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 .
Status of Claims
Claims 1-12 are currently pending and under consideration.
Priority
The present application is a divisional of US application 17/263,410 (now US Patent no. 12247244), filed on 05/03/2021, which claims status as a 371 (National Stage) of PCT/JP2019/029424 filed on 07/26/2019, and claims priority to Japanese application JP2018-144171. Acknowledgment is made of applicant' s claim for foreign priority and papers submitted under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. JP2018-144171, filed on 07/31/2018. The present application and all claims are being examined with an effective filing date of July 31, 2018. Please note that the Japanese application is in a foreign language and therefore cannot be reviewed. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/11/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Rejections - 35 USC § 112(b)
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 11-12 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 11 and 12 attempt to claim a process without setting forth any steps involved in the process. Merely reciting a use without any active, positive steps delimiting how this use is actually practiced, renders the claim indefinite (see MPEP 2173. 05(q)).
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.
Claims 1-3, 5-8 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Barnea et al. (The Genetic Design of Signaling Cascades to Record Receptor Activation, Proc. Natl. Acad. Sci. USA 105:64–69, cited in PTO-892), Bliss et al. (ERK Signaling, But Not c-Raf, Is Required for Gonadotropin-Releasing Hormone (GnRH)-Induced Regulation of Nur77 in Pituitary Gonadotropes, Endocrinology 153:700–711, cited in PTO-892), and Deisseroth et al. (WO2017205395, cited in PTO-892).
Regarding claim 1, Barnea et al. teaches the Tango assay, which includes: (i) a first construct encoding a membrane receptor fused to a transcriptional activator, wherein a site for cleavage by a specific protease is interposed between the receptor, which anchors the fusion at the cell membrane, and the transcriptional activator; (ii) a second construct encoding the specific protease fused to a cellular protein that interacts with the activated receptor; and (iii) a reporter construct comprising a reporter gene responsive to the transcriptional activator. In a GPCR embodiment, Barnea et al. teaches an arginine vasopressin receptor 2 (AVPR2)-TCS-tTA fusion, wherein AVPR2 constitutes the cell membrane anchor portion, TCS is a TEV protease cleavage site positioned between the membrane anchor portion and the transcription factor portion, and tTA constitutes the transcription factor portion. Barnea et al. further teaches a β-arrestin2-TEV protease fusion, wherein TEV protease is capable of cleaving TCS. Ligand activation of AVPR2 recruits the β-arrestin2-TEV protease fusion to the activated receptor, permitting cleavage of the intervening TEV site, release and nuclear entry of tTA, and expression of the tTA-responsive reporter gene (pg. 64–65, Fig. 1). Barnea et al. does not teach that the nucleotide sequence encoding the cell membrane-anchored transcription factor is operably linked to a transcriptional regulatory region of a first gene whose expression is induced by activation of the membrane protein. Nor does Barnea et al. teach that the nucleotide sequence encoding the protease is operably linked to a transcriptional regulatory region of a second gene whose expression is induced by activation of the membrane protein.
Bliss et al. teaches that activation of a membrane receptor can induce transcription of downstream immediate-early genes. In particular, Bliss et al. teaches that stimulation of pituitary gonadotropes by GnRH induces expression of the immediate-early gene Nur77/NR4A1 (pg. 700, Abstract). Thus, Bliss et al. establishes that activation of a membrane protein responsible for signal transduction can provide a transcriptional input through induction of a downstream responsive gene.
Deisseroth et al. teaches activity-dependent expression constructs in which an activity-responsive regulatory sequence associated with an endogenous gene is operably linked to a heterologous coding sequence such that activation of the regulatory sequence drives expression of the encoded polypeptide. Specifically, Deisseroth et al. teaches an expression cassette comprising a regulatory sequence containing a c-Fos 5′ non-coding region and c-Fos first-intron sequence operably linked to a polypeptide coding sequence, wherein the encoded polypeptide is expressed upon activity-dependent activation of the regulatory sequence (Specification, para 0006–0008, 0050, and claim 1). Deisseroth et al. further teaches that the coding sequence may be heterologous to the c-Fos regulatory sequence and may encode functional proteins including a receptor, nuclease, transcription factor, or fusion protein (para 0104–0112, 0134–0136; also claims 8 and 14–17).
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, Bliss et al. teaches that membrane-receptor activation can provide a transcriptional input by inducing transcription of downstream responsive genes, including the immediate-early gene Nur77/NR4A1, and Deisseroth et al. teaches that an activity-responsive regulatory region associated with an induced endogenous gene, such as c-Fos, can be operably linked to a heterologous coding sequence to provide activity-dependent expression of a functional polypeptide. A person of ordinary skill in the art would therefore have had reason to use such known activation-responsive regulatory regions, as taught by Bliss and Deisseroth, to control expression of Barnea’s heterologous membrane-anchored transcription-factor fusion and protease fusion. Such modification would couple expression of those components to the activated signaling state, thereby adding a known transcriptional layer of signal-responsive control to Barnea’s established proteolytic reporter pathway. Therefore, it would have been obvious to a person of ordinary skill in the art to modify the first and second constructs of Barnea et al. by placing their respective coding sequences under the control of transcriptional regulatory regions associated with genes whose expression is induced downstream of activation of the membrane protein. There is a reasonable expectation of success because Barnea et al. demonstrates the operative membrane-anchored transcription-factor/protease-cleavage/reporter arrangement; Bliss demonstrates receptor-induced transcriptional expression of a downstream responsive gene; and Deisseroth et al. demonstrates the use of an activity-responsive endogenous-gene regulatory region to drive expression of heterologous functional proteins. The modification therefore represents the predictable application of known signal-responsive transcriptional control elements to Barnea’s known synthetic-reporter components according to their established functions. Therefore, the invention, as a whole, would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 2-3, as indicated above, Barnea et al. teaches wherein the membrane protein is a G protein-coupled receptor (GPCR), specifically an AVPR2-based receptor construct.
Regarding claim 5, Barnea further teaches wherein the label is luciferase. Specifically, Barnea et al. employs a tTA-responsive luciferase reporter for detecting receptor activation (Fig. 1-2).
Regarding claim 6, as described above, Deisseroth et al. teaches c-FOS as the gene associated with the activity responsive regulatory sequence.
Regarding claims 7-8 and 10, Barnea et al. teaches the Tango assay described above, wherein HEK293T cells are transfected with the constructs (Fig. 1 and pg. 69). With respect to claim 10, the recited kit comprises the cell of claim 7 and does not require any additional structural components. Accordingly, the cell comprising the constructs, as taught by and made obvious by Barnea et al., Bliss et al., and Deisseroth et al., satisfies the structural limitations of the recited kit.
Regarding claims 11 and 12, Barnea et al. teaches contacting cells comprising the Tango assay constructs with test compounds (i.e., arginine vasopressin) and determining the effect of the compounds on activation of the membrane protein based upon reporter activity (pg. 64-65).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Barnea et al., Bliss et al., and Deisseroth et al., as applied to claims 1 and 7 above, and further in view of Brown et al. (A Defect in Nurturing in Mice Lacking the Immediate Early Gene fosB, Jul 1996, Cell, Vol. 86, 297–309, cited in PTO-892).
The teachings of Barnea, Bliss and Deisseroth, as applied to claims 1 and 7, are being relied upon and have already been discussed above. The combined teachings of Barnea, Bliss, and Deisseroth make obvious a cell comprising a combination of constructs according to claim 1, but does not teach wherein the second gene (wherein the cell is a HEK293T cell) is FOSB.
Brown et al. teaches that FOSB is a member of the Fos family of immediate-early genes. Specifically, Brown et al. teaches that the Fos family consists of c-FOS, FOSB, FRA-1 and FRA-2, that expression of Fos family transcription factors is induced by environmental stimuli that trigger cellular responses, and that Fos-family genes are activated during a wide variety of adaptive cellular responses. Brown et al. experimentally demonstrates stimulus-induced expression of both FosB and c-Fos in response to the same stimulus, reporting clear induction of FosB following exposure to pups and further reporting that induction of c-Fos was also observed in the same brain region at the same time (pg. 297 and 305). Thus, Brown et al. establishes that FOSB and c-FOS were both known in the art as stimulus-responsive Fos-family immediate-early genes.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, given the teachings of Brown et al., that FOSB and c-FOS were both known in the art as stimulus-responsive Fos-family immediate-early genes, it would have been obvious to a person of ordinary skill in the art to substitute FOSB for c-FOS as the second gene in the combination made obvious by Barnea et al., Bliss et al., and Deisseroth et al. and expect predictable results (see MPEP 2144.06, “Substituting equivalents known for the same purpose”). Brown et al. establishes that FOSB and c-FOS provide the same relevant function of stimulus-responsive gene expression; therefore, one of ordinary skill in the art would have reasonably expected FOSB to provide stimulus-responsive expression when substituted for c-FOS for this purpose and such substitution of art-recognized alternatives known for the same purpose would have been obvious. Therefore, the invention, as a whole, would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Barnea et al., Bliss et al., and Deisseroth et al., as applied to claims 1-3 above, and further in view of Aoki, J. and Inoue, A. (WO2015128894, herein “Aoki”, Espacenet English translation relied upon, cited in PTO-892).
The teachings of Barnea, Bliss and Deisseroth, as applied to claims 1 and 7, are being relied upon and have already been discussed above. The combined teachings of Barnea, Bliss, and Deisseroth do not teach the recited chimeric G-protein alpha subunit.
Aoki teaches chimeric Gα proteins comprising an N-terminal domain of a G12-family protein and a C-terminal domain of a Gα protein other than the G12 family. Aoki further teaches that the chimeric protein includes a protein in which amino acid residues in the C-terminal domain of the G12-family protein are substituted with corresponding amino acid residues of a Gα protein other than the G12 family, and teaches that amino acid residues at the C terminus, particularly the third and fourth residues, are important for Gα function (page 10). Furthermore, Aoki teaches the use of such Gα chimeric proteins for detecting GPCR signal-transduction activation (pages 2 and 7).
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to incorporate the chimeric Gα protein taught by Aoki into the GPCR assay system made obvious by Barnea et al., Bliss et al., and Deisseroth et al. A person of ordinary skill in the art would have been motivated to employ Aoki’s known Gα chimera because Aoki teaches that modification of the C-terminal region of a Gα protein permits coupling and detection of GPCR-mediated signaling through different Gα proteins. There would have been a reasonable expectation of success because Aoki demonstrates the successful use of such chimeric Gα proteins for detecting GPCR signal-transduction activation. Therefore, the invention, as a whole, would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NAGHMEH NINA MOAZZAMI whose telephone number is (703)756-4770. The examiner can normally be reached Monday-Friday, 9:00-5:00.
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/NAGHMEH NINA MOAZZAMI/ Examiner, Art Unit 1652
/ROBERT B MONDESI/ Supervisory Patent Examiner, Art Unit 1652
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