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 communications filed 1-8-26.
Claims 2-4, 6-15, 17, 19, 20, 26, 29 and 37 are pending in the instant application.
Withdrawn Rejections
Any rejections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 19 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). The claim encompasses recombinant cells in an organism, including a human.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 29 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for in vitro target gene inhibition using the instantly claimed compositions, does not reasonably provide enablement for methods of treatment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The breadth of the claims:
The claim is drawn to methods of treating Huntington’s diseases in a subject comprising administration of an isolated nucleic acid comprising a first AAV inverted terminal repeat (ITR) and a second region comprising a transgene encoding one or more miRNAs comprising any one of SEQ ID Nos. 1-22 flanked by a miRNA backbone sequence, which miRNA hybridizes with SEQ ID No. 25.
The teachings in the specification:
The specification teaches the following:
[0059] Fig. 1 is a schematic showing the construct of artificial miRNAs. pPEMBL-D(4)-Syn1- hCG intron is a control vector, which is inserted with empty human chorionic gonadotropin (hCG) intron and driven with synapsin promoter. Two copies of control miRNA precursor (random sequences or non-functional mutation) are inserted into hCGin in the vector PEMBL-D(+)-Syn1- hCGin-2x control pre-miR. Two copies of artificial pre-miR (perfect match with 3’-UTR targeting sequences, including about 100-150bp flanked upstream and downstream sequences) are cloned into between the hCG introns. The vector pEMBL-D(+)-Syn1-CYP46A 1-hCGin-2x artificial pre-miR is a combo construct, which could produce both CYP46A1 and artificial miRNA at the same time. In order to identify whether the pre-miRNA could be processed into mature miRNA and combined with HTT targeting sequences including CAG expansions, which are perfectly complementary with mature miRNA, are inserted behind luciferase gene. For the limit of package size, small poly A is used in the constructs.
[0063] Fig. 5 is a schematic showing the artificial miRNAs’ locations in the HTT gene (or mRNA). miHTT-H2 is located at region I; miHTT-H4 and miHTT-H5 are located at the 5’ and 3” jumpers of the CAG repeats; miHTT-H14 is located at region IV; miHTT-H15, H17, H19 and H21 are located at region V.
[0064] Fig. 6 is a schematic showing the regions of the HTT gene. CAG Repeats are located in region I.
Fig. 8B is a bar graph showing that the artificial miRNAs inhibited luciferase gene expression with targeting sequences by co- transfection. After 48-hour co-transfection, PEMBL-CMV-hCGin-miHTT-H2 and miHTT-H5 could efficiently inhibit luciferase activity about 46.4% and 54.8%, individually, compared with pEMBL- CMV-hCGin (as a controls)…
Fig. 11A-11B show that AAVRH10 mediated-artificial miRNAs inhibited luciferase gene expression with targeting sequences in vitro. AAVRH10-CMV-hCGin-miHTT-H2 and H5 combined with their respective targeting sequences inserted into luciferase gene and greatly inhibited luciferase activity about 84.9% and 76.9%, compared with AAVRH10-CMV-hCGin (as a control). … vs. AAVRH10-CMV-hCGin.
[0071] Fig. 13 is presents western blots showing HTT protein levels in human neural cell line U87. After AAVRH10-CMV-hCGin-miHTT-H1-H5S treatment in U87 cells, HTT protein expression was reduced by AAVRH10-CMV-hCGin-miHTT-H2, -miHTT-H4 and —-miHTT-HS. B-actin is used as a loading control.
[0072] Fig. 14 is a bar graph showing the quantitative data of the HTT western blot in human neural cell line U87 (see e.g., Fig. 12). HTT protein expression was inhibited up to 73.2% by AAVRH10-CMV-hCGin-miHTT-H2, 58.5% by miHTT4 and 41.5% by miHTT-HS
[0075] Fig, 17 is a bar graph showing the second round screening with sequences from 3’-UTR. Artificial miRNAs inhibited luciferase gene expression with targeting sequences by co-transfection. In the second round screening, after 48-hour co-transfection, PEMBL-CMV-hCGin-miHTT-H14, H15, H17, H19 (miR-137) and miHTT-H21 (miR-216) efficiently inhibited luciferase activity compared with pEMBL-CMV-hCGin (as a control). MiHTT-H2, H4 and H5 were used as positive controls. MiDMPK-M5, M7 and M9 for targeting the dystrophia myotonica protein kinase (DMPK) gene were also used as negative controls.
[0076] Fig, 18 is a bar graph showing the second round screening with sequences from 3’-UTR. Artificial miRNAs inhibited luciferase gene expression with targeting sequences by co-transfection. After 48-hour co-transfection, PEMBL-CMV-hCGin-miHTT-H14, H15, H17, H19 (miR-137) and miHTT-H21 (miR-216) efficiently inhibited luciferase activity compared with pPEMBL-CMV-hCGin (as a control). Related to the control (100%), the activity of luciferase was 2.45% (H14), 8.75% (H15), 9.2% (H17), 12.89% (miR-137), and 4.17% (miR-216), individually. MiHTT-H2, H4 and H5 were used as positive controls. MiDMPK-MS5, M7 and M9 for targeting the DMPK gene were also used as negative controls vs.PEMBL-CMV-hCGin.
[0077] Fig. 19 is a schematic showing the second round screening with sequences from 3’-UTR. Specifically, the schematic shows the artificial miRNAs’ locations in the HTT gene. miHTT-H2 is located at region I; mi HTT-H4 and miHTT-HS are located at 5° and 3” jumper of CAG repeats, respectively; mHTT-H1]14 is located at region IV; and mHTT-H15, H17, H19 and H21 are located at region V.
[0082] Fig, 24 is a schematic showing the expression vectors of optimized CYP46A1. pAAV2.1- Syn1-GFP-sPA is a single-stranded vector used as a control. pAA V2. 1-Syn1-CYP46A1-sPA is used for overexpressing CYP46A1, which is driven with muscle specific promoter Syn1. The vector pAAV2.1-Synl1-CYP46A1-hCGin-2x miHTT is a combo construct, which can produce both CYP46A1 and 2 copies of artificial miHTT at the same time.
[0083] Fig, 25 is a schematic showing a map of pAAV2.1-Synl1-CYP46A1-hCGin-2x miHTT.
[0085] Fig, 27 is a series of schematics and images showing the construct of artificial miRNAs based on the backbone of miR-30 precursor and associated blots.
The specification teaches the screening of the claimed miRNA constructs in vitro for target gene inhibition. The specification teaches in paragraphs 00339-00341 the selection of appropriate mouse models for in vivo testing. These teachings refer to prophetic experiments. The examples provided in the instant specification, of the in vitro screening of the claimed miRNA constructs, and the listing of mouse models for future studies, are not representative or correlative of the ability to provide treatment in a subject as instantly claimed.
In light of the teachings in the art and the specification, one skilled in the art would not accept on its face the examples provided in the instant disclosure as being correlative or representative of the ability to provide treatment effects in a subject. Since the specification fails to provide the requisite guidance for the treatment in any subject, and since determination of the factors required for accomplishing this in any subject is highly unpredictable, it would require undue experimentation to practice the invention over the broad scope claimed.
For these reasons, the instant rejection for lacking enablement over the full scope claimed is proper.
Allowable Subject Matter
Claims 2-4, 6-15, 17, 20, 26 and 37 are allowed.
Conclusion
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.
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
2-20-26
/JANE J ZARA/Primary Examiner, Art Unit 1637