - 35 USC § 103 – modified slightly due to claim amendments
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 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 65, 68-71 and 73-75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aznarez et al. (Patent No. 11,083,745), Crooke (et al. 2008. Mechanisms of Antisense Drug Action, an Introduction. Chapter 1 in Antisense Drug Technology, 2nd Ed. Florida: CRC Press), Berryer, Martin H., et al. "Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency." Human mutation 34.2 (2013): 385-394), Valnegri et al. (Chapter 19 Valnegri, Pamela, Carlo Sala, and Maria Passafaro. "Synaptic dysfunction and intellectual disability." Synaptic plasticity: Dynamics, development and disease (2012): 433-449)(All of record cited on 892 mailed 03/06/2025) and McMahon, A. C., et al. ("SynGAP isoforms exert opposing effects on synaptic strength." Nature communications 3.1 (2012)).
Regarding claims 65, 67, 74 and 75, Aznarez et al. teach methods of treating mental retardation (a neurodevelopmental disorder comprising intellectual disability) comprising administering an antisense oligonucleotide targeted to SynGap1 (see claims 2). Aznarez et al. teach the antisense oligonucleotide consisting of SEQ ID No. 1054 (see claim 12). SEQ ID No. 1054 is complementary to the instantly claimed target region of SEQ ID No. 32 (see alignment below). Aznarez et al. teach SEQ ID No. 1054 which has 18 out of 20 nucleotides identical to the instantly claimed SEQ ID No. 82.
Patent No. 11083745
GENERAL INFORMATION
APPLICANT: COLD SPRING HARBOR LABORATORY
APPLICANT: STOKE THERAPEUTICS, INC.
TITLE OF INVENTION: ANTISENSE OLIGOMERS FOR TREATMENT OF AUTOSOMAL DOMINANT MENTAL
TITLE OF INVENTION: RETARDATION-5 AND DRAVET SYNDROME
FILE REFERENCE: 47991-708.831
CURRENT APPLICATION NUMBER: US/16/062,286A
CURRENT FILING DATE: 2018-06-14
PRIOR APPLICATION NUMBER: PCT/US2016/066708
PRIOR FILING DATE: 2016-12-14
PRIOR APPLICATION NUMBER: 62/267,251
PRIOR FILING DATE: 2015-12-14
NUMBER OF SEQ ID NOS: 2618
SEQ ID NO 1054
LENGTH: 18
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
oligonucleotide
Query Match 90.0%; Score 18; Length 18;
Score over Length 100.0%;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TATCTTCTCCGTGTCCCA 18 SEQ ID No. 32
||||||||||||||||||
Db 18 ATAGAAGAGGCACAGGGT 1 SEQ ID No. 1054
Aznarez et al. teach the antisense oligonucleotide targeting SynGap1 can be from 8 to 50 nucleotides in length (see col. 11, lines 26-51) and the antisense can comprise thymine or uracil (see col. 34 lines 62-68).
It would have been obvious to use the oligonucleotide taught by Aznarez and increase the length of the antisense oligonucleotide to determine the optimal length that correlates with the optimal activity for methods of targeting SynGAP and treating a neurodevelopmental disorder. It is well known in the art that increasing or decreasing an oligonucleotides length is routine optimization to determine the optimal length for therapeutic use as taught by Crooke et al. Crooke et al. teach in designing antisense oligonucleotides for therapeutic use, it is necessary to explore different lengths of oligonucleotides to find an optimal length that correlates with optimal activity as it relates to a therapeutic drug. Crooke et al. found that by varying the length of the oligonucleotide, an oligonucleotide can be identified having optimal specificity (see page 13, 1.3.2). Therefore in designing a method of treatment of a SynGAP-associated neurodevelopmental disorder in subjects, it would have been obvious and routine to vary the length to the antisense oligonucleotide to find one with optimal therapeutic activity.
Regarding claims 70 and 71, Aznarez et al. teach methods of administration of the antisense oligonucleotide targeted to SynGAP1 and therefore the method steps of increasing expression of SynGap1 protein or one or more isoforms of SynGap1 are an inherent features of the method of administration.
Regarding claim 68, Aznarez et al. further teach measuring or detecting production of SynGAP1 protein in the cell after administration of an antisense oligonucleotide (see col 30, lines 45-53). It would have been obvious to measure the amount of SynGAP1 produced to determine a therapeutic effect.
Regarding claim 69, along with measuring for SynGAP1 expression, the prior art teach Ras and Rap1 proteins are also associated with SynGAP1 protein expression. SynGAP1 encodes for a Ras protein that is critical for cognition and synapse function and mutations of this gene were found in patients having intellectual disabilities. Therefore it would have been obvious to measure aberrant expression of these proteins along with SynGAP1 to evaluate the methods of treatment (see 19.7 of Valnegri et al.).
Regarding the amendment adding the limitation the ASO modulates expression of one or more isoforms of synaptic GTPase-activating protein (SynGAP1) a1 isoform, Berryer et al. teach mutations in SynGAP1 cause neurodevelopmental disorders such as autism, intellectual disability and specific forms of epilepsy (page 386 left col.) and identified certain isoforms such as a2, a1 and b (see Figure 1). McMahon et al. teach mice with reduced SynGAP expression show a decrease in hippocampal LTP and impaired spatial learning and in humans, de novo mutations of SYNGAP have been identified in cases of non-syndromic mental retardation and autism spectrum disorder (page 2). McMahon et al. SYNGAP has four known isoform mutations in the C-terminus with SynGAP α1 being the most studied, as it contains the PDZ-binding domain (QTRV) that mediates binding to scaffolding proteins of the PSD (page 3).
It would have been obvious for one of ordinary skill in art in methods of treating a SYNGAP-associated neurodevelopmental disorder in a subject, to target the SYNGAP α1 using the methods of Aznarez et al. Aznarez et al. teach methods of treating mental retardation (a neurodevelopmental disorder) comprising intellectual disability comprising administering an antisense oligonucleotide targeted to SynGap1 and teach the claimed sequences. Because Berryer et al. teach mutations in SynGAP1 cause neurodevelopmental disorders such as autism, intellectual disability and specific forms of epilepsy (page 386 left col.) and identified certain isoforms such as a2, a1 and b (see Figure 1) and because McMahon et al. teach of the SYNGAP isoforms, SynGAP α1 being the most studied, it would have been obvious try using the methods of Aznarez et al. Because there was a known problem of finding treatments of neurodevelopmental disorders and a finite number of solutions, such as targeting SYNGAP and one of four isoforms, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007).
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Response to Applicant’s Arguments
Applicant argues Aznarez et al. discloses the antisense oligonucleotide does not increase the target protein or functional RNA by modulating alternative splicing of the pre-mRNA transcribed for a gene encoding the target protein (col. 5 lines 42-50) and thus would not have been obvious to target SynGAP1 a1 isoform.
In response, nowhere in Aznarez et al. is it taught that these alternative splicing SYNGAP1 is specifically talking about isoforms including SynGAP1 a1 isoform. The reference to isoforms of the SYNGAP1 gene and an description of alternative splicing in Aznarez et al. is stated [a]lternative splicing of the SYNGAP1 gene results in the expression of three isoforms of SYNGAP1 (Hamdan, et al., 2009) (col. 17, lines 18-30). A review of the Hamdan et al. ("Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation." New England Journal of Medicine 360.6 (2009)) reference defines alternative splicing of SYNGAP1 and isoforms three SYNGAP1 isoforms that are shown correspond to GenBank complementary DNA accession numbers AB067525 (for isoform 1), AK307888 (for isoform 2), and AL713634 (for isoform 3) (see page 600).
Applicant argues the specification at paragraphs 0128, 0158, Tables 2 and 4 demonstrate that ASO can increase the expression of SynGAP1 a1 isoform. The Examiner assumes that paragraphs 0128, 0158 are in reference to the published application US20230374510 and thus will base the response to the argument as such. Paragraphs 0128 and 0158 do not describe the claimed ASO as increasing the expression of SynGAP1 a1 isoform. Table 2 is drawn to ASO that suppress the a2 isoform and Table 4 is drawn to Beta ASO that suppress expression.
The instant specification in paragraph 0156 of the published application US20230374510 describes ASOs were transfected into HEK293 cells which increased SYNGAP1 expression. Paragraph 0159 describes ASOs targeting exon 11 suppressed a2 and gamma isoforms and increased overall STNGAP1 expression in cells. The specification does not directly describe the embodiment as argued by Applicant.
Applicant then argues that Berryer does not indicate any particular isoform as more important than the others. In response, the prior art of McMahan et al. teach mutations of SYNGAP have been identified in cases of non-syndromic mental retardation and autism spectrum disorder SYNGAP has four known isoform mutations in the C-terminus with SYNGAP α1 being the most studied and Berryer et al. has identified the four different isoforms in relation to causes of neurodevelopmental disorders such as autism, intellectual disability and specific forms of epilepsy.
Closest Prior Art
The closest prior art for SEQ ID No. 163 is taught by Bentwich et al. (Patent No. 7250496 of record) who teach a nucleic acid sequence having 14 nucleotides that are identical to the instant sequence and do not teach this sequence targets SynGAP.
Patent No. 7250496
GENERAL INFORMATION
APPLICANT: Bentwich, Isaac
SEQ ID NO 622576
LENGTH: 25
TYPE: DNA
ORGANISM: Human
Query Match 71.0%; Score 14.2; Length 25;
Best Local Similarity 63.2%;
Matches 12; Conservative 4; Mismatches 3; Indels 0; Gaps 0;
Qy 2 ACGGGCTTCAGTGGGGTTA 20
Db 1 AGGGGCUACAGUCGGGUUA 19
The closest prior art for SEQ ID No. 136 is taught by Mattanovich et al. (Patent No, 10752907 of record) who teach a nucleic acid sequence having 9 nucleotides that are identical to the instant sequence and do not teach this sequence targets SynGAP.
Patent No. 10752907
GENERAL INFORMATION
APPLICANT: Mattanovich et al.
SEQ ID NO 288
LENGTH: 9
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: TFBS
Query Match 45.0%; Score 9; Length 9;
Score over Length 100.0%;
Best Local Similarity 100.0%;
Matches 9; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 2 AACCCCACT 10
Db 1 AACCCCACT 9
The prior art of Aznarez et al. above teach specific sequence targeted to the SYNGAP gene as described above. Aznarez et al. do not teach any specific region to target. The GenBank Accession number of SYNGAP is known (NM_006772) and while there are known programs to design antisense oligonucleotides, the prior art of Watts et al. ("Silencing disease genes in the laboratory and the clinic." The Journal of pathology 226.2 (2012): 365-379) teach designing inhibitory oligonucleotides can be challenging using different programs wherein each program results in different oligonucleotides that have to be further tested to determine if they can reduce the target sequence in a cell. Thus nothing in Watts et al. would lead one of skill in the art to a predictable computational tool to design inhibitory oligonucleotides sequences targeted to SYNGAP.
There is no motivation for one of skill in the art to identify any specific region of the SYNGAP gene to target, then choose any of the computational tools to design the claimed sequence to arrive at the claimed oligonucleotide. Furthermore there is not a design need or market demand to design the claimed antisense to SYNGAP because Aznarez et al. already teach methods and antisense targeted to SYNGAP. Lastly there is not a finite number of identified and predictable solutions to make it obvious to try because the prior art does not teach a target region that would predictably yield the claimed oligonucleotides. (MPEP 2143 KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007)).
Conclusion
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).
706.07(a) Final Rejection, When Proper on Second Action [R-07.2015]
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Second or any subsequent actions on the merits shall be final, except where the examiner introduces a new ground of rejection that is neither necessitated by applicant’s amendment of the claims, nor based on information submitted in an information disclosure statement filed during the period set forth in 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p). Where information is submitted in an information disclosure statement during the period set forth in 37 CFR 1.97(c) with a fee, the examiner may use the information submitted, e.g., a printed publication or evidence of public use, and make the next Office action final whether or not the claims have been amended, provided that no other new ground of rejection which was not necessitated by amendment to the claims is introduced by the examiner. See MPEP § 609.04(b).
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY CHONG at 571-272-3111. The examiner can normally be reached Monday thru Friday 9-5 pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/Primary Examiner, Art Unit 1636