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 .
Applicant's response filed 5/14/2025 has been fully considered. The following rejections
and/or objections are either reiterated or newly applied.
Status of Claims
Claims 1-2, 4-10, and 12-19 pending and examined on the merits.
Claims 3 and 11 cancelled.
Priority
The instant application filed on 10/19/2020 claims the benefit of priority to U.S. Patent Application No. 15/602,917 filed on 5/23/2017 (now allowed as U.S. Patent No. 10,808,256 on 10/20/2020), which claims the benefit of priority to U.S. Provisional Patent Application No. 62/340,116 filed on 5/23/2016. Thus, the effective filing date of the claims is 5/23/2016.
The applicant is reminded that amendments to the claims and specification must comply with 35 U.S.C. § 120 and 37 C.F.R. § 1.121 to maintain priority to an earlier-filed application. Claim amendments may impact the effective filing date if new subject matter is introduced that lacks support in the originally filed disclosure. If an amendment adds limitations that were not adequately described in the parent application, the claim may no longer be entitled to the priority date of the earlier filing.
Specification
The objection to the abstract is maintained despite Applicant's assertion that a corrected Abstract to address the typographical error has been submitted (Remarks 5/14/2026 page 1). Examiner notes that no corrected Abstract has been submitted and/or is not present in the file wrapper.
The disclosure is objected to because of the following informalities:
Abstract, line 3, "the correlation off such metabolites" should read "the correlation of such metabolites".
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 4-10, and 12-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of a mental process, a mathematical concept, organizing human activity, or a law of nature or natural phenomenon without significantly more. In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 1: “screening metabolites produced by the host system to identify metabolite features produced by the test pBGC” provides an evaluation (screening requires an evaluation of [metabolite] features) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“calculating a score for a metabolite feature based on a combination of (i) abundance of the metabolite feature in a sample from the host system and (ii) uniqueness of the feature compared to one or more control samples” provides a mathematical calculation (calculating score from abundance or uniqueness) that is considered a mathematical concept, which is an abstract idea. It also provides a comparison (comparing sample data to control data) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“identifying: (i) the test pBGC as a biosynthetic gene cluster (BGC), and/or (ii) the metabolite feature as being produced by the test pBGC, if the score identifies the metabolite feature as being unique and abundant relative to other scored metabolite features” provides an evaluation (identifying gene clusters or metabolite features requires evaluation of data or scores) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 16: “identifying the particular metabolite” provides an evaluation (identifying a metabolite requires evaluation of data from techniques listed in claim 14) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 17: “dividing the abundance of the metabolite feature in the test sample by the average abundance of the metabolite feature in the one or more control samples” provides a mathematical calculation (dividing requires mathematical calculation) that is considered a mathematical concept, which is an abstract idea.
Claim 18: “multiplying the uniqueness of the metabolite feature among samples tested by the abundance of the metabolite feature in the test sample” provides a mathematical calculation (multiplying requires mathematical calculation) that is considered a mathematical concept, which is an abstract idea.
These recitations are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or are mathematical relationships. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. As such, claims 1-2, 4-10, and 12-19 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exceptions listed above are not integrated into a practical application because the claims do not recite an additional element or elements that reflects an improvement to technology. Specifically, the claims recite the following additional elements:
Claim 1: “expressing a test putative biosynthetic gene cluster (pBGC) in a host system” provides insignificant extra-solution activities (expressing genes in a host system is a pre solution activity involving sample manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
“validating the identification made in step (d) by repeating steps (a) and (b) with a validation pBGC comprising a deletion within the test pBGC, wherein the validation confirms that the test pBGC is a BGC that produces the metabolite if the deletion reduces or eliminates production of the metabolite by the host system” provides insignificant extra-solution activities (validating an identification using a knock-out test is a post-solution activity involving sample manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 10: “subjecting the host system or test sample derived therefrom to the one or more bioanalytical techniques to identify bioanalytical features that correlate to metabolites produced by the host system expressing the test pBGC” provides insignificant extra-solution activities (running bioanalytical techniques is a pre-solution activity involving sample manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 15: “isolating the particular metabolite” provides insignificant extra-solution activities (isolating a metabolite is a pre-solution activity involving sample manipulation steps - per instant spec page 12) that do not serve to integrate the judicial exceptions into a practical application.
The steps for expressing genes, validating results via knock-outs, running bioanalytical techniques, and isolating metabolites are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application because they are pre- and post solution activities involving sample manipulation steps (see MPEP 2106.04(d)(2)). Therefore, claims 1-2, 4-10, and 12-19 are directed to an abstract idea (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application, or equate to mere instructions to apply the recited exception in a generic way or in a generic computing environment.
The limitations for expressing genes, validating results via knock-outs, running bioanalytical techniques, and isolating metabolites are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application. Furthermore, no inventive concept is claimed by these limitations as they are well-understood, routine, and conventional, as evidenced by Galli-Taliadoros et al. on page 4 col 1 paragraph 2 "the underlying principles for generation of gene knock-out mice are straightforward and many aspects of the technique are standardized and well documented" (Galli-Taliadoros et al. "Gene knock-out technology: a methodological overview for the interested novice." Journal of immunological methods 181.1 (1995): 1-15).
The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-2, 4-10, and 12-19 are not patent eligible.
Response to Arguments under 35 USC § 101
Applicant’s arguments filed 5/14/2025 are fully considered but they are not persuasive.
Applicant asserts that the claims do "integrate the alleged judicial exceptions into a practical application" because "claim 1 recites a specific method that produces a specific, tangible result" and that "this is not a claim to an abstract idea with generic data-gathering tacked on" (Remarks 5/14/2026 pages 1-2). Applicant further asserts that "the Supreme Court and the Federal Circuit confirms that claims reciting an ordered combination of specific steps [. . .] are patent-eligible when the claims, as a whole, are directed to a specific technological process and are not merely an attempt to monopolize an abstract principle" and goes on to cite several cases where "the court emphasized that the claimed process used specific rules in a specific order to achieve a technological improvement over the prior process" (Remarks 5/14/2026 pages 2-3). Examiner notes that the alleged improvement to technology of "combining uniqueness and abundance" for a "specific scoring system" is not a unique approach in the omics field as evidenced by Mandal et al. (Genomics, proteomics & bioinformatics 13.3 (2015): 148-158) which provides are survey of over a dozen tools that use both abundance and uniqueness for profiling molecular data (page 7 table 3). Additionally, Examiner notes that Vinaixa et al. has already been indicated as teaching this limitation of claim 1 in section "Claim Rejections - 35 USC 103". Therefore, Applicant's argument regarding an improvement to technology is moot.
Finally, Applicant asserts that step (e) "underscores the integration of the analytical steps into a practical application" because it "requires constructing a validation pBGC comprising a targeted deletion within the test pBGC, re-expressing the deletion construct in the host system, re-screening for metabolite production, and confirming that the deletion reduces or eliminates production of the metabolite" (Remarks 5/14/2026 page 3). Applicant also asserts that Examiner has not supported the Step 2B finding with evidence (Remarks 5/14/2026 pages 3-4). Examiner notes that this step has been identified as containing additional elements because it essentially is describing a gene knock-out experiment as a validation step, which is well-understood, routine, and conventional as evidenced by Galli-Taliadoros et al. on page 4 col 1 paragraph 2 "the underlying principles for generation of gene knock-out mice are straightforward and many aspects of the technique are standardized and well documented" (Galli-Taliadoros et al. "Gene knock-out technology: a methodological overview for the interested novice." Journal of immunological methods 181.1 (1995): 1-15).
Therefore, the rejection of claims 1-2, 4-10, and 12-19 under 35 USC 101 is maintained.
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.
Claims 1-2, 4, 6, 8-9, 12-13, and 16-19 rejected under 35 U.S.C. 103 as being unpatentable over Shetty et al. (US-20150315599) in view of Vinaixa et al. (Vinaixa et al. "A guideline to univariate statistical analysis for LC/MS-based untargeted metabolomics-derived data." Metabolites 2.4 (2012): 775-795).
Regarding claim 1, Shetty teaches a method of screening for metabolites (Para.0110 " the present invention provides a method for identifying candidate proteins or enzymes of interest capable of performing a desired metabolic activity").
Shetty also teaches expressing a test putative biosynthetic gene cluster (pBGC) in a host system (Para.0086 "The term “expression vector” refers to a vector which is capable of expressing of a gene that has been cloned into it. Such expression can occur after transformation into a host cell, or in IVPS systems").
Shetty also teaches identifying: (i) the test pBGC as a biosynthetic gene cluster (BGC), and/or (ii) the metabolite feature as being produced by the test pBGC, if the score identifies the metabolite feature as being unique and abundant relative to other scored metabolite features (Para.0110 " the present invention provides a method for identifying candidate proteins or enzymes of interest capable of performing a desired metabolic activity").
Shetty does not explicitly teach: screening metabolites produced by the host system to identify metabolite features produced by the test pBGC; calculating a score for a metabolite feature based on a combination of (i) abundance of the metabolite feature in a sample from the host system and (ii) uniqueness of the feature compared to one or more control samples; nor validating the identification made in step (d) by repeating steps (a) and (b) with a validation pBGC comprising a deletion within the test pBGC, wherein the validation confirms that the test pBGC is a BGC that produces the metabolite if the deletion reduces or eliminates production of the metabolite by the host system.
However, Vinaixa teaches screening metabolites produced by the host system to identify metabolite features produced by the test pBGC (Page 14 paragraph 1 "it has been demonstrated that controlling the FDR at the screening stage of the research carries a benefit for the next research stages").
Vinaixa also teaches obtaining the uniqueness value of a mass-to-charge ratio as well as an intensity value indicative of abundance, the combination of which is an obvious design choice because there is no technical improvement shown (Page 2 paragraph 1 "Thousands of so called metabolite features (i.e., peaks corresponding to individual ions with a unique mass-to-charge ratio and a unique retention time or mzRT features from now on) can be routinely detected in biological samples. In addition, each mzRT feature in the dataset is associated with an intensity value (or area under the peak), which indicates its relative abundance in the sample").
Vinaixa also teaches validation studies and using knock-outs for comparison (page 15 paragraph 1 "In addition, we would like to comment that whenever a follow-up targeted validation study was going to be attempted, we would recommend considering those metabolites showing statistical significance after strict Bonferroni correction" and page 4 Table 1).
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Shetty as taught by Vinaixa in order to apply the appropriate statistics to discover significantly altered features between samples (page 1 abstract "Statistical analysis, however, is needed in order to discover those features significantly altered between samples"). One skilled in the art would have a reasonable expectation of success because both methods utilize bioanalytical techniques for metabolite feature identification.
Regarding claim 2, Shetty in view of Vinaixa teach the methods of Claim 1 on which this claim depends/these claims depend, respectively. Vinaixa also teaches untargeted screening (Page 1 abstract "Characteristics and challenges of this analysis are discussed and illustrated using four different real LC/MS untargeted metabolomic datasets").
Regarding claim 4, Shetty in view of Vinaixa teach the methods of Claim 1 on which this claim depends/these claims depend, respectively. Shetty also teaches the test pBGC comprises a sequence derived from genomic DNA of a fungus of interest (Para.0107 "sources of encoding nucleic acids for enzymes for a biosynthetic pathway can include, for example, any species where the encoded gene product is capable of catalyzing the referenced reaction. Exemplary species for such sources include [] fungi").
Regarding claims 6 and 8, Shetty in view of Vinaixa teach the methods of Claim 1 on which this claim depends/these claims depend, respectively. Shetty also teaches the host system is a fungal cell or a fungal cell lysate (Para.0222 "Such types of models have been applied, for example, to analyze metabolic fluxes in organisms responsible for enhanced biological phosphorus removal in wastewater treatment reactors and in filamentous fungi producing polyketides", and a lysate is an obvious variant of a fungal host system, as analysis of metabolites would require lysis of the sample cells).
Regarding claim 9, Shetty in view of Vinaixa teach the methods of Claim 1 on which this claim depends/these claims depend, respectively. Shetty also teaches the host system is an in vitro expression system (Para.0035 "a method of introducing a conjugative plasmid into methylotrophic host cells is provided" and para.0083 "An mRNA lacking the Kozak consensus sequence may also be translated efficiently in an in vitro systems if it possesses a moderately long 5′-UTR that lacks stable secondary structure").
Regarding claims 12 and 13, Shetty in view of Vinaixa teach the methods of Claim 1 on which this claim depends/these claims depend, respectively. Vinaixa also suggests using control samples for examining variation, which includes comparing samples (Page 6 last paragraph "The ideal method to examine analytical variation is to analyze quality control (QC) samples, which will provide robust quality assurance of each detected mzRT feature").
Regarding claim 16, Shetty in view of Vinaixa teach the methods of Claim 1 on which this claim depends/these claims depend, respectively. Vinaixa also teaches identifying the particular metabolite (Page 1 Abstract "By comparing the retention time and MS/MS data of a model compound to that from the altered feature of interest in the research sample, metabolites can be then unequivocally identified").
Regarding claims 17 and 18, Shetty in view of Vinaixa teach the methods of Claim 1 on which this claim depends/these claims depend, respectively. Vinaixa also teaches simple data manipulation to compare and/or combine metabolite features, and dividing/multiplying abundance feature values is an obvious design choice because there is no technical improvement shown (Page 1 Abstract "By comparing the retention time and MS/MS data of a model compound to that from the altered feature of interest in the research sample, metabolites can be then unequivocally identified").
Regarding claim 19, Shetty in view of Vinaixa teach the methods of Claim 1 on which this claim depends/these claims depend, respectively. Vinaixa also teaches using control samples to examine analytical variation (Page 6 last paragraph "The ideal method to examine analytical variation is to analyze quality control (QC) samples").
Claims 5 and 7 rejected under 35 U.S.C. 103 as being unpatentable over Shetty et al. (US 20150315599) in view of Vinaixa et al. (Vinaixa et al. "A guideline to univariate statistical analysis for LC/MS-based untargeted metabolomics-derived data." Metabolites 2.4 (2012): 775-795) as applied to claims 1-2, 4, 6, 8-9, 12-13, and 16-19 above, and further in view of Bier et al. (WO-2016073559).
Shetty et al. in view of Vinaixa et al. are applied to claims 1-2, 4, 6, 8-9, 12-13, and 16-19.
Regarding claims 5 and 7, Shetty in view of Vinaixa teach the method of Claim 1 on which this claim depends/these claims depend.
Shetty nor Vinaixa explicitly teach the test pBGC has been inserted into a fungal artificial chromosome (FAC).
However, Bier teaches using an artificial chromosome in a model fungal organism, as well as the group of fungal cell organisms consisting of Ashbya gossypii, Aspergillus nidulans, Coprinus cinereus, Cryptococcus neoformans, Neurospora crassa, Saccharomyces cerevisiae, Schizophyllum commune, Schizosaccharomyces pombe, and Ustilago maydis (Para.0027 "In some embodiments of any one of the methods or constructs described herein, the gene encoding an endonuclease is located on a plasmid or artificial chromosome", and Para.0156 "Fungal model organisms include, but are not limited to, Ashbya gossypii; Aspergillus nidulans; Coprinus cinereus; Cryptococcus neoformans; Cunninghamella elegans; Neurospora crassa; Saccharomyces cerevisiae; Schizophyllum commune; Schizosaccharomyces pombe; Ustilago maydis; and any combination thereof").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Shetty and Vinaixa as taught by Bier in order to integrate multiple elements into a genome (para.0005 "MCR [mutagenic chain reaction] for autocatalytic genome editing is based on genomic integration of an MCR construct containing multiple elements"). One skilled in the art would have a reasonable expectation of success because both methods utilize transformed organisms for validation of results or production of molecules.
Claims 10 and 14-15 rejected under 35 U.S.C. 103 as being unpatentable over Shetty et al. (US 20150315599) in view of Vinaixa et al. (Vinaixa et al. "A guideline to univariate statistical analysis for LC/MS-based untargeted metabolomics-derived data." Metabolites 2.4 (2012): 775-795) as applied to claims 1-2, 4, 6, 8-9, 12-13, and 16-19 above, and further in view of Paillard et al. (WO-2016005527).
Shetty et al. in view of Vinaixa et al. are applied to claims 1-2, 4, 6, 8-9, 12-13, and 16-19.
Regarding claims 10 and 14-15, Shetty in view of Vinaixa teach the method of Claim 1 on which this claim depends/these claims depend.
Shetty nor Vinaixa explicitly teach: screening comprises subjecting the host system or test sample derived therefrom to the one or more bioanalytical techniques to identify bioanalytical features that correlate to metabolites produced by the host system expressing the test pBGC; the one or more bioanalytical techniques are selected from the group consisting of mass spectrometry (MS), tandem mass spectrometry (MS2), high performance liquid chromatography (HPLC), gas chromatography, ultra performance liquid chromatography (UPLC), supercritical fluid chromatography, nuclear magnetic resonance (NMR), liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-diode array detection (LC-DAD), capillary electrophoresis mass spectrometry (CE-MS), and liquid chromatography-tandem mass spectrometry (LC-MS2); nor isolating the particular metabolite.
However, Paillard teaches bioanalytical techniques to identify bioanalytical features that correlate to metabolites produced by the host system expressing products, the one or more bioanalytical techniques are selected from the group consisting of mass spectrometry (MS), tandem mass spectrometry (MS2), high performance liquid chromatography (HPLC), gas chromatography, ultra performance liquid chromatography (UPLC), supercritical fluid chromatography, nuclear magnetic resonance (NMR), liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-diode array detection (LC-DAD), capillary electrophoresis mass spectrometry (CE-MS), and liquid chromatography-tandem mass spectrometry (LC-MS2), and further comprising isolating the particular metabolite (Page 8 line 23 "As example, mention may be made of a validated LC-MS/MS (liquid chromatography-tandem mass spectrometry) bioanalytical method, preferably comprising preparing samples by solid phase extraction using ethyl acetate, drying, dissolving in a mixture of acetonitrile and ammonium acetate, performing a chromatographic separation in this liquid mobile phase and detecting by tandem mass spectrometry. Other bioanalytical methods can be based on techniques such as HPLC (high performance liquid chromatography), GC (gas chromatography), UPLC (ultra performance liquid chromatography), supercritical fluid chromatography, mass spectrometry, nuclear magnetic resonance, electrophoresis, ligand binding assays (dual polarisation interferometry, ELISA - enzyme-linked immunosorbent assay, MIA - magnetic immunoassay, RIA - radioimmunoassay), LC-MS (liquid chromatography-mass spectrometry), GC-MS (gas chromatography-mass spectrometry), LC- DAD (liquid chromatography-diode array detection), CE-MS (capillary electrophoresis-mass spectrometry). General reference is made to Venn, Principles and Practice of Bioanalysis (2.sup.n Edition, CRC Press, 2008)", as MS (and other techniques listed) isolate metabolites as described on page 13 of the instant specification).
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Shetty and Vinaixa as taught by Paillard in order to quantify compounds in a sample (Page 8 line 24 "The quantification of befiradol in plasma samples can be realized with any convenient validated analytical method as determined by those skilled in the art). One skilled in the art would have a reasonable expectation of success because both methods are concerned with quantifying compounds using various techniques known in the art.
Response to Arguments under 35 USC § 103
Applicant’s arguments filed 5/14/2025 are fully considered but they are not persuasive.
Applicant asserts that "Shetty does not teach expressing a pBGC to discover unknown metabolites" (Remarks 5/14/2026 page 4). Examiner notes that Shetty does in fact teach or suggest untargeted or discovery based approaches for metabolomics (para.0227 "Selective pressure provides a valuable means for testing and optimizing the engineered methylotrophs of the present invention. Alternatively, an evolved methylotroph having selected functionality after such selection can be further engineered to include additional or altered functionality. In some embodiments, the engineered methylotrophs of the invention can be evolved under selective pressure to optimize production of a carbon-based product from a C1 compound or that confer other useful functions onto the host organism" and para.0228 "Evolution can occur as a result of either spontaneous, natural mutation or by addition of mutagenic agents or conditions to live cells. [. . .] Alternatively, genetic variation may be introduced via untargeted genetic mutagenesis techniques such as transposon insertion" demonstrates an untargeted approach with undefined outcomes). Examiner also notes that it 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 to employ combinations and sub-combinations of these complementary embodiments, because Shetty et al. explicitly motivates doing so at least in para.0308 ("The present invention provides among other things novel methods and systems for synthetic biology. While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations") and otherwise motivating experimentation and optimization. Additionally, doing so merely combines prior art elements according to known methods to yield predictable results.
Applicant asserts that "Vinaixa does not teach the claimed scoring system" or the "validation via deletion" limitation (Remarks 5/14/2026 page 5-6). Examiner notes that Vinaixa does indeed teach or suggest the claimed scoring system using both abundance and uniqueness (Page 2 paragraph 1 "Thousands of so called metabolite features (i.e., peaks corresponding to individual ions with a unique mass-to-charge ratio and a unique retention time or mzRT features from now on) can be routinely detected in biological samples. In addition, each mzRT feature in the dataset is associated with an intensity value (or area under the peak), which indicates its relative abundance in the sample"), and that the combination of which is an obvious design choice because there is no technical improvement shown in how these data types are utilized. Examiner notes that Vinaixa does indeed teach or suggest the limitation of a validation via deletion because Vinaixa utilized a gene knock-out model for its validation testing, also evidenced by Galli-Taliadoros et al. (page 11 clearly depicts that gene knock-out models may comprise multiple types of gene deletions for a validation study). Applicant goes on to argue that the word "unique" is not used in same way in Vinaixa as it is in the instant specification, because Vinaixa is used in the context of a mass to charge ratio as opposed to a comparison to a control. As indicated for claim 13, Vinaixa also suggests using control samples for examining variation, which includes comparing samples (Page 6 last paragraph "The ideal method to examine analytical variation is to analyze quality control (QC) samples, which will provide robust quality assurance of each detected mzRT feature"). Applicant asserts that Vinaixa "does not teach combining uniqueness and abundance into a single composite score", however there is no claim of a composite score in claim 1, which simply states a "calculating a score for a metabolite feature based on a combination of (i) abundance of the metabolite feature in a sample from the host system and (ii) uniqueness of the feature compared to one or more control samples" which is fairly suggested by Vinaixa in that they explicitly address a uniqueness value being associated with an abundance value (Page 2 paragraph 1 "Thousands of so called metabolite features (i.e., peaks corresponding to individual ions with a unique mass-to-charge ratio and a unique retention time or mzRT features from now on) can be routinely detected in biological samples. In addition, each mzRT feature in the dataset is associated with an intensity value (or area under the peak), which indicates its relative abundance in the sample").
Applicant asserts that there is no motivation to combine Shetty and Vinaixa because "the claimed invention is not merely 'applying statistics to metabolomics data.' It is a specific method for biosynthetic gene cluster discovery and validation" and because "there is no rational basis for combining these references because they operate in fundamentally different technological contexts" (Remarks 5/14/2026 pages 6-7). Examiner notes that by Applicant's own admission Vinaixa is concerned with the study of metabolomics. Examiner also notes that Shetty explicitly identifies itself as a method for identifying candidate proteins or enzymes of interest, which implicitly includes gene clusters responsible for producing those proteins or enzymes (para.0110). The context of both Shetty and Vinaixa is in the field of metabolomics, specifically for identifying metabolites produced by genes or groups of genes in a targeted or untargeted methodology. Examiner also notes above the rationale and motivation for combining these references in section "Claim Rejections - 35 USC 103".
Regarding dependent claims 5 and 7, Application asserts that "Bier does not cure the deficiencies of Shetty and Vinaixa" because "Biers mention of a plasmid or artificial chromosome is in the context of delivering a gene[,] not in the context of cloning an uncharacterized biosynthetic gene cluster", and that "Examiner provides no explanation for why a person of ordinary skill working in metabolite discovery would look to a gene drive reference for guidance on vector selection for BGC expression" (Remarks 5/14/2026 pages 7-8). Examiner notes that in the context of expressing and validating genes or gene clusters in an organism (Shetty and Vinaixa), it would be obvious to one of ordinary skill in the art to look to Bier for methods of modifying said organism with said sequences for expression in order to integrate multiple elements into a genome (as mentioned above in section "Claim Rejections - 35 USC 103"). Likewise, regarding dependent claims 10 and 14-15, Application asserts that "Examiners characterization of Paillard is materially incorrect" because "Paillard has no connection whatsoever to metabolomics, biosynthetic gene clusters, host expression systems, or metabolite discovery", and that "the technological context of Paillard, pharmaceutical pharmacokinetic analysis, is entirely different from the context of the claimed invention"; and that there is no motivation to combine (Remarks 5/14/2026 pages 8-9). Examiner notes that in the context of identifying compounds produced by the expression of genes or gene clusters (Shetty and Vinaixa), it would be obvious to one of ordinary skill in the art to look to Paillard for methods of quantify compounds in a sample (Page 8 line 24 "The quantification of befiradol in plasma samples can be realized with any convenient validated analytical method as determined by those skilled in the art). Additionally, as Examiner has mentioned above, it 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 to employ combinations and sub-combinations of these complementary embodiments, because Shetty et al. explicitly motivates doing so at least in para.0308 ("The present invention provides among other things novel methods and systems for synthetic biology. While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations") and otherwise motivating experimentation and optimization. Additionally, doing so merely combines prior art elements according to known methods to yield predictable results.
Therefore, the rejection of claims 1-2, 4-10, and 12-19 under 35 USC 103 is maintained.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Galli-Taliadoros et al. "Gene knock-out technology: a methodological overview for the interested novice." Journal of immunological methods 181.1 (1995): 1-15
Mandal et al. "Metagenomic surveys of gut microbiota." Genomics, proteomics & bioinformatics 13.3 (2015): 148-158
US-20040161828
US-20040241759
US-20050070005
US-20050118590
US-20110143394
US-20130137131
US-20130172215
US-20140295457
US-7393946
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 TH REE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this finaI action.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert A. Player whose telephone number is (571)272-6350. The examiner can normally be reached Mon-Fri, 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Larry D. Riggs can be reached on 571-270-3062. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/R.A.P./Examiner, Art Unit 1686
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687
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