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 .
Election/Restrictions
Applicant’s election of SEQ ID NO: 15, SEQ ID NO: 38, SEQ ID NO: 58, SEQ ID NO: 78 and SEQ ID NO: 86 in the reply filed on 2/2/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Accordingly, claim 5 is withdrawn from consideration for being directed to non-elected subject matter. Claims 1-4 and 6-20 are currently under examination.
The elected sequences SEQ ID NO: 15, 38, 58, 78 and 86 are free from prior art. The sequence search has been extended to non-elected species recited in claims 6-13 and 16.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). The sequences in Table 1 and drawing Figure 1B and 1C do not have a sequence identifier number.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is objected to because the some teaching is unclear: on page 10, 2nd paragraph describes SEQ ID NO: 36 and SEQ ID NO: 39 being shRNA of miR#7mod and miR#10, but the sequences listed as SEQ ID NO:36 and 39 is labeled as miR#6mod and miR#8.
Appropriate correction is required.
Claim Objections
Claim 19 is objected to because of the following informalities: Claim 19 recites “the group consisting of hematopoietic stem/progenitor cells, hematopoietic progenitor cells, hematopoietic stem cell,” which is redundant.
Claim 15 is objected to for reciting “a least one silent mutation,” it is suggested to amendment the claim to “at least one silent mutation.”
Appropriate correction 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) 1, 14, 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Samakoglu et al (IDS)., as evidenced by Miccio (WO2018/220211, and alignment).
Samakoglu teaches a method of coregulating transgene expression and RNAi in hematopoietic stem cells (abstract). Samakoglu teaches inserting DNA encoding a promoterless shRNA within the intron of a tissue specific transgene, wherein the intron is the second globin intron, and the microRNA is targeting βs (page 90, Figure 1a, and legend). The shRNA consists two 19-bp stems linked by a 9 base loop (Figure 1 legend). Samakoglu further teaches that the globin intron described may be linked to any gene (page 93, 1st col., line 2-3). Although Samakoglu does not teach the sequence of the inserted site of said shRNA, a sequence search identified that SEQ ID NO: 1 of the present application is 100% identical to a short version of intron 2 of β-globin as shown in Figure 10A, 10C and Figure 14 of WO2018/220211, Miccio et al. (see attached alignment).
The only difference between the claimed invention of claim 1 and Samakoglu is that Samakoglu does not specifically teach which position of the shRNA is inserted in between the nucleotides of β-globin intron 2.
It would have been obvious to an ordinary skilled in the art that β-globin intron 2 is suitable for insertion of shRNA targeting βs based on teaching from Samakoglu because Samakoglu demonstrated that at least two position, one near splice acceptor and one near splice donor site of intron 2, result in expression of the shRNA that reduces the expression of βs target gene in hematopoietic stem cells (page 92, 1st col., and Figure 4 and legend). Finding a position within the prior art known sequence of β-globin intron 2 for efficient expression of a microRNA such as between 85-86 or 146-147 of SEQ ID NO: 1 as claimed in claim 1 would have been routine optimization, and within the capability of an ordinary skilled in the art. Therefore, the claimed invention of claim 1 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claim 14, Samakoglu teaches the transgene encoding γ-globin and shRNA targeting βs. (Figure 1a).
Regarding claim 17, the vector taught by Samakoglu is a lentiviral vector (Figure 1a and legend).
Regarding claim 18-19, Samakoglu teaches CD34+ hematopoietic progenitor cells from patients with sickle cell anemia and normal individual were transduced with the transgene that encodes γ-globin and shRNA targeting βs. (page 91, 2nd col., last paragraph).
Claim(s) 2, 3 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Samakoglu, in view of Veres (WO2018/183692).
The teaching from Samakoglu is discussed above. However, Samakoglu does not teach the microRNA is embedded into a miRNA backbone.
Veres teaches lentiviral vector comprising an erythroid specific promoter operably linked to a polynucleotide encoding s shmiR that comprises an antisense sequence that hybridizes to a human BCL11A mRNA (page 3, line 1-3). Veres teaches in a preferred embodiment, a shRNA is embedded in a miRNA scaffold, shmiR, and a shRNA directed against BCL11A is embedded in has-miR-223 scaffold (page 12, lines 9-12). Veres teaches the sense and antisense strands are embedded into an miRNA scaffold, which retains the miRNA flanking regions and loop, and this design adds Drosha processing site to the shRNA construct and has been shown to greatly increase knockdown efficiency (page 23, lines 9-18).
It would have been obvious to an ordinary skilled in the art that embedding the shRNA targeting βs target gene taught by Samakoglu in a miRNA scaffold would increase its knockdown efficiency as taught by Veres. The ordinary skilled in the art would be motivated to embed the shRNA taught by Samakoglu into a miRNA scaffold such as miR-223 because Veres has demonstrated that this strategy increases shRNA expression and targeting efficiency. Therefore, the claimed invention of claims 2 and 3 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claim 20, Veres teaches the host cells or target cells transduced with a viral vector expressing the shmiR targeting BCL11A is administered to a subject to treat hemoglobinopathy (page 44, lines 24-26).
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Samakoglu, in view of Miccio (WO 2018/220211).
The teaching from Samakoglu has been discussed above. However, Samakoglu does not teach a transgene that comprises an βAS3 polypeptide comprises a silent mutation.
Miccio teaches recombinant lentiviral vector that encodes an anti-sickling β-like globin gene, beta AS3 (page 37, example 1 and Figure 1). Miccio teaches said beta AS3 transgene comprises silent mutation(s) inserted by site directed mutagenesis in order to impair the gRNA binding to the transgene (page 48, lines 3-8, Figure 10B).
It would have been obvious to an ordinary skilled in the art to make a transgene that comprises a modified βAS3 that comprises a silent mutation and further comprise the shRNA directed to following combined teaching from Samakoglu and Miccio. The ordinary skilled in the art would be motivated to modify βAS3 that comprises a silent mutation to prevent shRNA binding which may cause reduced expression of the βAS3. Since Miccio already demonstrated silent mutation that gRNA binding, using site directed mutagenesis induce mutation to prevent shRNA binding would have been within the capability of an ordinary skilled in the art. Therefore, the claimed invention of claim 15 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Claim(s) 4 and 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Samakoglu and Veres, as applied to claim 1 and 2, further in view of Adam (IDS) and HUMHBB5D2 (Vanin, et al., 1993)
The teaching from Samakoglu and Veres has been discussed above. However, neither reference teaches the sequence encoding for guide strand that comprises SEQ ID NO: 18.
HUMHBB5D2 has 100% sequence identity with presently claimed SEQ ID NO:18 (see alignment).
Adam teaches systematically improved vector based shRNAmiR expression to produce a complete and versatile lentiviral all in one system for conditional RNAi based on natural human miR-30a backbone (page 103, 1st col., 4th paragraph). Adam reanalyzed a published large scale shRNA efficacy data set and discovered new sequence features refining previously established shRNA design rules for better prediction of potent RNAi, and developed an online tool that incudes sensor criterial and the shRNA design rules for improved shRNAs (page 103, 1st col., 4th paragraph).
It would have been obvious to an ordinary skilled in the art to use online tools taught by Adam for designing shRNA mirR vector which demonstrated improved cloning efficiency and potency for the shRNA for designing shRNA targeting βs based on combined teaching from Samakoglu, Veres and Adam. Since the sequence encoding β globin is known in prior art, wherein HUMHBB3D2 is a sequence originates upstream from beta globin gene cluster on chromosome 11 in the sequence given as HUMHBB52, breakage and reunion at base 200 below leads to thalassemic condition gamma-delta-thal-2, the ordinary skilled in the art would design shRNA sequence that comprises said sequence as guide sequence for targeting β globin mutational gene. Therefore, the claimed invention of claims 4 and 6 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Samakoglu and Veres, as applied to claim 1 and 2, further in view of the sequence AY866261 (Berezikov et al., 2005).
The teaching from Samakoglu and Veres has been discussed above. However, neither reference teaches shRNA having the loop of SEQ ID NO: 25.
The sequence having accession number AY866261 is part of microRNA mir-223 that has 100% sequence homology with SEQ ID NO: 25 (see attached alignment).
Veres teaches shmir comprises 21-nt of dsRNA and a 15-nt loop from a miRNA, and adding the miRNA loop and flanking sequences on either or both sides of the hairpin results in greater than 10 fold increase in Drosha and Dicer processing of the expressed hairpins when compared with conventional shRNA designs without miRNA, which means greater shRNA/miRNA production and greater potency for expressed hairpins. Veres teaches a preferred miRNA is miR-223 primary transcript. It would have been obvious to an ordinary skilled in the art that shRNA embedded in miR-223 would comprise sequence set forth in SEQ ID NO: 25 because SEQ ID NO: 25 is part of miR-223, which is used for scaffold for embedding shRNA targeting βglobin as taught by Veres. Therefore, the claimed invention of claim 7 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Allowable Subject Matter
Claims 8, 9, 10, 11, 12, 13 and 16 are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/Primary Examiner, Art Unit 1637