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 .
Application Status
The preliminary amendment filed 12 March 2024 has been acknowledged and entered. Claims 3-4, 6, 8 and 10 are amended. Claims 1-12 are pending and being examined on the merits.
Priority
The application is a 371 PCT of application JP2022/008055 filed 02/25/2022. Acknowledgment is made of applicant's claim for foreign priority based application JP2021-033464 filed 03/03/2021 in Japan. Receipt is acknowledged of certified copies of papers and English translation required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements filed 04/24/2024 and 04/14/2025 had been considered.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
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 incorporation-by-reference paragraph, 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
Minor informalities: Pleiomorphic is misspelled on page 7.
The use of the terms Addgene and BioLegend, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. A cursory review of the specification has revealed these trademarks or names. It would be remedial to check the specification for additional trademarks or names and amend all upon amendment.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 7 and 8 are objected to because of the following informalities:
Claim 7's structure is somewhat awkward because the Dyrk1a-suppressing component can apparently be either a vector comprising an miR-shRNA expression cassette or an siRNA/miRNA. The punctuation makes it unclear whether the “siRNA or miRNA” is part of element (b). It would be remedial to amend to claim to a similar language: “(b) a Dyrk1a-suppressing agent selected from: (i) a vector comprising a nucleic acid sequence encoding an miR-shRNA against Dyrk1a operably linked to a promoter; (ii) an siRNA against Dyrk1a; and (iii) an miRNA against Dyrk1a.”
Claim 8: "Cells" is plural while the claim is presented as a single claimed statutory subject. It would be remedial to amend to claim to a similar language: "A cell transformed with the vector according to claim 4." or "A population of cells transformed with the vector according to claim 4."
Appropriate correction is required.
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 10-12 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 10 is directed to a pharmaceutical composition, i.e., a product, but recites that “the composition is used for treatment of a neurodegenerative disease or an inner ear disease.” It is unclear whether this language is intended merely to identify an intended use or capability of the claimed pharmaceutical composition, or whether actual use of the composition to treat the recited disease is required to satisfy the claim. The claim therefore creates uncertainty as to whether the claimed subject matter is the pharmaceutical composition itself or a method involving use of the pharmaceutical composition.
Claim 11 depends from claim 10 and further recites that “the composition is administered to a subject” by one of several specified administration routes. The recitation of an act of administering introduces an additional method step into a claim otherwise directed to a pharmaceutical composition and creates uncertainty as to whether the claim is satisfied by a composition suitable for such administration or only when the act of administration is actually performed.
For both claims 10 and 11, Applicant is required to amend the claims so that each claim is directed clearly to a single statutory category. For example, applicant may claim the pharmaceutical composition structurally or functionally as a product, or alternatively recast the subject matter as a method of treatment or administration.
Claim 12 recites “a step of causing a test substance to act on neural stem cells or inner ear supporting cells to measure expression of a Plagl2 gene and a Dyrk1a gene.” It is unclear whether the phrase “to measure expression” requires a separate step of measuring expression of the Plagl2 gene and a Dyrk1a genes after the cells are contacted with the test substance, or whether the test substance itself is intended to cause or otherwise facilitate the measurement of gene expression. The former appears to be intended in view of the subsequent selection step but is not clearly recited. Further, the claim requires selecting a test substance having the ability to “enhance” Plagl2 expression and/or “suppress” Dyrk1a expression, but the preceding step merely recites measuring expression and does not specific the reference or comparison by which enhancement or suppression is determined. Accordingly, the metes and bounds of the claimed screening method are unclear.
Claim 12 recites alternative selection steps (2-1) and (2-2). Step (2-1) recites selecting a test substance having both Plagl2 expression-enhancing ability and Dyrk1a expression-suppressing ability. Step (2-2), in contrast, recites selecting a test substance having Plagl2 expression-enhancing ability and a test substance having Dyrk1a expression-suppressing ability. It is unclear whether the two recitations of “a test substance” in step (2-2) require two different test substances, i.e., a first substance having Plagl2 expression-enhancing ability and a second substance having Dyrk1a expression-suppressing ability, or whether the same test substance may satisfy both recitations. Under the latter interpretation, the scope of step (2-2) substantially overlaps with the single-substance alternative recited in step (2-1). Under the former interpretation, the requirement that two different substances be selected is not expressly recited. Applicant may overcome the rejection, if supported by the originally filed disclosure, by clarifying the alternatives to recite, for example: (2-1) selecting a single test substance having both Plagl2 expression-enhancing ability and Dyrk1a expression-suppressing ability; or (2-2) selecting a first test substance having Plagl2 expression-enhancing ability and a second test substance having Dyrk1a expression-suppressing ability.
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 1-2, 4-5, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (Cancer cell 17.5 (2010): 497-509; “Zheng”) in view of Hagiwara et al. (US 2016/0303089 A1; “Hagiwara”) and Geiling et al. (PLoS One 8.10 (2013): e76279; “Geiling”).
Regarding claim 1, Zheng teaches that nine ORFs, including PLAGL2, “were placed in the pLenti6-V5-DEST expression vector and introduced individually” into cells, and that, “of the 9 cancer gene candidates, only PLAGL2 induced colony formation.” [p. 3, first full paragraph]. Thus, Zheng expressly teaches incorporating a nucleic acid sequence encoding PLAGL2 into an expression vector, thereby teaching the claimed “nucleic acid sequence of a Plagl2 gene.” Zheng further teaches the biological effect of expressing that PLAGL2 nucleic acid in neural stem cells. Zheng reports that “PlagL2-expressing p53−/− NSC cells retained their stem/progenitor-like morphology” and that “70% of PlagL2-expressing cells retained Nestin expression compared with 5% of control cells.” [pp. 4–5, see section entitled “PLAGL2 promotes renewal of NSC/progenitor cells by inhibiting their differentiation.”] Zheng further reports that PlagL2-expressing cells exhibited “robust BrdU incorporation” under differentiation conditions. [p. 4, paragraph 3]. Zheng expressly concludes that “enforced PlagL2 expression impedes NSC differentiation and preserves their stem cell features such as self-renewal potential and proliferation under differentiation induction.” [p. 5, first paragraph.] Thus, Zheng teaches not only the claimed Plagl2 nucleic acid but also provides a reason known in the art for expressing Plagl2 in neural stem/progenitor cells—namely, maintaining self-renewal and proliferation.
Zheng, however, does not teach that the PLAGL2 expression construct further comprises a nucleic acid sequence of an miR-shRNA against Dyrk1a. Zheng also does not specifically teach combining PLAGL2 expression with suppression of DYRK1A in the same polynucleotide.
Hagiwara teaches the missing DYRK1A suppression in the same relevant cell type. Hagiwara expressly states that “[t]he effect of specifically suppressing the expression of DYRK1A that belongs to the DYRK family on neurogenesis was studied by using cultured neural stem cells.” [0243] Hagiwara further teaches that “[t]he isolated and cultured neural stem cells were infected with lentivirus expressing short-hairpin RNA (shRNA) that induces the decomposition of mRNA of DYRK1A.” [0244] This expressly teaches a nucleic-acid-encoded short-hairpin RNA directed against Dyrk1a. Hagiwara further teaches the functional consequence of that Dyrk1a suppression. Specifically, Hagiwara reports that “the amount of incorporation of BrdU (cell proliferation marker) was increased in the cultured neural stem cells, in which the expression of DYRK1A was suppressed” and that “the expression level of cyclin D1, which is a positive growth factor, was increased.” [0245] Hagiwara concludes that “the growth of the cultured neural stem cells was activated by suppressing the expression of DYRK1A. In other words, neurogenesis can be activated by inhibiting the DYRK activity.” [0245]. Hagiwara therefore teaches the claimed strategy of suppressing Dyrk1a by an shRNA and, importantly, teaches that such suppression produces a desirable proliferative/neurogenic effect in the same general cell population—neural stem cells—in which Zheng teaches that PLAGL2 expression preserves self-renewal and proliferation.
Hagiwara does not expressly characterize its DYRK1A-directed shRNA as an “miR-shRNA (microRNA adapted short hairpin RNA)” and does not teach placing the PLAGL2 cDNA and Dyrk1a shRNA into the same polynucleotide.
Geiling expressly teaches that “shRNA sequences embedded in microRNA (typically human miRNA-30-based) have allowed for stable expression of shRNAs from RNA polymerase II promoters” and that, because these are Pol-II-initiated transcripts, “they can be manipulated to permit stable, inducible, or tissue-specific expression in viral vectors.” [p. 1, right column, Introduction.] This teaching corresponds directly to the claimed “microRNA adapted short hairpin RNA.” Geiling expressly describes its system as comprising lentiviral vectors that “permit the efficient transduction of cells with one or more cDNAs and are capable of simultaneously delivering one or more miRNA30-based shRNAs (shRNAmirs) to knockdown the expression of multiple targets in mammalian cells.” [p. 2, left column, paragraph 2] Geiling further states that its system allows investigators to “‘mix-and-match’ cDNAs, markers, and shRNAmirs.” [p. 2, left column, paragraph 2]. Geiling teaches the generation of “an entry vector encoding a miR30-embedded shRNA to knockdown targeted gene expression,” and that “[s]pecifically, shRNAs are cloned into a modified miRNA-30 ... such that the shRNA-miR30 (herein called shRNAmir) ... allow[s] their placement downstream of the cDNA/selection cassette after recombination.” [p. 6, left column, first paragraph; Fig. 2.] This is a direct teaching of the claimed miR-shRNA architecture and of positioning such a miR-shRNA in the same recombinant construct with an upstream cDNA. Geiling additionally teaches that its vectors include a promoter operably associated with the introduced nucleic acids: In describing its pLEG vector, Geiling teaches that the vector contains the relevant sequences “downstream of CMV promoter/enhancer sequences” and that “[i]ntegrated viruses express a single bicistronic transcript emanating from the CMV promoter/enhancer.” [p. 5, left column, section entitled “Development of Retroviral and Lentiviral Expression Vectors with Multiple Markers”; Fig. 1A.] Accordingly, Geiling teaches a promoter operably linked to the nucleic acid sequences in a recombinant lentiviral expression construct.
Regarding claim 2, Zheng teaches the Plagl2 gene is a mammalian gene because Zheng expressly utilized “murine p53−/− NSCs” and reports confirmatory studies in “wild-type ... mouse NSC cultures.” [p. 4, first full paragraph]. Hagiwara likewise expressly teaches that the Dyrk1a gene is mammalian because “[c]ells separated from the fetal mouse brain” were isolated and the resulting neural stem cells were infected with the DYRK1A shRNA lentivirus. [0244]
Regarding claim 4, Zheng expressly teaches that the relevant ORFs, including PLAGL2, “were placed in the pLenti6-V5-DEST expression vector.” [p. 3, first full paragraph] Geiling expressly teaches production of “novel lentiviral (pLEG) ... vectors” capable of “expressing cDNAs with or without inhibitory RNAs (shRNAmirs).” [Abstract] Geiling further expressly identifies the resulting products as “two lentiviral vectors pLEG(R1–R3) and pLEG(R1–R4).” [p. 3, left column.]
Regarding claim 5, the claimed alternatives include lentivirus. Geiling expressly teaches “novel lentiviral (pLEG)” vectors [Abstract] and specifically identifies “two lentiviral vectors pLEG(R1–R3) and pLEG(R1–R4).” [p. 3, left column.]. Hagiwara independently teaches that its cultured neural stem cells were “infected with lentivirus expressing short-hairpin RNA (shRNA)” directed against DYRK1A. [0244]
Regarding claim 8, the prior art expressly teaches cells transformed/transduced with the relevant vector systems. Zheng studies “PlagL2-expressing p53−/− NSC cells” and reports that those cells retained their stem/progenitor-like morphology. [p. 4.]. Geiling teaches that its p53 shRNAmirs were recombined into a lentiviral destination plasmid together with eGFP cDNA, after which “[l]entiviruses were produced, used to infect NIH 3T3 cells and pooled puromycin-resistant clones were obtained for each construct.” [p. 7, left column, paragraph 2] Geiling further teaches that recombinant lentivirus was “transduced into HEK 293T cells” and produced stable expression. [p. 5.]
It would have been obvious to one of ordinary skill in the art before the effective date of the claimed invention to modify Zheng's PLAGL2 expression construct to additionally suppress DYRK1A using the miR30-adapted shRNA architecture taught by Hagiwara and Geiling. The motivation for the combination arises directly from the biological teachings of Zheng and Hagiwara. Both references expressly identify genetic manipulations directed toward promoting or maintaining proliferative/neurogenic properties of neural stem cells. A POSITA seeking to increase or maintain neural stem-cell activity therefore would have had reason to employ the two known manipulations together. Furthermore, Geiling would have provided the POSITA with an expressly taught means of implementing those two manipulations in the claimed configuration. It therefore would have been obvious to use PLAGL2 as Geiling's expressed cDNA and an shRNA directed against DYRK1A as Geiling's miR30-embedded shRNA, because Zheng and Hagiwara had already identified those respective manipulations as affecting neural stem-cell renewal/proliferation. This modification would have amounted to using Geiling's known modular expression/knockdown system for its expressly intended purpose—simultaneous expression of a selected cDNA and knockdown of a selected endogenous target—with the particular cDNA and target selected according to the biological teachings of Zheng and Hagiwara. Accordingly, because each individual biological manipulation had been experimentally demonstrated, and the precise general vector architecture for simultaneously expressing a cDNA and an miR30-adapted shRNA had also been experimentally demonstrated, a POSITA would have had a reasonable expectation of successfully constructing and expressing the combined PLAGL2/DYRK1A-shRNAmir polynucleotide.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (Cancer cell 17.5 (2010): 497-509; “Zheng”) in view of Hagiwara et al. (US 2016/0303089 A1; “Hagiwara”) and Geiling et al. (PLoS One 8.10 (2013): e76279; “Geiling”) as applied to claim 1, and further in view of Sueda et al (Genes & development 33.9-10 (2019): 511-523 “Sueda”).
The teachings of Zheng, Hagiwara, and Geiling are discussed above as applied to claim 1 and similarly apply to claim 3.
The Zheng/Hagiwara/Geiling combination does not specifically teach one of these four claimed promoters. Geiling instead exemplifies a CMV promoter/enhancer, while teaching more generally that Pol-II-driven miRNA-embedded shRNAs “can be manipulated to permit stable, inducible, or tissue-specific expression in viral vectors.” [Geiling, p. 1, right column.]
Sueda states that “the Hes5 promoter can induce gene expression in neural stem cells” and experimentally confirms that “injecting a lentivirus carrying Hes5 promoter-driven Venus cDNA successfully induced Venus expression in GFAP+;Sox2+ neural stem cells in the SGZ of the adult mouse hippocampus.” [pg. 517, col. 2, paragraph 3].
It would have been obvious to one of ordinary skill in the art before the effective date of the claimed invention to substitute Sueda's known neural-stem-cell-active Hes5 promoter for the promoter of the Zheng/Hagiwara/Geiling expression construct because Geiling expressly contemplates tissue-specific Pol-II expression and Sueda identifies Hes5 as a promoter that successfully drives lentiviral expression in neural stem cells—the same relevant cell population targeted by Zheng and Hagiwara. A POSITA would therefore have had reason to select Hes5 to direct the combined genetic manipulation to neural stem cells. A reasonable expectation of success follows directly from Sueda's experimental demonstration that a lentivirus carrying a Hes5-promoter-driven cDNA “successfully induced” expression in GFAP+/Sox2+ neural stem cells, together with Geiling's demonstration that Pol-II-driven miRNA-embedded shRNAs are compatible with lentiviral expression systems.
Claims 6-7 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (Cancer cell 17.5 (2010): 497-509; “Zheng”) in view of Hagiwara et al. (US 2016/0303089 A1; “Hagiwara”) and Geiling et al. (PLoS One 8.10 (2013): e76279; “Geiling”) as applied to claim 1, and further in view of Kelleher et al. (US 2018/0112220 A1).
The teachings of Zheng, Hagiwara, and Geiling are discussed above as applied to claim 1 and similarly apply to claims 6-7 and 10.
The combination of Zheng, Hagiwara, and Geiling teaches the vector of claim 4 but does not expressly disclose formulating that vector as a pharmaceutical composition.
Regrading claims 6-7, Kelleher concerns expression vectors for therapeutic gene delivery and expressly notes that HIV-based lentiviral vectors were being developed for “clinical gene transfer applications” and “therapeutic gene delivery.” [0007]. Kelleher expressly teaches embodiments in which “the expression vector is a viral vector” and, more particularly, “the viral vector is a lentiviral vector or a retroviral vector.” [0015]. Kelleher states that its disclosure encompasses “compositions, such as compositions comprising an expression vector,” and expressly describes “a composition, including a pharmaceutical composition, comprising an expression vector.” Kelleher further teaches that “[i]n some embodiments, the expression vector is a lentiviral vector” and that “[i]n some embodiments, the composition further comprises a pharmaceutically acceptable carrier.” [0020]. Kelleher additionally describes pharmaceutical formulations including emulsions, micelles, nanoparticles, nanocapsules, polymers, and liposomes. [0020]. Kelleher describes “a composition comprising (i) an expression vector comprising at least two nucleic acids” and “(ii) a nucleic acid that encodes at least one transcriptional gene silencing element,” and expressly teaches that “[i]n some embodiments, the expression vector is a lentiviral vector.” [0021]. Kelleher further identifies the silencing nucleic acid as an RNA duplex and expressly teaches embodiments in which the silencing nucleic acid is “an siRNA.” [0022]. Kelleher additionally teaches methods employing “a composition comprising an expression vector and/or other components or active agents,” as well as “co-administering a composition comprising (a) an expression vector, and (b) another component or active agent.” [0023]. Thus, Kelleher does not merely establish that vectors and silencing RNAs were independently known pharmaceutical agents; it expressly teaches combining an expression vector with a separate nucleic-acid silencing component in a composition and teaches pharmaceutical formulation of such compositions. It would have been obvious to one of ordinary skill in the art before the effective date of the claimed invention to formulate Zheng/Hagiwara/Geiling expression construct in a pharmaceutical composition according to Kelleher. One of ordinary skill therefore would have been motivated to place the Plagl2-expression vector and Dyrk1a-suppressing siRNA in the same pharmaceutical composition so that the independently desirable genetic interventions could be provided together to the target cells, using the known vector-plus-silencing-nucleic-acid composition architecture taught by Kelleher. One of ordinary skill also would have had a reasonable expectation of success because Kelleher expressly teaches compositions comprising expression vectors together with separate nucleic-acid silencing components, expressly identifies siRNA as a suitable silencing nucleic acid, identifies lentiviral vectors as suitable expression vectors, and teaches pharmaceutical compositions containing these components and pharmaceutically acceptable carriers.
Regarding claim 10, “wherein the pharmaceutical composition is used for treatment of a neurodegenerative disease or an inner ear disease” is interpreted as intended use of the claimed composition and do not further structurally distinguish the composition from the prior art as discussed above. However, Hagiwara teaches that its pharmaceutical composition “can activate neurogenesis, and thus have the effects of preventing, improving, inhibiting the development of, and/or treating diseases or disorders of the central and/or peripheral nervous systems when they are administered to a Subject.” [0034]. Hagiwara expressly identifies among those disorders “Alzheimer's disease or other dementias caused by degeneration and metabolic disorder, Parkinson's disease; Huntington's disease.” [0034]. Hagiwara further states that “the present disclosure relates to a pharmaceutical composition for preventing, improving, inhibiting the development of and/or treating diseases or disorders of the central and/or peripheral nervous systems.” [0035]
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (Cancer cell 17.5 (2010): 497-509; “Zheng”) in view of Hagiwara et al. (US 2016/0303089 A1; “Hagiwara”) and Geiling et al. (PLoS One 8.10 (2013): e76279; “Geiling”) as applied to claims 1, 4, and 8, and further in view of Porteus et al. (US 2017/0298348 A1).
The teachings of Zheng, Hagiwara, and Geiling are discussed above as applied to claims 1, 4, and 8 and similarly apply to claim 9.
Zheng, Hagiwara, and Geiling do not expressly teach a pharmaceutical composition comprising the transformed cells.
Porteus teaches “a pharmaceutical composition comprising the genetically modified human neural stem cell of the invention and a pharmaceutically acceptable carrier” [0011]. Porteus similarly teaches that “[a]nother aspect of the present application provides a pharmaceutical composition comprising the genetically modified human neural stem cells described above and a pharmaceutically acceptable carrier” [0256].
It would have been obvious to one of ordinary skill in the art to formulate the transformed neural stem cells suggested by Zheng, Hagiwara, and Geiling as a pharmaceutical composition as taught by Porteus because Porteus expressly teaches pharmaceutical formulation of genetically modified neural stem cells with pharmaceutically acceptable carriers. One of ordinary skill would have reasonably expected success because Porteus expressly teaches such genetically modified neural stem-cell pharmaceutical compositions.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (Cancer cell 17.5 (2010): 497-509; “Zheng”) in view of Hagiwara et al. (US 2016/0303089 A1; “Hagiwara”) and Geiling et al. (PLoS One 8.10 (2013): e76279; “Geiling”), and Kelleher et al. (US 2018/0112220 A1) as applied to claims 1, 6, and 10, and further in view of Charneau et al. (US 2014/0248306 A1).
The teachings of Zheng, Hagiwara, Geiling, and Kelleher are discussed above as applied to claims 1, 6, and 10 and similarly apply to claim 11.
Their combination does not expressly teach administration of the viral-vector pharmaceutical composition by one of the routes recited in claim 11, including subcutaneous injection. Of note, “wherein the pharmaceutical composition is administered to a subject by intracerebroventricular injection, intrathecal bolus injection or infusion, intraganglionic injection, intraneural injection, subcutaneous injection, or intratympanic injection” is interpreted as intended use of the claimed composition and do not further structurally distinguish the composition from the prior art as discussed above.
Charneau expressly teaches that lentiviral-vector-containing compositions “can be injected in a host via different routes: subcutaneous (s.c), intradermal (i.d.), intramuscular (i.m.) or intravenous (i.v.) injection.” [0282] Charneau further teaches that “[w]hen formulated for subcutaneous injection, the immunogenic composition of the invention preferably comprises between 1 and 100 μg of the lentiviral vector per body weight of the host.” [0283].
It would have been obvious to one of ordinary skill in the art to administer the lentiviral-vector pharmaceutical composition suggested by Zheng, Hagiwara, Geiling, and Kelleher by subcutaneous injection as taught by Charneau because Charneau expressly identifies subcutaneous injection as a suitable route for lentiviral-vector compositions. One of ordinary skill would have reasonably expected success because Charneau expressly teaches formulation and administration of lentiviral-vector compositions by that route.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (Cancer cell 17.5 (2010): 497-509; “Zheng”) in view of Hagiwara et al. (US 2016/0303089 A1; “Hagiwara”) and Readhead et al. (Nature Communications 9:4412 (2018); Readhead).
The teachings of Zheng and Hagiwara are discussed above as applied to claim 1 and similarly apply to claim 12.
Zheng and Hagiwara do not teach screening test substances by measuring Plagl2 and Dyrk1a expression and selecting substances producing the desired expression changes.
Readhead teaches gene-expression-based drug screening in neural progenitor cells, stating that the authors tested whether “hiPSC-derived neural progenitor cell (hiPSC NPC)-focused gene expression-based screening represented a scalable alternative approach.” [pg. 2, col. 1, paragraph 2] Readhead screened 135 drugs in neural progenitor cells and compared their transcriptional responses, generating 4,320 drug-response transcriptional signatures [abstract; entire article].
It would have been obvious to one of ordinary skill in the art before the effective date of the claimed invention to apply Readhead's expression-based screening method to Plagl2 and Dyrk1a because Zheng identifies enhancement of Plagl2 as a desirable neural stem-cell effect and Hagiwara identifies suppression of Dyrk1a as a desirable neural stem-cell effect. One of ordinary skill therefore would have had reason to contact neural stem/progenitor cells with test substances, measure the resulting Plagl2 and Dyrk1a expression, and select substances producing those predetermined expression changes, with a reasonable expectation of success based on Readhead's successful expression-based screening of drug-treated neural progenitor cells.
With respect particularly to alternative (2-2), it would have been obvious to select a first test substance that enhances Plagl2 expression and a second test substance that suppresses Dyrk1a expression, because Readhead teaches screening individual compounds according to their drug-induced gene-expression profiles, while Zheng and Hagiwara supply the respective desired expression criteria. Claim 12 is written in the alternative; therefore, the obviousness of the method encompassed by alternative (2-2) is sufficient to render the claim unpatentable.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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