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
This Office Action is a response to Applicant’s Amendment and Remarks filed August 29, 2025. Claims 3, 4, 6-13, 15-22 and 25-30 have been cancelled. Claims 1 and 42 have been amended.
Claims 1, 23, 24 and 31-42 are pending in the instant application.
Claims 1, 23, 24 and 31-42 have been examined on the merits as detailed below:
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Drawings
In the previous Office Action mailed April 30, 2025, the Drawings were objected to because some Drawings referenced the colors, "red" and "orange" without an accompanying petition. This objection is withdrawn in view of Applicant’s Amendment filed August 29, 2025 to remove reference to color drawings.
The Drawings filed July 22, 2025 are acknowledged and have been accepted by the Examiner.
Claim Objections
In the previous Office Action mailed April 30, 2025, claims 12 and 42 were objected to because of minor informalities. This objection is moot against claim 12 in view of Applicant’s Amendment filed August 29, 2025 to cancel this claim. This objection is withdrawn against claim 42 in view of Applicant’s Amendment to the claim filed August 29, 2025.
Claim Rejections - 35 USC § 112
In the previous Office Action mailed April 30, 2025, claims 3, 6, 8 and 10 were 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. This rejection is moot in view of Applicant’s Amendment filed August 29, 2025 to cancel claims 3, 6, 8 and 10.
Claim Rejections - 35 USC § 102
In the previous Office Action mailed April 30, 2025, claims 1, 3, 4, 8, 10, 15-18, 20, 22, 23, 25, 27 and 29-42 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by YINGXIAO SHI ET AL. NATURE MEDICINE, Vol. 24, No. 3, 5 February 2018 (2018-02-05), pages 313-325, plus Supplementary Data (submitted and made of record on the IDS filed February 27, 2024). This rejection is moot against claims 3, 4, 8, 10, 15-18, 20, 22 in view of Applicant’s Amendment filed August 29, 2025 to cancel these claims. This rejection is withdrawn against the remaining claims in view of Applicant’s Amendment to the claims filed August 29, 2025.
Claim Rejections - 35 USC § 103
In the previous Office Action mailed April 30, 2025, claims 1, 3, 4, 6-13, 15-23, 25 and 27-42 were rejected under 35 U.S.C. 103 as being obvious over YINGXIAO SHI ET AL. NATURE MEDICINE, Vol. 24, No. 3, 5 February 2018 (2018-02-05), pages 313-325, plus Supplementary Data (submitted and made of record on the IDS filed February 27, 2024) in view of U.S. Patent Publication 20200362337. This rejection is moot against claims 1, 3, 4, 6-13, 15-22 in view of Applicant’s Amendment filed August 29, 2025 to cancel these claims. This rejection is withdrawn against the remaining claims in view of Applicant’s Amendment to the claims filed August 29, 2025 and in favor of the new 35 U.S.C. 103 rejection as detailed below:
Claim Rejections - 35 USC § 101
In the previous Office Action mailed April 30, 2025, claims 1, 22-24 and 31-33 were rejected under 35 U.S.C. 101. This rejection is moot against claims 1 and 22 in view of Applicant’s Amendment filed August 29, 2025 to cancel these claims. This rejection is withdrawn against the remaining claims in view of Applicant’s Amendment to the claims filed August 29, 2025.
Applicant’s Amendment filed August 29, 2025 necessitated a new grounds of rejection as presented below:
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.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 23 and 31-42 are rejected under 35 U.S.C. 103 as being obvious over YINGXIAO SHI ET AL. NATURE MEDICINE, Vol. 24, No. 3, 5 February 2018 (2018-02-05), pages 313-325, plus Supplementary Data (submitted and made of record on the IDS filed February 27, 2024) in view of Xue-Hai Liang et al. (Molecular Therapy Vol. 25 No 9 September 2017, pages 2075-2092) and evidenced by Geary et al. (Clin Pharmacokinet (2015) 54:133-146) and Shemesh et al. (Molecular Therapy: Nucleic Acids Vol. 9 December 2017, pages 34-47).
The claims are drawn to a single stranded antisense oligonucleotide (ASO) that suppresses the expression of a PIKFYVE encoded by the sequence of SEQ ID NO: 137,wherein the ASO comprises from 5' to 3': a 5' wing segment consisting of 5 2'-O-methoxyethyl nucleosides linked by internucleoside linkages, wherein each of the internucleoside linkages within the 5' wing segment is a phosphorothioate linkage or a phosphodiester linkage, wherein the 5' wing segment comprise at least one phosphorothioate linkage and at least one phosphodiester linkage; a gap segment consisting of 10 deoxynucleosides linked by internucleoside linkages, wherein each internucleoside linkage within the gap segment is a phosphorothioate linkage, wherein the internucleoside linkage between the 5' wing segment and the gap segment is a phosphorothioate linkage or a phosphodiester linkage; and a 3' wing segment consisting of 5 2'-O-methoxyethyl nucleosides linked by internucleoside linkages, wherein each of the internucleoside linkages within the 3' wing segment is a phosphorothioate linkage or a phosphodiester linkage, wherein the 3' wing segment comprise at least one phosphorothioate linkage and at least one phosphodiester linkage, wherein the internucleoside linkage between the gap segment and the 3' wing segment is a phosphorothioate linkage or a phosphodiester linkage.
YINGXIAO SHI teaches two single stranded antisense oligonucleotides (ASOs) that suppress the expression of PIKFYVE, for the treatment of amyotrophic lateral sclerosis (ALS) (Results, page 321, left column; Figure 6d, page 322). The ASOs are 20 nucleotides long and the internucleoside linkages are modified with phosphorothioate linkages. The ASOs are gapmers with a 5' and a 3' wings of 5 nucleotides each, whose sugar moieties are 2'OMe modified, and a central gap segment of 10 unmodified nucleotides. The sequences of the two ASOs are identical to SEQ ID NO. 136 and 9 of the present invention. See YINGXIAO SHI Supplementary data Table 4, page 53, PIKFYVE ASO 1 and PIKFYVE ASO 2.
The administration of the ASOs of YINGXIAO SHI rescued the ex vivo motor neurons of ALS patients (Results, page 321). The ALS patient of the YINGXIAO SHI study is haplosufficient for the C9ORF72 gene. The haplosufficiency results in a 50% greater reduction in C9ORF72 protein activity. See Supplementary Figure 4J. The C9ORF72 gene product comprises a dipeptide repeat resulting from a (GGGGCC)n expansion. The dipeptide repeat is cytotoxic. It is noted that the ALS disorder taught and disclosed by YINGXIAO SHI is associated with neuronal hyperexcitability and aberrant endosomal and lysosomal trafficking.
YINGXIAO SHI does not teach particular chemical modification, 5' to 3': a 5' wing segment consisting of 5 2'-O-methoxyethyl nucleosides linked by internucleoside linkages, wherein each of the internucleoside linkages within the 5' wing segment is a phosphorothioate linkage or a phosphodiester linkage, wherein the 5' wing segment comprise at least one phosphorothioate linkage and at least one phosphodiester linkage; a gap segment consisting of 10 deoxynucleosides linked by internucleoside linkages, wherein each internucleoside linkage within the gap segment is a phosphorothioate linkage, wherein the internucleoside linkage between the 5' wing segment and the gap segment is a phosphorothioate linkage or a phosphodiester linkage; and a 3' wing segment consisting of 5 2'-O-methoxyethyl nucleosides linked by internucleoside linkages, wherein each of the internucleoside linkages within the 3' wing segment is a phosphorothioate linkage or a phosphodiester linkage, wherein the 3' wing segment comprise at least one phosphorothioate linkage and at least one phosphodiester linkage, wherein the internucleoside linkage between the gap segment and the 3' wing segment is a phosphorothioate linkage or a phosphodiester linkage as now recited in claim 1.
Xue-Hai Liang et al. are explicit in teaching:
“Second-generation ASOs are designed in a 5-10-5 gapmer configuration that contains 10 deoxynucleotides in the central portion flanked at both ends with five ribonucleotides modified with 2’-O-methoxyethyl (MOE)”. The nucleotides are linked with phosphorothioate (PS) backbones.
Before the effective filing date of the claimed invention, a single stranded antisense oligonucleotide (ASO) that suppresses the expression of a PIKFYVE encoded by the sequence of SEQ ID NO:137 of the present invention was routinely used in the art for the purpose of treating a subject having a neurological disease, such as ALS as taught and suggested by YINGXIAO SHI.
Before the effective filing date of the claimed invention, the particular 5’ to 3’ chemical modification recited in claim 1 (e.g. gapmers with 2′-MOE- wings on a full phosphorothioate (PS) backbone) was known and routinely used in the art as taught and suggested by Xue-Hai Liang et al.; and evidenced by Geary et al. (see Figure 1, Gapmer Design) and Shemesh et al. (see Test Articles, page 43).
A person of ordinary skill in the art would have been motivated and expected reasonable success to chemically modify the ASO of YINGXIAO SHI as taught and suggested by Xue-Hai Liang et al. for the purpose of facilitating internalization of the ASO and increasing stability of the nucleic acid.
The combination of the prior art of YINGXIAO SHI in view of Xue-Hai Liang et al. renders the present claims unpatentable because a person of ordinary skill in the art would have found the instant invention prima facie obvious.
Conclusion
Claim 24 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.
Claims Free of the Prior Art
The following subject matter is free of the prior art:
Claims drawn to a single stranded antisense oligonucleotide (ASO) that suppresses the expression of a PIKFYVE encoded by the sequence of SEQ ID NO: 137,wherein the ASO comprises from 5' to 3': a 5' wing segment consisting of 5 2'-O-methoxyethyl nucleosides linked by internucleoside linkages, wherein each of the internucleoside linkages within the 5' wing segment is a phosphorothioate linkage or a phosphodiester linkage, wherein the 5' wing segment comprise at least one phosphorothioate linkage and at least one phosphodiester linkage; a gap segment consisting of 10 deoxynucleosides linked by internucleoside linkages, wherein each internucleoside linkage within the gap segment is a phosphorothioate linkage, wherein the internucleoside linkage between the 5' wing segment and the gap segment is a phosphorothioate linkage or a phosphodiester linkage; and a 3' wing segment consisting of 5 2'-O-methoxyethyl nucleosides linked by internucleoside linkages, wherein each of the internucleoside linkages within the 3' wing segment is a phosphorothioate linkage or a phosphodiester linkage, wherein the 3' wing segment comprise at least one phosphorothioate linkage and at least one phosphodiester linkage, wherein the internucleoside linkage between the gap segment and the 3' wing segment is a phosphorothioate linkage or a phosphodiester linkage; and wherein the ASO has the nucleobase sequence of any one of SEQ ID NOs:46, 49, 56, 60, 62, 64, 65, 70, 71, 73 and 105 are free of the prior art.
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 Terra C. Gibbs whose telephone number is 571-272-0758. The Examiner can normally be reached from 8 am - 5 pm M-F.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Ram Shukla can be reached on 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TERRA C GIBBS/Primary Examiner, Art Unit 1635