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
Acknowledgement is hereby made of receipt and entry of the communication filed on Sep. 13, 2023. Claims 1-10 are pending and currently examined.
Foreign Priority
Acknowledgment is made of Applicant's claim for foreign priority based on an application 102021000007061 filed in Italy on March 23, 2021 and submission of a certified copy of the priority document. Since the priority document is not in English, an English translation must also be provided for the examiner to determine whether the document provides a written description for the instant claims.
Claim Objections
Claims 1-10 are objected to because of the following informalities:
1) Claim 1 recites phrases “wherein to search for pathogenic microorganisms” and “present thereinside”, where appear to be atypical in the English language.
2) Claims 2-10 recite “Method as claimed in claim……” which should be “The method as claimed in claim……”.
3) Claim 3 recites “upstream of said step (a) of collecting said biological sample”. Here, “upstream” can be changed to “before”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-10 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. This rejection has the following grounds.
A. The base claim 1 recites “c) providing a microarray with chips or wells in each of which there is in suspension a first culture medium for bacteria and a second culture medium for fungi different from said first culture medium, for introducing respectively said bacterial cells and said fungi separated in said step b)”. This limitation is not clear in at least the following aspects.
(1) The phrase “in each of which there is in suspension a first culture medium for bacteria and a second culture medium for fungi different from said first culture medium” is not clear. First, it is not clear how to interpret the phrase “in suspension” here. Does it mean that the culture media are in liquid form? Secondly, it is not clear how to interpret the phrase “in each of which”. If this phrase refers to all of the “chips or wells” on the microarray, then it is not clear why each of the “chips or wells” can contain the medium for bacteria AND the medium for fungi, as claimed.
(2) The phrase “for introducing respectively said bacterial cells and said fungi separated in said step b)” is not clear. First, this limitation appears to an intended use of the microarray being provided. It is not clear if this intended use is required to be actively performed or not. Secondly, it is not clear how to interpret the term “introducing.” E.g., does it mean that the bacterial or fungi cells are to be inoculated into the “chips or wells” containing culture media or something else?
B. Claim 1 also recites the limitation “d) analysing and/or treating the material collected in said culture media” which is not clear. First, the phrase “the material collected in said culture media” does not have antecedent basis since claim 1 does not specify collecting a material in culture media. Moreover, the phrase “said culture media” is not clear because it is not clear what media the phrase refers to. E.g., it is not clear if the phrase “said culture media” refers only to the media dispensed in the “chips or wells” with “introduction” (inoculation) of flow-cytometry sorted samples, or it refers to any media used in the claimed method.
C. Claim 2 recites “Method as claimed in claim 1, characterized in that said step d) is selected from one of the following steps: - cell culture on selective media; - carrying out RT-PCR (Real Time, Polymerase Chain Reaction) on single bacteria/fungi to examine their genome and consequently the species; - analysis of the viral load present in said chips, for example by means of a PCR or antigen test buffer; - filtrating the suspension present in each of said chips and inoculating in experimental animals or in the blood or in organoids to evaluate the reaction of the tissue or of the immune system.” Claim 2 is not clear in at least the following aspects.
(1) Claim 2 recites "- cell culture on selective media” as a step. However, this phrase does not appear to be an active step. It is not clear if it refers to a step of culturing bacteria/fungi on selective media, or something else. To facilitate examination, this limitation is interpreted as referring to a step of culturing bacterial/fungal cells on media respectively specific for bacteria and fungi.
(2) Claim 2 recites “- carrying out RT-PCR (Real Time, Polymerase Chain Reaction) on single bacteria/fungi to examine their genome and consequently the species” which is not clear. First, the term “single bacteria/fungi” is not clear. The words bacteria and fungi are in plural forms, meaning multiple bacterial/fungal cells. Secondly, it is not clear if the term “single bacteria/fungi” refers just one bacterial or fungal cells (which may not provide sufficient template for RT-PCR to analyze their species), or if the term refers to bacterial/fungal cells propagated from the initial inoculation of one individual bacterial/fungal cell generated by flow cytometry into “chips or wells” on a microarray.
(3) Claim 2 recites “- analysis of the viral load present in said chips, for example by means of a PCR or antigen test buffer”. It is not clear what “the viral load present in said chips” refers to since claim 1 which claim 2 depends from does not mention any virus.
(4) Claim 2 recites “- filtrating the suspension present in each of said chips and inoculating in experimental animals or in the blood or in organoids to evaluate the reaction of the tissue or of the immune system” which is not clear. First, the limitation “the suspension present in each of said chips” is not clear. It is noticed that claim 1 recites “there is in suspension a first culture medium……and a second culture medium……”. To facilitate examination, the phrase “the suspension present in each of said chips” is interpreted as referring to the culture results generated in the culture media in the “chips or wells” specified in claim 1.
(5) Claim 2 recites “for example by means of a PCR or antigen test buffer”. Here, the phrase “for example” renders the claim not clear, it is not clear it the limitation after it is required or not.
D. Claim 3 recites “Method as claimed in claim 1, characterized by providing, upstream of said step a) of collecting said biological sample, a step e) of carrying out a mass spectrometry to identify the molecules present in the patient's serum.” This claim is not clear in at least the following aspects.
(1) The phrase “characterized by providing” is not clear here. E.g., it is not clear if claim 3 requires the step e) of carrying out a mass spectrometry to identify the molecules present in the patient's serum. To facilitate examination, the phrase “characterized by providing” is interpreted as if it were “further comprising”.
(2) The phrase “the molecules present in the patient’s serum” is not clear since the terms “the molecules” and “the patient’s serum” do not have antecedent basis.
E. Claim 4 recites “Method as claimed in claim 2, wherein said chips also contain antibodies and/or fluorescent enzymes bound to the bottom and which recognize the molecules found in said step e).” This claim is not clear in at least the following aspects.
(1) Claim 2 which claim 4 depends from does not recite a step e). Therefore, the limitation “said step e)” in claim 4 does not have antecedent basis.
(2) It is not clear how to interpret “the bottom” of a “chip”. Claim 1 recites microarray “chips and wells” that contain bacterial/fungal media. It is expected that “wells” have bottoms as opposed to the walls. However, “chips” are expected to have surfaces not “bottoms.”
To facilitate examination, claim 4 is considered as if it depended from claim 3, rather than claim 2.
F. Claim 5 recites “Method as claimed in claim 3, wherein said step d) provides for the recognition of the bacterium or fungus responsible for the production of said molecules by means of the sandwich ELISA technique, if antibodies are used, or use of fluorescent receptors, if enzymes are used.” This claim is not clear in at the least the following aspects.
(1) The phrase “provides for” is not clear since it is not clear how the specified step d) is to be accomplished.
(2) The phrase “the recognition of the bacterium or fungus responsible for the production of said molecules by means of ……” is not clear. Claim 3 from which claim 5 depends specifies “carrying out a mass spectrometry to identify the molecules present in the patient's serum”, but it does not specify what “the molecules present in the patient’s serum” could or should be; it does not even specify what properties or functions these “molecules” are related. Therefore, it is not clear how “the recognition of the bacterium or fungus responsible for the production of said molecules” can be interpreted when “said molecules” are not defined.
G. Claims 6 and 7 recite “Method as claimed in claim 2, wherein said step d) provides for the filtering of the solution with ultrafilters and subsequent analysis with UHPLC-HRMS (Ultra High Performance Liquid Chromatography + High Resolution Mass Spectrometry) for the determination of the bacterium or fungus responsible for the production of said molecules.” These claims have similar issues as claim 5, in at least the following aspects.
(1) It recites “provides for the filtering of the solution with ultrafilters……”. This limitation is not clear since it is not clear how the specified step d) is to be accomplished.
(2) The terms “the solution” and “said molecules” lack antecedent basis.
(3) The limitation “subsequent analysis with UHPLC-HRMS (Ultra High Performance Liquid Chromatography + High Resolution Mass Spectrometry) for the determination of the bacterium or fungus responsible for the production of said molecules” is not clear. Similar as indicated above for claim 5, since the limitation “said molecules” is not defined and highly general, it is not clear how analysis with UHPLC-HRMS (Ultra High Performance Liquid Chromatography + High Resolution Mass Spectrometry) can be done and determination of “the bacterium or fungus responsible for the production of said molecules” can be made.
To facilitate examination, claim 6 is considered as if it depended from claim 3 (instead of claim 2) which specifies identifying “molecules present in the patient's serum.”
H. Claims 8-9 recite “Method as claimed in claim 3, wherein, upstream of said step b), a step is provided for the incubation of said sample with one or more viruses having phage function, labeled with isotope 32P and for the subsequent removal of said one or more viruses.” It is not clear how to interpret the limitation of “a step is provided for the incubation of said sample… and for the subsequent removal of…...”.
Claim 9 recites “Method as claimed in claim 8, wherein only the bacteria and/or fungi affected by the phage and which will make the respective chip fluorescent will be cultured to determine which bacterium or fungus is responsible for the production of said molecules, a subsequent step being also provided for the growing and the identification of said bacterium or fungus for the subsequent extraction and analysis of its DNA.” It is not clear over what mechanisms the wells are made fluorescent.
To facilitate examination, claim 8 is considered as if it were “A method as claimed in claim 3, further comprising, upstream of said step b), incubating said sample with one or more viruses having phage function, labeled with isotope 32P, and subsequently removing said one or more viruses.”
It is noted any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
Claim Rejections - 35 USC § 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 of this title, 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 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Alou et al. (Clin Microbiol Rev, 2021, 34:e00129-19; published Oct. 28, 2020) and Cross et al. (Nature Biotechnology, volume 37, pages1314–1321 (2019)), in view of Bleichrodt et al. (Fungal Biology Reviews. 2019, 33: 1-15).
These claims are directed to a method for searching for pathogenic microorganisms inside the human or animal microbiota, comprising the following steps: a) collecting a human or animal biological sample wherein to search for pathogenic microorganisms; b) treating said biological sample by flow cytometry to individually separate the bacterial cells and the fungi present thereinside; c) providing a microarray with chips or wells in each of which there is in suspension a first culture medium for bacteria and a second culture medium for fungi different from said first culture medium, for introducing respectively said bacterial cells and said fungi separated in said step b); d) analysing and/or treating the material collected in said culture media.
Alou reviews the state of the art in the culture of the human microbiota. Alou teaches that high-throughput methods have been developed to study bacterial diversity with culture conditions aimed at mimicking the gut environment by using rich media such as YCFA (yeast extract, casein hydrolysate, fatty acids) and Gifu anaerobic medium in an anaerobic workstation, as well as media enriched with rumen and blood and coculture, to mimic the symbiosis of the gut microbiota. Other culture conditions target phenotypic and metabolic features of bacterial species to facilitate their isolation. Preexisting technologies such as next-generation sequencing and flow cytometry have also been utilized to develop innovative methods to isolate previously uncultured bacteria or explore viability in samples of interest. These techniques have been applied to isolate CPR (Candidate Phyla Radiation) among other, more classic approaches. Methanogenic archaeal and fungal cultures present different challenges than bacterial cultures. Efforts to improve the available systems to grow archaea have been successful through coculture systems. For fungi that are more easily isolated from the human microbiota, the challenge resides in the identification of the isolates, which has been approached by applying matrix-assisted laser desorption ionization–time of flight mass spectrometry technology to fungi. Bacteriotherapy represents a nonnegligible avenue in the future of medicine to correct dysbiosis and improve health or response to therapy. Although great strides have been achieved in the last 5 years, efforts in bacterial culture need to be sustained to continue deciphering the dark matter of metagenomics, particularly CPR, and extend these methods to archaea and fungi. See Abstract. This teaching indicates that high throughput culturing approaches are used in the study of bacteria and fungi in microbiota samples, along with other techniques, including flow cytometry which is used for isolation of bacteria or explore viability in samples of interest.
Figure 3 of Alou summarizes innovative methods to isolate fastidious species of microorganisms from a human sample. The reverse genomics culture method includes staining microorganisms with fluorescence-labeled antibodies specific to epitopes on the surface of the microorganisms (C-F), sorting the microorganisms by flow cytometry (G), and culturing the sorted fractions to isolate the targeted microorganisms (H).
Alou further teaches that Cross et al. described an important breakthrough in the cultivation of previously uncultured microorganisms (ref 10) and used a technique called reverse genomics, which combines genomics and flow cytometry with culture (Fig. 3). First, genes coding for membrane proteins from single-cell amplified genomes or metagenome-assembled genomes were identified. Then, the predicted target proteins with an extracellular domain were selected as epitopes. Specific antibodies were produced, purified, and labeled with a fluorochrome. Target cells were stained using the produced antibody, sorted, and subsequently sequenced and cultured. This method was used to sort Saccharibacteria from a human oral sample. The sorted fraction was cultured in different liquid media (BHI medium, OTEB medium, MTGE medium, and TSB medium supplemented with various additional factors) under anaerobic or hypoxic conditions. The reverse genomics method could be used for the targeted culture of other fastidious or previously uncultured microorganisms. See page 9, para 3.
Alou teaches that studies have used various media to isolate fungi from human samples at various incubation temperatures. Through the application of the principles of culturomics consisting of a variation of physicochemical parameters to explore the human mycobiota as exhaustively as possible, several culture conditions were used to explore the fungal diversity of a sample as exhaustively as possible. Twelve culture conditions were used in the most notable study, with supplementation with blood and rumen and plating on five culture media (Sabouraud agar, Dixon agar, potato dextrose agar, modified Schaedler agar, and banana agar medium) supplemented with three antibiotics (colistin, vancomycin, and imipenem) and incubation under aerobic and anaerobic conditions at 22, 28, and 42°C (123). The culturomics concept applied to fungal culture combines MALDI-TOF MS and ITS sequencing to identify the high number of isolates in record time (123). See page 13, last para.
Teachings of Cross (cited by Alou as ref 10) is summarized in Alou as described above. Cross further teaches human oral samples (saliva, subgingival fluid) from healthy donors or individuals with periodontitis were incubated with fluorescently labeled anti-PBP2 or anti-CpsC IgGs. Stained samples were analyzed by flow cytometry, revealing a distinct population of fluorescent cells (0.1–5%, depending on the sample) (Fig. 2a,b). To determine whether Saccharibacteria were labeled by either IgG, the authors initially sorted pools of 10–100 fluorescent cells and used multiple displacement genomic amplification (MDA) followed by PCR with specific primers (see Methods) targeting the small subunit rRNA (SSU rRNA) gene. PCR products were analyzed by MiSeq amplicon sequencing of the V4 region of the SSU rRNA gene amplified with universal primers (Supplementary Table 1, SRA data). See page 1315, right column.
Cross further teaches that having demonstrated that anti-TM7 antibodies can label target cells in biological samples and enable sorting by flow cytometry, they next tested whether antibody-sorted cells were viable and could be propagated in culture. Importantly, cultivation could enable identification of potential physiological interactions between various Saccharibacteria (TM7) lineages and other bacteria in the oral microbiota. Using freshly collected oral samples, they labeled bacteria with anti-PBP2 and anti-CpsC antibodies and sorted individual fluorescent cells onto different liquid and solid culture media (see Methods). Following incubation in anaerobic or hypoxic conditions, cultured cells were assayed using 16S rRNA amplicon sequencing (Supplementary Datasets 1–3). See para bridging pages 1315 and 1316.
Cross teaches that for cultivation, the authors used saliva samples collected recurrently from three healthy donors and processed them as detailed in the section “Sample collection and processing”. Antibody staining was performed as described under "Immunofluorescence labeling of oral microbiota samples and flow cytometry". For the initial cultivation tests, in 200 μl liquid medium in 96-well plates, they used as basal media commercial or home-made brain heart infusion (BHI; Difco), Oral Treponeme Enrichment Broth (OTEB; Anaerobe Systems), Membrane Tryptone Glucose Extract (MTGE) Broth (Anaerobe Systems) and Tryptic Soy Broth (TSB; Difco), supplemented with various additional factors (ATCC vitamins, trace minerals, clarified filtered saliva, pig gastric mucin, sugars, amino acids and nucleobases, N-acetylmuramic acid, N-acetylglucosamine, pyruvate). Following flow sorting, performed as described under “Immunofluorescence labeling of oral microbiota samples and flow cytometry,” the plates were incubated in an anaerobic chamber (COY) at 37 °C, under 85% N2, 10% CO2, 5% H2, or in anaerobic jars to which they added air via a syringe port to reach 2% O2. See page 1322, right column, last para.
Accordingly, Alou and Cross combined teach a method for searching for microorganisms in a human sample (which include pathogenic microorganisms in human microbiota) comprising a) collecting a human sample (e.g., an oral sample in Cross), b) treating the sample by flow cytometry to individually separate the microorganism cells, c) culturing the sorted microorganism cells in a culture medium, and d) analyzing the cultured material for presence or absence of the target microorganisms (e.g., by PCR). Alou further teaches high throughput culturation of bacteria and fungi in microbiota (e.g., culturomics). Cross further teaches the use of 96-well plates to culturing bacteria. However, Alou and Cross are silent on the claimed step of “providing a microarray with chips or wells in each of which there is in suspension a first culture medium for bacteria and a second culture medium for fungi different from said first culture medium, for introducing respectively said bacterial cells and said fungi separated in said step b)”. In other words, Alou and Cross are silent on the use of a microarray with chips or wells containing both bacterial and fungal culture media.
Bleichrodt reviews the applications of flow cytometry and FACS in studies of filamentous fungi. Bleichrodt teaches that Flow cytometry is an automated, laser- or impedance-based, high throughput method that allows very rapid analysis of multiple chemical and physical characteristics of single cells within a cell population. It is an extremely powerful technology that has been used for over four decades with filamentous fungi. Although single cells within a cell population are normally analyzed rapidly on a cell-by-cell basis using the technique, flow cytometry can also be used to analyze cell (e.g. spore) aggregates or entire microcolonies. Living or fixed cells can be stained with a wide range of fluorescent reporters to label different cell components or measure different physiological processes. A big advantage over microscopy is when using FACS, cells with desired characteristics can be sorted for downstream experimentation (e.g. for growth, infection, enzyme production, gene expression assays or ‘omics’ approaches). In this review, the authors describe the wide range of applications in which these powerful technologies have been used with filamentous fungi. See Abstract.
Specifically, Bleichrodt teaches that strain improvement and mutant screening can immensely benefit from the high throughput capabilities of flow cytometry and FACS. It is usually very tedious to screen thousands of UV-generatedmutants on agar plates or by microscopy. However, flow cytometry can easily measure thousands of cells per second and subsequently isolate desired cells by FACS in minutes. Bleichrodt then summarizes several studies using flow cytometry in the analysis of fungal cells and spores. See page 10, right column, para 3. Bleichrodt teaches a list of flow cytometry markers that can be used in the detection and diagnostics of fungi. See Table 3 shown below:
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Accordingly, teachings of Bleichrodt indicate that the flow cytometry technology has been established for fungal studies, including fungal cell sorting for downstream experimentation such as growth, infection, enzyme production, gene expression assays or ‘omics’ approaches.
It is noted that the Specification does not define the term “microarray with chips or wells”. The term is considered to read on a small-scale (or micro-scale) multi-well plate, which can be considered as a scaled-down version of the 96-well plate used in culturation of microorganisms disclosed in Cross.
It would have been prima facie obvious for one of ordinary skill in the art before the filing date of the current invention to combine the teachings Alou, Cross and Bleichrodt to arrive at the invention as claimed. One would have been motivated to do so to extend the flow cytometry study disclosed for analysis of bacteria, disclosed in Alou and Cross, to also cover fungi as disclosed in Bleichrotd, which are potentially also microbial components of interest in human microbiota (as taught in Alou). As to the claimed limitation of “microarray with chips or wells”, one of skill in the art would have found it obvious to use a small/micro-scale version of multi-well plate to substitute the 96-well plated used in the study of Cross to increase the throughput of the culture process.
Regarding claim 10, Alou teaches that fecal samples can be analyzed in culturomics studies. See e.g., page 7, para 1. One of skill in the art would have found it obvious to test organisms in any samples based on the study needs, including fecal samples.
Claims 3-9 are rejected under 35 U.S.C. 103 as being unpatentable over Alou et al. (Clin Microbiol Rev, 2021, 34:e00129-19; published Oct. 28, 2020) and Cross et al. (Nature Biotechnology, volume 37, pages1314–1321 (2019)), in view of Bleichrodt et al. (Fungal Biology Reviews. 2019, 33: 1-15), as applied above, and further in view of Wang et al. (Front. Cell. Infect. Microbiol. 10:24).
Claims 3, 5 and 8-9 are directed to the method of claim 1, further specifying, upstream of step a), a step e) of carrying out a mass spectrometry to identify the molecules present in the patient's serum (see claim 3). As indicated in the 112(b) rejection above, claims 4 and 6-7 are considered as if they depended from claim 3.
Relevance of Alou, Cross and Bleichrodt is set forth above. However, they are silent on a step of carrying out a mass spectrometry to identify the molecules present in the patient's serum. It is noted that the claims do not specify what kind of molecules present in the patient’s serum (here, “the patient” is considered as referring to the subject from whom the biological sample of claim 1 is obtained). Thus, “the molecules” are considered to read on any molecules in a serum with a significance for analyzing.
Wang teaches a study on gut microbiome and metabolome analysis leading to identification of unsaturated fatty acids and butanoate metabolism induced by microbiota in patients with chronic spontaneous urticaria (CSU). Wang teaches that the authors collected feces and blood samples from CSU patients and healthy controls and the relationship between gut microbiota and serum metabolites was assessed using 16S rRNA gene sequencing and untargeted metabolomic analyses. The CSU group exhibited decreased alpha diversity of the microbial population compared to the control group. The abundance of unidentified Enterobacteriaceae was increased, while the abundance of Bacteroides, Faecalibacterium, Bifidobacterium, and unidentified Ruminococcaceae was significantly reduced in CSU patients. The serum metabolome analysis revealed altered levels of docosahexaenoic acid, arachidonic acid, glutamate, and succinic acid, suggesting changes in unsaturated fatty acids and the butanoate metabolism pathway. The combined serum metabolomics and gut microbiome datasets were correlated; specifically, docosahexaenoic acid, and arachidonic acid were positively correlated with Bacteroides. See Abstract.
Specifically, Wang teaches that UHPLC-MS/MS Analysis was used in the study for analysis of molecules in serum samples. Approximately 200 ul of serum samples were obtained from patients and healthy controls and stored at −80◦C for further analysis. The filtrate was injected into the liquid chromatography-tandem mass spectrometry (LC-MS/MS) system after a series of treatments. LC-MS/MS analyses were performed using a Vanquish ultra-high-pressure liquid chromatograph (UHPLC) system (Thermo Fisher, Philadelphia, Massachusetts, USA) coupled with an Orbitrap Q Exactive HF-X mass spectrometer (Thermo Fisher, Philadelphia, Massachusetts, USA). The raw data files generated by UHPLC-MS/MS were processed using Compound Discoverer 3.0 (CD 3.0, Thermo Fisher, Philadelphia, Massachusetts, USA) to perform peak alignment, peak picking, and quantification for each metabolite. Then, peak intensities were normalized to the total spectral intensity. The normalized data were used to predict the molecular formula based on additive ions, molecular ion peaks, and fragment ions. See page 2, right column, last para.
Accordingly, Wang teaches a study to analyze metabolic molecules by mass spectrometry and the association of certain identified metabolic molecules with the patient’s gut microbiota.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to introduce the analysis of serum metabolic molecules by mass spectrometry taught in Wang into the studies taught in Alou, Cross and Bleichrodt to arrive at the invention as claimed. One would have been motivated to do so to find out if there is any change in metabolism in the subject being studied for microbiota microorganisms, in a way similar to that shown in Wang.
Regarding claims 4-9, these claims have 112(b) issues, particularly those with the highly general “molecules” to be identified in serum of a patient and how the method and/or elements specified in the basic claim 1 are related with these serum “molecules”. One of skill in the art would have found it obvious to study serum molecules and their potential association with microbiota in a patient, as disclosed in Wang, with any techniques known and available to one of ordinary skill in the art at the time of invention, such as immunoassays, PCR assays, phage sensitivity assays, etc., as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671