DETAILED ACTION
Status of the Claims
Applicant’s response dated July 6, 2026 has been entered. Claims 1-13 are pending. Claims 1-11 are under examination. Claims 12 and 13 are withdrawn from consideration pursuant to election by original presentation as being directed to a non-elected invention. No claims have been canceled.
Election/Restrictions
Newly submitted claims 12 and 13 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
Claims 12 and 13 are distinct from the product claims because claims 1-11 are directed to the antisense oligonucleotide compounds and pharmaceutical compositions themselves, whereas claims 12 and 13 are directed to methods of using such oligonucleotides in a specific cellular/therapeutic process. In particular, claims 12 and 13 require the affirmative step of transfecting glioma cells with selected antisense oligonucleotides under conditions effective to reduce HTT and MGMT expression, and further recite method purposes of sensitizing glioma cells to anti-cancer treatment or preventing glioblastoma tumor recurrence. These process limitations require examination of operative method steps, treatment context, cell transfection conditions, and therapeutic effects that are not required to make or identify the claimed oligonucleotide products themselves. Thus, notwithstanding overlap in the recited oligonucleotide sequences, the method claims are drawn to a distinct invention from the elected product/composition claims because the product claims can be examined based on the structure and properties of the oligonucleotides, while the method claims require a separate inquiry into their use in glioma-cell transfection and anti-cancer treatment/recurrence-prevention methods.
Since Applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 12 and 13 withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, Applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should Applicant traverse on the ground that the inventions are not patentably distinct, Applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Specification Objection – Withdrawn
The objection to the specification based on the missing incorporation-by-reference paragraph required by 37 CFR 1.82(c)(1) is withdrawn. Applicant has provided a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125, including the required incorporation-by-reference paragraph for the sequence listing.
Claim Rejections - 35 USC § 101 – Withdrawn
The rejection of claims 1-11 under 35 U.S.C. § 101 set forth in the prior Office action is withdrawn in view of Applicant’s amendment and reconsideration of the record. In particular, amended claim 1 now recites antisense oligonucleotides comprising 2’-O-methoxyethyl (MOE) groups at the respective nucleotides of the 3’ and 5’ ends, which further defines the claimed oligonucleotides as chemically modified compositions. Accordingly, the prior eligibility rejection is not maintained in this action.
Claim Rejections - 35 USC § 102 – Withdrawn
The rejection of claims 1-11 under 35 U.S.C. § 102 set forth in the prior Office action is withdrawn in view of Applicant’s amendment and reconsideration of the prior art. The amended claims now recite additional structural limitations, including that the antisense oligonucleotide comprises a 2’-O-methoxyethyl (MOE) group added to each of the respective nucleotides of a 3’ end and a 5’ end, such that the prior anticipation rejection is no longer maintained.
Claim Rejections - 35 USC § 103 – New Grounds
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.
Claim(s) 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Hung et al. (WO 2007/089584 A2; 9 August 2007).
Regarding claim 1, Hung et al. teach antisense oligonucleotide molecules for modulating huntingtin expression (see pg. 4-6, Summary; pg. 14-17, Pharmaceutical compositions). The reference teaches claimed SEQ ID NOs: 1, 2, and 3:
SEQ ID NO: 1 (as claimed)
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SEQ ID NO: 2 (as claimed)
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SEQ ID NO: 3 (as claimed)
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Hung et al. further disclose huntingtin-targeted antisense oligonucleotides comprising 2’-O-methoxyethyl (MOE) wings, a 10-nucleotide deoxy gap, phosphorothioate internucleoside linkages, and 5-methylcytosine residues. See [0012]-[0015], [0027]-[0045], [0097]-[0107], [0113]-[0115], [0170]-[0175].
It would have been prima facie obvious to one of ordinary skill in the art as of the filing date to modify the disclosed sequences by adding MOE groups to the nucleotides at both the 3’ and 5’ ends, because Hung et al. expressly teach that such 2’-MOE wing modifications are a routine and preferred structural feature of gapmer antisense oligonucleotides and are used to improve antisense performance, including stability, nuclease resistance, binding affinity, and pharmacokinetic properties. See [0050], [0068]-[0070], [0097]-[0107], [0113]-[0115].
The recitation that the antisense oligonucleotide has the ability to reduce HTT and MGMT protein in glioma cells does not patentably distinguish the claimed compound because Applicant has not provided evidence, and the record does not otherwise establish, that such functional properties would have been unexpected in view of Hung et al.’s disclosure that analogous huntingtin-targeted antisense oligonucleotides reduce target expression in cultured cells and in vivo. See [0137]-[0143], [0171]-[0183].
Regarding claim 2, Hung et al. disclose that antisense oligonucleotides targeted to huntingtin modulate gene expression and are therapeutically useful in slowing or preventing Huntington’s disease progression. See [0023]-[0026], [0057]-[0064], [0137], [0171]-[0183], [0192]-[0199]. It would have been obvious to one of ordinary skill in the art to select the disclosed antisense oligonucleotide of claim 1 for use in a sensitization context, because the sensitization language merely recites an intended result of the same known antisense structure.
Regarding claim 3, Hung et al. expressly disclose antisense compounds of 12 to 35 nucleobases in length, including preferred 20-nucleotide gapmers. See [0080]-[0085], [0091]-[0094], [0170]-[0175]. Accordingly, it would have been obvious to select the claimed length for the disclosed antisense oligonucleotide of claim 1.
Regarding claims 4-8, Hung et al. disclose the same huntingtin-targeted antisense oligonucleotide structures and further teach that such compounds reduce target expression in cultured cells and in vivo. See [0137]-[0143], [0162]-[0189]. It would have been obvious to apply the disclosed antisense oligonucleotide of claim 1 in the recited anti-cancer treatment contexts, including DNA-damaging treatments, alkylating agents, TMZ, lomustine, carmustine, procarbazine, carboplatin, and radiation, because these limitations merely recite treatment contexts for the same disclosed antisense structure and do not impart patentable distinction. Applicant has not provided evidence that the claimed functional outcomes in these treatment contexts would have been unexpected in view of Hung et al.
Regarding claim 9, Hung et al. expressly disclose pharmaceutical compositions comprising antisense oligonucleotides targeted to huntingtin and pharmaceutically acceptable diluents or carriers. See [0016], [0062]-[0069]. It would have been obvious to prepare the claimed pharmaceutical composition comprising the antisense oligonucleotide of claim 1 in view of Hung et al.’s express teachings.
Regarding claims 10 and 11, Hung et al. disclose therapeutic methods for administering antisense oligonucleotides targeted to huntingtin and state that such compounds are useful in treating Huntington’s disease and may be administered to the central nervous system. See [0048]-[0051], [0057]-[0064], [0192]-[0199]. It would have been obvious to use the disclosed antisense oligonucleotide of claim 1 in the recited brain tumor, glioblastoma multiforme, or type IV astrocytoma treatment contexts, as these limitations merely specify a therapeutic use of the same disclosed structure.
Claim(s) 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Hung et al. (WO 2011/032045 A1; 17 March 2011).
Regarding claim 1, Hung et al. teach antisense oligonucleotide molecules for modulating huntingtin expression. See pg. 41-48, Antisense compounds. The reference teaches claimed SEQ ID NO: 4:
SEQ ID NO: 4 (as claimed)
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Hung et al. teach the claimed antisense oligonucleotide sequence corresponding to Applicant’s SEQ ID NO: 4, as shown by the sequence alignment of record, and disclose that such compounds are useful for reducing huntingtin mRNA and protein in an animal. See pages 41-48; Examples 1-11. Hung further expressly discloses that the antisense oligonucleotides of the invention may be modified oligonucleotides having a gapmer motif, including a 5-10-5 MOE gapmer in which the 5’ wing segment and 3’ wing segment each comprise 2’-MOE modified nucleosides, the gap comprises 10 linked deoxynucleosides, and the backbone comprises phosphorothioate linkages. See pages 25-27, Antisense compounds; Example 1.
It would have been prima facie obvious to one of ordinary skill in the art as of the filing date to modify the disclosed huntingtin-targeted oligonucleotides corresponding to SEQ ID NO: 4 by using the disclosed 2’-MOE wings at both the 5’ and 3’ ends, because Hung expressly teaches that such MOE gapmers are preferred, routine antisense designs for improving binding affinity, nuclease stability, potency, and pharmacokinetic properties. Applicant has not provided evidence, and the record does not otherwise establish, that the functional properties recited in the claims would have been unexpected in view of Hung et al.’s disclosure that the claimed class of antisense oligonucleotides reduces huntingtin expression in vitro and in vivo. See Examples 2-21.
Regarding claim 2, Hung et al. disclose that antisense compounds targeted to huntingtin reduce huntingtin expression and are useful to treat, prevent, delay, or ameliorate Huntington’s disease or symptoms thereof. See pages 41-48; Examples 1-11. It would have been obvious to one of ordinary skill in the art to use the disclosed antisense oligonucleotide of claim 1 in the recited sensitization context, because the sensitization language merely recites an intended result of the same known huntingtin-targeted antisense structure.
Regarding claim 3, Hung et al. expressly disclose antisense compounds having a length of 12 to 30 linked nucleosides, as well as other overlapping ranges including 15 to 25, 18 to 21, and 20 linked nucleosides. See pages 21-24; Example 1. Accordingly, it would have been obvious to select the claimed length for the disclosed antisense oligonucleotide of claim 1.
Regarding claims 4-8, Hung et al. disclose administration of the disclosed huntingtin-targeted antisense oligonucleotides to animals by parenteral, intracranial, intrathecal, intracerebroventricular, and intraparenchymal routes, and disclose that the compounds reduce huntingtin mRNA and protein expression and improve Huntington’s disease-related phenotypes. See pages 47-49; Examples 4-21. It would have been obvious to apply the disclosed antisense oligonucleotide of claim 1 in the recited treatment contexts, including any combination with anti-cancer agents or radiation, because these limitations merely recite therapeutic contexts for the same disclosed antisense structure and do not impart patentable distinction. Applicant has not provided evidence that the claimed functional outcomes in these treatment contexts would have been unexpected in view of Hung et al.
Regarding claim 9, Hung et al. expressly disclose pharmaceutical compositions comprising antisense compounds targeted to huntingtin and a pharmaceutically acceptable diluent or carrier, including PBS. See page 36-37. It would have been obvious to prepare the claimed pharmaceutical composition comprising the antisense oligonucleotide of claim 1 in view of Hung et al.’s express teachings.
Regarding claims 10 and 11, Hung et al. expressly disclose methods of treating Huntington’s disease by administering the disclosed antisense compounds to a human, including by intracranial, intrathecal, or intracerebroventricular administration, and further disclose that such treatment may reduce or prevent disease progression and symptoms. See See pages 47-49; Examples 4-21. It would have been obvious to use the disclosed antisense oligonucleotide of claim 1 in the recited disease-treatment contexts because those limitations merely specify a therapeutic use of the same disclosed structure.
Conclusion
No claims are 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 CHRISTOPHER M BABIC whose telephone number is (571)272-8507. The examiner can normally be reached Mon - Fri, 8:30 AM - 5 PM.
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/CHRISTOPHER M BABIC/ Supervisory Patent Examiner, Art Unit 1633
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