DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/22/2026 has been entered.
Response to Amendment
The Amendment filed 01/05/2026 in which claims 1, 6, 9, 20 were amended, and claims 8 was canceled has been acknowledged. Claims 3-5, and 7 were previously canceled.
Claims 1-2, 6, 9-20 are under examination on the merits.
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.
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 1-2, 6, 9-20 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.
Amended claims 1 and 20 recite “cell surface proteomics”. It is unclear what this term refers to or how the term is to be understood. The specification lacks a proper definition of this term. The scope of the claimed invention is indefinite where the meets and bounds of the term were not defined in the specification. The dependent claims do not add additional clarity and, therefore, are also indefinite. For purposes of compact prosecution and applying prior art, claims 1 and 20 were herein interpreted as referring to measuring an expression level of at least two of the recited genes.
Amended claim 9 recites “The method of claim 1, wherein oxygen levels of the subject who is determined to have a severity signature profile are measured at least once daily”. It remains unclear whether this recitation is an additional step of the method in claim 1 or not. Further, under MPEP § 2111.04, the broadest reasonable interpretation of a method claim requires only the steps that must be performed and excludes steps that are not required because the conditions precedent are not met. In the instant case, claim 9 recites a step which appears to be practiced independently from the claimed method of claim 1. Further, it is unclear if the recitation of measuring oxygen levels at least once daily in claim 9, imparts any additional features already present in the method of claim 1, because the method of claim 1 already recites a method of treating comprising administering one or more COVID-19 therapies. Therefore the claim is indefinite.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 6, 9-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. This judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
See claims 1-2, 6, 9-20 as submitted on 01/05/2026.
As previously indicated, the claims are directed to a process, which is one of the four statutory categories of invention (Step 1: YES).
The instant claims are directed to the natural correlation between the expression levels of the various genes recited in claims 1 and 20 and COVID-19 severity. The instant claims are further directed to the mental step of appreciating the natural correlation to determine a severity signature profile. As such, the instant claims recite judicial expectations (JEs) in the form of a law of nature and abstract idea (Step 2A, Prong One: YES).
The crux of the amended claimed method is the appreciation of the natural correlation between expression levels of the various genes recited in claims 1 and 20. Obtaining and detecting the natural correlation in a biological sample would constitute insignificant extra-solution activities.
It is noted that the amended claims further require “performing single-cell RNA sequencing and cell surface proteomics to measure an expression level…” in steps “b” and “c”. Generally linking of the use of the judicial exception to a particular technological environment or field of use is not indicative of integration into a practical application. Further the amended claims further require “administering one or more COVID- 19 therapies…wherein the one or more COVID- 19 therapies comprise ritonavir-boosted nirmatrelvir, bebtelovimab, molnupiravir, sotrovimab, or dexamethasone” This not a particular treatment or prophylaxis, but, rather, a generic instruction to administer one or more COVID- 19 therapies based upon appreciation of the severity signature profile obtained from the natural correlation. Although, the amended claims recite specific therapies, the claims as a whole are not limited to a particular treatment or prophylaxis because the open-ended language of “comprises” constitutes a generic instruction to treat. Further, generally linking of the use of the judicial exception to a particular technological environment or field of use is not indicative of integration into a practical application.
As such, the instant claims do not recite additional elements that integrate the JEs into a practical application (Step 2A, Prone Two: NO).
As previously discussed in detail, it was well-understood, routine, and conventional (WURC) at the time of filing to construct severity signature profiles based on aberrant gene expression. As such, beyond the JEs, the amended claims only recite WURC data-gathering steps and generic instructions to apply the JE. These constitute insignificant extra-solution activities, which do not reasonably provide an inventive concept.
As such, the amended claims do not recite significantly more than the JE (Step 2B: NO).
Accordingly, the amended claims do not constitute patent eligible subject matter under 35 U.S.C § 101.
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, 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.
Claims 1, 2, 6, 10-20 are rejected under 35 U.S.C. 103 as being unpatentable over Herazo-Maya et al., in view of Spagnolo et al., as evidenced by Rosenheim, et al., further in view of Tu et al. (prior art of record) and Wilk, Aaron J et al. “A single-cell atlas of the peripheral immune response in patients with severe COVID-19.” Nature medicine vol. 26,7 (2020): 1070-1076. Cited in Applicant’s IDS submitted on 07/08/2022.
See claims 1, 2, 6, 10-20 as submitted on 01/05/2026.
Regarding claim 1, as previously explained Herazo-Maya et al. teach a method of treating a patient with interstitial lung disease, specifically idiopathic pulmonary fibrosis (IPF) (Abstract, page 3) comprising:
a) obtaining a blood sample from the subject with IPF (page 4);
b) measuring expression level of 52 genes including PLBD1, TPST1, MCEMP1,IL1R2, HP, FLT3 and S100A12 using expression microarrays (page 4; page 5; Figs. 2A, 3A, S5);
c) determining a score for the measured expression level of the 52 genes in the microarray (pages 4, 5);
d) using the scores of step c) to determine a high-risk signature profile (page 5);
e) determining that the severity signature profile comprises scores of at least one or more of the genes, wherein the scores of one or more of the genes indicate greater expression level than a gene-specific standard, such that expression of at least one of the two or more genes is increased (page 4; page 5; Figs. 2A, 3A, S5);
f) administering treatment to the subject (pages 8, 9)
Herazo-Maya et al. do not explicitly teach the method describe above for severe COVID-19.
However, Spagnolo et al. teach that pulmonary fibrosis is a recognized sequelae of acute respiratory distress syndrome (ARDS) (page 2). Spagnolo et al. further teach that about 40% of patients with COVID-19 develop ARDS, and 20% of ARDS cases are severe. Spagnolo et al. further teach that a relatively small degree of residual but non-progressive fibrosis could result in considerable morbidity and mortality in patients who had COVID-19. The teachings of Spagnolo et al. demonstrate a clear link between lung fibrosis and severe COVID-19 and further indicate that both conditions are associated with development of progressive, fibrotic irreversible interstitial lung disease and IPF (page 3).
Tu et al. were cited for teaching therapeutic agents for the treatment of COVID-19 for the benefit of targeting the SARS-CoV-2 virus replication cycle, boosting innate antiviral immune responses, and alleviating damage induced by dysregulated inflammatory responses (Abstract). Tu et al. specifically teach antiviral drugs such as ritonavir (page 8) as well as other FDA-approved therapies for COVID-19 such as hydroxychloroquine (page 10).
Wilk et al. were cited for teaching single cell RNA sequencing as a novel method for profiling peripheral blood mononuclear cells (PBMCs) from patients diagnosed with COVID-19 who were also diagnosed with acute respiratory distress syndrome (ARDS) (page 1). Wilk et al. further teach that single-cell RNA sequencing allows for observation of marked changes in the immune cell composition, phenotype in SARS-CoV-2 infection and immunological features of severe COVID-19 (pages 1, 6).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to have applied the method taught by Herazo-Maya et al. and Wilk et al. to a patient population with severe COVID-19 as taught by Spagnolo et al. with the therapeutic agents taught by Tu et al. for the benefit of assessing the risk level associated with severe COVID-19 and assess changes in immune cell composition and for the benefit of targeting the SARS-CoV-2 virus replication cycle, boosting innate antiviral immune responses, and alleviating damage induced by dysregulated inflammatory responses. Further motivation derives from the need for prognostic factors to guide treatment decisions and personalize therapies for severe COVID-19.
One of ordinary skill in the art would have had reasonable expectation of success in applying the method taught by Herazo-Maya et al. to a patient population with severe COVID-19 with the therapeutic agents taught by Tu et al. given that the methods of biomarker quantification and genomic profiling followed by administration of COVID-19 therapies are well known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Regarding claim 2, it is noted that no amendments were introduced to claim 2 in the amendment filed on 01/05/2026. As previously explained, Herazo-Maya et al. and Spagnolo et al. in combination teach the method of claim 1 where in the method is applied to patients with severe COVID-19.
Regarding claim 6, Tu et al. teach various dose regimens for various drugs. For example for administration of immunoglobulins, Tu et al. teach doses of 0.2-0.4g/kg for replacement therapy in cases of antibody deficiency, and doses of up to 2g/kg for immunomodulatory functions. Tu et al. further teach the need for further research to establish drug safety-profiles and adequate dosing for treating COVID-19 (page 9). The recitation referring to dosing in claim 6 “wherein the one or more COVID-19 therapies is given in a higher dose or for longer time period…” is considered to be one determined by routine optimization according to one of skill in the art in view of the teachings of Tu et al. See MPEP 2144.05 Optimization Within Prior Art Conditions or Through Routine Experimentation. Further, it is noted that the recitation of “wherein the one or more COVID-19 therapies is given in a higher dose or for longer time period than that given to a subject without severe COVID-19” does not impart any additional features already present in the method of claim 1, because the method of claim 1 already recites a method of treating comprising administering one or more COVID-19 therapies. Therefore, these recitations are considered to flow from the step of “administering” already present in the method of claim 1.
Regarding claims 10-12, it is noted that no amendments were introduced to claims 10-12 in the amendment filed on 01/05/2026. As previously explained, Herazo-Maya et al. teach a blood sample for total RNA extraction (page 4). The sample types recited in claims 11 and 12 of a mucous sample and a nasal swab also contain host cells suited for RNA extraction and further genome profiling as evidenced by the teachings of Rosenheim, J et al. (Abstract, page 2). Therefore, a mucous swab and a nasal swab merely represent obvious sample type variants of a blood sample as taught by Herazo-Maya et al. because they serve the same purpose of providing total RNAs from a host cell. It is prima facie obvious to substitute known equivalents for the same purpose. See MPEP 2144.06(II) Substituting Equivalents Known For The Same Purpose: In order to rely on equivalence as a rationale supporting an obviousness rejection, the equivalency must be recognized in the prior art, and cannot be based on applicant’s disclosure or the mere fact that the components at issue are functional or mechanical equivalents. In re Ruff, 256 F.2d 590, 118 USPQ 340 (CCPA 1958).
Regarding claims 13-18, it is noted that no amendments were introduced to claims 13-18 in the amendment filed on 01/05/206. As previously explained, Herazo-Maya et al. teach measuring all seven genes recited in claims 13-17, PLBD1, TPST1, MCEMP1,IL1R2, HP, FLT3, and S100A12 (page 4; page 5; Figs. 2A, 3A, S5), wherein an increase in expression levels over a standard was observed for all of the seven genes indicated above (page 4; page 5; Figs. 2A, 3A, S5).
Regarding claim 19, it is noted that no amendments were introduced to claim 19 in the amendment filed on 01/05/206. As previously explained, Herazo-Maya et al. teach a Scoring Algorithm of Molecular Subphenotypes (SAMs) to calculate gene scores and a severity signature profile (page 2).
Regarding claim 20, as previously explained, Herazo-Maya et al., Wil et al., Spagnolo et al., and Tu et al. in combination teach the method of claim 1. Claim 20 recites an additional step than those in claim 1, step c): “performing single-cell RNA sequencing and cell surface proteomics to measure an expression level of at least one of the following genes from the subject: LCK, CAMK2D, NUP43, SLAMF7, LRRC39, ICOS, CD47, LBH, SH2D1A, CNOT6L, METTL8, ETS1, C2orf27A, P2RY10, TRAT1, BTN3A1, LARP4, TC2N, GPR183, MORC4, STAT4, LPAR6, CPED1, DOCK10, ARHGAP5, HLA-DPA1, BIRC3, GPR174, CD28, UTRN, CD2, HLA-DPB1, ARL4C, BTN3A3, CXCR6, DYNC2LI1, BTN3A2, ITK, SNHG1, CD96, GBP4, SiPRi, NAP1L2, KLF12, IL7R)”. As indicated previously and above, Herazo-Maya et al. further teach measuring genes expression levels for other 45 genes including LCK, CAMK2D, NUP43, etc. (page 4; page 5; Figs. 2A, 3A, S5) and Wilk et al. teach single-cell RNA sequencing.
Accordingly, the limitations of claims 1, 2, 10-20 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 01/05/2026 have been fully considered but they are not persuasive.
Applicant contents on pages 8 and 9 of the Remarks submitted on 01/05/2026:
“Applicant asserts that the methods of the presently claimed invention disclose specific COVID-19 therapies, which integrate the alleged judicial exceptions into practical application of treating a subject with severe COVID-19 with ritonavir-boosted nirmatrelvir, bebtelovimab, molnupiravir, sotrovimab, or dexamethasone. In light of the amendments to claims 1 and 20, Applicant asserts that the presently claimed invention constitutes patent eligible subject matter and respectfully requests withdrawal of the rejection.”
In response:
Applicant’s Remarks indicated above are not persuasive because they fail to explain how claims 1 and 20 as amended are not directed to a natural correlation as explained in detail in the Office Action mailed on 05/15/2025 and above. Applicant has not provided any explanation to address the previous rejection under 35 USC § 101. Further, as explained previously and above, the recitation of “COVID- 19 therapies comprise ritonavir-boosted nirmatrelvir, bebtelovimab, molnupiravir, sotrovimab, or dexamethasone” constitutes a generic instruction to treat. Merely asserting or restating the claims as amended is not an explanation of how the claims as amended constitute patent eligible subject matter.
Applicant contents on page 10 and 11 of the Remarks submitted on 01/05/2026:
“[N]one of the art cited alone, or in combination with or without the general knowledge of the art at the time the application was filed, can account for all the limitations of claims 1, 2, and 10-20… Neither Herazo-Maya, Rosenheim, nor Tu disclose performing single-cell RNA sequencing and cell surface proteomics to measure an expression level of any of the genes list above.”
In response:
It is noted that the rejections to instant claims set forth in the present Office Action are based on a different combination of references than those from previous Office Actions. Therefore, this response has been constructed to address Applicant’s remarks as they apply to the present rejections, and not with regard to the specific references on record which were not cited in the present Office Action. Applicant’s remarks are not persuasive because Wilk et al. teach single-cell RNA sequencing as a method of measuring gene expression levels. Further, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As explained in detail previously and above, Herazo-Maya et al., Wilk et al, Spagnolo et al. and Tu et al. in combination teach the exact method of claims 1 and 20.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARLENE V BUCKMASTER whose telephone number is (703)756-5371. The examiner can normally be reached M-R 8:00 AM - 5:00 PM.
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/MARLENE V BUCKMASTER/Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/Primary Examiner, Art Unit 1672
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