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 .
This action is in response to the amendment filed 10/23/2025, in which claims 2, 3, 7, 11, 22, 26, 30, 40, 41, 45, 49, 53 and 55 were previously presented, claims 1 and 21 were amended, claims 15, 17, 18, 20 and 34 were canceled and claim 59 is new. Claims 1-3, 7, 11, 21, 22, 26, 30, 40, 41, 45, 49, 53, 55 and 59 are currently pending.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the
reasons that follow. Any rejection and objections not reiterated in this action have been
withdrawn. This action is FINAL.
Election/Restriction
Applicant's election without traverse of Group I, drawn to claims 1-3, 7, 11, 15, 17-18, 20-22, 26, 30 and 34, in the reply filed on 06/02/2025 is acknowledged.
Applicant also elected the following Group I species without traverse in the reply: A)
Exon 17 and B) SEQ ID NO: 49. In the course of examination, prior art relevant to additional
NFl pre-mRNA exons and SEQ ID NOs was uncovered. The Group I species elections are
withdrawn, accordingly.
Claims 40-41, 45, 49, 53 and 55 are withdrawn from further consideration pursuant to 37
CPR l.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 06/02/2025.
Claims 1-3, 7, 11, 21, 22, 26, 30 and 59 are currently under consideration.
Response to Amendments - Specification
The previous objection to the specification as containing embedded hyperlinks has been withdrawn in view of Applicant’s amendments to the claims as filed on 10/23/2025.
Claim Rejections - 35 USC § 101
The previous rejection of claims 1-3, 7, 11, 15, 21, 22, 26, 30 and 34 under 35 U.S.C. 101 has been withdrawn in view of Applicant’s amendments to the claims filed on 10/32/2025.
Claim Rejections - 35 USC § 102
The previous rejection of claims 1, 2 and 21 under 35 U.S.C. 102(a)(1) as being anticipated by Park et al (J Med Genet. 1998; 35: 813-820) has been withdrawn in view of applicant’s amendments to the claims filed on 10/23/2025.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries 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 1-3, 7, 11, 21, 22, 26, 30 and 59 are rejected under 35 U.S.C. 103 as being
unpatentable by Park et al (J Med Genet. 1998; 35: 813-820; cited in a prior action) in view of Buerki et al (WO 2014/028884 A2), Cali et al (European Journal of Medical Genetics 60, 93-99; 2017) and Buck et al (BioTechniques, 27:3, 528-536; 1999; cited in a prior action) as evidenced by GenBank Accession No. NM_000267.3 (Published September 10th, 2019; cited in a prior action). This is a NEW rejection necessitated by the amendments Applicant filed on 10/23/2025.
Park teaches a protein truncation assay to screen for mutations in 15 NFl patients and
obtained positive results in 11 of them (Page 813, Abstract). Park teaches mutations identified in
cDNA was confirmed by direct sequencing of PCR products generated using genomic DNA and
exon specific primers (Page 815, Column 1). Park teaches investigating the genomic basis of
exon skipping, specific exons were amplified from genomic DNA and used for direct sequencing
(Page 816, Column 2). Park teaches the sequences listed as "F" in table 2 are all 100% identical
to exons within NM_ 000267.3 (See Appendix A). Park teaches primers listed as "R" or reverse in table 2 are all 100% identical to exons within NM_000267.3 (See Appendix B). Park teaches
primers capable of hybridizing to a continuous stretch of at least 20 nucleotides within exons 12
and 20 of the NFl sequence (Page 815, Table 2).
Park does not teach wherein the antisense oligonucleotide is selected from the group consisting of: an oligonucleotide comprising a non-natural backbone; a phosphorodiamidate morpholino oligonucleotide; an oligonucleotide containing at least one residue that is modified to increase nuclease resistance, to increase the affinity of the oligonucleotide for the target nucleotide sequence, or both; or a combination of two or more of the foregoing.
Buerki teaches the use of modified probes and/or primers for the detection and targeting a plurality of target sequences [0168 and 0215]. Buerki teaches modified or substituted backbone of the probes or primers provide desirable properties such as enhanced affinity for a target gene and increased stability [0209].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Park to include the modified backbone of primers as taught by Buerki because Park teaches it is within the ordinary skill in the art to use primers capable of hybridizing to a continuous stretch of at least 20 nucleotides within exons of the NFl sequence and Buerki teaches the use of modified probes and/or primers for the detection and targeting a plurality of target sequences.
One would have been motivated to make such a modification in order to receive the expected benefit of desirable properties such as enhanced affinity for a target gene and increased stability by modified probes/primers as taught by Buerki.
Park does not teach the specific sequences listed in claims 3, 7, 11, 15, 22, 26, 30 and 34
such as SEQ ID NOs: 1-24, 49, 57, 63, 64 and/or 65.
Cali teaches that the mutations occur in each of the exons such as exons 17, 4 7, 5 2, and
13 (Page 96-97, Table 1). Cali teaches that comprehensive analysis of the entire NFl gene using
NGS was known, possible, and relevant owing to substantial genetic heterogeneity in NFl
patients (Page 95, Column 2). Cali teaches making primers to the entire NFl coding sequence
(Page 94, Column 1 to Column 2). Cali teaches that NFl is one of the largest human genes,
composed of 57 exons such as GenBank Accession number as NM_00267.3 (Page 93, Column
2).
While teaching primers covering the entire NFl transcript, Cali does not teach the primer
sequences.
Buck teaches the idealized primer characteristics for primer design such as the
sequencing primers should be 18-24 nt in length (Page 532, Column 2). Buck teaches This study
confirms earlier observations that there is a broad tolerance in these and other characteristics of
sequencing primers (Page 535, Column 2). Buck et al expressly provide evidence of the
equivalence of primers. Specifically, Buck et al invited primer submissions from a number of
labs (39) (e.g., page 532, column 3), with 69 different primers being submitted (e.g., page 530,
column 1). Buck et al also tested 95 primers spaced at 3 nucleotide intervals along the entire
sequence at issue, thereby testing more than 1/3 of all possible 18 mer primers on the 300 base-pair sequence (e.g., page 530, column 1). When Buck et al tested each of the primers selected by the methods of the different labs, Buck found that every single primer worked (e.g., page 533,
column 1). Only one primer ever failed, No. 8, and that primer functioned when repeated.
Further, every single control primer functioned as well (e.g., page 533, column 1). Buck et al expressly states "The results of the empirical sequencing analysis were surprising in that nearly all of the primers yielded data of extremely high quality (page 535, column 2)." Therefore, Buck et al provides direct evidence that all primers would be expected to function, and in particular, all primers selected according to the ordinary criteria, however different, used by 39 different laboratories. It is particularly striking that all 95 control primers functioned, which represent 1/3 of all possible primers in the target region. This clearly shows that every primer would have an expectation of success.
It would have been obvious before the effective filing date of the claimed invention to
have designed primers covering the complete coding sequence of the NFl gene taught by Cali
(i.e., GenBank NM_00267.3), using the primer design principles of Buck, for use in analysis of
NFl genotype and use of primers in NFl patients as taught by Park.
Before the effective filing date, it was known that NFl patients exhibit genetic heterogeneity (see Cali), and that as taught by Park, identification of patients with NFl mutations
and the use of primers for exon splicing for the correction of those mutations. Cali provides a
method for comprehensively analyzing genotype of NFl patients, but does not teach the primer
sequences used in the method. The sequence of NFl was known and is 12381 nucleotides in
length. Buck teaches that primers are 25 nts in length. Accordingly, there are a finite number of
potential primers 25-nts in length which are 100% complementary to the NFl gene taught by
Cali (i.e., GenBank NM_00267.3). Among these potential solutions are SEQ ID NOs: 1-18, 51,
53, 57 and 63-65, which are themselves 100% complementary to the NFl gene taught by Cali (i.e., GenBank NM_00267.3) (See appendices 1-XXIV). The skilled artisan could have pursued
the finite, predictable solutions with a reasonable expectation of success because primer design
principles were known as evidenced by at least Buck and Cali, and because Buck teaches that
every primer works.
The skilled artisan would have been motivated to design primers for use in
the method of Cali because Park teaches identification of NFl mutations in patients and the
successful use of primers for exon splicing for the correction of the mutations within the patients.
Accordingly, claims 1-3, 7, 11 and 59 are obvious.
Regarding claims 21, 22, 26 and 30, Cali teaches a composition comprising the
primers (see section 2.2 NGS sequencing).
Claims 1, 2, 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Pros et al (Human Mutation, Vol 30 No 3, Pages 454-462; March 2009; cited in a prior action); in view of Xu et al (International Journal of Molecular Medicine, Vol 34 No 1, Pages 53-60; July 2014; cited in a prior action) as evidenced by GenBank Accession No. NM_000267.3 (Published September 10th, 2019; cited in a prior action). This is a NEW rejection necessitated by the amendments Applicant filed on 10/23/2025.
Regarding claim 1, Pros teaches the use of antisense morpholino oligomers to restore
normal splicing in primary fibroblast and lymphocyte cell lines derived from six NFl patients
bearing three deep intronic mutations in the NFl gene (Abstract). Pros teaches a method
comprising administering to a subject a therapeutically effective amount of a composition
comprising an antisense oligonucleotide that specifically hybridizes to a continuous stretch of at
least 20 nucleotides within NFl pre-mRNA from at least one exon (Abstract and Page 456,
column 1). Pros teaches along with antisense oligonucleotides, antisense phosphorodiamidate
morpholino oligomers (AMOs) are analogs of oligonucleotides with a six-membered morpholino ring replacing ribose or deoxyribose (Page 455, Column 1). Pros teaches AMOs have high
binding specificity, stability, and resistance to nucleases, and their activity is highly durable
(Page 455, Column 1). Pros teaches treatment of the six NFl patients harboring three different
deep intronic NFl mutation cell lines with specifically designed AMOs showed that this
antisense approach corrected aberrant splicing and significantly increased the levels of wild-type
NFl transcripts (Page 461, Column 1). Pros teaches specific AMOs to block the effect of three
independent NFl deep intronic mutations that causes the inclusion of cryptic exons in NFl
patients (Page 455, Column 1). Pros teaches that the designed AMOs target the newly created 5'
splice site to prevent the incorporation of cryptic exons (Page 457, Column 2). Pros teaches
AMO treatment decreased the active Ras-GTP levels in the same cells, which is consistent with
the hypothetical restoration of neurofibromin GTPase activity to wild-type levels (Page 461,
Column 1). Pros teaches the same or similar therapeutic strategies could possibly be applied to
other types of NFl mutations as well as to other genetic disorders (Page 462, Column 1).
Pros does not teach antisense oligonucleotides that specifically hybridize to the specific exons such as exons 17, 52, 47, 9, 12, 13, 20, 21, 25, 36 or 41 of NFl.
Xu teaches exon skipping in NFl exons 21 and 25 identified from clinically diagnosed individuals having NFl (Page 56, Table 2, Splicing mutations at the consensus splice sites).
While Pros provides motivation to provide AMOs that specifically hybridize to a target exon in NFl pre-mRNA to remedy aberrant splicing caused by mutation, and Xu teaches a mutation in exons 21 and 25 that causes aberrant splicing of NFl pre-mRNA, neither Pros or Xu teach the NFl pre-mRNA sequence such that the skilled artisan could prepare AMOs to exons 21 and 25.
However, GenBank Accession No. NM_000267.3 teaches the sequence of NFl premRNA, including exons 21 and 25, which corresponds to nucleotides 2793-3233 and nucleotides 4358-4493, respectively.
It would have been obvious to one of ordinary skill in the art to modify the isolated antisense oligonucleotide that specifically hybridizes to NFl pre-mRNA, as taught by Pros, to include or instead target exons 21 or 25 as taught by Xu. Pros teaches that one of ordinary skill in the art to use therapeutic antisense oligonucleotides targeting NFl splice sites to restore normal intron-exon splicing while Xu teaches NFl mutations identified from clinically diagnosed individuals having NFl related disease, including those producing IVS in exons 21 and 25 which form inactive splice sites. This combination would allow the method and antisense oligonucleotide therapeutics of Pros to target other clinically relevant NFl mutations on exons 21 and 25 taught by Xu.
One would have been motivated to make such a modification in order to receive the expected benefit of the method of using AMO therapeutics to target mutations of the NFl gene as taught by Pros to target other clinically relevant NFl mutations, such as on exons 21 and 25 as taught by Xu.
Regarding claim 2, Pros AMO is 25-nts in length (Page 456, Column 1, Morpholino
Oligomer Design and Treatment).
Regarding claims 17-18, and 20, Pros AMO is a phosphorodiamidate morpholino oligonucleotide, which comprises a non-natural backbone, and is modified to increase nuclease resistance and affinity for its target ("Among AONs, antisense phosphorodiamidate morpholino oligomers (AMOs) are analogs of oligonucleotides with a six-membered morpholino ring replacing ribose or deoxyribose.AMOs have high binding specificity, stability, and resistanceto nucleases, and their activity is highly durable," pg. 455, left col.).
Regarding claim 21, Pros teaches a composition comprising the AMO (Page 456, Column 1 bridging to Column 2).
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claims 1-3, 7, 11, 21, 22, 26, 30 and 59 under 35 U.S.C. 103 as being unpatentable by Park et al (J Med Genet. 1998; 35: 813-820) in view of Cali et al (European Journal of Medical Genetics 60, 93-99; 2017) and Buck et al (BioTechniques, 27:3, 528-536; 1999) as evidenced by GenBank Accession No. NM_000267.3 (Published September 10th, 2019) has been withdrawn in view of the amendments filed on 10/23/2025.
Applicants’ amendments to the claims overcame the previous rejection of record and therefore a new rejection was established to address the amendments to the claims filed on 10/23/2025.
As stated above, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Park to include the modified backbone of primers as taught by Buerki because Park teaches it is within the ordinary skill in the art to use primers capable of hybridizing to a continuous stretch of at least 20 nucleotides within exons of the NFl sequence and Buerki teaches the use of modified probes and/or primers for the detection and targeting a plurality of target sequences.
Therefore, claims 1 and 21 are obvious, as well as the claims relied upon the independent claims, in view of the combination of Park and Buerki.
The previous rejection of claims 1, 2, 17, 18, 20 and 21 under 35 U.S.C. 103 as being unpatentable over Pros et al (Human Mutation, Vol 30 No 3, Pages 454-462; March 2009) in view of Jang et al (Journal of Human Genetics (2016) 61, Pgs. 705-709) as evidenced by GenBank Accession No. NM_000267.3 (Published September 10th, 2019) has been withdrawn in view of the amendments filed on 10/23/2025.
Applicants’ amendments to the claims overcame the previous rejection of record and therefore a new rejection was established to address the amendments to the claims filed on 10/23/2025.
As stated above, it would have been obvious to one of ordinary skill in the art to modify the isolated antisense oligonucleotide that specifically hybridizes to NFl pre-mRNA, as taught by Pros, to include or instead target exons 21 or 25 as taught by Xu. Pros teaches that one of ordinary skill in the art to use therapeutic antisense oligonucleotides targeting NFl splice sites to restore normal intron-exon splicing while Xu teaches NFl mutations identified from clinically diagnosed individuals having NFl related disease, including those producing IVS in exons 21 and 25 which form inactive splice sites. This combination would allow the method and antisense oligonucleotide therapeutics of Pros to target other clinically relevant NFl mutations on exons 21 and 25 taught by Xu.
Therefore, claims 1 and 21 are obvious, as well as the claims relied upon the independent claims, in view of the combination of Pros and Xu.
Double Patenting (Warning)
Applicant is advised that should claims 1, 3, 7, 11 and 15 are be found allowable, claims 21, 22, 26, 30 and 34 will be objected to under 37 CPR 1.75 as being a substantial duplicate
thereof. When two claims in an application are duplicates or else are so close in content that they
both cover the same thing, despite a slight difference in wording, it is proper after allowing one
claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP
§ 608.0l(m). The composition claims only require the presence of the antisense oligonucleotide.
Thus, both claims are drawn to the same structure.
Conclusion
No claims 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 ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637