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 .
This Office Action is in reply to Applicant’s correspondence of 4/7/2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put this application in condition for allowance. New grounds of rejection, as necessitated by amendments, are presented in this Office Action. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action. This Action is FINAL.
Please note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Status
Claims 1-6, 8-9, 12, 15-17, 19-20, 24-25, and 29-30 are pending and being examined on the merits.
Information Disclosure Statement
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." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
No IDSs were filed in the response received on 4/7/2026. Therefore, any references not cited on an IDS or by the examiner on form PTO-892 remain unconsidered.
Drawings
The objection to the drawings is withdrawn in light of Applicant’s submission of replacement drawings in black and white.
Specification
The objection to the specification is withdrawn in light of Applicant’s amendments to remove references to colors in the figures.
Claim Objections
Withdrawn: The objections to claims 9, 14-16, 25, and 29, as detailed in the Office Action of 1/7/2026, are withdrawn in light of Applicant’s amendments to the claims and cancellation of claim 14.
Maintained: The objection to claim 15 is maintained. Claim 15 reads “wherein one or more high risk therapy is administered to a patient classified as high risk” and should read “wherein one or more high risk [[therapy is]]therapies are administered to a patient classified as high risk”.
New: Claims 9 and 19 are objected to because of the following informalities:
Claim 9 reads “wherein the patient demographic data” and should read “wherein the one or more patient demographic data” to maintain consistent claim terminology with claim 8, from which claim 9 depends.
Claim 19 reads “to generate a gene expression mosaic for the patient” and should read “to generate a gene reference mosaic for the patient” to maintain consistent claim terminology with claim 1, from which claim 19 depends.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 101
The rejection of claims 1-6, 8-9, 12, and 30 under 35 U.S.C. 101 is withdrawn in light of Applicant’s amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 112b - Indefiniteness
The rejection of claims 1-6, 8-9, 12, 14-20, 24-25, and 29-30 under 35 U.S.C. 112(b) are withdrawn in light of Applicant’s amendments to the claims and cancellation of claims 14 and 18.
Withdrawn Claim Rejections - 35 USC § 112d – Failure to Further Limit
The rejection of claims 18 and 30 under 35 U.S.C. 112(d) is withdrawn in light of Applicant’s amendments to the claims and cancellation of claim 18.
Withdrawn Claim Rejections - 35 USC § 102 and 103
The rejections of claims 1-2, 5-6, 8-9, 12, and 30 under 35 U.S.C. 102(a)(1) as being anticipated by Wong 2015 (Wong et al., American journal of respiratory and critical care medicine, 2015; cited on IDS of 10/12/2023, C18), claim 4 under 35 U.S.C. 103 as obvious over Wong 2015 (Wong et al., American journal of respiratory and critical care medicine, 2015; cited on IDS of 10/12/2023, C18), claim 3 under 35 U.S.C. 103 as being unpatentable over Wong 2015 (Wong et al., American journal of respiratory and critical care medicine, 2015; cited on IDS of 10/12/2023, C18) as applied to claims 1-2, 5-6, 8-9, 12, and 30 above and further in view of Gauthier (Gauthier et al., Bone Marrow Transplant 2019), and claims 14-20, 24-25, and 29 under 35 U.S.C. 103 as being unpatentable over Wong 2015 (Wong et al., American journal of respiratory and critical care medicine, 2015; cited on IDS of 10/12/2023, C18) as applied to claims 1-2, 5-6, 8-9, 12, and 30 above and further in view of Wong 2019 (US2019/0065666A1; cited on IDS of 10/12/2023, A1), are withdrawn in light of Applicant’s amendments to the claims and cancellation of claims 14 and 18.
New Claim Rejections - 35 USC § 103
Necessitated by Amendments
Claims 1-2, 4-6, 8-9, 12, 15-17, 19-20, 24-25, 29, and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wong 2015 (Wong et al., American journal of respiratory and critical care medicine, 2015; cited on IDS of 10/12/2023, C18) in view of Wong 2019 (Wong et al., US2019/0065666A1; cited on IDS of 10/12/2023, A1).
Claim 1: Wong 2015 teaches classifying a pediatric patient with septic shock into specific endotype groups (A or B), in which endotype A patients had a higher mortality rate and a higher rate of a complicated course than those in endotype B (this reads on high risk of adverse outcome and/or mortality or other than high risk of adverse outcome and/or mortality). Wong 2015 teaches obtaining samples from pediatric patients with septic shock (pg 310, col 3) and analyzing the samples to determine the expression levels of 100 biomarkers to generate a gene expression mosaic for the patient (pg 310, col 3). Wong 2015 teaches determining a Z value for the patient wherein “absolute difference in RGB pixel-to-pixel intensity was calculated for each individual patient mosaic, relative to the reference mosaics” and “Final subclass allocation was based on the least difference between the individual patient mosaic and one of the reference mosaics representing the septic shock subclasses” (which reads on Equation 1). Wong 2015 teaches classifying the patient into one of the septic shock subclasses based on a threshold cutoff value wherein a score lower than the cutoff value was associated with subclass A (high risk) and a score greater than the cutoff value was associated with subclass B (other than high risk; pg 312, col 3). Wong 2015 teaches that the 100 biomarkers comprise all 100 of the listed genes in claim 1 (Supplementary Table 1).
Wong 2015 teaches that patients classified as endotype A (high risk) do not respond favorably to treatment with corticosteroids and exhibit an increased risk of mortality/worse outcome with corticosteroid treatment (pg 314, col 1 and 3). Though Wong 2015 implies that patients classified as not high risk can receive corticosteroids while those classified as high risk (subclass A) may benefit the most from more high risk therapies such as immune-enhancing therapies (pg 314, col 3), Wong 2015 does not explicitly teach administering a treatment based on the classification of high risk or other than high risk. However, administration of an appropriate treatment following classification of a patient as high risk or other than high risk (endotype A vs endotype B) is known in the art, as taught by Wong 2019.
Wong 2019 teaches a method for classifying a patient with septic shock as high risk (endotype A) or low risk (endotype B), in which two or more biomarkers selected from a 100 gene biomarker list are examined for expression levels (the same 100 biomarkers as taught in the instant application; paragraph [0007] and Table 1). Wong 2019 teaches “administering a treatment including one or more corticosteroid to a patient that is not endotype A/high risk, or administering a treatment including one or more therapy excluding a corticosteroid to a patient that is classified as endotype A/high risk, to provide a method of treating a pediatric patient with septic shock” (paragraph [0016]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Wong 2015 (who teaches that patients classified as not high risk can receive corticosteroids while those classified as high risk (subclass A) may benefit the most from more high risk therapies such as immune-enhancing therapies) with that of Wong 2019 who teaches administering corticosteroids to those patients with septic shock not classified as high risk and teaches using therapies without corticosteroids for those with high risk. One would be motivated to administer therapies in this way given the combined teachings of both Wong 2015 and Wong 2019 that patients in the high risk endotype A subclass have a higher incidence of mortality when administered corticosteroids than those in other than endotype A subclass (Wong 2015: pg 314, col 3; Wong 2019: paragraphs [0075-0076]). One would have a reasonable expectation of success given that Wong 2015 and Wong 2019 are using the same gene set to classify pediatric septic shock patients into similar high risk and other than high risk categories.
Claim 2: Wong 2015 teaches that the cutoff value is determined by modeling an interaction between the value (GES score of each subclass) and the receipt of corticosteroids using logistic regression (“We used logistic regression to test the association between adjunctive corticosteroids and outcomes within each subclass”, pg 314, col 1).
Claim 4: Wong teaches that the threshold value can delineate between endotypes, and that the cutoff value in their calculations is 401 (pg 312, col 3). Wong 2015 does not teach that the cutoff value is about 15. However, Wong 2015 teaches that a threshold value based on a specific percentile of calculated endotype category can be successfully used to accurately classify patients. It would have been prima facie obvious to one skilled in the art to apply the same knowledge to the calculated single value for each mosaic, as demonstrated by the GES in Wong 2015. One would be motivated to use a threshold value for classification given the assertion by Wong 2015 that this allows for classification with a high level of sensitivity and specificity (pg 312, col 3). One would have a reasonable expectation of success given that Wong 2015 is also using gene expression mosaics to then calculate a single value (GES), which is used in an algorithm to establish a cutoff for classification.
Claim 5: Wong 2015 teaches the difference between the gene expression reference mosaic of the patient and the reference mosaic is calculated by a pixel-to-pixel intensity difference (“The absolute difference in RGB pixel-to-pixel intensity was calculated for each individual patient mosaic, relative to the reference mosaics”, pg 311, col 1).
Claim 6: Wong 2015 teaches that the biomarker expression levels are determined by mRNA quantification (“We measured expression of the 100 subclass defining genes using a multiplex messenger RNA (mRNA) quantification platform”, pg 310, col 2).
Claims 8 and 9: Wong 2015 teaches that the classification is combined with one or more patient demographic data and/or other clinical characteristics, specifically age, presence of co-morbidities of the patient, and illness severity (“we used logistic regression to test the association between class allocation and outcome adjusted for age, presence of comorbidity, and illness severity (PRISM scores)” pg 313, col 2-3).
Claim 12: Wong 2015 teaches that samples were obtained within the first 48 hours of presentation with septic shock (“Blood samples were obtained within 24 hours of initial presentation to the PICU with septic shock”, pg 310, col 3).
Claim 15: Wong 2019 teaches “one or more high risk therapy can be administered to a patient classified as endotype A/high risk” (paragraph [0016]).
Claim 16: Wong 2019 teaches “the one or more high risk therapy includes at least one of immune enhancing therapy, extracorporeal membrane oxygenation/life support, plasmapheresis, pulmonary artery catheterization, and/or high volume continuous hemofiltration” (paragraph [0016]).
Claim 17: Wong 2019 teaches “the immune enhancing therapy includes administration of GMCSF, interleukin-7, and/or anti-PD-I” (paragraph [0016]).
Claim 19: Wong 2019 teaches “obtaining a sample from a patient at a later time point, analyzing the subsequent expression levels of the two or more biomarkers selected from the biomarkers listed in Table 1, and determining whether the expression levels of the two or more biomarkers are non-elected above a cut-off levels, thereby determining if the patient’s endotype classification has changed”. Wong 2019 further teaches “maintaining the treatment being administered if that patient’s endotype classification has not changed, or changing the treatment being administered if the patient’s endotype classification has changed” (paragraph [0017]).
Claims 20 and 24: Wong 2019 teaches that the second time point is on day 3, relative to the first time point on day 1, therefore being in the range of 24 to 96 hours, or longer after the first time point (paragraph [0090]).
Claim 25: Wong 2019 teaches that “Corticosteroids were associated with increased risk of mortality among subjects who persisted as endotype A” (paragraph [0090]). While Wong 2019 does not explicitly teach administering another treatment after the second time point, it would be obvious to those skilled in the art that those classified as endotype A after the second time point should not be administered corticosteroids, in accordance with the findings and teachings regarding classification at the first time point.
Claim 29: Wong 2019 does not explicitly teach an instance in which a patient classified as high risk and administered a high risk therapy after the first time point is not classified as high risk after the second time point. However, Wong 2019 teaches administering a high risk therapy to a pediatric septic shock patient after classification of high risk at a first time point (paragraph [0016]). Wong 2019 additionally teaches that subjects exhibit transition between endotypes A and B during a 1 to 3 day comparison study (paragraph [0090]). Additionally, Wong 2019 teaches that administration of treatment of a high risk therapy to a patient classified as high risk includes “improving an outcome in a pediatric patient with septic shock” (paragraph [0016]). Therefore, it is an obvious desirable result that following administration of a high risk therapy to a patient after classification at a first time point would lead to the patient not being classified as high risk after the second time point, thus being an indication of an “improved outcome”.
Claim 30: Wong 2015 teaches that the patient is a pediatric patient (pg 310, col 3).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Wong 2015 (Wong et al., American journal of respiratory and critical care medicine, 2015; cited on IDS of 10/12/2023, C18) in view of Wong 2019 (Wong et al., US2019/0065666A1; cited on IDS of 10/12/2023, A1) as applied to claims 1-2, 4-6, 8-9, 12, 15-17, 19-20, 24-25, 29, and 30 above and further in view of Gauthier (Gauthier et al., Bone Marrow Transplant 2019; cited on PTO-892 of 1/7/2026).
The teachings of Wong 2015 are detailed in the 102 rejection above. Relevant to the instantly rejected claims, Wong 2015 teaches that the cutoff Z value is determined by modeling an interaction between the Z value (GES score of each subclass) and the receipt of corticosteroids using logistic regression (“We used logistic regression to test the association between adjunctive corticosteroids and outcomes within each subclass”, pg 314, col 1).
Wong 2015 does not teach that fitting the Z value using cubic splines. However, using cubic splines to model continuous variables with respect to a clinical outcome is known in the art, as taught by Gauthier.
Gauthier teach using an alternative modeling strategy that enables exploration of non-linear continuous associations between a continuous variable and clinical outcomes, particular cubic splines (pg 676, col 2, paragraph 2).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Wong 2015 with that of Gauthier to fit the Z value using cubic splines. One would be motivated to do so given the assertion by Gauthier that using linear regression to dichotomize or impose a linear relationship between a variable and an outcome “can lead to loss of information” which “might impair the predictive ability of the model” (pg 676, col 1, paragraph 1). One would have a reasonable expectation of success given that Wong 2015 is attempting to use an association between a continuous variable (Z value) and an outcome (high risk of adverse outcome vs other than high risk of adverse outcome) to create a predictive model, which Gauthier teaches cubic splines can be particularly beneficial for constructing (pg 679, col 2, paragraph 3).
Response to Remarks
Applicant's arguments filed 4/7/2026 have been fully considered but they are not deemed persuasive for the following reasons. Applicant argues on pg 15 of Remarks that “Wong 2015 does not include any step of classifying a patient based on calculating a Z value based on the difference between two separate calculations, based on differences between the reference mosaic with each of two separate reference endotypes. Rather, in the method described by Wong 2015, "Final subclass allocation was based on the least difference between the individual patient mosaic and one of the reference mosaics representing the septic shock subclasses" (emphasis added) (see "Gene Expression Mosaics and Computer-assisted Image Analysis" of Wong 2015).” The examiner respectfully disagrees. Wong teaches a procedure of classification that is mathematically identical, if in words rather than equation, to the claimed steps. Obtaining the difference between two separate calculations of |Ref – Patient| for each endotype to calculate a Z value is not mathematically different than classifying according to “least difference” of |Ref – Patient| relative to each individual reference. In the Z value equation, the readout will be positive or negative depending on which |Ref-Patient| comparison is the “least different”. Therefore, Wong 2015 teaches the mathematical procedure as claimed in claim 1. Wong 2015 no longer “anticipates” claim 1 given Applicant’s amendment to the claim to include treatment, therefore claim 1 is now rejected under 35 USC 103 as obvious over Wong 2015 in view of Wong 2019, as presented above.
Applicant’s arguments against the rejections of all dependent claims are in regards to Wong 2015 not teaching Equation 1 of claim 1. This argument has been addressed above and therefore the rejection of said dependent claims as laid out above are maintained.
Conclusion
No claims are allowed.
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 KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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