DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 5-14-26.
Claims 45-59 are pending in the instant application.
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 45-59 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The phrase “having complementarity” recited in lines 4-5 of claim 45 is vague and unclear. This phrase appears to encompass partial and full complementarity.
Appropriate correction/clarification is required.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 45, 48-59 is/are rejected under 35 U.S.C. 103 as being unpatentable over Avino et al (J. Nucleic Acids, Vol. 2011, Article IC586935, pages 1-7 (2011)), Agrawal et al (USPN 6,489,464) and Kokoris et al (US 2017/0037456), the combination in view of and Prakash et al (WO 2014/205451), Brown et al (US 2015/0184160) and McSwiggen et al (US 2007/0004664).
The claims are drawn to compositions comprising a dibranched oligonucleotide comprising two siRNA molecules covalently bound to one another by way of a linker wherein each siRNA comprises an antisense having complementarity to a target gene and a sense strand having complementarity to the antisense strand, 80-100% of the nucleotides in each siRNA are chemically modified and each antisense and sense strand are from 15-30 nucleotides in length or wherein the 5’ end of each antisense strand optionally comprises an E vinylphosphonate terminal group, or wherein the nucleotides of each antisense and sense strand consist of chemically modified nucleotides selected from 2’-methoxy and 2’-fluoro ribonucleotides which are optionally alternating, or which siRNA optionally comprises an unpaired overhang of at least 2-5 nucleotides optionally connected via phosphorothioate linkages.
Avino et al (J. Nucleic Acids, Vol. 2011, Article IC586935, pages 1-7 (2011)), Agrawal et al (USPN 6,489,464) and Kokoris et al (US 2017/0037456), the combination in view of and Prakash et al (WO 2014/205451) and McSwiggen et al (US 2007/0004664).
Avino et al (J. Nucleic Acids, Vol. 2011, Article IC586935 (2011)) (See IDS filed 4-10-24) teach branched siRNA for enhancing potency of siRNA target gene silencing, which branched RNA are linked via their 5’ or 3’ termini via phosphate and other chemical linkers, and optionally comprise sugar and backbone modifications for enhancing target binding, cellular uptake and stability (see esp. the abstract and introduction, pages 1-2, Figure 1, page 2, Figure 2, page 3, Figure 6 on page 5, and Table 1 on page 6, conclusion on page 6).
Agrawal et al (USPN 6,489,464) teach branched oligonucleotides linked via their 3’ or 5’ termini, which oligonucleotides are therapeutic nucleic acids targeting viral target genes (see esp. col. 1-4, Table 1, col. 8-9).
Kokoris et al (US 2017/0037456) teach branched oligonucleotides for generating multiplexes for enhancing targeting of complementary sequences, which branched oligonucleotides optionally are linked via polyethylene glycol linkers and comprise 10-100 nucleobases (see esp. col. 2-3, 5-8, ¶ 0099, col. 9, page 13, Figures 1-3, 7-13, claims 1, 2, 8-11).
The primary references do not teach the modification patterns or E-vinylphosphonate modifications of siRNA termini as instantly claimed.
Prakash et al (WO 2014/205451) teach oligomeric conjugates comprising double stranded nucleic acids optionally comprising RNA, DNA, and/or various constellations of modifications thereof, which modifications optionally comprise 2’-O-methyl or 2’-fluoro substituents, the incorporation of cell targeting moieties including to the liver, hydrophobic moieties, and terminal phosphorothioates. Prakash teaches the targeting of mRNA in neuronal cells. Prakash also teaches linkers and terminal phosphate groups. Prakash teaches the incorporation of 5’ and/or 3’ phosphorothioate overhangs and the effects of incorporating these differently modified groups on target binding and stability of the double stranded nucleic acids. Prakash teaches E-vinylphosphonate modifications of siRNA termini (Example 5) (see esp. the abstract, pp. 1-8, embodiment 40, pp 15-20, 52, claims 1-93, 111).
Brown et al (US 2015/0184160) teach oligonucleotides with alternating 2’-methoxy and 2’-fluoro modifications (see esp. para [0424].
McSwiggen et al (US 2007/0004664) teach the incorporation of numerous modifications and the conjugation of various linkers onto double stranded nucleic acid molecules, and the effects of these modifications on siRNA targeting, stability, uptake and target gene inhibition (see esp. the abstract, pages 6-18, Figures 3-77).
It would have been obvious to design and generate the branched constructs as instantly claimed because the branching of oligonucleotides, both single stranded and double stranded, were well known in the art at the time of filing, relying on the teachings of Avino, Agrawal, Prakash and Kokoris. One would have been motivated to design such multiplex compounds for enhancing the binding, detection and/or inhibition of expression of target molecules, including neuronal target molecules, by using multiple oligonucleotides targeting the same molecule. One would have been motivated to incorporate the modifications instantly claimed, including 2’-O-methyl and 2’-fluoro groups, phosphorothioates because these modifications were well known in the art to enhance the stability, binding and uptake of siRNA, as taught previously by Brown, McSwiggen and Prakash. One of skill in the art would have reasonably expected that such multiplexed, branched oligonucleotides have increased stability and binding capacities compared to non-modified entities. The techniques to generate and optimize the modified compounds as instantly claimed would have involved routine experimentation, as disclosed by Avino, McSwiggen, Agrawal, Kokoris, Brown, and Prakash.
For these reasons, the instant invention would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 45-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20, 22, 23 of U.S. Patent No. 10,478,503. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a branched oligonucleotide compound comprising two siRNA molecules covalently bound to one another by way of a linker, wherein (a) each siRNA molecule comprises an antisense strand having complementarity to a target gene and a sense strand having complementarity to the antisense strand; (b) from 80% to 100% of the nucleotides in each siRNA molecule are chemically modified; and (c) each antisense strand and each sense strand are, independently, from 15 to 30 nucleotides in length, wherein the 5' end of each antisense strand, independently, comprises a terminal group represented by a formula selected from (Xl) - (X8).
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
8-25-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
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