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 .
DETAILED ACTION
Application Status
This application is a DIV of US patent application 16/634,388, filed on 12/01/2022, which was a 371 of PCT/EP2014/062815, filed on 07/30/2018.
Claims 1-12 and 13 are currently pending in the instant application.
In response to a previous Office action, a Final Rejection Office action (mailed on 07/23/2025), Applicants filed a response and an amendment on 10/23/2025, amending claim 2 is acknowledged.
A request for continued examination (RCE) under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/23/2025 has been entered.
Applicants' arguments filed on 10/23/2025, have been fully considered and are deemed persuasive to overcome some of the rejections previously applied. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 1-12 and 13 are present for examination.
Priority
Acknowledgement is made of applicants claim for priority of US patent application 16/634,388, filed on 01/27/2020, now US patent 11549950, which was a 371 of PCT/EP2014/062815, filed on 07/30/2018.
Withdrawn-Claim Rejections - 35 U.S.C. § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
According to MPEP 2143:
“Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield
predictable results;
(B) Simple substitution of one known element for another to obtain predictable
results;
(C) Use of known technique to improve similar devices (methods, or products)
in the same way;
(D) Applying a known technique to a known device (method, or product) ready
for improvement to yield predictable results;
(E) “ Obvious to try ” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in
either the same field or a different one based on design incentives or other market
forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art
reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.”
The previous rejection of Claims 1-9, 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Spohn et al. (Overproduction of Ristomycin A, a cryptic metabolite by activation of a silent gene, a gene which does not express any protein, and the silent gene cluster is in Amycolaptosis japonicum MG417-CF17. Antimicrobial Agents Chemotherapy (2014), 58(10), 6185-6196), in view of Seyedsayamdost et al. (Method for awakening silent gene clusters in bacteria and discovery of cryptic metabolites. WO 2015/138442A1) and Vertes et al. (Methods for detecting metabolic states by laser ablation electrospray ionization mass spectrometry (LAESI-MS). US2010/0285446A1, publication 11/11/2010, see IDS), is withdrawn, in view of Applicant’s amendment to the claims and persuasive arguments.
New-Claim Rejections - 35 U.S.C. § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
According to MPEP 2143:
“Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield
predictable results;
(B) Simple substitution of one known element for another to obtain predictable
results;
(C) Use of known technique to improve similar devices (methods, or products)
in the same way;
(D) Applying a known technique to a known device (method, or product) ready
for improvement to yield predictable results;
(E) “ Obvious to try ” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in
either the same field or a different one based on design incentives or other market
forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art
reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.”
Claims 1-9, 10, 11-12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Spohn et al. (Overproduction of Ristomycin A, a cryptic metabolite by activation of a silent gene, a gene which does not express any protein, and the silent gene cluster is in Amycolaptosis japonicum MG417-CF17. Antimicrobial Agents Chemotherapy (2014), 58(10), 6185-6196, see PTO892), in view of Seyedsayamdost et al. (Method for awakening silent gene clusters in bacteria and discovery of cryptic metabolites. US 2017/0022532A1, publication 01/26/2017, claim benefit of 61/950,291, filed on 03/10/2014, see IDS), and Vertes et al. (Methods for detecting metabolic states by laser ablation electrospray ionization mass spectrometry (LAESI-MS). US2010/0285446A1, publication 11/11/2010, see IDS).
The Broadest Reasonable Interpretation (BRI) of claim 1, which is drawn to a method for rapid eliciting cryptic metabolites, the method comprising the steps of providing a first well comprising a first quantity of a medium and at least one wild-type microorganism from a first species; providing a plurality of additional wells, each comprising the medium, at least one wild-type microorganism from the first species, and at least one compound; growing microorganisms in each well; imaging each well with mass spectrometry; and identifying a difference in the mass spectrometry images between at least one of the additional wells and the first well, and identifying the at least one compound that elicited the difference, wherein the microorganism is Amycolaptosis.
Regarding claim 1-9, 10, 11-12 and 13, Spohn et al. teach overproduction of Ristomycin A, a cryptic metabolite by activation of a silent gene, a gene which does not express any protein, and the silent gene cluster is in Amycolaptosis japonicum MG417-CF17, a gram-positive bacterial cell, . Spohn et al. also teach the emergence of antibiotic-resistant pathogenic bacteria is one reason for the urgent need for new antibacterial agents, and a strategy to discover new anti-infective compounds is the evaluation of the genetic capacity of secondary metabolite producers and the activation of cryptic gene clusters (genome mining), wherein the one genus of microorganism known for its potential to synthesize medically important products are Amycolaptosis. However, Amycolaptosis japonicum does not produce an antibiotic under standard laboratory conditions. In contrast to most Amycolaptosis strains, A. japonicum is genetically tractable with different methods, and in order to activate a possible silent glycopeptide cluster, a gene was introduced encoding the transcriptional activator of balhimycin biosynthesis, the bbr gene from Amycolaptosis balhimycin (bbrAba), into A. japonicum, which was cultured in a medium in a flask and the non-transformed A. japonicum was used as a negative control, wherein the production of Ristomycin A, a cryptic metabolite is determined by high-performance liquid chromatography and mass spectrometry (HPLC-MS), tandem mass spectrometry (MS/MS), and nuclear magnetic resonance (NMR) spectroscopy confirmed the in-silico prediction that the recombinant A. japonicum/pRM4-bbrAba synthesizes ristomycin A, which resulted in the production of an antibiotically active compound, following whole-genome sequencing of A. japonicum, 29 cryptic gene clusters were identified by genome mining, wherein one of these gene clusters is a putative glycopeptide biosynthesis gene cluster, and using bioinformatic tools, ristomycin (syn. ristocetin), a type III glycopeptide, which has antibacterial activity and is used for the diagnosis of von Willebrand disease and Bernard-Soulier syndrome, and was deduced as a possible product of the gene cluster, and further chemical analyses by high-performance liquid chromatography and mass spectrometry (HPLC-MS), tandem mass spectrometry (MS/MS), and nuclear magnetic resonance (NMR) spectroscopy confirmed the in-silico prediction that the recombinant A. japonicum/pRM4-bbrAba synthesizes ristomycin A, wherein the metabolites are isolated by centrifugation, filtration, absorption chromatography or extraction and isolation. Spohn et al. also teach that wild-type Streptomyces coelicolor, Streptomyces avermitilis, Streptomyces griseus, and Saccharopolyspora erythraea are each known to produce three to five secondary metabolites as crypto-metabolites in addition to Amycolaptosis japonicum (see, whole document, in particular abstract, pg6185, para left Col, para 1, right Col, para 1-3, pg6186, left Col, para 2-3, 4-7, right Col, para 4, pg 6187, left Col, 2-3, and Fig. 1-2, 4, 5-8).
Spohn et al. do not teach using 96 well plate and detecting by imaging Mass Spectroscopy or adding culture medium with same or different microorganism either gram positive, negative bacteria or fungus with known genome sequence or unknown genome sequence repeatedly, do not teach using compounds of small molecule library the claimed method of producing cryptic metabolites (for claim 12) and using laser ablation electrospray ionization mass spectrometry (LAESI-MS) for detecting and determining concentration of cryptic metabolites (for claim 7).
However, Seyedsayamdost et al. (2017) teach method for awakening silent gene clusters in bacteria and producing cryptic metabolites, and further teach a high-throughput screening method for discovering an agent which is able to activate silent bacterial gene clusters, comprising providing at least a first and second bacterial cell, wherein the bacterial cells contains at least one gene cluster that is silent or lowly-expressed and wherein the gene cluster is genetically modified to include at least one reporter gene within the gene cluster; exposing the second bacterial cell to a test compound; measuring the expression of at least one reporter gene in the first bacterial cell; measuring the expression of at least one reporter gene in the second bacterial cell; and identifying activation of gene clusters by determining whether at least one reporter gene has been expressed by the second bacterial cell by a statistically significant amount greater than is expressed by the first bacterial cell, wherein the reporter gene is lacZ, a fluorescent protein, incudes green fluorescent protein (GFP), wherein the at least a first and second bacterial cell are of a species that occurs naturally in soil, wherein the bacterial cell is Burkholderia Thailanders, a gram negative bacterial cell, wherein cells are cultured in 384-well plate, wherein the method further comprising identification of a molecule that results from the activation of said gene clusters, wherein the molecule that is identified is a cryptic metabolite, which was analyzed using RT-qPCR,, GC, HPLC, NMR, and Mass Spectrometry, and further teach small molecule modulator, or small molecule library. Seyedsayamdost et al. (2017) also teach a method for high throughput screening of elicitors of cryptic metabolites, a method for producing cryptic metabolites, and a new family of cryptic metabolites, the acybolins, as well as their complete structural elucidation (see, abstract, title, para 5, 8, 13, 14, 16, 17-20, claims 1-7, and 11-15).
Seyedsayamdost et al. (2017) do not teach detecting by imaging Mass Spectroscopy (for claims 1-2, and 13), and using laser ablation electrospray ionization mass spectrometry (LAESI-MS) for detecting and determining concentration of cryptic metabolites (for claim 7).
However, Vertes et al. teach a method of mass spectrometry comprising subjecting a sample comprising an indicator to laser ablation electrospray ionization mass spectrometry;
determining a relative intensity of the indicator; and comparing the relative intensity of the indicator to a standard indicator intensity, and classifying the sample as belonging to or not belonging to the standard indicator intensity, wherein the indicator comprises at least one biomarker, wherein the at least one biomarker is related to a disease state, wherein not belonging to the standard indicator intensity indicates that the sample is predicted to comprise the disease state, wherein the indicator comprises a plurality of indicators, and determining the relative intensity of each indicator to form a sample metabolite pattern, comparing the sample metabolite pattern to a standard metabolite pattern comprising the standard indicator intensity of each of the plurality of indicators, and classifying the sample as belonging to or not belonging to the standard metabolite pattern, wherein not belonging to the standard metabolite pattern indicates that the sample is predicted to comprise the disease state, wherein the disease state is associated with at least one of a viral infection, a bacterial infection, and a metabolic disorder, wherein the indicator is selected from the group consisting of metabolites, lipids, lipid precursors, lipid components, nucleic acids, proteins, peptides, carbohydrates, and combinations thereof, wherein the disease state is at least one of human immunodeficiency virus, human T-lymphotropic virus type 1, human T-lymphotropic virus type 3, and the indicators are selected from the group consisting of glutathione, spermine, spermidine, putrescine, arginine, creatine, choline, phosphocholine, glycerophosphocholine, glycerophosphocholine lipids, ATP, ADP, AMP, cAMP, dopamine, dopamine metabolites, and any combination thereof, wherein the sample is selected from the group consisting of a single cell, cells, biofilms, and tissues, wherein the single cell has a smallest dimension from 5 micrometers to 50 micrometers, wherein subjecting to laser ablation electrospray ionization mass spectrometry comprises, ablating the sample with an infrared laser under ambient conditions to form an ablation plume; intercepting the ablation plume by an electrospray plume; and detecting the indicator by mass spectrometry, wherein subjecting to laser ablation electrospray ionization mass spectrometry excludes pretreating the sample with a matrix material, wherein the standard indicator intensity comprises at least one of an internal reference and an external reference (see, claims 1-15).
Therefore, before the effective filing date, it would have been obvious to one of ordinary skill in the art to arrive the claimed invention as a whole the invention was made by combining the teachings of Spohn et al., Seyedsayamdost et al. and Vertes et al. to make and use compounds of small molecule library as claimed in the method of producing cryptic metabolites as taught by Seyedsayamdost et al., and using laser ablation electrospray ionization mass spectrometry (LAESI-MS) for detecting and determining concentration of cryptic metabolites as taught by Vertes et al. and modify Spohn et al. for producing cryptic metabolites to be used in the method of treating diseases to arrive the claimed invention.
One of ordinary skilled in the art would have been motivated t to make and use compounds of small molecule library the claimed method of producing cryptic metabolites to be used in the method of treating diseases, which is therapeutically, pharmaceutically, commercially, and financially beneficial. One of ordinary skilled in the art would have a reasonable expectation of success because Spohn et al. and Seyedsayamdost et al. could successfully produce cryptic metabolites in microorganisms including Amycolaptosis japonicum MG417-CF17.
Thus, the above references render the claims prima facie obvious to one of ordinary skill in the art.
Conclusion
Status of the claims:
Claims 1-12 and 13 stand/are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Iqbal H Chowdhury whose telephone number is (571)272-8137. The examiner can normally be reached on 9 am to 5 pm Monday thru Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao, can be reached on 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Iqbal H. Chowdhury, Primary Examiner
Art Unit 1656 (Recombinant Enzymes & Protein Crystallography)
US Patent and Trademark Office
Ph. (571)-272-8137 and Fax (571)-273-8137
/IQBAL H CHOWDHURY/Primary Examiner, Art Unit 1656