DETAILED ACTION
Status of the Claims
Claims 115-121, 123, 125-134, and 137-138 are currently pending.
Claims 115, 126, 128, and 138-138 are amended.
Claims 1-114, 122, 124, and 135-136 are canceled.
Claims 115-121, 123, 125-134, and 137-138 are the subject of this Office action.
The following Office Action is in response to Applicant’s communication dated 10/23/2025. Rejection(s) and/or objection(s) not reiterated from previous office actions are hereby withdrawn. Specifically, the objection to claim 137 and the rejections to claim 138 under 35 U.S.C. 112(a) and 35 U.S.C. 112(b) are withdrawn in light of amendments and persuasive arguments from Applicant. The following rejection(s) and/or objection(s) are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Modified Claim Rejections – 35 U.S.C. 103(a)
Necessitated by Amendments
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.
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 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Galinski, Koener & Hermans, Koener, Schucht et al., and Emery
Claims 115-117, 125, and 127-132 are rejected under 35 U.S.C. 103 as being unpatentable over Galinski (Multiplexed cell-based assays to profile GPCR activities and cellular signaling. Georg-August-University Gӧttingen dissertation. 2016, cited in the IDS filed 04/24/2020, of record) in view of Koener & Hermans (Methods in Molecular Biology, vol. 746, DOI 10.1007/978-1-61779-126-0_1, 2011, pp. 3-20, of record) further in view of Keoner (Koener, Beryl (dissertation) Third generation of antipsychotics: critical views on dopamine D2 partial agonism in neuropsychopharmacology. Prom.: Hermans, Emmanuel; Maloteaux, Jean-Marie http://hdl.handle.net/2078.1/89791, 2011, of record) and further in view of Schucht et al. (Journal of Biomolecular Screening, 2011, 16(3), of record), further in view of Emery (Human Gene Therapy 22:761-774 (2011), of record).
Regarding claims 115 and 128, Galinski teaches a population of mammalian cells comprising (e.g., Fig. 32-33; PC12 cells):
a) an exogenous nucleic acid encoding a heterologous GPCR receptor gene (e.g., GPCRs as per Fig. 32-33, Table 7, and pages 93+), and
b) an inducible reporter (e.g., Fig. 32; “EXT sensor library”) comprising a receptor-responsive element,
wherein the receptor responsive element comprises a camp response element (CRE) (e.g., Fig. 32-33 and p. 93; “CRE cis-element activity is driven by the transcription factor CREB, which in turn is activated by the cAMP pathway”),
wherein the inducible reporter is induced upon activation of a heterologous-receptor protein encoded by the heterologous receptor gene (e.g., Fig. 32-33 and section 5.3),
wherein the inducible reporter comprises a barcode comprising an index region that is unique to the heterologous receptor gene (e.g., p. 63; “For monitoring the receptor activation of multiple GPCRs simultaneously in one experiment, a new class of reporter constructs was generated (Fig. 10). Expressed oligonucleotide tags (EXTs) are unique barcode sequences that were used to replace classical reporter proteins as read out” and Fig. 32-33), and
wherein the individual mammalian cells of the population of mammalian cells express different heterologous receptors (e.g., Fig. 32-33; “multiplex”).
However, it is noted that Galinski is silent on the limitation of the receptor being operatively coupled to an inducible promoter and wherein the heterologous receptor gene is expressed upon activation of the inducible promoter, as set forth in claim 115, or wherein the inducible promoter comprises a reverse tetracycline-controlled transactivator (rtTA), as set forth in claims 116 and 129. Instead, Galinski appears to rely on the use of a CMV promoter, which is a constitutive promoter.
Koener & Hermans teach the use of inducible promoters, including an inducible promoter system that comprises a reverse tetracycline-controlled transactivator (rtTA), also known as Tet-ON (e.g., as per page 5).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to use a Tet-ON based promoter system that comprises a reverse tetracycline-controlled transactivator (rtTA) as per Koener & Hermans in the multiplex cell-based G-PCR assay of Galinski. One of ordinary skill in the art would have been motivated to do so since Koener & Hermans teach that a “functional receptor expression system is required (e.g., for pharmacological screening)” and by “[u]sing such systems, the expression level of the cloned gene can be tightly controlled through the addition or elimination of a given reagent in the culture medium (chemical inducer)”, which “allows the study of the influence of receptor density on the pharmacological properties of ligands [and] allows alterations of the stoichiometry between the receptor and interacting signaling partners” (e.g., as per the Introduction section). Koener (dissertation) further discloses a clear preference for a Tet-ON inducible promoter system, wherein receptor density is dose-responsive to the amount of tetracycline added, stating “[d]espite the existence of several inducible expression systems for GPCRs, the choice of this system relies on the fact that it permits high levels of expression of the cloned GPCR, a tool that was required for our study”. Koener (dissertation) teaches the importance of using inducible promoters for pharmaceutical screening and assaying of G-PCR partial agonists, stating “the pharmacodynamic properties of a partial agonist are known to depend on receptor density and sensitivity. Therefore, the clinical response to such compounds can be quite unpredictable, as receptor density and sensitivity vary depending on brain areas and can be remodeled due to the pathological patient status and/or by previous antipsychotic treatment” (e.g., as per the Abstract).
One of ordinary skill in the art would have had a reasonable expectation of success as of the application’s effective filing date in combining the teachings of the prior art references to arrive at the invention as presently claimed since such Tet-ON systems were commercially available and use thereof was readily within reach of the skilled artisan.
It is further noted that the references of Galinski and Koener & Hermans are silent regarding the exogenous nucleic acid encoding the heterologous receptor gene is integrated by a transposase or a recombinase into a genome of a cell of the population of mammalian cells, as set forth in claims 115 and 128.
Schucht discloses a method for rapid establishment of GPCR-expressing cell lines by integrating a heterologous receptor gene into a genome using a recombinase (e.g., Abstract and throughout).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to integrate the GPCRs into the genomes of cell lines as per Schucht in the multiplex cell-based GPCR assay of Galinski. One of ordinary skill in the art would have been motivated to do so since Schuct teaches that “Because the recombinase-driven cassette exchange itself is a highly site specific event, all positive expression characteristics of the master cell line are transferred to the resulting subclonal producers”, such as consistent and stable expression (e.g., as per the INTRODUCTION section).
One of ordinary skill in the art would have had a reasonable expectation of success as of the application’s effective filing date in combining the teachings of the prior art references to arrive at the invention as presently claimed since the recombinase-mediated integration method as per Schucht was thoroughly detailed and thereof was readily within reach of the skilled artisan.
Regarding claims 115, 126, 128, and 133-134, Galinski is relied upon for the teaching of the GPCR EXT assay, but is silent on using insulator sequences flanking the receptor and reporter gene constructs. It is noted that Galinski does suggest stable integration of the receptor and reporter gene constructs (e.g., as per page 105).
Emery teaches utilizing insulator sequences in vectors for gene transfer (e.g., Abstract).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the gene construct for transfection using insulator sequences. One would have been motivated to do so because Emery teaches this can “improve the expression and safety of gene transfer vectors”, as per the abstract. The ordinary artisan would have a reasonable expectation of success in practicing the invention because Galinksi suggests stable transfection and Emery teaches a safe and effective way to execute transfection.
Regarding claim 117, Galinski disclose the use of mammalian cells (e.g., Table 6).
Regarding claim 125, Galinski teaches wherein the barcode and/or index region comprises at least 10 nucleotides (e.g., 13mer barcodes as per Fig. 6).
Regarding claim 127, which requires at least 50 heterologous receptor genes, it is noted that as per MPEP 2144.04(IV)(B) citing In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960), the court held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced.
Regarding claim 130, Galinski teaches wherein the exogenous nucleic acid comprising a heterologous receptor gene or the reporter further comprises a recombination site (e.g., Fig. 29).
Regarding claim 131, Galinski teaches wherein the recombination site is a Bxb1 attp recombination site (e.g., Fig. 29; “attB1”).
Regarding claim 132, Galinski teaches wherein the barcode and/or index region comprises at least 10 nucleotides (e.g., Fig. 6).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to stably transfect the gene/reporter construct into the cell lines. One would be motivated to do so because Galinski states “stable cell lines expressing the adapter protein and/or reporter constructs might enhance the robustness and sensitivity of the assay, especially for weak receptor activations cause by partial agonists”, as per p. 105. The ordinary artisan would have a reasonable expectation of success in practicing the invention because Galinski is an expert in her field and suggests stable integration would actually be a successful, advantageous experiment.
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Response to Arguments
The 10/23/2025 remarks argue that there is no motivation to add 5’- and 3’-flanking insulator sequences to the reporter to arrive at the claimed invention. Applicant characterizes Emery as teaching to add insulator sequences to avoid gene silencing and/or vector-mediated toxicity. Applicant then asserts that one of ordinary skill in the art reading Emery would expect that adding insulator sequences would “increase background signal, as the reporter would create additional expression” (e.g., as per the remarks at page 8). Applicant notes that they instead observe a reduced expression of reporter when adding insulator sequences, allegedly due to high background signal. Applicant concludes that “[s]uch an issue of high background activity would not even be considered by one of skill in the art in view of Emery because high background activity would not be an issue at all in light of the disclosure of Emery” (e.g., as per page 9).
In response, it is respectfully noted that Emery does not disclose the use of insulator sequences to only increase gene expression (e.g., by avoiding silencing effects from chromosomal positioning), but rather to remove all positional effects. Emery states “the genomic sequences and/or overall chromatin structures flanking the sites of vector integration can influence the level and pattern of vector expression, a phenomenon referred to as chromosomal position effects. This typically manifests as overt vector silencing or as position effect variegation, wherein expression levels are highly variable between, and even within, the progeny of transduced cell clones” (e.g., as per page 761). Thus, Emery teaches that insulator sequences can help stabilize (i.e., remove variability) gene expression levels, which would be highly desirable to Galinski et al. (above) since they are interested in quantitative measurements of EXT reporters (e.g., as per p. 13). The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Galinski, Koener & Hermans, Koener, Schucht et al., Emery, and Ruan
Claims 115-121, 123, 125, and 127-132 are rejected under 35 U.S.C. 103 as being unpatentable over Galinski (Multiplexed cell-based assays to profile GPCR activities and cellular signaling. Georg-August-University Gӧttingen dissertation. 2016, cited in the IDS filed 04/24/2020, of record) in view of Koener & Hermans (Methods in Molecular Biology, vol. 746, DOI 10.1007/978-1-61779-126-0_1, 2011, pp. 3-20, of record) further in view of Keoner (Koener, Beryl (dissertation) Third generation of antipsychotics: critical views on dopamine D2 partial agonism in neuropsychopharmacology. Prom. : Hermans, Emmanuel ; Maloteaux, Jean-Marie http://hdl.handle.net/2078.1/89791, 2011, of record), further in view of Emery (Human Gene Therapy 22:761-774 (2011), of record), further in view of Ruan et al. (Highly efficient CRISPR/Cas9-mediated transgene knockin at the H11 locus in pigs. Sci Rep 5, 14253 (2015), of record) and further in view of Schucht et al. (Journal of Biomolecular Screening, 2011, 16(3), of record).
Galinski in view of Koener & Hermans, Koener (dissertation), and Schucht is relied on as above for the rejection of claims 115-117, 125, and 127-132.
Regarding claims 118-121, and 123, Galinksi in view of Koener & Hermans, Koener, and Schucht is relied upon for the teaching of claim 115 and suggests stable transfection, however, Galinski is silent on a method for stable integration. Ruan teaches stable transfection using a CRISPR/Cas9 system into the safe harbor locus pH11 in mammalian cells (e.g., see Abstract).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to take the GPCR multiplexed assay system of Galinski, Koener & Hermans, and Koener and use the transfection method of Ruan. One would have been motivated to do so because Ruan teaches “a new genomic ‘safe harbor’ locus, named pH11, which enables stable and robust transgene expression…and that the gene inserted into the pH11 locus is highly expressed in cells, embryos and animals.” The ordinary artisan would have a reasonable expectation of success in practicing the invention since Galinski suggests stable transfection and Ruan recites a highly successful method using the safe harbor locus (e.g., p. 2 “Identification of the pH11 locus” of Ruan).
Regarding claim 123, Ruan also teaches incorporation of a single copy of the gene into the genome of the mammalian cells (e.g., p. 6, Discussion).
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Response to Arguments
Applicant does not offer further arguments regarding the above obviousness rejections beyond what was set forth with regard to the 35 U.S.C. § 103 rejection, above. To the extent that Applicant is merely repeating their previous argument, the Examiner contends that those issues were adequately addressed in the above sections, which are incorporated in their entireties herein by reference.
Galinski, Koener & Hermans, Koener, Schucht et al., Emery, and Calos et al.
Claims 115-117, 125, and 127-132 are rejected under 35 U.S.C. 103 as being unpatentable over Galinski (Multiplexed cell-based assays to profile GPCR activities and cellular signaling. Georg-August-University Gӧttingen dissertation. 2016, cited in the IDS filed 04/24/2020, of record) in view of Koener & Hermans (Methods in Molecular Biology, vol. 746, DOI 10.1007/978-1-61779-126-0_1, 2011, pp. 3-20, of record) further in view of Keoner (Koener, Beryl (dissertation) Third generation of antipsychotics: critical views on dopamine D2 partial agonism in neuropsychopharmacology. Prom. : Hermans, Emmanuel ; Maloteaux, Jean-Marie http://hdl.handle.net/2078.1/89791, 2011, of record) further in view of Schucht et al. (Journal of Biomolecular Screening, 2011, 16(3), of record), further in view of Emery (Human Gene Therapy 22:761-774 (2011), of record), and further in view of Calos et al. (US PGPUB US 2015/0140665 A1, published 05/21/2015, of record).
Galinski in view of Koener & Hermans, Koener (dissertation), and Schucht is relied on as above for the rejection of claims 115-117, 125, and 127-132.
Galinski, Koener & Hermans, and Koener is relied upon for the teaching of the GPCR EXT multiplex assay and suggests stable integration would be effective but is silent on a method for stable integration of the GPCR assay.
Regarding claims 118-119 and 121-122, Calos teaches integrating a gene construct into the H11 locus of a human cell (e.g., Abstract).
Regarding claim 120, Calos teaches a method of stable integration into a human cell (e.g., Abstract).
Regarding claim 123, Calos teaches integrating a single copy of the gene construct into the human cell (e.g., Fig. 1 and abstract).
Regarding claim 124, Calos teaches a stable integration into the human cell using a bxb1 attp recombinase site (e.g., Fig. 1 and abstract).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to use the GPCR assay of Galinski, Koener & Hermans, and Koener and stably transfect human cells using the method of Calos. One would have been motivated to do so because Calos teaches that their method overcomes “lack of control over transgene insertion site, copy number, and orientation compromises the precision of experiments” as per para. [0003] of Calos. The ordinary artisan would have a reasonable expectation of success in practicing the invention because Galinksi suggests stable integration and Calos gives a highly efficient method for successfully integrating a gene construct into a human genome.
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Response to Arguments
Applicant does not offer further arguments regarding the above obviousness rejections beyond what was set forth with regard to the 35 U.S.C. § 103 rejection, above. To the extent that Applicant is merely repeating their previous argument, the Examiner contends that those issues were adequately addressed in the above sections, which are incorporated in their entireties herein by reference.
Galinski, Koener & Hermans, Koener, Emery, and Woodard et al.
Claims 115-117, 125, 127-132 and 137 are rejected under 35 U.S.C. 103 as being unpatentable over Galinski (Multiplexed cell-based assays to profile GPCR activities and cellular signaling. Georg-August-University Gӧttingen dissertation. 2016, cited in the IDS filed 04/24/2020, of record) in view of Koener & Hermans (Methods in Molecular Biology, vol. 746, DOI 10.1007/978-1-61779-126-0_1, 2011, pp. 3-20, of record) further in view of Keoner (Koener, Beryl (dissertation) Third generation of antipsychotics: critical views on dopamine D2 partial agonism in neuropsychopharmacology. Prom. : Hermans, Emmanuel ; Maloteaux, Jean-Marie http://hdl.handle.net/2078.1/89791, 2011, of record), further in view of Emery (Human Gene Therapy 22:761-774 (2011), of record), and further in view of Woodard et al. (Trends in Biotechnology, 2015, 33(9):525-533, of record).
Galinski in view of Koener & Hermans, and Koener (dissertation) is relied on as above for the rejection of claims 115-117, 125, and 127-132.
However, the references are silent on the limitation of the exogenous nucleic acid encoding the heterologous receptor gene operatively coupled to the inducible promoter is integrated by the transposase into a genome of a cell of the population of mammalian cells, as set forth in claim 137.
Woodard teaches methods of integrating genes into mammalian genomes using the piggyBac transposon system, including G protein-coupled receptors (e.g., as per the Abstract and Box 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to use the GPCR assay of Galinski, Koener & Hermans, and Koener to stably transfect human cells using the method of Woodard. One would have been motivated to do so because Woodard notes that “Multiplexed gene integration with piggyBac permits the design of novel cell-based assays for drug discovery, whether the target is a multiprotein complex, such as a G protein-coupled receptor, or a multisubunit ion channel complex. The ability to use a plasmid-based system to create stable cell lines expressing multiple transgenes should improve current drug discovery methodology” (e.g., as per Box 3).
The ordinary artisan would have a reasonable expectation of success in practicing the invention because Galinksi suggests stable integration and Woodard discloses a highly efficient and veratile method for successfully integrating a gene construct into a human genome.
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Response to Arguments
Applicant does not offer further arguments regarding the above obviousness rejections beyond what was set forth with regard to the 35 U.S.C. § 103 rejection, above. To the extent that Applicant is merely repeating their previous argument, the Examiner contends that those issues were adequately addressed in the above sections, which are incorporated in their entireties herein by reference.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEREMY FLINDERS whose telephone number is (571)270-1022. The examiner can normally be reached M-F 10-6:00 EST.
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/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684