Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Application status
Claims 1-7, 9-11, 14 and 16-24 are pending in this application.
Priority
The instant application is the 371 national stage entry of PCT/EP2022/077015, filed on 09/28/2022.
Acknowledgment is made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to a foreign patent application EPO EP21199905.7 filed on 09/29/2021.
Election
Applicant's election without traverse of Group I, claims 1-7 and 16-24 in the response filed on 07/20/2026, is acknowledged.
Claims 9-11 and 14 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b) as being drawn to a non-elected invention.
For the reasons provided above, this restriction requirement is deemed proper, and therefore, it is made final.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/28/2024 and 01/16/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objections to the Specification
The abstract is objected to because it exceeds 150 words (194 words found). Further, the abstract contains a legal phraseology, i.e., said, in 6 different locations.
Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words. It is important that the abstract not exceed 150 words in length since the space provided for the abstract on the computer tape used by the printer is limited. The form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. See MPEP 608.01 (b).
Appropriate correction is required.
Claim Objections
Claims 1 and 22 are objected to because of the following informalities:
Claims 1 and 22 are objected to because the recitation of “MR-proADM”, “sFlt-1”, “GDF15” and “ESM1” (abbreviations) should be in parenthesis and follow the phrase it abbreviates when used for the first time in a claim. The Examiner suggests writing out the abbreviations, i.e.:
Mid-regional pro-adrenomedullin (MR-proADM);
Soluble fms-like tyrosine kinase-1 (sFlt-1);
Growth-Differentiation factor 15 (GDF15); and
Endothelial cell-specific molecule 1 (ESM1).
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-7 and 16-24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a natural phenomenon) without significantly more.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of the following steps:
(1) whether the claim is directed to one of the four categories recited in §101 (process, machine, manufacture or composition of matter);
(Revised 2A - Prong 1) do the claims recite an abstract idea (mathematical concepts, mental processes or method of organizing human activity), law of nature or natural phenomenon;
(Revised 2A - Prong 2) do the claims recite additional elements that integrate the judicial exception into a practical application; and
(2B) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. (See 2019 Revised Patent Subject Matter Eligibility Guidance (2019 PEG))
Question 1: Yes; the claims are directed to a process.
Question 2A – Prong 1: Yes, the claims recite a judicial exception, namely, a natural correlation between circulating levels of MR-proAMD and sFlt-1/GDF-15/ESM1 and the presence or risk of infection with mental steps of comparing amounts to a reference and/or calculating a score. This is a law of nature with an abstract idea.
Question 2A – Prong 2: No, the claims do not recite anything additional which integrate the naturally occurring process into a practical application. It is noted by Examiner that claim 22 recites obtaining a sample. However, claims 22 and 24 are basic diagnostic observation of a natural phenomenon, ultimately adding nothing in the claims which amounts to significantly more or significantly different from that found in nature.
Question 2B: As noted in answering that of 2A –there is nothing in the claims which amounts to significantly more, even considering dependent claims. For instance, blood/plasma sampling and sandwich immunoassays for these exact analytes were conventional well before 2021 (see claims and para [0243] of US Patent Application Publication No. 2021/0109118 A1 published on 04/15/2021). Regarding claims 17-19 which recite conventional reagents, i.e., adding ‘apply it on a computer, trained tree, or weighted score’ does not integrate the exception into a practical application. Thus, claims are drawn to a judicial exception, namely, a naturally occurring process.
Claim Rejections - 35 U.S.C. § 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.
Claims 5, 20-21 and 24 are rejected under 35 U.S.C. § 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 5 and 24 recite the phrase, “essentially identical or similar to” which is indefinite. It is unclear what the metes and bounds of the noted phrase “essentially identical or similar” is as it may be subjective and differ based on the person making the assessment. In the interest of advancing prosecution, the noted phrase is interpreted as “overlap with”.
Claim 20 recites the phrase “the first biomarker and the second biomarker are weighted in accordance with their contribution to the establishment of the assessment” which is indefinite. It is unclear how a person of ordinary skill in the art (POSITA) can identify the weighting algorithm, or how the contribution is measured. In the interest of advancing prosecution, the noted phrase is not given a patentable weight.
Claim 21 recites the phrase “the score is calculated from a decision tree or a set of decision trees that has been trained on the first biomarker and the second biomarker” which is indefinite. It is unclear how a POSITA can identify decision tree(s), training set or criteria that are used to calculate the score. In the interest of advancing prosecution, the noted phrase is not given a patentable weight.
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.
Claims 1-7 and 16-24 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson (US Patent Application Publication No. 20210109118) in view of Hess et al. (US Patent Application Publication No. 20130071953 A1), Lassalle (US Patent No. 9945873), Aird et al. (WO2007/009071, see IDS), Jang et al. (Use of a Comprehensive Metabolic Panel Point-of-Care Test to Reduce Length of Stay in the Emergency Department: A Randomized Controlled Trial, Annals of Emergency Medicine, Volume 61, No. 2: 2013, pp 145-151), Christ-Crain et al. (Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study, Crit. Care 9: R816-R824, 11/15/2005, see IDS), Schuetz et al. (Optimizing triage and hospitalization in adult general medical emergency patients: the triage project, BMC Emerg. Med., 13: 12 (2013), see IDS) and KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007).
The instant claims are drawn to a method for assessing a subject with suspected infection comprising the steps of: (a) determining an amount of a first biomarker in a sample of the subject, said first biomarker being MR-proADM; (b) determining an amount of a second biomarker in a sample of the subject, wherein said second biomarker is selected from the group consisting of sFlt-1, GDF15 and ESMl; (c) comparing the amounts of the biomarkers to references for said biomarkers and/or calculating a score for assessing the subject with suspected infection based on the amounts of the biomarkers; and (d) assessing said subject based on the comparison and/or the calculation made in step (c); and a method for measuring a panel of biomarkers in a subject with suspected infection, the method comprising: obtaining a sample from the subject; determining a measurement for a panel of biomarkers in the sample, wherein the panel comprises the biomarker MR-proADM and a biomarker selected from the group consisting of sFlt-1, GDF15 and ESM1, wherein the measurement comprises determining an amount of each of the biomarkers in the panel.
Wilson teaches a method for antibiotic therapy guidance, stratification and/or control in a patient suspected of having an infection, said method (a) determining an amount of a first biomarker in a sample of a human subject with suspected infection, said first biomarker being MR-proADM; (b) comparing the amounts of MR-proADM to references and/or calculating a score for assessing the subject with suspected infection based on the amounts of MR-proADM; and (c) assessing said subject based on the comparison and/or the calculation made in step (b), i.e., predicting severe sepsis within 48 hours (see claims 1-7; example KRYPTOR double-sandwich immuneassay in para [0110], [0115], [0128], [0197], [0206] and [0243]; measurements on 213 emergency department (ED) suspected-infection patients in para [0243]; example logistic/Cox models and AUROC cut-offs (Tables 4, 6, 7, 12 and 14-17; also see para [0259])). Wilson further teaches assessing deterioration of the patient's general clinical signs or symptoms (see para [0134]). Wilson also teach the use of anti-proADM polyclonal antibody in cryptate assay (see para [0111], [0118], [0195] and [0204] with a fluorescent dye (like XL665 fluorescent dye). The methods taught by Wilson further comprises determining a level of at least one additional biomarker (see claim 16).
Wilson does not teach the use of additional biomarkers such as sFlt-1, GDF15 or ESM1, and aspartate or alanine aminotrasferase.
Hess et al. teach determining the amount of GDF-15 (a biomarker) in a sample, i.e., blood, plasma or serum, of a subject with acute inflammation, SIRS or sepsis, and comparing the amount determined to a reference, which allows one to predict an increased risk for mortality in subjects. Hess et al. further teach that GDF-015 is determined with sandwich immune-assays using COBAS-analyzers from Roche/Hitachi. The assays comprise two monoclonal antibodies with the first is biotinylated and the second one labelled with a Tris(2,2’-bipyridyl)ruthenium(II)-complex (see all claims; all Examples; and para [0096]).
Lassalle teaches a method of measuring the concentration of ESM-1 (also known as endocan), as a biomarker, in a blood sample, i.e., blood, serum or plasma sample, obtained from a septic patient, and determining if the septic patient is at risk of deteriorating conditions in 48-72 hours following ICU admission. Lassalle further teaches the use of sandwich immunoassays, i.e., ELISA with antibodies against ESM-1 (see claim 1, and entire disclosure).
Aird et al. teach a method of diagnosing severe sepsis or septic shock in a human subject, comprising analyzing the level of sFlt-1 (as a biomarker) in a sample, i.e., blood, plasma, serum, isolated from the subject (see all claims), and comparing the level of sFlt-1 to a reference/control.
Jang et al. teach that patients of emergency department are tested routinely with a comprehensive metabolic panel which includes alanine aminotransferase and aspartate aminotransferase among other biomarkers (see pg. 146, right column, 2nd paragraph under “Selection of Participants” heading).
Crhist-Crain et al. teach that MR-proADM is a new prognostic biomarker and is helpful in individual risk assessment of septic patients (see Abstract/Results/Conclusion).
Schuetz et al. teach that proADM as a blood biomarker which has very high prognostic accuracy in the range of clinical risk scores, and that this is true across different medical conditions (see page 8, 2nd to last paragraph) based on a regression model (see abstract; Figure 1; Table 1 and Methods/design).
It would have been obvious to a person of ordinary skill in the art (POSITA) prior to the effective filing date of the instant application to the method taught by Wilson and determine the level of additional markers, sFlt-1, GDF15 or ESM1, and aspartate or alanine aminotransferase as taught by Hess et al., Lasselle, Aird et al. and Jang et al. A POSTIA would have been motivated to practice such methods because [1] Wilson already invites a POSITA to use additional biomarkers, and [2] for a POSITA looking for additional biomarkers, sFlt-1, GDF15 or ESM1, and aspartate or alanine aminotransferase would be obvious candidates as they have already been validated as a biomarker for sepsis or bacteremia and/or included in the routine metabolic panel for ED patients. A POSITA would have had a reasonable expectation of success to practice such methods because [1] all of the biochemic reagents and required techniques for determining the levels of biomarkers were taught by Wilson, Hess et al., Lasselle, Aird et al. and Jang et al.; [2] teachings of Wilson and Christ-Crain, already demonstrated that the level of MR-proADM can be used to assess the severity (SIRS/sepsis/shock/death) of patients; [3] Hess et al., Lasselle, Aird et al. show the same assessments for their biomarkers, and [4] logistic combination of two or more such markers has been demonstrated to be reliable based on the regression models of triage cohort taught by Schuetz. prior to the filing of the instant application.
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Conclusion
Claims 1-7 and 16-24 are rejected for the reasons as stated above. Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
The instant Office action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571)272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656(p.r)
Prosecution Insights