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 .
Priority
The application is a DIV of 16/335,663 filed 03/21/2019 which is a 371 PCT of US2017/053127 filed 09/23/2017 that claim priority to 62/399,101 filed 09/23/2016.
Information Disclosure Statement
The information disclosure statements filed 10/13/2023 have been considered.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 103
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 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.
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.
Claims 1-12 and 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over Takaku (US 20070082862 A1) in view of Lok (Lok et al. Biochemistry 2002, 41, 3457-3467).
Regarding claim 1-5 and 14, Takaku teaches a method for treating or preventing HIV, comprising administering to a subject in need thereof novel antisense oligonucleotide in an amount effective therefor [0001-0003; 0012; example 3]. Takaku teaches that antisense phosphorothioate oligonucleotides (S-ODNs) were synthesized on the basis of the nucleotide sequence of the DIS (Dimerization Initiation Site) located in the DLS (Dimer Linkage Structure) region of HIV-1 [0057, Fig. 1]. Takaku teaches that the oligonucleotides exhibits an anti-HIV activity suppressing an expression of mRNAs or proteins of HIV-1 [0051]. Specifically, Takaku teaches that the S-ODN "Anti-703" significantly inhibited the HIV-1 production, and an extremely high activity (99% or more) of inhibiting the HIV-1 production was confirmed due to Anti-703 specifically binding to the target sequence [0073, Figs. 1-2]. Takaku teaches that the oligonucleotide of the present invention consisting of a nucleotide sequence complementary to a nucleotide sequence consisting of at least 15 successive nucleotides in the nucleotide sequence consisting of nucleotides 6-44 of SEQ ID NO: 1 (DIS). Takaku teaches that it was found that the inhibitory effect of the selected S-ODN for the HIV-1 production was caused by the decrease of the HIV-1 protein expression and the decrease of the amount of RNA, and that the S-ODN (Anti-703) specifically bound to the target RNA (DIS in HIV-1) and inhibited the production of viral particles [0092]. Takaku teaches that according to the anti-HIV agent of the present invention, an HIV infection may be effectively treated and/or prevented [0100].
Takaku does not teach where the oligonucleotide comprises 2'-deoxy-2'- fluoroarabinonucleotide (2'-FANA)-modified nucleotide sequence having a nucleotide gap sequence consists of about 6 to 9 unmodified nucleotides.
Lok teaches phosphorothioate deoxyribonucleotides (PS-DNA) are among the most widely used antisense inhibitors [abstract]. Lok teaches that PS-DNA exhibits desirable properties such as enhanced nuclease resistance, improved bioavailability, and the ability to induce RNase H mediated degradation of target RNA; however, they can possess a relatively low binding affinity for target RNA that impacts on its potency in antisense applications [abstract]. Lok teaches that phosphodiester-linked oligonucleotides comprised of 2’-deoxy-2’-fluoro-D-arabinonucleic acid (FANA) exhibit both high binding affinity for target RNA and the ability to elicit RNase H degradation of target RNA [abstract]. Lok teaches that mixed backbone oligomers comprised of PS-FANA flanking a central core of PS-DNA were found to possess potent antisense activity [abstract]. Lok teaches PS-FANA strands containing DNA gaps from 1 to 10 nucleotides [table 1]. Lok teaches that the PS-FANA/deoxy chimers with 6 to 8-nt gapmer were the most potent antisense molecule [Table 1; pg. 3460, col. 1, para 2-3].
Regarding claims 12 and 19, Lok teaches a PS-FANA strand containing DNA gaps where the oligonucleotide has 8 PS-DNA nucleotides flanked on each side by 2'-PANA-modified nucleotides to form a synthetic oligonucleotide of 18 nucleotides in length as claimed.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to substitute the conventional antisense oligonucleotides of Takaku with the PS-[FANA-DNA-FANA] gapmer oligonucleotides taught by Lok because Lok teaches that such gapmers exhibit superior hybridization affinity, retain RNase H-mediated cleavage, and provide substantially improved antisense potency, particularly with DNA gap lengths of 6-8 nucleotides, making them desirable alternatives for sequence-specific antisense inhibition of any known RNA target, including the HIV DIS taught by Takaku.
Regarding claim 6, Takaku teaches transfection (i.e., contacting) of cells comprising HIV with the S-ODNs. [0060-0062; examples 2-3].
Regarding claims 7 and 15, Takaku teaches hybridization of S-ODNs to the HIV DIS and inhibition of HIV replication and Lok teaches that FANA-DNA-FANA gapmers are expressly designed to retain RNase H-mediated cleavage after hybridization as discussed above. Therefore, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention that the modified S-ODN as taught and suggested my Takaku and Lok would result inhibition of HIV RNA by RNase mediated cleavage.
Regarding claims 8 and 16, Takaku teaches that Anti-703 as SEQ ID NO: 4 [Fig. 1; 0059]. SEQ ID NO: 4 is 100% identical to 20 successful nucleotides of SEQ ID NO: 1.
Regarding claims 9 and 17, Takaku’s SEQ ID NO: 4 comprises a nucleotide sequence of each of SEQ ID NO: 10 and 11 (e.g., TGCCGTG and CTTCAGCAA).
Regarding claims 10 and 18, Takaku teaches that all internucleotide bonds are phosphorothioate bonds [0057; see the sequence listing for SEQ ID NO: 4].
Regarding claim 11, Lok teaches phosphorothioate FANA-DNA-FANA gapmer antisense oligonucleotides having central DNA gaps of varying lengths, including 6-, 8- (potent antisense activity) and 10- nucleotide gaps, and demonstrate that optimization of the DNA gap length affects antisense activity while maintaining RNase-mediated cleavage [table]. It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to select a 9-nucleotide DNA gap , an intermediate value between the expressly taught 8- and 10- nucleotide gaps, through routine optimization to achieve the desired balance of hybridization affinity and RNase H activity. Such optimization would have involved only routine experimentation and yielded predictable results.
Claims 13 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Takaku (US 20070082862 A1) in view of Lok (Lok et al. Biochemistry 2002, 41, 3457-3467) as applied to claims 1 and 14, and further in view of Stein (Stein, C. A., et al. Nucleic acids research 38.1 (2010): e3-e3).
The teachings of Takaku and Lok are discussed above as applied to claims 1 and 14 and similarly apply to claims 13 and 20.
Takaku and Lok do not teach where the delivery of the synthetic oligonucleotide is via gymnotic delivery.
Stein teaches gymnotic delivery, i.e. cellular uptake and antisense activity of synthetic antisense oligonucleotides without the use of transfection reagents or delivery additives [abstract; pg. 8, col. 1, para 3]. Stein teaches that chemically modified antisense oligonucleotides are capable of entering cells and producing gene silencing under ordinary culture conditions without lipid-mediated transfection disadvantages [pg. 8, col. 1, para 3; Fig. 5; pg. 6, col 1-2, bridging paragraph].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to administer the antisense oligonucleotide as taught and suggested by Takaku and Lok using the gymnotic delivery method taught by Stein because Stein teaches that this delivery technique effectively introduces chemically modified antisense oligonucleotides into cells while avoiding the disadvantages associated with transfection reagents. Employing one known delivery method for another known delivery method to obtain the predictable result of intracellular uptake of antisense oligonucleotides constitutes no more than the predictable use of prior art elements according to their established functions.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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