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
Status of Claims
Applicant's preliminary amendment of the instant application, which was originally submitted on 08/17/2023 and later amended on 02/27/2024, 10/24/2024, and 03/12/2026, is acknowledged by the Examiner. The cancellation of claims 3 – 6, 10, 13, 15 – 22, 25, 27, 28, 30, 34 – 38, 40 – 49, 51 – 53, 55 – 57, 59, 60, 62, 65, 67, 71 – 74, 78, 81, 83 – 91, 93, and 95 pursuant to the amendment on 03/12/2026 is acknowledged. Claims 1, 2, 7 – 9, 11, 12, 14, 23, 24, 26, 29, 31 – 33, 39, 50, 54, 58, 61, 63, 64, 66, 68 – 70, 75 – 77, 79, 80, 82, 92, 94, and 96 were previously examined and restricted in the Office Action mailed on 01/15/2026.
Election/Restrictions
On 03/02/2026, Ming Zhang, Ph.D., i.e., the Attorney of Record, contacted Michael Allen, i.e., the Examiner’s supervisor, seeking clarification on the species election for claims 24 and 26. It was explained by Allen that Applicant must elect one, or a distinct set thereof, of markers for the prognosis of the claim. The Attorney understood the clarification and responded accordingly.
Applicant’s election of Group I in the reply filed on 03/12/2026 is acknowledged. Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant’s election without traverse of a method of treating a barrier tissue infection in a subject, wherein the infection is a respiratory barrier tissue infection and/or viral infection that is optionally caused by SARS-CoV-2, i.e., Group I, in the reply filed on 03/12/2026 is acknowledged. Applicant’s election of the cell type, genes, and/or markers in claims 8, 24, 26, and 68 and detection method in claim 58 as ciliated cells with interferon-stimulated genes: STAT1, STAT2, IRF1, and IRF9; indicators of infection in claims 8, 9, and 14 as decreased interferon-stimulated gene (ISG) induction, specifically the downregulation of STAT1, STAT2, IRF1, and IRF9; materials for risk categorization as (a) proinflammatory cytokines comprising at least one or more of: IL1B, TNF, CXCL8, CCL2, CCL3, CXCL9, CXCL10, and CXCL11 for the severe risk group in claim 24 and (c) upregulated ciliated cell genes comprising at least one or more of: IFI44L, STAT1,IFITMI, MX1, IFITM3, OAS1, OAS2, OAS3, STAT2, TAP1, HLA-C, ADAR, XAF1, IRF1, CTSS, and CTSB for the mild/moderate risk group in claim 26; and treatment options in claims 29, 31 – 33, 39, 50, and 54 as kinase inhibitors, specifically Janus kinase inhibitors: baricitinib, ruxolitinib, and tofacitinib in the reply filed on 03/12/2026 is also acknowledged.
Claims 63, 64, 66, 69, 70, 75 – 77, 79, 80, 82, 92, 94, and 96 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 12, 14, 32, 50, and 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Election was made without traverse in the reply filed on 03/12/2026. Claims 1, 2, 7 – 9, 11, 23, 24, 26, 29, 31, 33, 39, 58, 61, and 68 are pending and under review.
Priority
The instant application is a National Stage Entry of International Patent Application No. US2022017082 filed on 02/18/2022, which claims priority to United States Provisional Application No. 63203514 filed on 07/26/2021 and United States Provisional Application No. 63151002 filed on 02/18/2021. Priority is granted to United States Provisional Application No. 63151002 filed on 02/18/2021 for claims 1, 2, 7 – 9, 11, 23, 24, 26, 29, 31, 33, 39, 58, 61, and 68 of the instant application. Thus, the U.S. effective filing date of the instant application is 02/18/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/17/2023, 02/28/2025, and 03/12/2026 have been considered by the Examiner. Notably, the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Thus, unless the references have been cited by the Examiner on form PTO-892, they have not been considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. Also, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The use of the term BIACORE™ on page 56, and possibly others in the specification, which is a trade name or a mark used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, ℠, or ® following the terms. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Applicant is required to properly annotate all trade names and/or marks that are present in the specification.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 31, 34, 76, and 127 – 131. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http://, www., or other browser-executable code. See MPEP § 608.01.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which Applicant may become aware in the specification.
Drawings
The drawings are objected to because it is difficult to read the genes on the volcano plots in Figures 3D and 3F.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the Examiner, the Applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The instant application contains at least one drawing executed in color. At a minimum, figures 1A – 1H, 1J – 1O, 2A – 2R, 3A – 3J, 4A, 4F, 4H, 5A, 5C, 5D, 6A, 6C – 6E, 7A – 7H, 7J, 7N, 8A, 8C – 8F, 9A – 9K, 10A – 10E, 10G, 10H, 11A – 11D, 11F, 11I, 11J, 12A, 12G, 12H, 13A – 13C, and possibly others, have multiple parts that refer to and are differentiated by various colors.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claims 2 and 7 are objected to because of the following informalities:
In claim 2, line 4, the acronym “SARS-CoV2” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “SARS-CoV2” is interpreted to mean “severe acute respiratory syndrome coronavirus 2”. Also, there is a missing hyphen in the acronym, wherein the appropriate acronym is “SARS-CoV-2” and not “SARS-CoV2” as presently recited;
In claim 7, line 2, the acronym “WHO” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “WHO” is interpreted to mean the “World Health Organization”, as defined in the instant specification.
Recommended amendments are underlined. Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 USC § 112(b)
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 8, 24, 26, 58, 61, and 68 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.
Claims 8, 24, 26, and 68 refer to materials that are set forth in tables of the specification. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for Applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). See MPEP § 608.01(m) and 2173.05(s).
Claims 58 and 68 recite the limitation “cell types” in lines 3 and 1, respectively. There is insufficient antecedent basis for this limitation in the claim. There is no recitation of cell types in claim 1, upon which claims 58 and 68 depend. However, there is a recitation of “one of more of epithelial, immune, stromal, and neuronal cells” in line 4 of claim 1. For examination of the instant application, it will be inferred that “cell types” is referring to the list of one or more cells in claim 1. However, an appropriate amendment is required.
Claim 61 recites the limitation “single cell expression” and “expression” in lines 1 and 2, respectively. There is insufficient antecedent basis for this limitation in the claim. There is no recitation of cell expression in claim 58, upon which claim 61 depends, and so it is unclear what cell expression is to be measured in claim 61. However, there is a mention of markers that are differentially expressed in the cells in lines 3 and 4 of claim 58. For examination of the instant application, it will be inferred that the RNA-seq method of claim 61 is employed to determine the expression of the different markers on the cells. However, an appropriate amendment is required.
It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this Office Action. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejection(s) and art may be applied in a subsequent Office Action.
Improper Markush Rejection
Claims 8, 24, 26, 31, 33, 39, 58, and 68 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. Second, where a Markush grouping describes alternative chemical compounds, the members of a proper group there should share (1) a common utility and (2) a substantial structural feature essential to that utility. See MPEP § 803.02 and 2117.
The Markush grouping of claims 8, 24, 26, 31, 33, 39, 58, and 68 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: All of the members of each group do not appear to share a common utility that is required for any shared function. Thus, the groups are improper and the claims are rejected due to a lack of a common function and/or a common substantial structure feature that is essential to a common function.
The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial structural feature and a common use that flows from the substantial structural feature for the following reasons:
Regarding claims 8, 24, 26, 58, and 68, a person having ordinary skill in the art would readily appreciate that the recited cell types, genes, and/or markers, i.e., indicators of infection and/or risk indicators, all differ in their structure and function. The specification defines a cell type or subset as being distinguished by a parent cell type that expresses a specific gene signature or cell state that can further distinguish the cell from other cells of the parent cell type (page 22, paragraph 0053). For example, any interferon (IFN) gene ciliated cell is defined as being a distinctive cell subset with its own differentially expressed genes in comparison to other cell types or subsets (page 23, paragraph 0054). In other words, each cell type or subset and its associated genes and/or markers constitute a subpopulation of cells that are uniquely identifiable and set apart from other cells of the same cell type (page 28, paragraph 0064). The recited cell types, genes, and/or markers do not share a common core structure and do not have a common function as they would all be expressed in different locations and/or at different times. Thus, the recited cell types, genes, and/or markers, i.e., indicators of infection and/or risk indicators, are an improper Markush group.
Regarding claims 31, 33, and 39, a person having ordinary skill in the art would readily appreciate that the recited treatment options all differ in their structure and function. The specification defines the therapeutic agent as being a small molecule inhibitor, small molecule degrader, genetic modifying agent, antibody, antibody fragment, antibody-like protein scaffold, aptamer, protein, or any combination thereof (page 49, paragraph 0124), wherein each class of agent would have a different function and structure. For example, an antibody has a much different structure compared to that of a small molecule inhibitor. Moreover, a therapeutic agent within the same “class”, i.e., an antibody, would have much different structure, based on its sequence, and thus, function (page 57, paragraph 0146). The recited treatment options do not share a common core structure and do not have a common function. Thus, the recited treatment options are an improper Markush group.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. It is recommended that Applicant amend the claims to encompass only the elected species set forth above in paragraph 5. To be more specific, it is recommended that claims 8, 58, and 68 be amended to read on the ciliated cells with the interferon (IFN)-stimulated genes: STAT1, STAT2, IRF1, and IRF9. Claims 24 and 26 should be amended to read on the elected materials to categorize the subject in the severe and mild/moderate group, i.e., proinflammatory cytokines and upregulated ciliated cell genes, respectively. Furthermore, claims 31, 33, and 39 should read on the kinase inhibitors: baricitinib, ruxolitinib, and tofacitinib.
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, 7 – 9, 11, 23, 24, 26, 29, 31, 33, 39, 58, 61, and 68 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claims recite “detecting one or more indicators of infection from a sample obtained from the subject…comparing the indicators to control/healthy samples or disease reference values to determine whether the subject will progress to a risk group”. The correlation of infection indicators in a bodily sample and progression to different disease states, i.e., mild, moderate, and/or severe disease, is a natural correlation, i.e., a law of nature. 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:
The claims are drawn to a method to assess the likelihood that a subject will progress to a risk group due to a barrier tissue infection by detecting one or more indicators of infection. As such, the claimed method, which is drawn to a process, falls into one of the four categories of patent eligible subject matter (i.e., process, machine, manufacture, or composition of matter) (Step 1: YES). The claims are drawn to a judicial exception of a natural phenomenon or law of nature, specifically a natural correlation (Step 2A, Prong One: YES). Claim 1 recites “a method of treating a barrier tissue in a subject in need thereof comprising: detecting one or more indicators of infection from a sample obtained from the subject…comparing the indicators to control/healthy samples or disease reference values to determine whether the subject will progress to a risk group”. As presently written, the claims encompass a natural correlation as indicators of infection would be detectable during an active infection. The rejection affects all independent claims, i.e., claims 2, 7 – 9, 11, 23, 24, 26, 29, 31, 33, 39, 58, 61, and 68. Laws of nature and natural phenomena, as identified by the Courts, include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature. The law of nature and natural phenomenon exceptions reflect the Court's view that the basic tools of scientific and technological work are not patentable, because the "manifestations of laws of nature" are "part of the storehouse of knowledge," "free to all men and reserved exclusively to none." As an example, the Courts have identified a correlation that is the consequence of how a certain compound is metabolized by the body, Mayo Collaborative Servs. v. Prometheus Labs., 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012); and a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017) to be laws of nature or natural phenomena.
Overall, the claims as a whole are not limited to a method to treat a barrier tissue infection and constitute a natural correlation between indicators of infection and likelihood of progressing to different disease states. There is no indication in the specification that the indicators of infection claimed here have any structural or functional characteristics that differ from those naturally found in different disease states. Accordingly, the natural correlation between indicators of infection and risk of progressing to a disease state is a law of nature or natural phenomenon and directed to a judicial exception. However, there are additional elements recited in claims 29, 31, 33, 39, and 58 that integrate the judicial exception into a practical application (Step 2A, Prong Two: YES). These claims recite administering a treatment option, i.e., kinase inhibitors, to the patient according to their risk group, as a preventative or therapeutic intervention, thereby lowering the risk that the patient will progress to a higher disease state. Nonetheless, there are no additional elements recited in all other claims, i.e., claims 1, 2, 7 – 9, 11, 23, 24, 26, 61, and 68, that integrate the judicial exception into a practical application (Step 2A, Prong Two: NO). The claimed invention does not use or apply the judicial exception in a meaningful way to contribute to an inventive concept or amount to significantly more than the judicial exception (Step 2B: NO). Thus, the claims fail the subject matter eligibility test (Steps 1 and 2A, Prong One: YES; Steps 2A, Prong Two and 2B: NO) and are not eligible subject matter. See MPEP § 2106 and 2173.05(q). See also In re Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 589-91, 106 USPQ2d 1972, 1978-79 (2013) and In re University of Utah Research Foundation v. Ambry Genetics Corp., 774 F.3d 755, 761, 113 USPQ2d 1241, 1244 (Fed. Cir. 2014). In turn, as presently written, claims 29, 31, 33, 39, and 58 are not eligible subject matter due to their dependency on claim 1. It is recommended that the claims be rewritten to integrate the judicial exception into a practical application by making the treatment have more than a nominal or insignificant relationship to the exception. For example, the claims may be amended to have the “particular” treatment of kinase inhibitors, which is significantly related to the recited correlation, as the administrative step in the independent claim to integrate the law of nature into a practical application.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 8, 9, 11, 26, 29, 58, 61, and 68 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang, Q., et. al., (Science (New York, N.Y.), 370(6515), eabd4570; Published 10/23/2020; Cited in Applicant’s IDS on 03/12/2026 as Non-Patent Literature Document Cite No. 26), hereby Zhang.
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Zhang teaches that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects respiratory epithelial cells, i.e., a barrier tissue, wherein infections can range from silent to lethal coronavirus disease 2019 (COVID-19; abstract, see also the graphical abstract reproduced below), as set forth in instant claims 1 and 2. Patients hospitalized with life-threatening pneumonia caused by SARS-CoV-2, i.e., severe COVID-19, had an enrichment of rare genetic variants that result in a loss-of-function at loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity (abstract; page 1, entirety of left and center columns, first paragraph of right column; see also the research article summary), as required in instant claims 1 and 2. To be more specific, the genomic DNA of 659 patients with severe COVID-19, defined as patients who developed critical disease, whether pulmonary with mechanical ventilation (CPAP, BIPAP, intubation, hi-flow oxygen), septic shock, or with any other organ damage requiring admission to the ICU, was compared to a control population of 534 patients that were asymptomatic or developed mild, self-healing, ambulatory disease after SARS-CoV-2 infection (page 7, right column, second paragraph; page S3, patients section), as disclosed in instant claims 1 and 11. Sequencing of the genomic DNA was accomplished using next-generation sequencing, including RNA sequencing (RNA-seq), to determine the genetic marker expressed in the cell (page 5, center and right columns, figure 4; page S3 – S4, next-generation sequencing section), as defined in instant claims 58, 61, and 68. Three core genetic loci were considered, i.e., TLR3, IRF7, and IRF9, wherein 10 loci directly connected to these three core loci were also considered: TICAM1/TRIF, UNC93B1, TRAF3, TBK1, IRF3, and NEMO/IKBKG in the TLR3-dependent type I IFN induction pathway; and IFNAR1, IFNAR2, STAT1, and STAT2 in the IRF7- and IRF9-dependent type I IFN amplification pathway (page 1, right column, second paragraph), as required in instant claims 1, 9, 26, and 68. There was significant enrichment of genetic variants correlated to loss-of-function of type I IFN immunity in the patients with severe COVID-19 versus the control group, wherein 118 of the patients with severe COVID-19 were found to carry genetic variants correlated to loss-of-function of type I IFN immunity, but only one of the control patients had a genetic variant (page 1, right column, third paragraph; page 3, right column, first paragraph), as defined in instant claims 1, 9, and 26. Other methods employed to determine cell type and/or gene and their associated IFN response include fluorescence activated cell sorting (FACS), cytometric bead array, and ELISA (page 5, center and right columns; see also figures 3 – 5), as disclosed in instant claim 58. Immune cells isolated from patients with severe COVID-19 did not produce detectable type I or III IFNs in response to SARS-CoV-2, wherein this downregulation results in downregulation of interferon-stimulated genes (ISGs), which are located downstream, (page 5, center and right columns, figure 4; see also the graphical abstract as reproduced above), as required in instant claims 1, 8, 9, and 26. On the other hand, control patients had detectable responses, indicating the upregulation of IFN in response to SARS-CoV-2, as set forth in instant claims 9 and 11.
In essence, Zhang teaches that type I IFN cell-intrinsic immunity has an essential role in the control of SARS-CoV-2 infection in respiratory epithelial cells and patients with impaired type I IFN production, i.e., downregulation, are more likely to develop severe COVID-19 versus control patients, i.e., asymptomatic or mild patients, that would have upregulation of type I IFN responses (page 1, right column, second paragraph; page 6, right column – page 7, right column, first paragraph; figure 4; see also the graphical abstract reproduced above), as disclosed in instant claim 1. Furthermore, the administration of type I IFN to control SARS-CoV-2 infection may be of therapeutic benefit in these patients, especially early in infection (page 1, right column, second paragraph; page 6, right column, last paragraph – page 7, right column, first paragraph), as defined in instant claims 1 and 58.
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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang, Q., et. al., (Science (New York, N.Y.), 370(6515), eabd4570; Published 10/23/2020; Cited in Applicant’s IDS on 03/12/2026 as Non-Patent Literature Cite No. 26), hereby Zhang, as applied to claims 1, 2, 8, 9, 11, 26, 29, 58, 61, and 68 above, further in view of WHO Working Group on the Clinical Characterization and Management of COVID-19 infection (The Lancet. Infectious diseases, 20(8), e192–e197; Published 06/12/2020), hereby Marshall.
While Zhang teaches the classification of mild/moderate versus severe COVID-19 patients based on symptomology and hospitalization status, it does not explicitly teach the WHO score for the mild/moderate versus severe subjects, as required in instant claim 7.
However, Marshall teaches the implementation of a common outcome measurement, known as the WHO Clinical Progression Scale, to track the progress of patients with COVID-19 (abstract; see whole document). This scale provides a simple data set to measure of illness severity across a range from 0 to 10 (page 195). It is taught that patients with a WHO score of: (a) are not infected; (b) 1 – 3 have mild disease that is either asymptomatic (1) or symptomatic (2 and 3), but otherwise ambulatory, i.e., with no hospitalized required; (c) 4 – 5 have moderate disease with hospitalization and non-invasive ventilation required; (d) 6 – 9 have severe disease with hospitalization and oxygen support required by high flow (6) or mechanical ventilation (7 – 9); and (e) 10 are dead (page 195, panel 2 and figure), as recited in instant claim 7.
Zhang and Marshall are considered to be analogous to the claim invention because both are drawn to assigning disease states to patients infected with SARS-CoV-2. Based on the prior art teachings, it would have been obvious to a person having skill in the art to use the WHO score taught by Marshall for its intended purpose to determine the disease state of a patient and their likelihood of progressing, as taught by Zhang. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Zhang and Marshall before the effective filing date of the claimed invention with a reasonable expectation of success to facilitate data pooling across cohort studies and clinical trials, with the objective of expediting the exchange of knowledge to benefit patients infected with SARS-CoV-2 (Marshall; page 196, left column, last paragraph). All the claimed elements were known in the prior art. Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP § 2143F and 2143.02.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang, Q., et. al., (Science (New York, N.Y.), 370(6515), eabd4570; Published 10/23/2020; Cited in Applicant’s IDS on 03/12/2026 as Non-Patent Literature Cite No. 26), hereby Zhang, as applied to claims 1, 2, 8, 9, 11, 26, 29, 58, 61, and 68 above, and further in view of Gonzalez, V. D., et. al., (Cell reports, 22(7), 1875–1888; Published 02/13/2018), hereby Gonzalez.
Zhang does not teach employment of the Simpson’s Index for determining the diversity of the indicator of infection, as set forth in instant claim 23.
However, Gonzalez teaches the usage of the Simpson’s index to determine the diversity of cell subsets across tumors (abstract; page 1878, quantification of heterogeneity by Simpson’s Diversity Index section; page 1885, right column, Simpson’s Diversity Index section). This Index is an algorithm used for determining the number of species and their abundance in ecosystems, wherein a higher diversity index correlates with higher cell diversity (page 1878, quantification of heterogeneity by Simpson’s Diversity Index section), as set forth in instant claim 23.
Zhang and Gonzalez are considered to be analogous to the claim invention because both are drawn to quantifying the cell type in a patient’s sample. Based on the prior art teachings, it would have been obvious to a person having skill in the art to use the Simpson’s Diversity Index taught by Gonzalez for its intended purpose to determine the disease state of a patient and their likelihood of progressing, as taught by Zhang. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Zhang and Gonzalez before the effective filing date of the claimed invention with a reasonable expectation of success to determine the cell type and their associated abundance in an ecosystem and correlate it with a disease state (Gonzalez; page 1878, quantification of heterogeneity by Simpson’s Diversity Index section; page 1883, right column, second paragraph). All the claimed elements were known in the prior art. Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP § 2143F and 2143.02.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang, Q., et. al., (Science (New York, N.Y.), 370(6515), eabd4570; Published 10/23/2020; Cited in Applicant’s IDS on 03/12/2026 as Non-Patent Literature Cite No. 26), hereby Zhang, as applied to claims 1, 2, 8, 9, 11, 26, 29, 58, 61, and 68 above, and further in view of Lucas, C., et. al., (Nature, 584(7821), 463–469; Published 07/27/2020), hereby Lucas.
Zhang does not teach that a subject will progress to severe COVID-19 if proinflammatory cytokines are detected in the sample, as defined in instant claim 24.
However, Lucas teaches that various proinflammatory cytokines, including CXCL9, CXCL10, IL-1β, TNF, and CCL2, among others, are reported in COVID-19 patients, wherein sustained elevations are correlated with disease severity and mortality (abstract; page 467, right column; page 468, right column, last paragraph), as required in instant claim 24.
Zhang and Lucas are considered to be analogous to the claim invention because both are drawn to quantifying the specific immune responses against SARS-CoV-2. Based on the prior art teachings, it would have been obvious to a person having skill in the art to have combined the proinflammatory cytokines taught by Lucas and the downregulated ISGs of Zhang to determine the disease state of a patient and their likelihood of progressing to a more severe state, as taught by both Lucas and Zhang. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Zhang and Lucas before the effective filing date of the claimed invention with a reasonable expectation of success to identify a maladapted immune response and poor clinical outcome in a patient to initiate targeted treatments that promote disease tolerance and prevent severe COVID-19 (Lucas; abstract; page 469, left column, last paragraph). All the claimed elements were known in the prior art. It would have been obvious to a person having ordinary skill in the art to have combined the elements as claimed by known methods with no change in their respective functions. The combination would have yielded nothing more than predictable results to one having ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP § 2143A and 2143.02.
Claims 31, 33, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang, Q., et. al., (Science (New York, N.Y.), 370(6515), eabd4570; Published 10/23/2020; Cited in Applicant’s IDS on 03/12/2026 as Non-Patent Literature Cite No. 26), hereby Zhang, as applied to claims 1, 2, 8, 9, 11, 26, 29, 58, 61, and 68 above, and further in view of Spinelli, F. R., Conti, F., and Gadina, M. (2020). HiJAKing SARS-CoV-2? The potential role of JAK inhibitors in the management of COVID-19. Science immunology, 5(47), eabc5367; Published 05/08/2020), hereby Spinelli.
Zhang does not teach that one or more kinase inhibitors are administered as the treatment option to patients at risk for progression to the severe risk group, as defined in instant claims 31, 33, and 39.
However, Spinelli teaches that patients requiring intensive care, i.e., those with severe COVID-19, had significantly serum levels of cytokines and chemokines, as compared to control patients, which correlates with a hyperimmune response and cytokine storm (page 1, center column, first and second paragraph). It is further taught that the use of Janus kinase (JAK) inhibitors, which target cytokines with JAK-dependent signaling, helps to manage the cytokine storm in patients with severe COVID-19 (abstract; page 1, center column, first paragraph; figure 1), as required in instant claims 31, 33, and 39. These JAK inhibitors include baricitinib, ruxolitinib, and tofacitinib (page 1, right column, last paragraph), as set forth in instant claim 39.
Zhang and Spinelli are considered to be analogous to the claim invention because both are drawn to the management of severe COVID-19, as caused by SARS-CoV-2. Based on the prior art teachings, it would have been obvious to a person having skill in the art to have used the JAK inhibitors taught by Spinelli in place of the type I IFN taught by Zhang to manage the likelihood that a patient would progress to severe COVID-19, as disclosed by both Spinelli and Zhang. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Zhang and Spinelli before the effective filing date of the claimed invention with a reasonable expectation of success to impair the early stages of SARS-CoV-2 spread while also inhibiting the cytokine cascade driving the cytokine storm in patients likely to progress to severe COVID-19 (Spinelli; abstract; page 1, right column, first paragraph; page 3, center column, second paragraph). All the claimed elements were known in the prior art. The simple substitution of one known element, i.e., JAK inhibitors, for another, i.e., type I IFN, is likely to be obvious when predictable results are achieved, i.e., treatment of SARS-CoV-2 in the early stages. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP § 2143B and 2143.02.
Conclusion
Claims 1, 2, 7 – 9, 11, 23, 24, 26, 29, 31, 33, 39, 58, 61, and 68 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Hallie N. Pennington, Ph.D. whose telephone number is (571)272-6781. The Examiner can normally be reached M-Th 7:30-5:30 ET.
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/HALLIE N. PENNINGTON, PH.D./Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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