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 .
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.
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 allowance or after an Office action under Ex Parte Quayle, 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). 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, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on 4/1/2026 has been entered.
Priority
The present application claims benefit under 35 U.S.C. 119(e) to provisional applications 63/404,778, 63/350,531 and 63/305,613 filed on 09/08/2022, 06/09/2022 and 02/01/2022, respectively.
Information Disclosure Statement
The information disclosure statement filed on 4/1/2026 is being considered by the examiner.
Claim Objections
Claims 1, 3 and 30-31 are objected to because of the following informalities:
In claim 1 line 7, Applicant uses the abbreviations “IL-8”, it is recommended that abbreviations be accompanied by their full meaning at least at first instance that the abbreviation is used in order to improve clarity and avoid confusion.
In claim 1 line 15, “patient that is not high risk” appears to be a typographical error, namely it is suggested that “patient that is not high risk” read as “patient that is not classified as high risk” (annotations added) as per line 14.
In claim 3 line 3, Applicant uses the abbreviation “MMP8”; and in claim 3 in line 5 Applicant uses the abbreviation “CCL3”, it is recommended that abbreviations be accompanied by their full meaning at least at first instance that the abbreviation is used in order to improve clarity and avoid confusion.
In claim 30 line 3, “the expression levels of expression levels of” appears to be a typographical error, namely it is suggested that “the expression levels of expression levels of” read as “the expression levels of
In claim 31 line 2, “the expression levels of expression levels of” appears to be a typographical error, namely it is suggested that “the expression levels of expression levels of” read as “the expression levels of
In claim 31 line 5, “determining platelet count” appears to be a typographical error, namely it is suggested that “determining platelet count” read as “determining the platelet count”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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, 3, 7-8, 12-14, 19-20, 24, 28, 30-31, 37, 43 and 49-50 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.
Claim 1 recites the limitation "the biomarkers" in lines 8 and 12. There is insufficient antecedent basis for this limitation in the claim. It is not clear what biomarkers are being referred because the claim fails to previously recite “biomarkers”. Although the claim does previously recite “at least one biomarker comprising IL-8” (lines 6-7), it is not clear that “the biomarkers” (lines 8 and 12) are referring to the “at least one biomarker comprising IL-8” because “the biomarkers” could be referring to other biomarkers, not the “at least one biomarker comprising IL-8”. Due to these multiple possible interpretations of the limitation “the biomarker” (in lines 8 and 12) a person having ordinary skill in the art would not be capable of recognizing the metes and bounds of the claim.
Claim 1 further recites “classifying the patient as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course, based on the determination of whether the serum levels of each of the biomarkers are greater than the respective cut-off serum level” (lines 10-12). However, it is not clear what is meant by “based on the determination of whether the serum levels of each of the biomarkers are greater than the respective cut-off serum level”. The limitation “based on” is vague. It is not clear how the serum levels are used and how these affect the classifying step. For example, it is not clear whether a classification step is performed if the levels are not greater than the cut-off level. Therefore, a person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Furthermore, the terms “non-elevated” and “highly-elevated” in claim 1 lines 22-23 are a relative term which renders the claim indefinite. The terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what is encompassed by a highly-elevated level of IL-8. A person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claim 3 recites “The method of claim 1, further comprising analyzing the sample to determine serum protein biomarker concentrations of one or more additional biomarkers comprising MMP8, and determining platelet count of the neonate patient, or analyzing the sample to determine serum protein biomarker concentrations of one or more additional biomarkers comprising CCL3, and wherein a classification of high risk of mortality and/or complicated course comprises: a) an elevated serum level of IL-8, and a non-elevated median platelet count per mm3; b) an elevated serum level of IL-8, an elevated median platelet count per mm3, and an elevated serum level of MMP8; or c) an elevated level of IL-8, and an elevated level of CCL3; and wherein a classification of other than high risk of mortality and/or complicated course comprises: d) an elevated serum level of IL-8, an elevated median platelet count per mm3 , and a non-elevated serum level of MMP8; e) a non-highly elevated level of IL-8, and a non-elevated level of CCL3; or f) a non-elevated level of IL-8, and an elevated level of CCL3”.
It is not clear in claim 3 which limitations are intended to be optional, i.e. are encompass by the “or” limitation in line 3 and which limitations are intended to be not optional. The “or” in line 3 suggests that all the limitations afterwards are optional. However, the recitation of “and wherein a classification of high risk of mortality and/or complicated course comprises:…” (line 5) suggests that the following limitations are not optional. Therefore, a person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Furthermore, the terms “elevated”, “non-elevated” and “non-highly elevated” in claim 3 lines 7-10 and 13-16 is a relative term which renders the claim indefinite. The terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what is encompassed by an elevated, non-elevated or highly-elevated serum level of IL-8, MMP8 and/or CCL3. A person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Furthermore, claim 3 is unclear because the claim recites “wherein a classification of high risk of mortality and/or complicated course comprises: a) an elevated serum level of IL-8, and a non-elevated median platelet count per mm3; b) an elevated serum level of IL-8, an elevated median platelet count per mm3, and an elevated serum level of MMP8; or c) an elevated level of IL-8, and an elevated level of CCL3; and wherein a classification of other than high risk of mortality and/or complicated course comprises: d) an elevated serum level of IL-8, an elevated median platelet count per mm3, and a non-elevated serum level of MMP8; e) a non-highly elevated level of IL-8, and a non-elevated level of CCL3; or f) a non-elevated level of IL-8, and an elevated level of CCL3”. Therefore, claim 3 appears to contradict the level of IL-8 used to classify the patient as either high risk or other. For example, how can both a classification of high risk and a classification of other than high risk comprise an elevated serum level of IL-8 and an elevated platelet count?. For example, it is not clear how the patient would be classified if the patient has an elevated IL-8. A person having ordinary skill in the art would not be capable of recognizing the metes and bounds of the claim.
Claim 8 recites “The method of claim 3, wherein the serum biomarker levels are determined by serum protein biomarker concentration and wherein the median platelet count is determined by counting the median number of platelets per mm3, and wherein: a) an elevated level of IL-8 corresponds to a serum IL-8 concentration greater than 297 pg/mL; b) an elevated median platelet count per mm3 corresponds to a median platelet count per mm3 greater than 127,000 per mm3; and c) an elevated level of MMP8 corresponds to a serum MMP8 concentration greater than 111,846 pg/mL; or wherein the serum biomarker levels are determined by serum protein biomarker concentration, and wherein: d) an elevated level of IL-8 corresponds to a serum IL-8 concentration greater than 297 pg/mL; e) a highly elevated level of IL-8 corresponds to a serum IL-8 concentration greater than 7465 pg/mL; and f) an elevated level of CCL3 corresponds to a serum CCL3 concentration greater than 47 pg/mL”.
The limitation "the serum biomarker levels " in claim 8 lines 1 and 10 is unclear. There is insufficient antecedent basis for this limitation in the claim. It is not clear what serum biomarker levels are being referred because “serum biomarker levels” is not previously recited in claims 1, 3 or 8. Although claim 1 does previously recite “at least one biomarker comprising IL-8” (lines 6-7), and claim 3 does previously recite “serum protein biomarker concentrations” it is not clear whether “the serum biomarker levels” (claim 8 lines 1 and 10) are referring to the “at least one biomarker comprising IL-8” or the “serum protein biomarker concentrations”. The limitation of claim 8, “the serum biomarker levels” could be referring to other biomarkers, not the “at least one biomarker comprising IL-8” or the “serum protein biomarker concentrations”. Due to these multiple possible interpretations of the limitation “the serum biomarker levels” (in claim 8 lines 1 and 10) a person having ordinary skill in the art would not be capable of recognizing the metes and bounds of the claim.
The limitation “determined by serum protein biomarker concentration” (claim 8 lines 2 and 10-11) is unclear. How can the serum biomarker levels be determined by serum protein biomarker concentration? The “serum protein biomarker concentration” is not a method to determine serum biomarker levels, rendering the claim indefinite. A person having ordinary skill in the art would be confused by the language used in claim 8.
The limitation “the median platelet count” in claim 8 line 2 lacks antecedent basis. It is not clear what median platelet count is being referred because a median platelet count is not previously recited in claims 1 or 3. A person having ordinary skill in the art would not recognize the metes and bounds of the claim.
It is not clear in claim 8 which limitations are intended to be optional, i.e. are encompass by the “or” limitation in line 9 and which limitations are intended to be not optional. The “or” in line 9 suggests that all the limitations afterwards are optional. However, the recitation of “and wherein:…” (line 11) suggests that the following limitations are not optional. Therefore, a person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claim 12 recites “The method of claim 1, wherein the determination of whether the levels of the one or more biomarkers are non-elevated above a cut-off level comprises applying the biomarker expression level data to a decision tree comprising the one or more biomarkers”.
The limitation "the one or more biomarkers" in lines 2-4 is unclear. There is insufficient antecedent basis for this limitation in the claim. Although the limitation appears to be referring to “the biomarkers” of claim 1 line 8, given that “the biomarkers” of claim 1 line 8 is unclear, “the one or more biomarkers” in claim 12 lines 2-4 is also unclear. A person having ordinary skill in the art would not be capable of readily recognizing the metes and bounds of the claim. Furthermore, claim 8 recites the limitation "the biomarker expression level data" in line 3. There is insufficient antecedent basis for this limitation in the claim. It is not clear what data is being referred to because “a biomarker expression level data” is not previously recited in claim 1 or 12.
Claim 19 recites “wherein the classification is combined with …one or more additional biomarkers”. However, it is not clear how a classification can be combined with one or more additional biomarkers. The specification paragraph 61 discloses that a “"biomarker" refers to a biological molecule”. Therefore, it is not clear how a classification of a patient can be combined with a biological molecule. A person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claim 20 recites “wherein the one or more additional biomarkers is selected from wherein the biomarkers further comprise one or more selected from the group consisting of…”. It is not clear what is meant by “selected from wherein the biomarkers further comprise one or more selected from the group consisting of”. A person having ordinary skill in the art would be confused by the language of claim 20.
Claim 20 recites the limitation "the sepsis causative organism" in lines 6-7. There is insufficient antecedent basis for this limitation in the claim. It is not clear what is meant by the sepsis causative organism because “a sepsis causative organism” is not previously recited in claims 1, or 19-20.
Claim 30 recites “the expression levels…of one or more biomarkers comprising IL-8” in lines 3-4. There is insufficient antecedent basis for this limitation in the claim. It is not clear what is meant by the expression levels of the one or more biomarkers comprising IL-8 because “expression levels of one or more biomarkers comprising IL-8” is not previously recited in claims 1, or 30. Although claim 1 previously recites “at least one biomarker comprising IL-8” (lines 6-7), it is not clear that “the expression levels…of one or more biomarkers comprising IL-8” in line 2 refers to the “at least one biomarker comprising IL-8” (claim 1 lines 6-7) because it could be referring to other biomarkers. Claim 30 further recites “the protein biomarker expression levels of each of the biomarkers” in line 5. There is insufficient antecedent basis for this limitation in the claim. It is not clear what is meant by the protein biomarker expression levels of each of the biomarkers because “a protein biomarker expression levels of each of the biomarkers” is not previously recited in claims 1, or 30. Although claim 30 previously recites “expression levels of one or more biomarkers comprising IL-8” ( line 3-4), it is not clear that “the protein biomarker expression levels of each of the biomarkers” in line 5 refers to the “one or more biomarkers comprising IL-8” because it could be referring to other biomarkers. A person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claim 30 further recites “ “classifying the patient as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course, based on the determination of whether the expression levels of each of the biomarkers are greater than the respective cut-off expression level” (lines 7-10). However, it is not clear what is meant by “based on the determination of whether the expression levels of each of the biomarkers are greater than the respective cut-off expression level”. Similar to claim 1, the limitation “based on” is vague. It is not clear how the expression levels are used and how these affect the classifying step. For example, it is not clear whether a classification step is performed if the levels are not greater than the cut-off level. Therefore, a person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claim 30 further recites “maintaining the treatment being administered” (line 11). This limitation appears to be referring to the “administering a treatment” step in claim 1. However, “maintaining the treatment being administered” (claim 30 line 11) is unclear because claim 1 and the classifying step and subsequent administering step of claim 1 are unclear. It seems that the treatment step of claim 1 is not necessarily performed if the levels are not greater than the cut-off because claim 1 recites “administering a treatment…to a neonate patient that is classified as high risk , or…not high risk”. However, claim 1 also recites “classifying the patient…based on…cut-off serum level”. Given that claim 1 recites classifying the patient “based on” a “cut-off” level, the broadest reasonable interpretation of the claim encompasses the not classifying of the patient. If the patient is not classified, then the administering step is not performed since the administering step is performed on the classified patient. Because of this possible lack of antecedent basis of the limitation “maintaining the treatment being administered” (line 11), claim 30 is further unclear.
Claim 31 recites the limitation "the expression levels of...one or more biomarkers comprising MMP8 and/or CCL3" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. It is not clear what is meant by "the expression levels of...one or more " because expression levels of is not previously recited in claims 1 or 30-31. Claim 31 further recites the limitation "the " in lines-4. There is insufficient antecedent basis for this limitation in the claim. It is not clear what is meant by "the " because protein biomarker expression levels of each of the biomarkers is not previously recited in claims 1 or 30-31. Although claim 31 does recite “the expression levels of...one or more biomarkers comprising MMP8 and/or CCL3” it is not clear that “the ” are referring to the expression levels of because “the ” could be referring to other biomarkers. A person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claims 7, 13-14, 24, 28, 37, 43 and 49-50 are included with this rejection because they depend from a rejected claim but fail to clarify the scope of patent protection sought.
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.
Claim(s) 1, 3, 7-8, 12-14, 19-20, 24, 28 and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (US 9,238,841 B2)-Cite No. A1 of IDS 6/13/2023 ("Wong").
Regarding claim 1, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, “the biomarkers” is interpreted to be referring to “at least one biomarker comprising IL-8”; and the classifying step is interpreted as “classifying the patient as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course, when the determination of whether the serum levels of each of the biomarkers are greater than the respective cut-off serum level”.
Wong teaches a method of treating a neonate patient with sepsis and classified as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course (“methods of providing individualized treatment for a pediatric patient with septic shock, wherein a patient classified as high risk via the methods described herein can be selected for one or more high risk therapies, and wherein a patient classified as low risk via the methods described herein can be excluded from one or more high risk therapies” col. 3 lines 45-47), the method comprising: obtaining a serum sample from a neonate patient with sepsis at a first time point (“obtaining a sample from the patient” col. 2 line 10), wherein the neonate patient is up to 12 months old or is admitted to a newborn intensive care unit (“a patient age of 0.5 years or younger” col. 2 line 66); analyzing the sample to determine serum protein biomarker concentrations of at least one biomarker comprising IL-8 (“the one or more biomarkers include all of CCL3, HSPA1B, IL8, GZMB, and MMP8” col. 2 lines 60-61); determining whether the serum levels of each of the biomarkers are greater than a respective cut-off serum level (“analyzing the sample to determine the level(s) of one or more biomarkers associated with septic shock in pediatric patients; determining whether the level(s) of the one or more biomarkers are elevated above a cut-off level” col. 2 lines 10-14); and classifying the patient as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course, based on the determination of whether the serum levels of each of the biomarkers are greater than the respective cut-off serum level (“multi-biomarker based methods to stratify pediatric septic shock patients into high and low risk groups” Abstract); and administering a treatment comprising one or more high risk therapy to a neonate patient that is classified as high risk, or administering a treatment excluding a high risk therapy to a neonate patient that is not high risk to provide a method of treating a neonate patient with sepsis, thereby improving an outcome in the patient with sepsis; wherein the one or more high risk therapy comprises at least one selected from the group consisting of immune enhancing and/or modulating therapy, high dose antibiotics, extracorporeal membrane oxygenation/life support, plasmapheresis, pulmonary artery catheterization, and/or high-volume continuous hemofiltration (“the one or more high risk therapies include extracorporeal membrane oxygenation/life support, plasmapheresis, pulmonary artery catheterization, and/or high volume continuous hemofiltration” col. 3 lines 51-55); and wherein a classification of high risk of mortality and/or complicated course comprises an elevated level of IL-8, and wherein a classification of other than high risk of mortality and/or complicated course comprises a non-elevated serum level of IL-8 (“elevated levels of CCL3 and IL8” col. 2 lines 65-66, “and a classification of low risk includes: … non-elevated levels of IL8” col. 3 lines 2-4). Wong further suggests and wherein a classification of high risk of mortality and/or complicated course comprises a highly elevated level of IL-8 (“and a highly elevated level of IL8” col. 3 lines 1-2). Wong further teaches that “[s]eptic shock is also a major problem in the pediatric age group as there are-42,000 cases of pediatric septic shock per year in the United States alone, with a mortality rate of ~10% … No reliable and widely accepted outcome risk stratification tool specific for septic shock in pediatric patients has heretofore been developed. Such a tool would be beneficial at several levels, including stratification for interventional clinical trials, better-informed decision making for individual patients, and as a metric for quality improvement efforts” col. 1 lines 48-50, 64-67 and col. 2 lines 1-3).
Wong fails to teach “wherein a classification of high risk of mortality and/or complicated course comprises a highly elevated level of IL8” in a manner consistent with anticipation, i.e. there is some picking and choosing involved to arrive at the “highly elevated level of IL-8” in the classification of high risk of mortality and/or complicated course. Wong teaches that the “classification of high risk includes: a)…b)… c) a non-elevated level of GZMB, elevated levels of CCL3 and IL8, and a patient age of 0.5 years or younger…d)…or e) non-elevated levels of CCL3 and HSPA1B, and a highly elevated level of IL8” col. 2 lines 61-67 and col. 3 lines 1-2). Therefore, Wong teaches the claimed method by combining “elevated levels of… IL8, and a patient age of 0.5 years or younger” (col. 2 lines 65-66), with “a highly elevated level of IL8” (col. 3 lines 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the “patient age of 0.5 years or younger” (col. 2 lines 65-66), with “a highly elevated level of IL8” (col. 3 lines 1-2) taught by Wong because Wong teaches that there is a need for better risk stratification of neonate patients with sepsis and classified as high risk of mortality and suggests that a highly elevated level of IL8 is a possible predictable solution for such a problem. A person having ordinary skill in the art would be motivated to make such a combination of embodiments because Wong suggests that this enables better-informed decision making for individual patients. A person having ordinary skill in the art would have had a reasonable expectation of success because Wong teaches “elevated levels of…IL8, and a patient age of 0.5 years or younger”, thereby providing a reasonable expectation of success in using a highly elevated level.
Regarding claim 3, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the “or” in line 3 is interpreted as making all the limitations either before or after the “or” optional. Wong further teaches analyzing the sample to determine serum protein biomarker concentrations of one or more additional biomarkers comprising CCL3, and wherein a classification of high risk of mortality and/or complicated course comprises: c) an elevated level of IL-8, and an elevated level of CCL3;and wherein a classification of other than high risk of mortality and/or complicated course comprises: f) a non-elevated level of IL-8, and an elevated level of CCL3 (“c) a non-elevated level of G ZMB, elevated levels of CCL3 and IL8, and a patient age of 0.5 years or younger… g) non-elevated levels of IL8 and MMP8 and an elevated level of CCL3” col. 2 lines 65-66 and col. 3 lines 4-5).
Regarding claim 7, Wong teaches wherein an elevated level of IL-8 corresponds to a serum IL-8 concentration greater than 297 pg/mL (“c) an elevated level of IL8 corresponds to a serum IL8 concentration greater than 507 pg/ml” col. 3 lines 11-13).
Regarding claim 8, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the claim is interpreted as referring to the “at least one biomarker comprising IL-8” of claim 1 lines 6-7 determined by a protein assay. Furthermore, the “or” in line 8 is interpreted as making all the limitations either before or after the “or” optional.
Wong further teaches wherein the serum biomarker levels are determined by serum protein biomarker concentration (“Serum Protein Biomarker Assays… Assays for the 12 candidate stratification biomarkers (see Table 5) were performed using a Luminex 200 multi-plex instrument (Luminex Corporation, Austin, Tex.) and antibody-coated magnetic beads (Millipore, Billerica, Mass.), per the manufacturer's specifications” col. 28 line 64 and col. 29 lines 13-17). Wong further teaches a) an elevated level of IL-8 corresponds to a serum IL-8 concentration greater than 297 pg/mL (“c) an elevated level of IL8 corresponds to a serum IL8 concentration greater than 507 pg/ml” col. 3 lines 11-13). Wong further suggests e) a highly elevated level of IL-8 corresponds to a serum IL-8 concentration greater than 7465 pg/mL (“d) a highly elevated level of IL8 corresponds to a serum IL8 concentration greater than 829 pg/ml” col. 3 lines 13-14). Wong further teaches and f) an elevated level of CCL3 corresponds to a serum CCL3 concentration greater than 47 pg/mL (“a) an elevated level of CCL3 corresponds to a serum CCL3 concentration greater than 160 pg/ml” col. 3 lines 8-9).
With regards to the claimed range of “a highly elevated level of IL-8… greater than 7465 pg/mL”, the prior art teaches “a highly elevated level of IL-8… greater than 829 pg/mL”. In such a case, since there is a substantial overlap of the claimed range and the prior art range, a prima facie case of obviousness exists because it would have been obvious to a person having ordinary skill in the art to arrive at the claimed range by selecting values disclosed within the prior art range. See MPEP 2144.05.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Wong to consider a concentration of 7465 pg/mL or greater of IL-8 as “a highly elevated” level of IL-8 instead of a concentration of 829 pg/mL or greater because known work in one field of endeavor may prompt variations. Given that Wong teaches that there is a need for better risk stratification of neonate patients with sepsis and classified as high risk of mortality, a person having ordinary skill in the art would have found it obvious to adjust the “highly elevated” level of IL-8 to encompass a concentration of 7465 pg/mL through routine optimization. One would have been motivated to make such a modification in order to try to minimize the deaths of pediatric sepsis. A person having ordinary skill in the art would have had a reasonable expectation of success because Wong teaches that “a highly elevated level of IL8 corresponds to a serum IL8 concentration greater than 829 pg/ml” (col. 3 lines 13-14).
Regarding claim 12, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the claim is interpreted as referring to the “at least one biomarker comprising IL-8” of claim 1 lines 6-7.
Wong suggests wherein the determination of whether the levels of the one or more biomarkers are non-elevated above a cut-off level comprises applying the biomarker expression level data to a decision tree comprising the one or more biomarkers (“In some embodiments, the determination of whether the level(s) of the one or more biomarkers are elevated above a cut-off level includes applying the patient to a decision tree including the one or more biomarkers” col. 3 lines 19-22).
Regarding claim 13, Wong teaches wherein the classification of other than high risk of mortality and/or complicated course comprises a classification of low risk of mortality and/or complicated course (“and a classification of low risk includes: … non-elevated levels of IL8” col. 3 lines 2-4).
Regarding claim 14, Wong suggests wherein the complicated course comprises cardiovascular, respiratory, renal, hepatic, hematologic, and/or neurologic dysfunction and/or wherein the complicated course comprises dysfunction in one or more organs selected from heart, lungs, kidneys, liver, blood, and brain (“In the absence of a formal, validated quality of life measurement tool for survivors of pediatric septic shock, resolution of organ failure was tracked as a secondary outcome measure…Specifically, cardiovascular, respiratory, renal, hepatic, hematologic, and neurologic failure were tracked” col. 6 lines 60-67 and col. 7 lines 1-6).
Regarding claim 19, Wong suggests wherein the classification is combined with one or more patient demographic data and/or clinical characteristics and/or results from other tests or indicia of sepsis and/or one or more additional biomarkers, and/or wherein the classification is combined with one or more additional population-based risk scores (“The classification tree consists of six biomarker based decision rules, one age-based decision rule, and fourteen daughter nodes” col. 5 lines 55-57, “Accordingly, such demographic data, clinical characteristics, and/or results from other tests or indicia of septic shock can be incorporated into the method” col. 18 lines 58-60, “the biomarker-based risk stratification model described herein can be used with one or more additional population-based risk scores” col. 20 lines 27-29).
Regarding claim 20, Wong suggests wherein the one or more additional biomarkers is selected from wherein the biomarkers further comprise one or more selected from the group consisting of Heat shock protein 70 kDA (HSP70), HSPA1b (Heatshock Protein A1b), GZMB (Granzyme B), lnterleukin-1 α (IL-1α), and CCL3 (CC Chemokine Ligand 3) (“The classification tree includes five of the twelve candidate stratification biomarkers: CCL3, HSPA1B, IL8, granzyme B (GZMB), and matrix metalloproteinase-8 (MMP8)” col. 5 lines 57-60); and/or wherein the patient demographic data and/or clinical characteristics and/or results from other tests or indicia of sepsis comprise at least one selected from the group consisting of the sepsis causative organism, the presence or absence or chronic disease, and/or the chronological age, gestational age at birth, birth weight, gender, race, and/or co-morbidities of the patient (“Such pediatric patient demographic data can include, for example, the patient's age, race, gender, and the like….Such patient clinical characteristics and/or results from other tests or indicia of septic shock can include, for example, the patient's co-morbidities and/or septic shock causative organism, and the like” col. 19 lines 1-2 and 20-23).
Regarding claim 24, Wong teaches wherein the sample is obtained within the first hour of presentation with sepsis, or wherein the sample is obtained within the first 24 hours of presentation with sepsis (“the sample can be obtained within the first hour of presentation with septic shock. … the sample can be obtained within the first 24 hours of presentation with septic shock” col. 3 lines 37-42).
Regarding claim 28, Wong suggests wherein the patient classified as high risk of mortality and/or complicated course is enrolled in a clinical trial (“selecting a pediatric patient with septic shock for a clinical trial, wherein a patient classified as high risk via the methods described herein can be selected for a moderate or high risk clinical trial” col. 3 lines 64-67).
Regarding claim 49, Wong teaches wherein the patient is up to 6 months old (“a patient age of 0.5 years or younger” col. 2 line 66).
Regarding claim 50, Wong suggests wherein the patient is up to 5 weeks old (“Full-term neonates (that is, <28 days of age) readmitted to the hospital for septic shock were included” col. 28 lines 30-31).
Claims 30 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Wong as applied to claim 3 above, and further in view of Lindsell et al. (US 10815526 B2)-Cite No. A6 of IDS 6/13/2023 (“Lindsell”).
Regarding claim 30, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the claim is interpreted as reciting “…analyzing the second sample to determine one or more biomarkers are greater than a respective cut-off
Wong teaches the method of claim 1 as discussed above.
Wong fails to teach obtaining a second sample from the treated patient at a second time point; analyzing the second sample to determine expression levels of one or more biomarkers comprising IL-8; determining whether the expression levels of each of the one or more biomarkers are greater than a respective cut-off biomarker expression level; classifying the patient as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course, based on the determination of whether the expression levels of each of the biomarkers are greater than the respective cut-off expression level; and maintaining the treatment being administered if the patient's high risk classification has not changed, or changing the treatment being administered if the patient's high risk classification has changed.
Lindsell teaches “temporal pediatric sepsis biomarker risk model” (Title). Lindsell further suggests a method of treating a pediatric patient with sepsis (“monitoring the therapeutic efficacy of a treatment being administered to a patient with septic shock” col. 2 lines 8-9) and classified as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course (“particularly as those responses relate to septic shock in pediatric patients.” Abstract), the method comprising: obtaining a serum sample; analyzing the sample to determine serum protein biomarker concentrations of at least one biomarker comprising IL-8 (“a first serum concentration level of each of three biomarkers consisting of C-C chemokine ligand 3 (CCL3), interleukin-8 (IL8) and heat shock protein 70 kDa 1B (HSPA1B);” claim 1); determining whether the serum levels of each of the biomarkers are greater than a respective cut-off serum level (“determining whether the level of each biomarker is elevated above a cut-off level” claim 1); and classifying the patient as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course, based on the determination of whether the serum levels of each of the biomarkers are greater than the respective cut-off serum level (“identifying the patient as at high risk for a poor outcome where any one of the following is true:… c) an elevated level of CCL3 and a highly elevated level of IL8” claim 1); wherein a classification of high risk of mortality and/or complicated course comprises an elevated level of IL-8, and wherein a classification of other than high risk of mortality and/or complicated course comprises a non-elevated serum level of IL-8 (claim 1). Lindsell further teaches obtaining a second sample from the treated patient at a second time point; analyzing the second sample to determine expression levels of one or more biomarkers comprising IL-8 (“analyzing a second sample that has been obtained from the patient at a second time point…to determine a second serum concentration level of each of the three biomarkers” claim 1); determining whether the expression levels of each of the one or more biomarkers are greater than a respective cut-off biomarker expression level (“determining whether the level of each biomarker is elevated above a cut-off level at each of the first and second time points” claim 1); classifying the patient as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course, based on the determination of whether the expression levels of each of the biomarkers are greater than the respective cut-off expression level (“identifying the patient as at high risk for a poor outcome where any one of the following is true:… and an elevated level of IL8 at the second time point” claim 1); and maintaining the treatment being administered if the patient's high risk classification has not changed, or changing the treatment being administered if the patient's high risk classification has changed (“The patient's risk for a poor outcome at each of the time points is then compared in order to determine if the patient's risk for a poor outcome increased or decreased between the time points, where an increased risk for a poor outcome indicates that a therapy has had a poor efficacy, and a reduced risk for a poor outcome indicates that a therapy has had a good efficacy…If a treatment is determined to have had a poor efficacy, that treatment is discontinued. The discontinued treatment which has had a poor efficacy is then replaced with a different treatment, in order to achieve an improved outcome” col. 21 lines 31-37 and 60-64). Lindsell further teaches that “[t]he various methods and techniques described above provide a number of ways to carry out the application” (col. 21 lines 66-67).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Wong to rely on the obtaining a second sample from the treated patient at a second time point; analyzing the second sample to determine expression levels of one or more biomarkers comprising IL-8; determining whether the expression levels of each of the one or more biomarkers are greater than a respective cut-off biomarker expression level; classifying the patient as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course, based on the determination of whether the expression levels of each of the biomarkers are greater than the respective cut-off expression level; and maintaining the treatment being administered if the patient's high risk classification has not changed, or changing the treatment being administered if the patient's high risk classification has changed suggested by Lindsell because Lindsell teaches that this enables better clinical outcomes, which is a current need in the field as pediatric septic shock is prevalent and deadly. A person having ordinary skill in the art would have had a reasonable expectation of success because both Wong and Lindsell teach a method of treating a pediatric patient with sepsis and classified as high risk of mortality comprising classifying the patient based on the level of at least one biomarker comprising IL-8. Furthermore, Lindsell teaches that “[t]he various methods and techniques described above provide a number of ways to carry out the application” (col. 21 lines 66-67).
Regarding claim 37, Wong in view of Lindsell teach the method of claim 30 as discussed above.
Wong in view of Lindsell further teach wherein the patient classified as high risk and administered one or more high risk therapy after the first time point is not classified as high risk after the second time point (col. 21 lines 31-37 of Lindsell).
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Wong in view of Lindsell as applied to claim 30 above, and further in view of Kim et al. Pediatric Surgery. 2012 Mar 21:1427–1452. doi: 10.1016/B978-0-323-02842-4.50095-4 (“Kim”).
Regarding claim 31, Wong in view of Lindsell teach the method of claim 30 as discussed above.
Wong in view of Lindsell further teach further comprising analyzing the second sample to determine the expression levels of expression levels of one or more biomarkers comprising MMP8 and/or CCL3, and determining whether the protein biomarker expression levels of each of the biomarkers are greater than a respective cut-off protein biomarker expression level (claim 1 of Lindsell).
Wong in view of Lindsell fail to teach and further comprising determining platelet count of the neonate patient.
Kim teaches “Necrotizing Enterocolitis” (Title). Kim further teaches that “Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in neonatal intensive care units (NICUs) around the world” (Abstract). Kim further teaches that necrotizing enterocolitis is associated with sepsis (“Infants with NEC usually have neutropenia, thrombocytopenia, and metabolic acidosis.…Thrombocytopenia is nearly universally present and seems to be associated with gram-negative sepsis” page 1435 col. 1 paras. 3-4). Kim further suggests determining a platelet count of the neonate patient (“in a cohort of 40 infants who underwent surgery for NEC, 95% had platelet counts less than 150,000 cells/mm3.” Page 1435 col. 1 para. 4). Kim further suggests that “[a] platelet count less than 109/L or a rapid fall is a poor prognostic indicator” (page 1435 col. 1 para. 4) of sepsis and necrotizing enterocolitis.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Wong in view of Lindsell to include the determining of the platelet count of the neonate patient taught by Kim because Kim suggests that the platelet count is a prognostic indicator of the necrotizing enterocolitis (NEC). A person having ordinary skill in the art would have been motivated to make such a modification because NEC is the leading cause of morbidity and mortality in neonatal intensive care units (NICUs) around the world, and Wong in view of Lindsell are interested in a method of treating neonates admitted into newborn intensive care units. A person having ordinary skill in the art would have had a reasonable expectation of success because Kim teaches that NEC is associated with sepsis and both Kim and Wong in view of Lindsell teach determining whether biomarker levels are greater than a cut-off in the context of neonatal care.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Wong as applied to claim 1 above, and further in view of Kim et al. Pediatric Surgery. 2012 Mar 21:1427–1452. doi: 10.1016/B978-0-323-02842-4.50095-4 (“Kim”).
Regarding claim 43, Wong teaches the method of claim 1 as discussed above.
Wong fails to teach wherein the patient additionally has necrotizing enterocolitis.
Kim teaches “Necrotizing Enterocolitis” (Title). Kim further teaches that “Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in neonatal intensive care units (NICUs) around the world” (Abstract). Kim further teaches that necrotizing enterocolitis is associated with sepsis (page 1435 col. 1 paras. 3-4). Kim further suggests determining a platelet count of the neonate patient (“in a cohort of 40 infants who underwent surgery for NEC, 95% had platelet counts less than 150,000 cells/mm3.” Page 1435 col. 1 para. 4). Kim further suggests that “[a] platelet count less than 109/L or a rapid fall is a poor prognostic indicator” (page 1435 col. 1 para. 4) of sepsis and necrotizing enterocolitis.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Wong to include patients with sepsis and necrotizing enterocolitis taught by Kim because Kim teaches that necrotizing enterocolitis is the leading cause of morbidity and mortality in neonatal intensive care units (NICUs) around the world, and Wong is interested in a method of treating neonates admitted into newborn intensive care units. A person having ordinary skill in the art would have had a reasonable expectation of success because Kim teaches that NEC is associated with sepsis and both Kim and Wong teach determining whether biomarker levels are greater than a cut-off in the context of neonatal care.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 7-8, 12-14, 19-20, 24, 28 and 49-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 9238841 B2 in view of Wong.
Claims 1, 3, 7-8, 12-14, 19-20, 24, 28 and 49-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10261068 B2 in view of Wong.
Claims 1, 3, 7-8, 12-14, 19-20, 24, 28 and 49-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10815526 B2 in view of Wong.
In the interest of compact prosecution, the analysis regarding the nonstatutory double patenting rejections are presented in the form of tables, showing what the claim recites, what the art teaches, what the double patents recite and the appropriate obviousness analysis and reasonable expectation of success:
Claims 1
and 49-50
Wong teaches:
Obviousness Analysis
Expectation of success
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
A method of treating a neonate patient, wherein the patient is up to 6 months old, ,wherein the patient is up to 5 weeks old, with sepsis and
classified as high risk of mortality and/or complicated course, or other than high risk of mortality
and/or complicated course, the method comprising…
col. 3 lines 45-47,
“Full-term neonates (that is, <28 days of age) readmitted to the hospital for septic shock were included” col. 28 lines 30-31
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of US Patent No. 9238841 B2, U.S. Patent No. 10261068 B2 and US Patent No. 10815526 B2 to include the treating of a neonate patient up to 5 weeks old with sepsis and classified as high risk based on a highly elevated level of IL-8 taught by Wong because Wong teaches that neonate sepsis is a serious and prevalent problem in the United States with a high mortality rate. Therefore, one would be motivated to include
the treating of a neonate patient, up to 5 weeks old with sepsis and classified as high risk in order to address the current need in the field and minimize the high mortality rate.
A person having ordinary skill in the art would have had a reasonable expectation of success because U.S. Patent No. 9238841 B2 is interested in pediatric patients with septic shock, U.S. Patent No. 10261068 B2 is interested in method of treating septic shock in a pediatric patient and U.S. Patent No. 10815526 B2 is interested in methods of treating septic shock in a patient.
“classifying a pediatric patient with septic shock” (claim 1)
“elevated levels of CCL3 and IL8, and a patient age of 0.5 years or younger” (claim 3)
“A method of treating septic shock in a pediatric patient presenting with multiple organ failure (MOF)” (claim 1)
“A method of monitoring the therapeutic efficacy of a first treatment administered to a patient with septic shock” (claim 1)
obtaining a serum sample from a neonate patient with sepsis at a first time point, wherein
the neonate patient is up to 12 months old or is admitted to a newborn intensive care unit;…
col. 2 line 10 and col. 2 line 66
“obtaining a sample from the patient” (claim 1)
“ IL8 corresponds to a serum IL8 concentration” (claim 2)
“obtaining at least one biological sample… determining a blood platelet count” (claim 1)
“wherein the protein biomarkers are blood proteins and the biological sample is whole blood or plasma, or a combination thereof” (claim 6)
“analyzing a first sample that has been obtained from the patient at a first time point…to determine a first serum concentration level of” (claim 1)
analyzing the sample to determine serum protein biomarker concentrations of at least one
biomarker comprising IL-8;…
col. 2 lines 60-61
“analyzing the sample to determine the level(s) of one or more biomarkers selected from the group consisting of the biomarkers listed in Table 1, wherein the one or more biomarkers comprise all of C-C chemokine ligand 3 (CCL3), heat shock protein 70 kDa 1B (HSPA1B), interleukin-8 (IL8), lipocalin 2 (LCN2), and elastase 2 (ELA2)” (claim 1)
“ the amount of each of the following protein biomarkers in the at least one biological sample: C-C chemokine ligand 3 (CCL3), heat shock protein 70 kDa 1B (HSPA1B), interleukin-8 (IL8), granzyme B (GZMB), and matrix metalloproteinase 8 (MMP8)” (claim 1)
“analyzing…each of three biomarkers consisting of C-C chemokine ligand 3 (CCL3), interleukin-8 (IL8) and heat shock protein 70 kDa 1B (HSPA1B)” (claim 1)
determining whether the serum levels of each of the biomarkers are greater than a
respective cut-off serum level; and…
col. 2 lines 10-14
“determining whether the level(s) of the one or more biomarkers are elevated above a cut-off level” (claim 1)
“and classifying the patient as intermediate risk if any of the following are true: a) an amount of CCL3 protein less than or equal to 150 pg/ml, an amount of HSPA1B greater than 90,000 pg/ml, an amount of IL8 protein greater than 200 pg/ml…” (claim 2)
“determining whether the level of each biomarker is elevated above a cut-off level at each of the first and second time points” (claim 1)
classifying the patient as high risk of mortality and/or complicated course, or other than
high risk of mortality and/or complicated course, based on the determination of whether the serum
levels of each of the biomarkers are greater than the respective cut-off serum level; and…
Abstract
“wherein the presence of an elevated level of one or more biomarkers associated with septic shock in pediatric patients indicates that the patient has an elevated likelihood of being classified as high risk and the absence of an elevated level of one or more biomarkers associated with septic shock in pediatric patients indicates that the patient has a reduced likelihood of being classified as high risk” (claim 1)
Claim 2
“identifying the patient as at high risk for a poor outcome where any one of the following is true: a) a non-elevated level of CCL3 and an elevated level of IL8 at the first time point, and a highly elevated level of IL8 at the second time point…” (claim 1)
administering a treatment comprising one or more high risk therapy to a neonate patient
that is classified as high risk, or administering a treatment excluding a high risk therapy to a
neonate patient that is not high risk to provide a method of treating a neonate patient with sepsis,
thereby improving an outcome in the patient with sepsis;…
col. 3 lines 51-55
“and treating the intermediate or high risk patient” (claim 1)
“discontinuing administration of the first treatment and administering to the patient identified as at high risk for a poor outcome a second treatment selected from one or more of extracorporeal membrane oxygenation/life support, plasmapheresis, pulmonary artery catheterization, and high volume continuous hemofiltration” (claim 1)
wherein the one or more high risk therapy comprises at least one selected from the group
consisting of immune enhancing and/or modulating therapy, high dose antibiotics, extracorporeal
membrane oxygenation/life support, plasmapheresis, pulmonary artery catheterization, and/or
high-volume continuous hemofiltration; and…
col. 3 lines 51-55
“with a treatment selected from the group consisting of extracorporeal membrane oxygenation/life support, plasmapheresis, plasma exchange, pulmonary artery catheterization, high volume continuous hemofiltration, and combinations thereof” (claim 1)
Claim 1
wherein a classification of high risk of mortality and/or complicated course comprises a
highly elevated level of IL-8, and wherein a classification of other than high risk of mortality
and/or complicated course comprises a non-elevated serum level of IL-8.
col. 3 lines 1-4
“a highly elevated level of IL8” (claim 3)
“an amount of IL8 protein less than or equal to 830 pg/ml…an amount of IL8 protein greater than 3,350 pg/ml” (claim 2)
and a highly elevated level of IL8 at the second time point…” (claim 1)
Claim 3
Wong teaches:
Obviousness Analysis
Expectation of success
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
analyzing the
sample to determine serum protein biomarker concentrations of one or more additional biomarkers
comprising MMP8, and determining platelet count of the neonate patient
Regarding claim 3, U.S. Patent No. 9238841 B2 and U.S. Patent No. 10261068 B2 recite the claimed method (see citations in their respective columns).
However, with regards to U.S. Patent No. 10815526 B2, although the patent recites wherein a classification of high risk comprises c) an elevated level of IL-8, and an elevated level of CCL3 (claim 1), U.S. Patent No. 10815526 B2 fails to recite the limitations regarding the classification of other than high risk of mortality and/or complicated course.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 10815526 B2 to include a classification of other than high risk of mortality and/or complicated course comprising d)-f) taught by Wong
because it would have been a simple matter of applying a known technique to a known method. In this case, both U.S. Patent No. 10815526 B2 and Wong teach classifying a patient with septic shock as high risk of mortality. Wong simply applies the art-recognized technique of classifying a patient with septic shock as low risk of mortality when there is a non-elevated level of IL-8, and an elevated level of CCL3. Therefore, a person having ordinary skill in the art would have found it obvious to apply the technique taught by Wong to the base method taught by both U.S. Patent No. 10815526 B2 and Wong.
A person having ordinary skill in the art would have had a reasonable expectation of success because both Wong and U.S. Patent No. 10815526 B2 are interested in methods of treating septic shock in a patient.
“determining a blood platelet count and the amount of each of the following protein biomarkers in the at least one biological sample: C-C chemokine ligand 3 (CCL3), heat shock protein 70 kDa 1B (HSPA1B), interleukin-8 (IL8), granzyme B (GZMB), and matrix metalloproteinase 8 (MMP8)” (claim 1)
or analyzing the sample to determine serum protein biomarker concentrations of one or more additional biomarkers
comprising CCL3, and wherein a classification of high risk of mortality and/or complicated course
comprises:
col. 2 lines 65-66
“one or more biomarkers comprise all of C-C chemokine ligand 3 (CCL3)” (claim 1)
“three biomarkers consisting of C-C chemokine ligand 3 (CCL3), interleukin-8 (IL8) and heat shock protein 70 kDa 1B (HSPA1B);… c) an elevated level of CCL3 and a highly elevated level of IL8 at the first time point” (claim 1)
a) an elevated serum level of IL-8, and a non-elevated median platelet count per mm3;
b) an elevated serum level of IL-8, an elevated median platelet count per mm3, and an
elevated serum level of MMP8; or
c) an elevated level of IL-8, and an elevated level of CCL3;
and wherein a classification of other than high risk of mortality and/or complicated course
comprises:
d) an elevated serum level of IL-8, an elevated median platelet count per mm3, and a nonelevated
serum level of MMP8;
e) a non-highly elevated level of IL-8, and a non-elevated level of CCL3; or
f) a non-elevated level of IL-8, and an elevated level of CCL3.
“c) a non-elevated level of G ZMB, elevated levels of CCL3 and IL8, and a patient age of 0.5 years or younger” col. 2 lines 65-66
g) non-elevated levels of IL8 and MMP8 and an elevated level of CCL3” col. 3 lines 4-5
“ wherein a classification of high risk comprises a) elevated levels of CCL3, IL8, and GZMB… wherein a classification of low risk comprises: f) non-elevated levels of CCL3 and HSPA1B, and a non-highly elevated level of IL8” (claim 3)
Claim 7
Wong teaches:
Obviousness Analysis
Expectation of success
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
wherein an elevated level of IL-8
corresponds to a serum IL-8 concentration greater than 297 pg/mL
“(“c) an elevated level of IL8 corresponds to a serum IL8 concentration greater than 507 pg/ml” col. 3 lines 11-13
With regards to the claimed range of “an elevated level of IL-8 corresponds to a serum IL-8 concentration greater than 297 pg/mL”, U.S. Patent No. 10815526 B2
recites “an elevated level of IL8 at the first time point corresponds to a serum IL8 concentration greater than 125 pg/ml”. In such a case, since there is a substantial overlap of the claimed range and the patent range, a prima facie case of obviousness exists because it would have been obvious to a person having ordinary skill in the art to arrive at the claimed range by selecting values disclosed within the prior art range. See MPEP 2144.05.
A person having ordinary skill in the art would have had a reasonable expectation of success because both Wong and U.S. Patent No. 10815526 B2 are interested in methods of treating septic shock in a patient
“an elevated level of IL8 corresponds to a serum IL8 concentration greater than 507 pg/ml” (claim 4)
“an amount of IL8 protein greater than 830 pg/ml” (claim 2)
“c) an elevated level of IL8 at the first time point corresponds to a serum IL8 concentration greater than 125 pg/ml” (claim 6)
Claim 8
Wong teaches:
Obviousness Analysis
Expectation of success
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
wherein the serum biomarker levels
are determined by serum protein biomarker concentration and wherein the median platelet count
is determined by counting the median number of platelets per mm3
, and wherein:
a) an elevated level of IL-8 corresponds to a serum IL-8 concentration greater than 297
pg/mL;
b) an elevated median platelet count per mm3 corresponds to a median platelet count per
mm3 greater than 127,000 per mm3
; and
c) an elevated level of MMP8 corresponds to a serum MMP8 concentration greater than
111,846 pg/mL;
With regards to the claimed range of “a highly elevated level of IL-8… greater than 7465 pg/mL”, the prior art teaches “a highly elevated level of IL-8… greater than 829 pg/mL” (Wong and US Patent No. 9238841 B2) and “436 pg/ml” (US Patent No. 10815526 B2). In such a case, since there is a substantial overlap of the claimed range and the prior art range, a prima facie case of obviousness exists because it would have been obvious to a person having ordinary skill in the art to arrive at the claimed range by selecting values disclosed within the prior art range. See MPEP 2144.05.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of US Patent No. 9238841 B2 and US Patent No. 10815526 B2 to consider a concentration of 7465 pg/mL or greater of IL-8 as “a highly elevated” level of IL-8 instead of a concentration of 829 pg/ml and 436 pg/ml or greater because known work in one field of endeavor may prompt variations. Given that Wong teaches that there is a need for better risk stratification of neonate patients with sepsis and classified as high risk of mortality, a person having ordinary skill in the art would have found it obvious to adjust the “highly elevated” level of IL-8 to encompass a concentration of 7465 pg/mL through routine optimization. One would have been motivated to make such a modification in order to try to minimize the deaths of pediatric sepsis.
A person having ordinary skill in the art would have had a reasonable expectation of success because Wong teaches that “a highly elevated level of IL8 corresponds to a serum IL8 concentration greater than 829 pg/ml” (col. 3 lines 13-14).
or
wherein the serum biomarker levels are determined by serum protein biomarker
concentration, and wherein:
d) an elevated level of IL-8 corresponds to a serum IL-8 concentration greater than 297
pg/mL; e) a highly elevated level of IL-8 corresponds to a serum IL-8 concentration greater than
7465 pg/mL; and
f) an elevated level of CCL3 corresponds to a serum CCL3 concentration greater than 47
pg/mL
“Protein Biomarker Assays” col. 28 l. 64 and col. 29 l. 13-17.
“c) an elevated level of IL8 corresponds to a serum IL8 concentration greater than 507 pg/ml” col. 3 l. 11-13
“d) a highly elevated level of IL8 corresponds to a serum IL8 concentration greater than 829 pg/ml” col. 3 l. 13-14
“a) an elevated level of CCL3 corresponds to a serum CCL3 concentration greater than 160 pg/ml” col. 3 l. 8-9
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of US Patent No. 10261068 B2 to include an elevated level of IL-8 corresponding to a serum IL-8 concentration greater than 297 pg/mL and a highly elevated level of IL-8 corresponding to a serum IL-8 concentration greater than 7465 pg/mL taught by Wong because Wong suggests these cut-offs help minimize the deaths of pediatric sepsis.
“wherein a) an elevated level of CCL3 corresponds to a serum CCL3 concentration greater than 160 pg/ml, b) an elevated level of HSPA1B corresponds to a serum HSPA1B concentration greater than 3.3 μg/ml, c) an elevated level of IL8 corresponds to a serum IL8 concentration greater than 507 pg/ml, d) a highly elevated level of IL8 corresponds to a serum IL8 concentration greater than 829 pg/ml,” (claim 4)
“f) an amount of CCL3 protein greater than 150 pg/ml” (claim 2)
“a) an elevated level of CCL3 at the first time point corresponds to a serum CCL3 concentration greater than 130 pg/ml…c) an elevated level of IL8 at the first time point corresponds to a serum IL8 concentration greater than 125 pg/ml, d) a highly elevated level of IL8 at the first time point corresponds to a serum IL8 concentration greater than 436 pg/ml” (claim 6)
Claim 12
Wong teaches:
Obviousness Analysis
Expectation of success
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
wherein the determination of
whether the levels of the one or more biomarkers are non-elevated above a cut-off level comprises
applying the biomarker expression level data to a decision tree comprising the one or more
biomarkers.
“applying the patient to a decision tree including the one or more biomarkers” col. 3 lines 19-22
“CART analysis is based on a binary recursive partitioning
algorithm and allows for the discovery of complex predictor variable interactions that may not be apparent with
more traditional methods” col. 4 lines 49-56
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 to include a decision tree taught by Wong because Wong suggests this improves the determination of whether the levels are above the cut-off, thereby making the method more sensitive.
A person having ordinary skill in the art would have had a reasonable expectation of success because both Wong and U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 are interested in methods of treating septic shock in a patient
“wherein the classifying is performed using a classification and regression tree methodology” (claim 3)
Claim 13
Wong teaches:
Obviousness Analysis
Expectation of success
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
wherein the classification of other
than high risk of mortality and/or complicated course comprises a classification of low risk of
mortality and/or complicated course
col. 3 lines 2-4
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 10815526 B2 and U.S. Patent No. 10261068 B2 to include a classification of low risk of
mortality and/or complicated course by Wong because Wong suggests this enables proper stratification.
A person having ordinary skill in the art would have had a reasonable expectation of success because both Wong and U.S. Patent No. 10815526 B2 and U.S. Patent No. 10261068 B2 are interested in methods of treating septic shock in a patient
“low risk” claim 1
Claim 14
Wong teaches:
Obviousness Analysis
Expectation of success
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
wherein the complicated course
comprises cardiovascular, respiratory, renal, hepatic, hematologic, and/or neurologic dysfunction;
and/or wherein the complicated course comprises persistence of two or more organ dysfunctions
on day 7 of illness and/or vasopressor use; and/or wherein the complicated course comprises
dysfunction in one or more organs selected from heart, lungs, kidneys, liver, blood, and brain.
col. 6 lines 60-67 and col. 7 lines 1-6
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 to include dysfunction in one or more organs selected from heart, lungs, kidneys, liver, blood, and brain taught by Wong because Wong suggests this enables proper stratification and treatment.
A person having ordinary skill in the art would have had a reasonable expectation of success because both Wong and U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 are interested in methods of treating septic shock in a patient.
“a pediatric patient with septic shock as high risk…”
“multiple organ failure (MOF)” claim 1
“a patient with septic shock” claim 1
Claim 19
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
wherein the classification is combined with one or more patient demographic data and/or clinical characteristics and/or results from other tests or indicia of sepsis and/or one or more additional biomarkers, and/or wherein the classification is combined with one or more additional population-based risk scores
“wherein the one or more biomarkers comprise all of C-C chemokine ligand 3 (CCL3),heat shock protein 70 kDa 1B (HSPA1B), interleukin-8 (IL8), granzyme B (GZMB), and matrix metalloproteinase-8 (MMP8)” claim 1
“platelets, C-C chemokine ligand 3 (CCL3), heat shock protein 70 kDa 1B (HSPA1B), interleukin-8 (IL8), granzyme B (GZMB), and matrix metalloproteinase 8 (MMP8)” claim 1
“three biomarkers consisting of C-C chemokine ligand 3 (CCL3), interleukin-8 (IL8) and heat shock protein 70 kDa 1B (HSPA1B)” claim 1
Claim 20
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
wherein the one or more additional biomarkers is selected from wherein the biomarkers further comprise one or more selected from the group consisting of Heat shock protein 70 kDA (HSP70), HSPA1b (Heatshock Protein A1b), GZMB (Granzyme B), lnterleukin-1 a (IL-la), and CCL3 (CC Chemokine Ligand 3); and/or wherein the patient demographic data and/or clinical characteristics and/or results from other tests or indicia of sepsis comprise at least one selected from the group consisting of the sepsis causative organism, the presence or absence or chronic disease, and/or the chronological age, gestational age at birth, birth weight, gender, race, and/or co-morbidities of the patient
Claim 1
Claim 1
Claim 1
Claim 24
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
wherein the sample is obtained
within the first hour of presentation with sepsis, or wherein the sample is obtained within the first
24 hours of presentation with sepsis.
“wherein the sample is obtained within the first hour of presentation with septic shock” claim 7
“wherein the sample is obtained within the first hour of presentation with septic shock” claim 4
“analyzing a first sample that has been obtained from the patient at a first time point, which is during day 1 of presentation with septic shock” claim 1
Claim 28
Wong teaches:
Obviousness Analysis
Expectation of success
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
wherein the patient classified as
high risk of mortality and/or complicated course is enrolled in a clinical trial
“selecting a pediatric patient with septic shock for a clinical trial, wherein a patient classified as high risk via the methods described herein can be selected for a moderate or high risk clinical trial” col. 3 lines 64-67
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 10261068 B2, U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 to include wherein the patient classified as
high risk of mortality and/or complicated course is enrolled in a clinical trial
taught by Wong because Wong suggests this enables proper stratification and treatment, i.e. only the patients with the most need would be selected for the high risk clinical trial.
A person having ordinary skill in the art would have had a reasonable expectation of success because both Wong and U.S. Patent No. 10261068 B2, U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 are interested in methods of treating septic shock in a patient.
Claims 30 and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 9238841 B2 in view of Wong as applied to claim 1 above, and further in view of Lindsell.
Claims 30 and 37are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10261068 B2 in view of Wong as applied to claim 1 above, and further in view of Lindsell.
Claims 30 and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10815526 B2 in view of Wong as applied to claim 1 above, and further in view of Lindsell.
Claims 30 and 37
Lindsell teaches:
Obviousness Analysis
Expectation of success
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
obtaining a second sample from the treated patient at a second time point…
“analyzing a second sample that has been obtained from the patient at a second time point…to determine a second serum concentration level of each of the three biomarkers” claim 1
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 10261068 B2, U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 to rely on the obtaining a second sample from the treated patient at a second time point; analyzing the second sample to determine expression levels of one or more biomarkers comprising IL-8; determining whether the expression levels of each of the one or more biomarkers are greater than a respective cut-off biomarker expression level; classifying the patient as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course, based on the determination of whether the expression levels of each of the biomarkers are greater than the respective cut-off expression level; and maintaining the treatment being administered if the patient's high risk classification has not changed, or changing the treatment being administered if the patient's high risk classification has changed suggested by Lindsell because Lindsell teaches that this enables better clinical outcomes, which is a current need in the field as pediatric septic shock is prevalent and deadly.
A person having ordinary skill in the art would have had a reasonable expectation of success because U.S. Patent No. 9238841 B2 is interested in pediatric patients with septic shock, U.S. Patent No. 10261068 B2 is interested in method of treating septic shock in a pediatric patient and U.S. Patent No. 10815526 B2 is interested in methods of treating septic shock in a patient; and Lindsell teaches “temporal pediatric sepsis risk model” (Title). Furthermore, Lindsell “provide[s] a number of ways to carry out the application” (col. 21 lines 66-67).
analyzing a second sample that has been obtained from the patient at a second time point…to determine a second serum concentration level of each of the three biomarkers” claim 1
analyzing the second sample to determine the expression levels of expression levels of one
or more biomarkers comprising IL-8;
Claim 1
claim 1
determining whether the protein biomarker expression levels of each of the biomarkers are
greater than a respective cut-off protein biomarker expression level;
“determining whether the level of each biomarker is elevated above a cut-off level at each of the first and second time points” claim 1
“determining whether the level of each biomarker is elevated above a cut-off level at each of the first and second time points” claim 1
classifying the patient as high risk of mortality and/or complicated course, or other than
high risk of mortality and/or complicated course, based on the determination of whether the
expression levels of each of the biomarkers are greater than the respective cut-off expression level;
and
“identifying the patient as at high risk for a poor outcome where any one of the following is true:… and an elevated level of IL8 at the second time point” claim 1
“identifying the patient as at high risk for a poor outcome where any one of the following is true:… and an elevated level of IL8 at the second time point” claim 1
maintaining the treatment being administered if the patient's high risk classification has not changed, or changing the treatment being administered if the patient's high risk classification
has changed, wherein the patient classified as high risk after the second time point is administered one or more high risk therapy, or wherein the patient classified as high risk and administered one or more high risk therapy after the first time point is not classified as high risk after the second time point.
col. 21 lines 31-37 and 60-64.
“[t]he various methods and techniques described above provide a number of ways to carry out the application” (col. 21 lines 66-67).
col. 21 lines 31-37
“discontinuing administration of the first treatment and administering to the patient identified as at high risk for a poor outcome a second treatment selected from one or more of extracorporeal membrane oxygenation/life support, plasmapheresis, pulmonary artery catheterization, and high volume continuous hemofiltration” claim 1
Claim 31 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 9238841 B2 in view of Wong and Lindsell as applied to claim 30 above, and further in view of Kim.
Claim 31 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10261068 B2 in view of Wong and Lindsell as applied to claim 30 above, and further in view of Kim.
Claim 31 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10815526 B2 in view of Wong and Lindsell as applied to claim 30 above, and further in view of Kim.
Claim 31
Kim teaches:
Obviousness Analysis
Expectation of success
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
further comprising analyzing the second sample
to determine the expression levels of expression levels of one or more biomarkers comprising
MMP8 and/or CCL3, and determining whether the protein biomarker expression levels of each of the biomarkers are greater than a respective cut--off protein biomarker expression level; and further
comprising determining platelet count of the neonate patient
page 1435 col. 1 para. 4.
“[a] platelet count less than 109/L or a rapid fall is a poor prognostic indicator” (page 1435 col. 1 para. 4) of sepsis and necrotizing enterocolitis.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 10261068 B2, U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 to include the determining of the platelet count of the neonate patient taught by Kim because Kim suggests that the platelet count is a prognostic indicator of the necrotizing enterocolitis (NEC), which is associated with sepsis and U.S. Patent No. 10261068 B2, U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 are interested in sepsis. A person having ordinary skill in the art would have been motivated to make such a modification because NEC is the leading cause of morbidity and mortality in neonatal intensive care units (NICUs) around the world.
A person having ordinary skill in the art would have had a reasonable expectation of success because both Wong in view of Lindsell and Kim and U.S. Patent No. 10261068 B2, U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 are interested in methods of treating septic shock in a patient.
“C-C chemokine ligand 3 (CCL3),heat shock protein 70 kDa 1B (HSPA1B), interleukin-8 (IL8), granzyme B (GZMB), and matrix metalloproteinase-8 (MMP8)” claim 1
“blood platelet count and the amount of each of the following protein biomarkers in the at least one biological sample: C-C chemokine ligand 3 (CCL3), heat shock protein 70 kDa 1B (HSPA1B), interleukin-8 (IL8), granzyme B (GZMB), and matrix metalloproteinase 8 (MMP8)” claim 1
“CCL3), interleukin-8 (IL8) and heat shock protein 70 kDa 1B (HSPA1B)” claim 1
Claim 43 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 9238841 B2 in view of Wong as applied to claim 1 above, and further in view of Kim.
Claim 43 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10261068 B2 in view of Wong as applied to claim 1 above, and further in view of Kim.
Claim 43 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10815526 B2 in view of Wong as applied to claim 1 above, and further in view of Kim.
Claim 43
Kim teaches:
Obviousness Analysis
Expectation of success
U.S. Patent No. 9238841 B2
recites:
U.S. Patent No. 10261068 B2
recites:
U.S. Patent No. 10815526 B2
recites:
wherein the patient additionally has
necrotizing enterocolitis
Title,
page 1435 col. 1 para. 4. page 1435 col. 1 para. 4.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 10261068 B2, U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 to include wherein the patient additionally has necrotizing enterocolitis taught by Kim because Kim teaches that NEC is associated with sepsis and U.S. Patent No. 10261068 B2, U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 are interested in sepsis. A person having ordinary skill in the art would have been motivated to make such a modification because NEC is the leading cause of morbidity and mortality in neonatal intensive care units (NICUs) around the world.
A person having ordinary skill in the art would have had a reasonable expectation of success because both Wong in view of Kim and U.S. Patent No. 10261068 B2, U.S. Patent No. 10815526 B2 and U.S. Patent No. 9238841 B2 are interested in methods of treating septic shock in a patient and NEC is associated with septic shock.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Wong (US 10261068 B2)-Cite No. A2 of IDS 6/13/2023 ("Hector").
Hector teaches “PERSEVERE-II: redefining the pediatric sepsis biomarker risk model with septic shock phenotype” (Title). Hector further suggests a method of treating a pediatric patient with sepsis (“The methods described here are useful for treating sepsis” Abstract) and
classified as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course (“for stratifying septic shock patients based on baseline mortality risk” Abstract), the method comprising: obtaining a serum sample; analyzing the sample to determine serum protein biomarker concentrations of at least one biomarker comprising IL-8 (“obtaining at least one biological sample from the patient; determining the blood platelet count and the amount of each of the following protein biomarkers in the at least one biological sample: C-C chemokine ligand 3 (CCL3), heat shock protein 70 kDa 1B (HSPA1B), interlenkin-8 (IL8),
granzyme B (GZMB), and matrix metalloproteinase 8 (MMP8);” col. 3 lines 43-49); determining whether the serum levels of each of the biomarkers are greater than a respective cut-off serum level; and classifying the patient as high risk of mortality and/or complicated course, or other than high risk of mortality and/or complicated course, based on the determination of whether the serum levels of each of the biomarkers are greater than the respective cut-off serum level (“classifying the patient as low, intermediate or high risk of mortality based on the blood platelet count and the amount of each of the protein biomarkers in the sample” col. 3 lines 49-51, “the determination of whether the level(s) of the one or more biomarkers are elevated above a cut-off
level can be combined with one or more additional population-based risk scores” col. 5 lines 23-26)); and administering a treatment comprising one or more high risk therapy to a neonate patient that is classified as high risk, or administering a treatment excluding a high risk therapy to a neonate patient that is not high risk to provide a method of treating a neonate patient with sepsis, thereby improving an outcome in the patient with sepsis; wherein the one or more high risk therapy comprises at least one selected from the group consisting of immune enhancing and/or modulating therapy, high dose antibiotics, extracorporeal membrane oxygenation/life support, plasmapheresis, pulmonary artery catheterization, and/or high-volume continuous hemofiltration (“and treating the intermediate or high risk patient with advanced treatment selected from the group consisting of extracorporeal membrane oxygenation/life support, plasmapheresis, plasma exchange, pulmonary artery catheterization, high volume continuous hemofiltration, and combinations thereof; and excluding the low risk patient from the aforementioned treatment” col. 3 lines 51-58). Hector further suggests determining a platelet count, wherein the platelet count is determined by counting the number of platelets per mm3 (“a platelet count greater than 90” col. 4 line 53) and wherein: a) an elevated level of IL-8 corresponds to a serum IL-8 concentration greater than 297 pg/mL (“an amount of IL8 protein greater than 200 pg/ml,” col. 4 line 50); b) an elevated platelet count per mm3 corresponds to a median platelet count per mm3 greater than 127,000 per mm3; (“Definition of TAMOF and MOF: TAMOF was defined as new onset thrombocytopenia (platelet count<l00,000/μL)” col. 23 lines 51-52) and f) an elevated level of CCL3 corresponds to a serum CCL3 concentration greater than 47 pg/mL (“an amount of CCL3 protein greater than 150 pg/ml” col. 4 line 52).
Hector fails to teach a neonate patient up to 12 months old or admitted to a newborn intensive care unit. Hector further fails to teach a “highly elevated level of IL-8”.
Response to Remarks
Applicant's remarks filed 4/1/2026 have been fully considered but they are not persuasive.
Applicant remarks that “[t]he proposed amendment is believed to place the application in condition for allowance. In view of the foregoing, Applicant respectfully requests that this amendment be entered and that the application re-examined and allowed on the merits” (page 7 para. 4).
However, upon re-examination of the claims, the claims are rejected under 112, 103 and nonstatutory double patenting (see rejections above).
Conclusion
No claim is allowed.
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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
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