Notice of Pre-AIA or AIA Status
The present application, 17628971, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The filing receipt, mailed 11/19/2025, states that this application, 17628971, was filed on 1/21/2022, and as stated by applicant in the ADS, that this application claims domestic priority benefit as a 371 of PCT/EP2020/070622, filed 07/22/2020, and claims benefit of European Patent Office (EPO) 19305967.2, filed 07/22/2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/21/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 6, 12 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.
Claims 6, 12 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.
Claim 6, dependent on claim 1, recites the limitation “the cell of point d.” There is insufficient antecedent basis for this limitation in the claim. The terms “the cell of point d” is not found in claim 1.
Claim 12, dependent upon claim 1, recites the limitation "sequences a to c, and d and e if present in the IDLV" in line 2. There is insufficient antecedent basis for this limitation in the claim. The terms “d and e” are not found in claim 1.
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.
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.
The claims are drawn to an integration-defective lentiviral vector (IDLV) comprising a nucleic acid, the nucleic acid comprising, between a 5’ LTR sequence and a 3’ LTR sequence: at least one nucleus export signaling sequence; at least one nucleic acid sequence of interest selected from the group consisting of a polyA signal; a splicing signal sequence; a DNA or RNA binding site; a promoter; and a transgene, or a fragment thereof, encoding a therapeutic protein or a therapeutic ribonucleic acid; and at least one nuclease site; and variations and methods thereof.
1. Claims 1, 2, 3, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20 are rejected under 35 U.S.C. 103 as being unpatentable over Negri (20916) Molecular Therapy, vol 24, number 11, pages 2021 to 2032; West, US 20150064149; and as evidenced by Fernandes 2012 RNA Biology, vol 9, number 1, pages 6-11.
Negri, throughout the publication and abstract, teaches integrase defective lentiviral vectors (IDLV) as a promising vaccine candidate against HIV-1 given their ability to induce durable and protective immune responses in mice using an IDLV-Env vaccine delivery platform. Negri, at p. 2022, 2d para, teaches generating a SIV-based IDLV expressing the clade C transmitted founder (T/F) HIV-1EnvC.1086 gp 140 (IDLV-Env) to evaluate safety and immunogenicity in non-human primates. See Negri, at pp. 2023 and 2028, Figure 1a, show an SIV-based Transfer Vector expressing HIV-1EnvC.1086 gp 140, as well as a Rev response element (RRE) adjacent to the splice acceptor site (SA).
The evidentiary review publication of Fernandes 2012 RNA Biology, vol 9, number 1, pages 6-11, throughout the publication, abstract and further, e.g., at pp. 6-7, teaches the HIV-1 Rev response element (RRE) is located within the HIV env region at nucleotides 7709-8063 of the HXB2 reference strain of the HIV-1 genome (Fig. 1B).
Negri, at Figure 1 teaches gp120 as a transgene and therapeutic protein, and which, absent objective evidence to the contrary, can be secreted and eventually taken up by non-modified cells to participate in the humoral or cellular immune response, as in claim10-12.
Negri, at p. 2023, teaches production of anti-Env antibodies from IDLV-Env and, at p. 2024, induced T-cell responses and a Wpre, identified in the legend as the woodchuck hepatitis virus post-transcriptional regulatory element.
Negri does not teach a nuclease site as recited in instant claim 1.
West, US 20150064149, teaches nuclease sites in IDLV, that allows for generation of a linear donor molecule, also reading on claim 3.
[0161] In certain embodiments, the nucleic acids are delivered using viral vectors such as lentiviral vectors. Viral vectors may be used to deliver the donor nucleic acids as well if the donor is flanked by the nuclease molecules or other nuclease target sites that would allow for the generation of a linear donor molecule with single stranded overhangs that are compatible with those at the integration site following nuclease cleavage. Lentiviral transfer vectors can be produced generally by methods well known in the art. Preferably, the lentivirus donor construct is an integrase deficient lentiviral vector (IDLV).
West, US 20150064149, at para 0161, emphasis added.
West at para [0110]-[0114], teach nuclease-mediated site-specific genome editing, including by CRISPR/Cas systems which involve RNA-guided DNA endonucleases; at para [0134], teach a nucleic acid of interest flanked by a first homology region and a second homology region wherein these homology regions share homology with 5’ and 3’ regions, respectively, of a genomic target site (TS), reading on at least one nuclease site of instant claim 1.
West at para [0103], teaches that the vector may optionally contain flanking nucleic acid sequences that direct site-specific homologous recombination into a desired genetic locus, reading on homology arms. West at para [0120] teaches tracrRNA promotion of crRNA processing required for activating RNA-guided cleavage by Cas9.
It would have been prima facie obvious before the filing date of the instant application for one of ordinary skill in the art to have combined a nuclease target site, as taught by West, in a IDLV, as taught by Negri.
One of ordinary skill in the art would have motivated to have combined a nuclease target site into the IDLV in order to deliver donor nucleic acids by generating linear donor molecules with single stranded overhangs that are compatible with those at the integration site following nuclease cleavage.
2. Claim(s) 2, 4, 5, 6, 7, 8, 9, 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Negri (20916) Molecular Therapy, vol 24, number 11, pages 2021 to 2032; West, US 20150064149; and as evidenced by Fernandes 2012 RNA Biology, vol 9, number 1, pages 6-11; as applied to claims 1, 2, 3, 10-16, 18-20 above, and further in view of Holmes, 20090117617; Cost, US 20180187173; and Naldini, US 20220251161.
Negri (20916) Molecular Therapy, vol 24, number 11, pages 2021 to 2032; West, US 20150064149; and as evidenced by Fernandes 2012 RNA Biology, vol 9, number 1, pages 6-11; are relied upon as cited in the above obviousness rejection.
The combination of Negri, West and Fernandes do not teach or suggest various combinations of components, as in claim 12, and including a Rev response element (RRE), a nuclease site, and a transgene or therapeutic protein, of an IDLV, in particular order as in instant claim 12; further does not teach various nuclease sites, as in instant claim 4-6; does not comprise a promoter, as in claim 8; wherein the endogenous genomic site of interest in comprised within a globin gene, as in instant claim 9; and methods for generating CAR-T cells, comprising integrating an IDLV encoding a chimeric antigen receptor against cancer cells.
Holmes, 20090117617, throughout the publication, abstract and at col. 3, line 24-col. 7, line 17, fig 1, 6, teach homology arms in IDLV, as in instant claim 2.
Holmes, at para [0173], teaches lentiviral construct II, Figure 3, includes a second positive selection marker that promoterless and requires the precise insertion of this marker downstream of an active gene to be expressed. Expression of this promoterless selection marker from an endogenous promoter can be achieved by directly fusing it in-frame to the native gene at the break site, through the use of a splice acceptor and its insertion, e.g., into an intron. This describes and suggests an IDLV without a promoter, as in instant claim 8.
Cost, US 20180187173, at para [0028], [0034], [0012], [0190] [0208], [0216], teach using an IDLV donor to make a site-specific gene correction in the beta globin gene, as in instant claim 9, in order to treat sickle cell disease.
Naldini, US 20220251161, foreign priority support, p. 6, lines 23-26, of the foreign application teaches CAR-T, p. 34, lines 17-19, Integration defective lentiviral vectors IDLVs. Naldini, US 20220251161, at para [0003], [0024], [0045] teach IL-2 interleukin, which targets the liver, and is comprised within an IDLV vector, to treat hepatitis B virus infection. Naldini, US 20220251161, at para [0003], [0057]-[0060] and [0230]-[0231], teach treating or preventing hepatocellular carcinoma.
It would have been prima facie obvious before the filing date of the instant application for one of ordinary skill in the art to have combined a Rev response element (RRE), a nuclease site, and a transgene or therapeutic protein, of an IDLV, in particular order; further does not teach various and more than one nuclease sites; does not comprise a promoter; wherein the endogenous genomic site of interest in comprised within a globin gene; and methods for generating CAR-T cells, comprising integrating an IDLV encoding a chimeric antigen receptor against cancer cells in an IDLV, and methods therefor, as taught and suggested by the combination of Negri, West and Fernandes.
One of ordinary skill in the art would have motivated to have combined a Rev response element (RRE), a nuclease site, and a transgene or therapeutic protein, of an IDLV, in particular order, in an IDLV, as a design choice. The specification does indicate a particular order of component as critical or advantageous, and the practitioner would be motivated to try various different combinations of IDLV component order, as described in the prior art reference of Holmes. One of ordinary skill in the art would have motivated to have combined identical or different nuclease sites, and promoterless IDLV treatment, to control recombination of the transgenes into the host genome, as taught by Holmes.
One of ordinary skill in the art would have motivated to have combined integration of a transgene into the endogenous globin gene to address sickle cell disease, as taught by Cost.
One of ordinary skill in the art would have motivated to have combined methods of making chimeric antigen receptor transgene delivery vectors using IDLV, for treating cancer, taught by Naldini.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mark L Shibuya whose telephone number is (571)272-0806. The examiner can normally be reached M-F, 9AM-4:30PM.
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MARK L. SHIBUYA
Primary Patent Examiner
Art Unit 1631
/MARK L SHIBUYA/Primary Patent Examiner, Art Unit 1631