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 .
Status of the Claims
Claims 1, 8-10, 13, 15, and 17-22 were pending.
Claims 10 is amended. Claim 23 is added.
Claims 1, 8-10, 13, 15, and 17-23 are examined herein.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL. —The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 10, 13, 15, and 20-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 10 is directed to a method of distinguishing chronic limb-threatening ischemia (CLTI) from intermittent claudication (IC) in a mammalian subject having PAD and treating the subject. Specifically, identifying that the level of each of the at least two biomarkers exhibits a difference of at least 20% as compared to the IC control.
The invention is directed to a diagnostic and treatment method; specifically, detecting in a biological sample from the subject the level of at least two metabolic biomarkers selected from the group consisting of: creatinine, carnitine, propionylcarnitine, cystine, trimethylamine-N-oxide, a fatty acid biomarker selected from the group consisting of stearic acid, linoleic acid, heptadecanoic acid, palmitic acid, oleic acid, heptadecenoic acid, pentadecanoic acid and eicosadienoic acid, and a ratiometric biomarker selected from the group consisting of stearic acid:carnitine and arginine: propionylcarnitine; and distinguishing chronic limb-threatening ischemia (CLTI) from intermittent claudication (IC) in a mammalian subject having PAD based on the level of the one or more detected biomarkers.
The prior art is silent on detecting in a biological sample from the subject the level of at least two metabolic biomarkers selected from the group consisting of: creatinine, carnitine, propionylcarnitine, cystine, trimethylamine-N-oxide, a fatty acid biomarker selected from the group consisting of stearic acid, linoleic acid, heptadecanoic acid, palmitic acid, oleic acid, heptadecenoic acid, pentadecanoic acid and eicosadienoic acid, and a ratiometric biomarker selected from the group consisting of stearic acid:carnitine and arginine: propionylcarnitine; and distinguishing chronic limb-threatening ischemia (CLTI) from intermittent claudication (IC) in a mammalian subject having PAD based on the level of the one or more detected biomarkers.
The specification discloses serum metabolite levels used to differentiate CLTI and IC patients ([0060], Tables 2 and 3). Regarding ratiometric biomarker arginine:propionylcarnitine the specification provides fold change data for propionylcarnitine, but corresponding data for arginine are missing.
The specification fails to provide support for ratiometric biomarker arginine:propionylcarnitine exhibiting a difference of 20%. The specification fails to provide either fold change for arginine:propionylcarnitine or fold change for arginine. Without arginine data a person skilled in the art would not have been able to calculate the fold change for ratiometric biomarker arginine:propionylcarnitine. Since the prior art is silent on the claimed biomarkers, the difference of at least 20% cannot be apparent to one of ordinary skill in the art.
Applicant has not pointed out where the claim is supported, nor does there appear to be a written description of the claim limitation ‘identifying that the level of each of the at least two biomarkers exhibits a difference of at least 20% as compared to the IC control’ in the application as filed.
Based on the above findings, one of ordinary skill in the art would conclude that the inventor was not in possession of the invention as claimed in view of the disclosure of the application as filed because the support for the limitation ‘identifying that the level of each of the at least two biomarkers exhibits a difference of at least 20% as compared to the IC control’ is not apparent, and applicant has not pointed out where the limitation is supported (MPEP 2163.04).
Amended claim 10 recites a new limitation in step iii) “an AUC (area under the curve) of 0.73-0.98 in a ROC curve of the biomarker”.
The prior art is silent on using an AUC for a ROC curve as a diagnostic parameter for distinguishing chronic limb-threatening ischemia (CLTI) from intermittent claudication (IC) in a mammalian subject having PAD.
The specification discloses “Figure 5 shows two top-ranked ratiometric biomarkers in serum with an AUC - 0.87 along with their 95% confidence intervals (0.73 - 0.98), namely 18:0/C0 and arginine (Arg)/C3” ([0061]). As such, paragraph [0061] and Fig. 5 do not disclose a range for AUC ROC curve values but instead a combined 95% confidence interval (0.73 - 0.98) from Fig. 5A – 0.728-0.971 and Fig. 5B – 0.732-0.978. The confidence interval is not a substitute for an AUC range. Additionally, combining confidence intervals for two different biomarkers is invalid statistical operation.
The confidence intervals in Fig. 5AB are ranges of values which are likely to contain (in repeated sampling) the true values of AUC, but they are not AUC ranges that Applicant actually determined in a number of experiments. Therefore, the claimed AUC range of 0.73-0.98 is not supported by the specification.
Based on the above findings, one of ordinary skill in the art would conclude that the inventor was not in possession of the invention as claimed in view of the disclosure of the application as filed because the support for the limitation AUC range of 0.73-0.98 is not apparent, and applicant has not pointed out where the limitation is supported (MPEP 2163.04).
This is a new matter rejection. Therefore, claim 10 and its dependent claims 13, 15, and 20-23 are rejected under 35 U.S.C. 112(a).
Response to Arguments
Applicant’s arguments, filed December 11, 2025 have been fully considered.
Applicant amends claim 10 and argues that “amendments are fully supported by the specification as filed, for example, at paragraphs [0061] and [0066], and in Fig. 5.A/B” (Remarks, pg. 5, par. 2 in 112(a) section).
The argument is not persuasive because as presented above in 112(a) rejection the recited AUC range of 0.73-0.98 is not supported by specification. The recited range is a combination of the confidence intervals, which by itself is an invalid operation with statistical parameters. The confidence interval is not a substitution for data disclosing actual measured AUC ranges.
Applicant argues that “While we believe that the arginine:propionylcamitine biomarker complies with the 20% fold change criteria for the reasons highlighted previously, it very definitely exhibits an AUC as claimed which demonstrates reliable discrimination of high risk of CL TI from lower risk IC patients (see last 9 lines of para. [0061]” (pg. 5, par. 3 in 112(a) section).
The argument is not persuasive because Applicant still fails to point out where in the specification any data are disclosed for “at least two biomarkers exhibits a difference of at least 20% as compared to the IC control” - paragraphs [0061] and [0066], and Fig. 5.A/B do not have the required data.
Applicant argues that “as further shown in Fig. 5 A), the AUC for the stearic acid:camitine biomarker is shown to be in the range of 0.728-0.971 with a p value of 3.25 x 10-5 (see bottom right of the ROC curve), and the AUC for the arginine:propionylcamitine biomarker is shown to be in the range of 0.732-0.978 with a p value of 4.42 x 10-5 (see bottom right of the ROC curve). The significance of these AUC values is also confirmed in the specification at paragraph [0066],
lines 21-23 which states that "both serum 18:01 CO and Arg/C3 display good accuracy in
differentiating CLTl from IC patients with an AUC = 0.870 (p = 4.0 x 10-5) from ROC
curves"” (pg. 5, par. 4 in 112(a) section).
The argument is not persuasive because as already discussed above Applicant represents data for the confidence intervals (0.728-0.971 and 0.732-0.978) instead of AUC ranges, which is improper evidence.
Subject Matter Free of the Prior Art
Claims 1, 8-10, 13, 15, and 17-23 are free of the prior art.
The prior art neither teaches nor suggests detecting in a biological sample from the subject the level of at least two metabolic biomarkers selected from the group consisting of: creatine, creatinine, phenylacetylglutamine, oxoproline, and monomethylarginine; or at least two metabolic biomarkers selected from the group consisting of: creatinine, carnitine, propionylcarnitine, cystine, trimethylamine-N-oxide, a fatty acid biomarker selected from the group consisting of stearic acid, linoleic acid, heptadecanoic acid, palmitic acid, oleic acid, heptadecenoic acid, pentadecanoic acid and eicosadienoic acid, and a ratiometric biomarker selected from the group consisting of stearic acid:carnitine and arginine:propionylcarnitine.
The closest prior art Ismaeel et al. (IDS; J Clin Med. 2019 Sep 14;8(9):1463) teach characterization of metabolomic profiles in patients with peripheral artery disease. Specifically, Ismaeel teaches a comparison of the serum metabolites of PAD patients and non-PAD patients by measuring more than 400 metabolites, including 21 amino acids, 21 biogenic amines, 55 acylcarnitines, 18 diglycerides, 42 triglycerides, 24 lysophosphatidylcholines, 172 phosphatidylcholines, 31 sphingomyelins, 9 ceramides, and 14 cholesteryl esters. However, Ismaeel does not teach at least two metabolic biomarkers selected from the group consisting of: creatine, phenylacetylglutamine, oxoproline, and monomethylarginine.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander Volkov whose telephone number is (571) 272-1899. The examiner can normally be reached M-F 9:00AM-5:00PM (EST).
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached on (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDER ALEXANDROVIC VOLKOV/Examiner, Art Unit 1677
/REBECCA M GIERE/Primary Examiner, Art Unit 1677