DETAILED ACTION
Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
2. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy filed on 10/19/2022 has been filed in parent Application No. SG10202109466S, filed on 08/30/2021.
Status of Claims
3. Claims 1-10 as amended and filed on 12/19/2025 are pending.
Information Disclosure Statement
4. The information disclosure statement (IDS) is not filed by the applicant.
Claim Interpretation (Amended)
5. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
The claims 1-9 is interpreted to be directed to treating a subject for respiratory infection, a coronavirus infection, the method comprises identification of one or more mass spectral peaks in breath sample from the subject. The presence of at least one of the claimed spectral peaks (e.g. about 38 m/z) or a value derived from the spectral peak as compared to a reference is used to detect the presence of the respiratory viral infection in the subject. The treatment comprises administering a therapeutically effective amount of an anti-viral agent to the subject. The claims 2-9 that depend on claim 1 has added limitations that comprise detecting at least one or more spectral peaks in a sample, the sample is a breath sample, detection of one or more risk factors or symptoms in the subject, respiratory viral infection is a coronavirus infection, and COVID-19 infection.
The claim 10 is interpreted to be directed to a method of treating a respiratory viral infection, a coronavirus infection in a subject, the method comprises conducting a mass spectral analysis on a sample from the subject. The presence of a respiratory viral infection, a coronavirus infection is characterized by identifying at least one of the claimed spectral peaks (e.g. about 38 m/z) or a value derived from the spectral peak as compared to a reference is used to detect the presence of the respiratory viral infection in the subject. The treatment comprises administering a therapeutically effective amount of an anti-viral agent to the subject.
A breath sample in claims 1-9 is also interpreted as a sample for the claim.
Claim Rejections - 35 USC § 112, (a), Written Description (Amended)
6. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims 1-10 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims 1-10 are directed to a method treating a respiratory viral infection in a subject based on the identification of the claimed one or more spectral peaks (e.g. 38 m/z) identified or detected in breath sample or on a sample as compared to a reference. A respiratory viral infection, a coronavirus infection, is broad and generic because there are several different species of corona viruses that cause respiratory infections in human and animal subjects, e.g. coronaviruses include SARS coronavirus (SARS- CoV or SARS-CoV-2), MERS coronavirus, transmissible gastroenteritis virus (TGEV), human respiratory coronavirus, porcine respiratory coronavirus, canine coronavirus, feline enteric coronavirus, feline infectious peritonitis virus, rabbit coronavirus, murine hepatitis virus, sialodacryoadenitis virus, porcine hemagglutinating encephalomyelitis virus, bovine coronavirus, avian infectious bronchitis virus, and turkey coronavirus (See, instant Specification para [0018]). The claims 1-10 read on all known and unknown species of coronaviruses and therefore the claims 1-10 are broader in the scope than the support available in the specification for multiple species of coronavirurs. The specification provides an example drawn to a SARS CoV-2 causing COVID 19 (See, para [0018]) and a specific therapeutic agents licensed for COVID-19 (See, para [0051]). The SARS CoV-2 causing COVID 19 is not a representative of all coronaviruses because of differences in viral genetics, viral replication, pathogenesis, the respiratory disease severity and required anti-viral treatment. In addition, the claim 9 is directed to added limitation a coronavirus infection is a COVID-19 (caused by SARS CoV-2 virus), however the claims do not recite a biomarker that is specific for a coronavirus or SARS CoV-2 virus, however, recites the mass spectral peaks for the host derived biomarkers or volatile organic compounds (VOCs) with numerical values in m/z unit. The specific biomarker would be the coronaviral or SARS COV-2 (COVID-19) viral antigen or the antibody or the nucleic acid. The specification recites a biomarker as a volatile organic compounds (VOCs) (See, para [0011], [0021]- [0022] and [0071]) identified by mass spectral peak values e.g. about 38 m/z without identification or recitation of the structure of a biomarker or a chemical name of the VOCs or a biomarker name (See, para [0079]). In addition, all coronaviruses in general would not induce production of the same VOCs. The VOCs does not provide or contribute to the specific structure (e.g. antigen or nucleic acid) of the virus and therefore the detection of a biomarker or a VOCs in a respiratory coronaviral infection in breath or a sample from the coronavirus or COVID-19 patient/subject (e.g. blood sample) does not provide the confirmatory diagnosis or detection of a particular species of a coronaviral infection or COVID-19 (See, para [0079]), however, can only be used as an adjunct for confirmatory diagnosis in combination with a specific test to detect a coronaviral infection e.g. PCR for nucleic acid or the coronaviral antigen detection test. The specification para ([0077]) recites “using the VOCs that were most significantly different between the positive and negative groups identified using the Wilcoxon test, 11 m/z were found to be sufficient to build the decision tree that met the goal of obtaining at least 85% sensitivity and 95% specificity. And from the classification result, our model achieved a sensitivity of 85.34% and specificity of 96.98%. Identification or detection of m/z values of the mass spectral peaks for VOCs (para [0079]) would not be sufficient for specific treatment of a respiratory coronaviral infection as exemplified in para [0051] for administration of the therapeutic agent for treating a coronavirus infection, such as COVID-19, include an anti-viral agent such as Remdesivir. The therapeutic agent may also comprise a therapeutic SARS-CoV-2 virus specific binding or neutralizing antibody such as Bamlanivimab or a combination of therapeutic antibodies comprising Casirivimab and Imdevimab. The claimed mass-to-charge ratio (m/z) spectrum of 11 biomarkers or 11 VOCs for COVID-19 (para [0079]) are not indicated whether these were obtained from the same patient or were collectively summarized from the different patients (See, para [0025], [0079]) and claimed as detection of one or more mass spectral peaks in instant claims 1-10 and figure 1 (filed on 10/18/2022). The anti-viral therapeutic (e.g Remdesivir) or antibodies comprising Bamlanivimab, Casirivimab and Imdevimab) would not be specific for all the species of coronaviral infection as claimed because a VOCs or a biomarker reads on a genus of coronaviruses that infect human or animal subjects. See e.g. MPEP 2161; 2163 and 2163.02.
Therefore, the instant application does not provide sufficient descriptive support for the scope of a coronavirus (coronaviruses) caused respiratory infections and/or the corresponding VOC structural peaks for each coronavirus species, to provide a diagnosis for the purposes of treatment.
Claim Rejections - 35 USC § 112 (b) (Amended)
7. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims recite one or more mass spectral peaks (e.g. about 38 m/z) as an element or claim limitation that is used as a marker for detection of a coronaviral respiratory infection or COVID-19 in a breath sample or sample derived from the subject. The specification additionally recites a biomarker or a volatile organic compound (VOCs). The mass spectral peak m/z values are a readout for the diagnostic test based on the detected biomarker or VOCs, and a spectral peak as recited in the claims does not identify an organic compound or structure or name of an organic compound (VOCs) or a biomarker. One of the ordinary skills in the art is not clear and cannot determine to which organic compound or a biomarker the claimed spectral peak corresponds to? The specification (para [0021], [0079]) does not identify the specific biomarker or VOCs that corresponds to the claimed spectral peaks with numerical m/z values. Therefore, the claimed, “spectral peak m/z values” in the claim limitations render the claims 1-10 indefinite because the scope of the claimed subject matter cannot be specifically determined in context to the biomarker or the volatile organic compound (VOCs).
Claim Rejections - 35 USC § 102 (Amended)
8. 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grassin-Delyle et al 2021 (EBioMedicine 63 (2021) 103154) and further evidenced by NIST US Department of Commerce 2025 (NIST Chemistry WebBook 69, US Department of Commerce, See attached PDF printouts for m/z values of VOC chemical names and visit https://webbook.nist.gov/chemistry/name-ser/)
Claims 1-10: Grassin-Delyle et al 2021 is in the art directed to a study on metabolomics of exhaled breath in critically ill COVID-19 patients caused by a coronavirus, SARS CoV-2 virus and anticipated instant claim 1-10 by disclosing diagnosis of coronavirus disease 2019 (COVID-19) with ARDS in human subjects by identifying one or more spectral peaks in a mass spectrum of a breath sample from the subjects as compared control patients who had non-COVID-19 associated ARDS. Grassin-Delyle et al 2021 performed a real-time non-invasive mass spectrometry to detect metabolomics or biomarkers or volatile organic compounds (VOCs) in exhaled breath of critically ill COVID-19 patients. Grassin-Delyle et al 2021 could differentiate between COVID-19 and non-COVID-19 ARDS (ARDS is acute respiratory distress syndrome) with accuracy of 93% (sensitivity: 90%, specificity: 94%, area under the receiver operating characteristic curve: 0·94-0·98, after cross-validation). The four most prominent volatile compounds in COVID-19 patients were methylpent-2-enal (m/z = 41), 2,4-octadiene (m/z = 81), 1-chloroheptane (m/z = 91), and nonanal (m/z = 57). Grassin-Delyle et al 2021 teaches therapeutically effective antiviral drug administration remdesivir, lopinavir/ritonavir and antibody eculizumab for the treatment of patients hospitalized for COVID-19-ARDS (See, abstract, Results Table 1 for one or more risk factors, entire research article).
The mass to charge (m/z) values for the VOC methylpent-2-enal (m/z = 41) anticipated the claimed spectral peak at about 38 m/z (See, for evidence NIST attached PDF printouts for m/z value of methylpent-2-enal).
The mass to charge (m/z) values for the VOC 2,4-octadiene (m/z = 81) anticipated the claimed spectral peak at about 77 m/z (See, for evidence NIST attached PDF printouts for m/z value of 2,4-octadiene).
The mass to charge (m/z) values for the VOC 1-chloroheptane (m/z = 91) anticipated the claimed spectral peak at about 94 m/z (See, for evidence NIST attached PDF printouts for m/z value of 1-chloroheptane).
The mass to charge (m/z) values for the nonanal (m/z = 57) anticipated the claimed spectral peak at about 51 m/z, about 55 m/z, about 59 m/z (See, for evidence NIST attached PDF printouts for m/z value of nonanal).
Grassin-Delyle et al 2021 teaches detecting one or more risk factors or symptoms in the subject e.g. body weight, body mass index, high blood pressure, chronic obstructive pulmonary disease, ischemic cardiac disease, body temperature, respiratory rate (See, table 1). Grassin-Delyle et al 2021 the four most prominent volatile compounds in COVID-19 patients were (i) methylpent-2-enal, (ii) 2,4-octadiene, (iii) 1-chloro-heptane, and (iv) nonanal, in exhaled breath may identify ARDS patients with COVID-19 (See, abstract).
Grassin-Delyle et al 2021 “putatively annotated” these VOCs for the four recited compounds with m/z values (See, Grassin-Delyle et al 2021, page 4, col 1 para 1)
However, one of the ordinary skills would reli on “the actual” confirmed m/z values for the VOCs (i) methylpent-2-enal, (ii) 2,4-octadiene, (iii) 1-chloro-heptane, and (iv) nonanal as evident in the database of National Institute of Standards and Technology Chemistry WebBook, SRD 69 (Data compilation copyright by the U.S. Secretary of Commerce on behalf of the U.S.A) available at: www.webbook.nist.gov, rather than “putative annotations” of m/z values and the VOC compounds reported by Grassin-Delyle et al 2021 that are different than “actual” and “confirmed” m/z values for the corresponding VOC chemical compounds/names available in NIST Chemistry WebBook (attached PDF printouts). The m/z values are available at: https://webbook.nist.gov/chemistry/name-ser/).
Thus, the amended instant claims 1-10 are anticipated by Grassin-Delyle et al 2021 as further evidenced by the “actual” and “confirmed” m/z values for the chemical compound VOCs (i) methylpent-2-enal, (ii) 2,4-octadiene, (iii) 1-chloro-heptane, and (iv) nonanal at the NIST US Department of Commerce (2025) https://webbook.nist.gov/chemistry/name-ser/ (PDF print out attached).
Claim Rejections - 35 USC § 103 (Amended)
9. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
10. Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Grassin-Delyle et al 2021 (EBioMedicine 63 (2021) 103154) as applied to claims 1-10 above, and further in view of Lapidot et al 2021 (WO2021186444A1 published 09/23/2021 with international filing PCT/IL2021/050297 filed on 03/18/2021), Ibrahim et al 2021 (ERJ Open Res 2021; 7: 00139-2021) and Mougang et al 2021 (iScience 24, 102851, August 20, 2021) and further evidenced by NIST US Department of Commerce 2025 (NIST Chemistry WebBook 69, US Department of Commerce, See attached PDF printouts for m/z values of VOC chemical names and visit https://webbook.nist.gov/chemistry/name-ser/).
Claims 1-10: Grassin-Delyle et al 2021 teaches instant claims 1-10 as further evidenced by NIST US Department of Commerce 2025 as recited supra and the teachings are incorporated here in entirety to render obvious the instant claims 1-10.
Grassin-Delyle et al 2021 (a) does not teach every claimed mass-spectral peak m/z value, (b) does not teach a sample other than breath sample (e.g. blood sample).
Lapidot et al 2021 (WO2021186444A1) is in the art and is directed to methods of screening and detecting volatile organic compounds associated with viral replication, (respiratory virus infection caused by members of virus families Coronavirideae, Adenoviruses, Orthomyxoviruses (influenza viruses), Picomaviruses and Rhinoviruses; coronavirus, it may include any one of SARS-CoV-2, SARS- CoV-19 (Covid-19 disease), MERS-CoV (MERS disease), SARS-CoV (SARS disease), as well as the more common human coronavirus strains known as Corona 229E, ML63, OC43 and HKU 1 (See, page 9), and use thereof for early detection of a variety of viral infections. Lapidot et al 2021 a method of determining viral infection in a subject comprises analyzing a breath sample, obtaining input data specifying one or more volatile organic compound (VOCs) associated with replication of a defined virus in a host cell; querying a database using said input data to identify a marker profile associated with the at least one of said specified one or more VOCs; and contingent upon the identification of said marker profile in said database, providing output data comprising said marker profile and the defined virus; wherein said one or more VOCs are specific to the defined virus and to a defined host cell; wherein said one or more VOCs are specific to a defined virus strain (See, claims 1-16). Lapidot et al 2021 teaches a method of monitoring a viral infection in a subject, the method comprises: a. obtaining from a breath sample of said subject input data specifying one or more volatile organic compounds (VOC) said sample being obtained at a determination time point, said determination time point is during treatment of said subject against the viral infection. (See, claims 17-21). Lapidot et al 2021 teaches a method of determining a treatment protocol for a subject being suspected of having a viral infection based on the VOC, and a method of treatment of a subject having a viral infection, anti-viral treatment suitable for said viral infection in said subject (See, claims 22-41, description of invention). The identification of the desorbed VOCs can be achieved by any analytical instrument without being limited thereto, gas chromatography (GC), GC -lined mass spectrometry (GC-MS), proton transfer reaction mass spectrometry (PTR- MS), electronic nose device, quartz crystal microbalance (QCM), infra-red spectroscopy (IR), ultraviolet spectroscopy (UV) and others. Lapidot et al 2021 teaches analyzing respiratory virus infected patient’s breath samples and identification of many biomarkers or VOCs induced by respiratory viral infection as presented in tables 1A-1E (See p. 21-27). The mass to charge ratio m/z values for the VOCs are evident for the VOCs in the database of National Institute of Standards and Technology Chemistry WebBook, SRD 69 (Data compilation copyright by the U.S. Secretary of Commerce on behalf of the U.S.A) available at, webbook.nist.gov. See, table 1 A, 1-Hexanol, 2-ethyl- has m/z value of 57 that teaches the claimed mass spectrum of about 51 m/z, about 55 m/z, about 59 m/z; Table 1A, 1,2-Benzenedicarbonitrile (m/z = 128) teaches claimed spectral peak about 122 m/z, Table 1C, Benzeneacetaldehyde (m/z = 91) teaches claimed spectral peak about 103 m/z, Table 1A, Acetophenone (m/z = 105) teaches claimed spectral peak about 109 m/z in claims 1-10.
Ibrahim et al 2021 is in the art and further teaches diagnosis of COVID-19 (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection) by exhaled breath analysis using gas chromatography-mass spectrometry. Ibrahim et al 2021 evaluated the role of exhaled breath volatile biomarkers in identifying patients with suspected or confirmed COVID-19 infection, based on their underlying PCR status and clinical probability. A prospective, real-world, observational study was carried out, recruiting adult patients with suspected or confirmed COVID-19 infection. Breath samples were collected using a standard breath collection bag, modified with appropriate filters to comply with local infection control recommendations, and samples were analyzed using gas chromatography-mass spectrometry (TD-GC-MS). 81 patients were recruited between April 29 and July 10, 2020, of whom 52 out of 81 (64%) tested positive for COVID-19 by reverse transcription-polymerase chain reaction (RT-PCR). A regression analysis identified a set of seven exhaled breath features (benzaldehyde, 1-propanol, 3,6-methylundecane, camphene, beta-cubebene, iodobenzene and an unidentified compound) that separated PCR-positive patients with an area under the curve (AUC): 0.836, sensitivity: 68%, specificity: 85%. GC-MS-detected exhaled breath biomarkers were able to identify PCR-positive COVID-19 patients. The mass to charge (m/z) values for the VOCs Benzaldehyde (m/z =77), Iodobenzene (m/z = 77), and Camphene (m/z =93) that teaches the claimed mass spectrum about 69 m/z, about 77 m/z, about 94 m/z as recited in claims 1-10). The mass to charge ratio m/z values for the VOCs are evident for the VOCs in the database of National Institute of Standards and Technology Chemistry WebBook, SRD 69 (Data compilation copyright by the U.S. Secretary of Commerce on behalf of the U.S.A) available at, webbook.nist.gov. Ibrahim et al 2021 teaches VOCs have been utilized as diagnostic, prognostic and treatment (teaches treatment know in the art before filing of the claimed invention, See p.2 para 2) response biomarkers for various respiratory illnesses, including infections. The rapid, cost-effective and noninvasive nature make VOCs a strong candidate as a potential COVID-19 biomarker, substantiated by preliminary studies highlighting its diagnostic potential and treatment (See, abstract, Table 1-2 for risk factors, entire article, p.2 para 2, and Ibrahim et al 2021 recited references 12, 13).
Mougang et al 2021 is in the art and teaches relationship of volatile organic compounds (VOCs) and COVID-19 to blood serum for diagnostic purpose. Blood samples were collected from subjects recruited at the emergency department of a large public hospital. The VOCs were analyzed with a gas chromatography mass spectrometer (GC/MS). GC/MS data show that in more than 100 different VOCs, the pattern of abundances of 17 compounds identifies COVID-19 from non-COVID with an accuracy of 89% (sensitivity 94% and specificity 83%). GC/MS analysis was complemented by an array of gas sensors whose data achieved an accuracy of 89% (sensitivity 94% and specificity 80%). Mougang et al 2021 teaches risk factors hypertension, diabetes, lung disease, obesity of patients with COVID-19 and non-COVID. Table 2. List of GC/MS peaks in serum with p value <0.05 respect to COVID-19. The VOCs identified in COVID-19 positive blood patients are e.g. Toluene (m/z = 91) teaches claimed spectral peak about 103 m/z, Heptane,3,3,5,-trimethyl (m/z = 71), Octane, 3,6-dimethyl- (m/z = 57), Benzene, 1,3,5-triethyl- (m/z = 147) teaches claimed spectral peak about 143 m/z, Heptane, 2,2,4,6,6-pentamethyl-(m/z = 57), 3-Hexanol, 3,5-dimethyl- (m/z =73) , 4-Heptanone (m/z = 71), 3-Heptanol (m/z = 59), Ethanol, 2-butoxy- (m/z = 57), 3-Hepten-2-one (m/z = 55) that renders obvious the mass spectrum claimed in instant claims 1-10. The mass to charge ratio m/z values for the VOCs are evident for the VOCs in the database of National Institute of Standards and Technology Chemistry WebBook, SRD 69 (Data compilation copyright by the U.S. Secretary of Commerce on behalf of the U.S.A) available at, webbook.nist.gov.
The combined prior art teachings of Grassin-Delyle et al 2021, Lapidot et al 2021, Ibrahim et al 2021 and Mougang et al 2021 as recited supra teaches all the claimed limitations (instant claims 1-10) on the spectral peak at about 38 m/z, about 51 m/z, about 55 m/z, about 59 m/z, about 69 m/z, about 77 m/z, about 94 m/z, about 103 m/z, about 109 m/z, about 122 m/z and about 143 m/z.
It would have been obvious to an artisan of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior teachings of Grassin-Delyle et al 2021 by incorporating additional teachings of prior arts by Lapidot et al 2021, Ibrahim et al 2021 and Mougang et al 2021 to arrive at the inventions of amended claims 1-10. The motivation would be to develop an alternative (alternative to viral antigen, antibody, or nucleic acid detection assays) or an adjunct diagnostic assay based on breath samples or samples (e.g. blood) using an analytical mass spectrometry instrument to improve the diagnostic validity of a respiratory virus infection and for commercial success. One of the ordinary skills in the art would have a reasonable expectation of success given the disclosures of the prior art teachings as applied to the instant claims 1-10 and as recited supra. This is analogous to 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 invention as claimed in amended claims 1-10. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Response to Arguments
11. Applicant's arguments filed on 12/19/2025 have been fully considered but they are not persuasive.
Applicant’s argument 1: Claims 1-10 stands rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims subject matter was not described in the specification in such a way to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-10 stands 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.
The examiner considered that claims 1-10 lack support and clarity because:
" A respiratory viral infection is broad and generic because several viruses can
cause respiratory infection;
" SARS CoV-2 causing COVID 19 is not a representative of all respiratory viruses;
" VOCs do not provide or contribute to the specific structure of the virus, so detection of a biomarker or a VOC in a respiratory viral infection in breath or a sample does not provide the confirmatory diagnosis or detection of a particular species of a respiratory viral infection on its own.
Present claim 1 is amended to specify that the respiratory viral infection is a coronavirus infection. Thus, it is submitted that the current scope of the claims is not broad and generic. The examples show the results from COVID-19 patients, and it is reasonable to a person skilled in the art that the invention could apply to other infections caused by other coronaviruses.
The applicant wishes to clarify that the present invention relates to a breath-diagnostic signature that is pattern-based instead of compound-based. The inventors have created a method of detecting the presence or likelihood of a respiratory viral infection in a subject using a mass spectrum pattern. This is in contrast to using compound-based detection, a method that is conventional in the field and used in the Grassin-Delyle, Ibrahim, and Mougang prior art references. Figure 1 in the specification showed that COVID-positive and COVID-negative patients present different mass spectrum profiles. The method works by comparing the pattern without need to identify individual VOCs, thus providing fast and effective detection.
In Response 1: The claims 1-10 recites a limitation identifying “at least one spectral peak m/z value” from the claimed spectral m/z values. The claims do not recite “a mass spectrum pattern”. It is not clear whether respiratory viruses other than coronavirus or COVID-19 in human subjects produce same pattern of VOC m/z and the VOC compound “chemical structure of a compound”. For a diagnostic assay or method, it is important to validate the results whether other respiratory viruses share the VOC compound structure with the VOC from coronavirus infection or COVID-19 because the claims also have added limitations on treatment of the viral infection. There is no support in the specification that the applicant has performed the clinical trials (experiments) to differentiate Coronavirus infection or COVID-19 from other respiratory virus infections. A coronavirus infection is a genus and there is only one species of coronavirus SARS-CoV-2 (COVID-19) infection in humans as a support in specification and VOC spectral peak m/z data on one species is not a sufficient representation of a genus coronavirus. The prior arts recited in the office action recites the chemical compound names for the VOCs whereas the instant application claims and specification fully relied on the spectral peak m/z values without investigating and providing a support for the VOC chemical compound name.
Applicant's arguments have been fully considered but not found persuasive and rejections under 35 USC 112 as recited supra are maintained.
Applicant’s argument 2: Claims 1-10 stand rejected under 35 U. S.C. 102(a)(1) as being anticipated by Grassin-Delyle, et al. 2020 Metabolomics of exhaled breath in critically ill COVID-19 patients: A pilot study. EBioMedicine. 2021 Jan; 63: 103154, 202 1(hereinafter "Grassin-Delyle"). Specifically, the Office Action asserts that Grassin-Delyle discloses that the 4 most prominent volatile compounds in COVID-19 patients were methylpent-2-enal (m/z = 41), 2,4-octadiene (m/z = 81), 1-chloroheptane (m/z = 91), and nonanal (m/z = 57). The Office Action further alleges that the disclosure of these compounds inherently discloses the claimed spectral peaks at about 38 m/z, about 51 m/z, about 55 m/z, about 59 m/z, 77 m/z, 94 m/z.
The applicant respectfully disagrees.
Grassin-Delyle teaches that the detection of methylpent-2-enal, 2,4-octadiene 1- chloroheptane, and nonanal in exhaled breath may identify COVID-19 patients with respiratory disease (Abstract). It discloses that the corresponding spectral peaks were m/z 99.08, 111.12, 135.09, and 143.15 respectively (page 3 right column, page 4 left column, page 5 right column). These spectral peaks differ from the spectral peaks m/z 41, 81, 91 and 57 that were mentioned in the Office Action.
Furthermore, it is not standard practice to convert identified compounds into assumed fragment peaks without showing actual spectra, and such does not meet the inherency standard.
Identification of a spectral pattern is not disclosed in Grassin-Delyle, Lapidot, Ibrahim, or Mougang. Rather, the cited prior art relates to identification of individual VOCs instead of a spectral pattern that is the present invention.
Thus, claims 1-10 are novel over the cited prior art.
In Response 2: The claims 1-10 recites a limitation identifying “at least one spectral peak” from the claimed spectral m/z values. The claims do not recite “a mass spectrum pattern”.
Grassin-Delyle, et al. 2020 disclose the annotations of the four VOC compound was as “The putative annotation” , The putative annotations for the four compounds at m/z 99.08, 111.12, 135.09, and 143.15 were respectively methylpent-2-enal, 2,4-octadiene 1-chloroheptane, and nonanal (See, page 4, col 1). “Putative”: In biology, putative means something is generally accepted or supposed to be true, acting as a placeholder for something likely but not yet definitively proven. It's used when there's strong evidence or computational prediction, but experimental confirmation of its exact role is still lacking, bridging hypothesis and established fact. What is putative? : The word putative denotes to a supposition that is based on what is commonly accepted rather than on actual proof. How about in biology? What does putative mean? In biology, the term “putative” is commonly used to describe an entity or a concept that is based on what is generally accepted or inferred even without direct proof of it, meaning it denotes something, like an inference or a supposition, that is accepted because it is deemed to be the case or what has been commonly believed even without solid evidence to back it up. (See: https://www.biologyonline.com/dictionary/putative). A synonyms of putative is commonly accepted or supposed or assumed to exist or to have existed (See: https://www.merriam-webster.com/dictionary/putative). The spectral peaks m/z 41, 81, 91 and 57 obtained from the database of National Institute of Standards and Technology U.S. Secretary of Commerce Chemistry WebBook, SRD 69 (Data compilation copyright by the U.S. Secretary of Commerce on behalf of the U.S.A, available at: www.webbook.nist.gov) are based on the chemical structure of the VOCs and these are the “actual” confirmed m/z values for the chemical compound VOCs and not the “putative annotations” for spectral peak m/z values as recited by Grassin-Delyle, et al. 2020. One of the ordinary skills would consider “actual” m/z values than the Grassin-Delyle, et al. 2020 reported/recited “putative annotations” of m/z values to the four chemical compound VOCs (i) methylpent-2-enal, (ii) 2,4-octadiene, (iii) 1-chloro-heptane, and (iv) nonanal.
Applicant's arguments have been fully considered but not found persuasive and rejections under 35 USC 102 as recited supra are maintained.
Applicant’s argument 3:
Claims 1-10 stand rejected under 35 U.S.C. 103 as being unpatentable by Grassin-Delyle as applied to claims 1-10 above, and further in view of Lapidot, et al., WO 2021186444 Al (hereinafter "Lapidot"), Ibrahim, et al. Diagnosis of COVID-19 by exhaled breath analysis using gas chromatography-mass spectrometry. ERJ Open Res. 2021 Jul 5; 7(3): 00139-2021, 2021 (hereinafter "Ibrahim"), and Mougang, et al. Sensor array and gas chromatographic detection of the blood serum volatolomic signature of COVID-19. iScience. 2021 Aug 20; 24(8): 102851, 2021 (hereinafter "Mougang").
As discussed above, it is common in the field to identify individual VOCs to detection a disease, as compared to a spectral pattern of the present invention. Therefore, the claimed pattern- based detection method is not obvious to a skilled person in view of the cited prior art or common general knowledge.
The prior art documents relied upon in the Office Action focus on GC-MS or sensor-array methods, or on VOC identification workflows different from the real-time mass-spectral-peak-based diagnostic signature of the present invention. VOC identification is labor-intensive, time-intensive, and expensive. In contrast, the claimed invention offers practical advantages in terms of speed, non-invasiveness, and suitability for point-of-care screening. A user can compare the spectral pattern without identifying individual VOCs, thus saving time, cost, and does not require a high skill level.
Therefore, claims 1-10 are non-obvious in view of the cited prior art.
In Response 3: The claims 1-10 recites a limitation identifying “at least one spectral peak” from the claimed spectral m/z values. The claims do not recite “a mass spectrum pattern”.
Grassin-Delyle, et al. 2020 disclose the annotations of the four VOC compound was as “The putative annotation” , The putative annotations for the four compounds at m/z 99.08, 111.12, 135.09, and 143.15 were respectively methylpent-2-enal, 2,4-octadiene 1-chloroheptane, and nonanal (See, page 4, col 1). “Putative”: In biology, putative means something is generally accepted or supposed to be true, acting as a placeholder for something likely but not yet definitively proven. It's used when there's strong evidence or computational prediction, but experimental confirmation of its exact role is still lacking, bridging hypothesis and established fact. What is putative? : The word putative denotes to a supposition that is based on what is commonly accepted rather than on actual proof. How about in biology? What does putative mean? In biology, the term “putative” is commonly used to describe an entity or a concept that is based on what is generally accepted or inferred even without direct proof of it, meaning it denotes something, like an inference or a supposition, that is accepted because it is deemed to be the case or what has been commonly believed even without solid evidence to back it up. (See: https://www.biologyonline.com/dictionary/putative). A synonym of putative is commonly accepted or supposed or assumed to exist or to have existed (See: https://www.merriam-webster.com/dictionary/putative).
The spectral peaks m/z 41, 81, 91 and 57 obtained from the database of National Institute of Standards and Technology U.S. Secretary of Commerce Chemistry WebBook, SRD 69 (Data compilation copyright by the U.S. Secretary of Commerce on behalf of the U.S.A, available at: www.webbook.nist.gov) are based on the chemical structure of the VOCs and these are the “actual” confirmed m/z values for the chemical compound VOCs and not the “putative annotations” for spectral peak m/z values as recited by Grassin-Delyle, et al. 2020. One of the ordinary skills would consider and would have reliance on “the actual” m/z values from the database of National Institute of Standards and Technology U.S. Secretary of Commerce Chemistry WebBook, SRD 69 than the Grassin-Delyle, et al. 2020 reported/recited “putative annotations” of m/z values to the four chemical compound VOCs (i) methylpent-2-enal, (ii) 2,4-octadiene, (iii) 1-chloro-heptane, and (iv) nonanal.
One of the arguments of the applicant is that “VOC identification is labor-intensive, time-intensive, and expensive”. In response to this argument, one of the ordinary skills in the art would expect a confirmatory validation of the chemical structure of a VOC that are known in the art and corresponding spectral peak (m/z) value(s). The database of National Institute of Standards and Technology U.S. Secretary of Commerce Chemistry WebBook, SRD 69 is available at https://webbook.nist.gov/chemistry/name-ser/. The confirmatory chemical structure for the corresponding VOCs validation is of utmost important for the claimed spectral peak m/z values and data on VOC spectral peak m/z values to confirm whether the same VOC spectral peaks are produced by non-coronavirus or non-COVID-19 respiratory pathogen or viral pathogen respiratory illness because the claims have added limitations for specific therapeutic treatment to be effective for the claimed coronaviral or COVID-19 respiratory disease.
Applicant's arguments have been fully considered but not found persuasive and rejections under 35 USC 103 as recited supra are maintained.
Conclusion
12. No claim is allowed.
13. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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 final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J Visone can be reached at 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Quality Assurance Specialist, Art Unit 1600