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 .
Applicants filed a Preliminary Amendment on May 17, 2024, in which amendments to the specification, drawings, and claims were made. Regarding the claim amendments, Applicants canceled claims 21-191 and amended claims 6, 15, and 18-20. Claims 1-20 are under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because the drawings filed May 17, 2024 refer to Figures 3B, 4B, and 14, and should refer to the figures as Fig. 3B, Fig. 4A, Fig. 4B, and Fig. 14. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
All genus and species names should be italicized.
The use of the terms TALEN at paragraphs [0047] and [00361]-[003612]; FLUOROLINK at paragraph [00109]; CASCADE BLUE at paragraph [00109]; OREGON GREEN at paragraph [00109]; TEXAS RED at paragraph [00109]; BODIPY at paragraph [00109]; MEGALIGN at paragraph [00124]; ACTIMAB at paragraph [00261]; BETALUTIN at paragraph [00261]; COTARA at paragraph [00261]; ENHANZE at paragraph [00261]; and IMMUTUNE at paragraph [00109]; which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
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.
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 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.
Claims 1, 6-9 and 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Peralta-Yahya et al. (U.S. Patent Application Publication No. 2016/0122832, published May 5, 2016) in view of Gao et al. (13(12) Nature Methods 1043-1048 and Online Methods (2016)).
Regarding claim 1, Peralta-Yahya discloses a system for regulating expression of a first target gene in a cell (paragraph [0098]). Peralta-Yahya discloses that the response unit can contain a signal molecule promoter operatively coupled to a signal molecule gene, where the signal molecule gene encodes or otherwise by activating other pathways in the cell that results in the production of a gene product and that the promoter can be configured to stimulate or extinguish transcription of the signal molecule gene (paragraph [01071]. Peralta-Yahya discloses the system comprises a first transmembrane receptor comprising a first ligand binding domain and a first signaling domain, which are physically distinct components that are operatively coupled to each other and can detect a chemical and generate a signal indicating the presence or absence of a chemical (paragraph [0094]). Peralta-Yahya discloses that the sensing unit can contain a G-protein coupled receptor (GPCR) that can bind to or otherwise interact with a chemical (paragraphs [0094]-[0095]). Peralta-Yahya discloses that the sensing unit can biologically interact with a processing unit, which in tum can biologically interact with the response unit (paragraph [0095] and Figure 1). Peralta-Yahya discloses that the first signaling domain activates a first signaling pathway of the cell upon binding of a first ligand to the first ligand binding domain; a chemical can bind, unbind, or otherwise interact with the GPCR of the sensing unit (paragraph [0095]). Peralta-Yahya discloses that, upon chemical interaction with the GPCR of the sensing unit the GPCR can biologically interact with the processing unit (paragraph [0095]). Peralta-Yahya discloses that the chemical binding with the GPCR of the sensing unit can stimulate, either directly or indirectly, a signal transduction pathway (paragraph [0096]). Peralta-Yahya discloses a first expression cassette comprising a nucleic acid sequence encoding a first gene placed under control of a first promoter, which can contain a signal molecule promoter operatively coupled to a signal molecule gene, where the signal molecule gene encodes or otherwise (paragraph [0107]).
Regarding Claim 6, Peralta-Yahya discloses that the first promoter comprises a first endogenous promoter that is activated upon binding of the first ligand to the first ligand binding domain (paragraph [0105]). Peralta-Yahya discloses that the biological interaction between the processing unit and the response unit can be direct or indirect regulation of a signaling molecule gene promoter (paragraph [0096] and Figure 1). Regarding claim 15, Peralta-Yahya further discloses wherein (i) the first promoter comprises a first exogenous promoter that is activated upon binding of the first ligand to the first ligand binding domain (The synthetic transcription factor can be configured to interact with... a synthetic promoter, Para. (0105]; The signal molecule promoter can be a synthetic promoter. Para. (0110]; a chemical 1400 can bind, unbind, or otherwise interact with the GPCR of the sensing unit 1100.Upon chemical interaction with the GPCR of the sensing unit 1100 the GPCR can biologically interact with the processing unit 1200. In some embodiments, chemical binding (or other interaction) with the GPCR of the sensing unit 1100 can stimulate, either directly or indirectly, a signal transduction pathway, Para. (0096]).
Regarding Claim 16, Peralta-Yahya further discloses that (i) the first exogenous promoter comprises a synthetic promoter sequence (paragraph [0110]).
Regarding claims 18 and 20, Peralta-Yahya discloses that the sensing unit can contain a G-protein coupled receptor(GPCR) that can bind to or otherwise interact with a chemical (paragraphs [0094]-[0095]).
Regarding claim 19, Peralta-Yahya discloses that the GPCR can include a synthetic response unit, which is interpreted as being a synthetic receptor (paragraphs [0130]-[0142]).
Peralta-Yahya fails to explicitly disclose a first gene modulating polypeptide (GMP), and wherein the first GMP comprises a first actuator moiety, and wherein the first promoter is activated to drive expression of the first GMP upon binding of the first ligand to the first ligand binding domain, wherein the expressed first GMP regulates expression of the first target gene.
Peralta-Yahya fails to explicitly disclose wherein (i) the nucleic acid sequence encoding the first GMP is operably linked to the first endogenous promoter, and/or (ii) the nucleic acid sequence encoding the second GMP is operably linked to the second endogenous promoter.
Peralta-Yahya fails to explicitly disclose wherein (i) the first expression cassette comprises a first gene encoding a first endogenous protein, wherein the first gene is located upstream of the nucleic acid sequence encoding the first GMP, and wherein expression of the first endogenous protein is driven by the first endogenous promoter, and/or (ii) the second expression cassette comprises a second gene encoding an second endogenous protein, wherein the second gene is located upstream of the nucleic acid sequence encoding the second GMP, and wherein expression of the second endogenous protein is driven by the second endogenous promoter.
Peralta-Yahya fails to explicitly disclose wherein (i) the first gene and the nucleic acid sequence encoding the first GMP are joined by a nucleic acid sequence encoding a first peptide linker, and/or
(ii) the second gene and the nucleic acid sequence encoding the second GMP are joined by a nucleic acid sequence encoding a second peptide linker.
Peralta-Yahya fails to explicitly disclose wherein (i) the nucleic acid sequencing encoding the first GMP is operably linked to the first exogenous promoter, and/or (ii) the nucleic acid sequencing encoding the second GMP is operably linked to the second exogenous promoter.
Gao is in the field of transcriptional modulation with inducible dCas9 regulators (Title) and discloses a first gene modulating polypeptide (GMP) by designing an inducible dCas9-based transcriptional regulation system in which dCas9 and a transcriptional effector are fused to complementary pairs of heterodimerization domains and only assemble in the presence of an extrinsic inducer (page 1044, column 1, first paragraph). Gao discloses that the first GMP comprises a first actuator moiety, noting that gene activation only occurred when S. pyogenes (Sp) dCas9 was expressed with Sp sgRNA (paragraph bridging pages 1045 and 1046). Gao discloses that the first promoter is activated to drive expression of the first GMP upon binding of the first ligand to the first ligand binding domain, by designing an inducible dCas9-based transcriptional regulation system in which dCas9 and a transcriptional effector are fused to complementary pairs of heterodimerization domains and only assemble in the presence of an extrinsic inducer (page 1044, column 1, first paragraph). Gao discloses that inducible repression in HEK293T cells was assessed by targeting a constitutive SV40 promoter (pSV40}-EGFP reporter (page 1045, column 1, first paragraph). Gao discloses that the expressed first GMP regulates expression of the first target gene by using the constitutive, direct fusion forms of KRAB-Sp dCas9 and VPR-Sa dCas9 to demonstrate simultaneous regulation of two genes, one activated and one repressed (page 1046, column 2, first p Pg. 4, right-hand column, top of first paragraph).
Regarding claim 7, Gao discloses that (i) a nucleic acid sequence encoding the first GMP is operably linked to the first endogenous promoter, which is a CMV promoter and used to drive expression of the second heterodimerizer-transcriptional effector cassette followed by an IRES-mCherry (Online Methods, page 1, column 1, seventh paragraph).
Regarding claim 8, Gao discloses (i) a first expression cassette comprises a first gene encoding a first endogenous protein, which is located upstream of the nucleic acid sequence encoding the first GMP and that expression of the first endogenous protein is driven by the first endogenous promoter by using the constitutive, direct fusion forms of KRAS-Sp dCas9 and VPR-Sa dCas9 to demonstrate simultaneous regulation of two genes, one activated and one repressed (page1046, column 2, first paragraph and Figure 3A). Gao discloses expression of Sp and/or Sa dCas9 constructs in a HEK293T pSV40-EGFP pTRE3G-mCherry dual reporter cell line (page1046, column 2, first paragraph and Figure 3A).
Regarding claim 9, Gao discloses (i) a first gene and the nucleic acid sequence encoding a first GMP are joined by a nucleic acid sequence encoding a first peptide linker, with the VPR activator22 assembled by fusing the activation domain of VP64 with the activation domains of p65 (p65AD) and RTA via two GS linkers, with expression of the transcriptional effector driven by a CAG promoter (Online Methods, page 1, column 1, third paragraph).
Regarding claim 17, Gao discloses (i) a nucleic acid sequencing encoding a first GMP is operably linked to a first exogenous promoter by expression Sp and/or Sa dCas9 constructs in a HEK293T pSV40-EGFP pTRE3G-mCherry dual reporter cell line along with Sp sgSV40 (page 1046, column 2, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Peralta-Yahya with the promoter of Gao in order to provide for independent temporal control of a desired target gene. By use of Gao’s promoter in the expression regulation system of Peralta-Yahya, one of ordinary skill in the art would be able to accurately control the desired expression of the target gene. It would also have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to modify Peralta-Yahya by expression of two genes of Gao, which will provide for accurate expression of two desired genes under the control of the promoters. As such, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Peralta-Yahya with Gao’s cas9 systems under the control of separate promoters for the purpose of allowing each cas9 to independently regulate expression of discrete endogenous gene targets.
Claims 2-5 are rejected under 35 U.S.C. 103 as being unpatentable over Peralta-Yahya in view of Gao, as applied to claims 1, 6-9 and 15-20 above, and further in view of Wang et al. (U.S. Patent Application Publication No. 2017/0157176, published June 8, 2017).
Peralta-Yahya and Gao disclose and suggest a system for regulating expression of target genes in a cell, as discussed above.
Peralta-Yahya and Gao fail to disclose or suggest a second transmembrane receptor comprising a second ligand binding domain and signaling domain, which activates a second signaling pathway of the cell when a second ligand binds to the second ligand binding domain.
Regarding claims 2-5, Wang discloses a second transmembrane receptor and that the extracellular element is capable of binding to an antigen and used for the chimeric antigen receptor, which comprises an oligopeptide or polypeptide that can bind to a target antigen (abstract and paragraph (0087]). Wang discloses a second ligand binding domain, which is an antigen-binding domain of an antibody and a ligand-binding domain of a receptor (paragraph (0087]). Wang discloses a second signaling domain, with the CAR comprising a transmembrane element and an intracellular signaling element comprising a functional signaling element derived from a stimulatory molecule, (paragraph (0086]). Wang discloses that the second signaling domain activates a second signaling pathway of the cell upon binding of a second ligand to the second ligand binding domain, where the intracellular element is a molecule that can transmit a signal into a cell when the extracellular element of CAR, Smart CAR, DE-CAR and/or Smart-DE-CAR binds to interacts with an antigen (paragraphs [0078] and [0104]). Wang discloses that the intracellular signaling element is generally responsible for activation of at least one of the normal effector functions (paragraph [0104]).
It would have been obvious to one of ordinary skill in the art at the time of the invention to include the two CAR transmembrane receptors of Wang in the expression regulation system of Peralta-Yahya and Gao in order to modulating expression of two target genes under the control of a second promoter in order to use dual transmembrane receptors to control the expression and signaling of more that a single pathway. This will result in greater control of desired target genes that are involved in signaling pathways in diseases, such as cancer, by targeting more than one antigen in a tumor. Claims 3-5 depend from claim 2, and thus, are also deemed to be obvious for the reasons above.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Peralta-Yahya in view of Gao, as applied to claims 1, 6-9 and 15-20 above, and further in view of Nirantar et al. (U.S. Patent Application Publication No. 2016/0109438, published April 21, 2016).
Peralta-Yahya and Gao disclose and suggest a system for regulating expression of target genes in a cell, as discussed above.
Peralta-Yahya and Gao fail to explicitly disclose or suggest that the first peptide linker and/or the second peptide linker comprise a protease recognition sequence.
Nirantar discloses peptide biosensors comprising a protease recognition site (abstract). Nirantar discloses a first peptide linker that comprises a protease recognition sequence (paragraph [0015]). Nirantar discloses that the peptide having a length that is sufficient to provide for a protease recognition site (paragraph [0030]). Nirantar discloses that the protease recognition sites allow for modulation interaction between signal generating moiety and a modulator, which provides for modulation of the signal generation by the signaling domain by interfering with the binding of the modulator with the signal generating moiety (paragraph (0052]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include the protease recognition site of Nirantar in the expression regulation system of Peralta-Yahya in order to modulate interaction between signal generating moiety and a modulator, which provides for modulation of the signal generation by the signaling domain by interfering with the binding of the modulator with the signal generating moiety.
Claims 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Peralta-Yahya in view of Gao, as applied to claims 1, 6-9 and 15-20 above, and further in view of Williams et al. (U.S. Patent Application Publication No. 2016/0333114, published November 17, 2016).
Peralta-Yahya and Gao disclose and suggest a system for regulating expression of target genes in a cell, as discussed above.
Peralta-Yahya and Gao fail to explicitly disclose or suggest that the first peptide linker and/or the second peptide linker comprises a self-cleaving segment, which can be T2A 2A peptide. Peralta-Yahya and Gao fail to explicitly disclose that the first gene and the nucleic acid sequence encoding the first GMP are joined by a nucleic acid sequence comprising a first internal ribosome entry site (IRES), and/or (ii) the second gene and the nucleic acid sequence encoding the second GMP are joined by a nucleic acid sequence comprising a second IRES.
Peralta-Yahya fails to disclose or suggest fails, Para. [0186]).
Regarding claim 11, Williams discloses a first peptide linker comprises a self-cleaving segment between the transmembrane domain and the intracellular T-cell signaling domain (paragraph [0195]).
Regarding claim 12, Williams discloses that the In embodiments, the self-cleaving peptidyl encoding sequence is a 2A encoding sequence (paragraph [0198]).
Regarding claim 13, Williams discloses that the 2A peptide is a T2A sequence (paragraph (0186]).
Regarding claim 14, Williams discloses a nucleic acid sequence comprising a first internal ribosome entry site (IRES), which is incorporated between the light and heavy chain or use of a ribosomal skip sequence such as the T2A (paragraphs [0134] and [0252]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate Williams’ T2A self-cleaving segment and IRES sequences in the system for regulating expression disclosed and suggested by Peralta-Yahya and Gao for the purpose of alteration of cellular signaling pathways, such as those disclosed and suggested by Peralta-Yahya and Gao. One of ordinary skill in the art would have been motivated to include Williams’ T2A self-cleaving and IRES sequences in the system of Peralta-Yahya and Gao in order to control the signaling pathways and ultimately the expression and control thereof of any desired target gene.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached on Monday - Thursday 8:00 AM - 6:30 PM.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
