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 .
Priority
The present application was filed on 03/25/2022. This application is a 371 of PCT/CA2020/05 1287 filed on 09/25/2020, which claims benefit of U.S. Provisional Patent Application 62/906,984 filed on 09/27/2019.
Claim status
Claims 1-112, and 123 are canceled. Claims 113-114, 116-122 and 125-127 are amended. Claims 131-132 are new.
Claims 113-122, and 124-132 are pending and examined.
Objections/Rejections Status
The objection of claims 116 and 121 is withdrawn in view of the amendment of the claims.
The rejection of claims 113-132 under 35 USC 101 is updated in view of the amendment of the claims.
The rejections of claims 114-115, 117-119, 121-122, 126 and 132 under 35 USC 112(b) are new in view of the amendment of the claims.
The rejections of claims 113-122 and 124-132 under 35 USC 103 are updated in view of the amendment of the claims.
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 113-132 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1 – Whether a claim is to a statutory category - YES
Claims 113-132 are directed a method of detecting a patient with peripheral artery disease by measuring the levels of one or more biomarkers from a sample. Therefore, the instantly claimed invention falls into one of the four statutory categories.
Step 2A Prong 1 – Whether the claim is directed to a judicial exception (i.e. Does the claim recite an abstract idea, law of nature, or natural phenomenon?) – YES
As explained in MPEP § 2106.04(II), a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim.
Claims 113, 117, 120, 125-127 recites a method of detecting a patient with peripheral artery disease (PAD) from a sample comprising the following steps: detecting the level of fatty acid-binding protein 3 (FABP3) in a subject, and at least one additional biomarker comparing the level of FABP3 and the additional marker to those in a control group;
determining that the patient having PAD based on the increasing levels of FABP3 in the subject in relative to the control.
The broadest reasonable interpretation of the steps of “comparing” and “determining” in the claims are abstract ideas, specifically, abstract mental processes.
The step of “determining” also constitutes an abstract mental process, involving assessing
the comparison of expression levels of at least one biomarker in a test subject, and then making
an evaluation or judgment as to whether the patient having PAD. The “comparing” and
“determining” steps could be performed in the human mind, or by a human using pen and paper,
insofar as it reads on comparing levels and drawing conclusions from this about the source of the
vesicles.
The “determining” step can also be regarded as a law of nature, namely, the naturally
occurring correlation between levels of one or more of the specific markers and the disease.
Thus, these claims fall into judicial exception.
Step 2A Prong 2 - Does the claim recite additional elements that integrate the judicial
exception into a practical application? NO
Step 2A, Prong 2 analysis requires identifying whether there are any additional
elements recited in the claim beyond the judicial exception(s), and evaluating those additional
elements to determine whether they integrate the exception into a practical application of the
exception.
Claims 114-116, 118-119, 121-122, and 128-132 do not recite any additional element that integrate the exception into a practical application of the exception. The additional steps of
obtaining a sample and analyzing an expression level are insufficient to integrate the exception
into a practical application because the purpose is merely to obtain data. As in In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989), such activity involving performing clinical tests on individuals constitutes mere data gathering, and does not go beyond insignificant extra-solution activity. See MPEP 2106.04(d)(I) and 2106.05(g).
Claims 113, 117, 120, 124-127 recite an active treatment step in patients with an elevated level of FABP3, wherein the active treatment is “administering a cardiovascular drug, surgical intervention, optionally revascularization surgery, or amputation of the effected limb or a portion thereof based on the elevated level of FABP3”. However, a cardiovascular drug or surgical intervention is not specifically directed toward treating PAD because a cardiovascular drug can be used for patients with heart diseases, e.g., hypertension, and a surgical intervention can be any act of performing surgery on someone for treating a symptom that does not relate to PAD, e.g., broken bone. Thus, a cardiovascular drug or surgical intervention is not a particular treatment or prophylaxis directed toward a PAD disease.
While revascularization surgery and amputation of the effected limb or a portion thereof can be particular treatments, these treatments are recited as optional treatments, which means that the patients having elevated level of FABP3 may not be treated with these particular treatments.
Moreover, revascularization surgery, or amputation of the effected limb or a portion thereof is not a particular treatment for all stages of PAD, e.g., a non-symptomatic or mild PAD may not need revascularization surgery, or amputation of the effected limb or a portion thereof. The claim is unclear to define at which elevated level of FABP3 that the patient should be administered a revascularization surgery or an amputation of the effected limb or a portion thereof. Therefore, the claims do not recite the clear relationship between an elevated level of FABP3 and each stage of PAD, so that a particular treatment or prophylaxis can be applied effectively. See MPEP §2106.05(f)(3).
Claim 124 depends on claim 120. Claim 120 has been amended to comprise the method of treating a subject with PAD which raises some issues as discussed above. Claim 124 does not provide any additional element to fix the issues in claim 120. Claim 124 merely recites the word “treating” with the judicial exception without any a particular treatment or prophylaxis for a disease or medical condition. See MPEP §2106.05(f).
Therefore, the treatment recited in claims 113, 117, 120, 124-127 does not integrate the exception into a practical application of the exception.
Step 2B: Whether the additional elements contribute an “inventive concept”
In the second step it is determined whether the claimed subject matter includes additional
elements that amount to significantly more than the judicial exception. See MPEP 2106.05.
Briefly, the claims 113-132 do not include additional elements that are sufficient to
amount to significantly more than the judicial exception because of the following reasons.
Simply appending well-understood, routine, conventional activities previously
known to the industry, specified at a high level of generality, to the judicial exception, has
been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The steps of obtaining and analyzing the sample do not add a meaningful limitation to the
instant method as the step of obtaining would have been routinely used by those of ordinary skill
in the art, while the step of analyzing does not refer to any particular assay technique and thus
could be performed by any technique known in the art including those disclosed in the instant
specification.
Defining the subject of the method does not add a meaningful limitation to the instant
method as the subject would have been routinely used by those of ordinary skill in the art.
The additional elements listed above are well-understood, routine, and conventional. This
position is supported by Jain et al. (Status of Cardiac Markers in Patients With Peripheral
Arterial Disease and Critical Limb Ischemia. Journal of Vascular Surgery, 2018, vol. 68, no 3, p.
e68-e69, IDS 03/24/2023) and Otaki et al. (Heart-type fatty acid binding protein and high-
sensitivity troponin T are myocardial damage markers that could predict adverse clinical
outcomes in patients with peripheral artery disease, BBA Clin. 2015 Jun 18:4:35-41, IDS
03/24/2023).
Jain discloses that FABP3 shows a positive correlation with the severity of PAD (see
page e68-e69: Result section).
Otaki is directed to assessing FABP3 and high sensitivity troponin T (hsTnT) as markers
of adverse clinical outcomes in patients with PAD, and concludes that "H-FABP [FABP3] and
hsTnT were increased in PAD patients with CLI and could predict MACCEs [major adverse
cardiovascular and cerebrovascular events] in PAD patients (see page 39 col.2 par.1; see Table
1).
For all of these reasons, the claims fail to include additional elements that are sufficient to
amount to significantly more than the judicial exception(s).
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they
are directed to a law of nature without significantly more. For additional guidance, applicant is
directed generally to MPEP § 2106.
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 113-119, 121-122, 126, and 128-132 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.
Regarding claim 113, the phrase "such as" in line 1 renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are positive limitations of the claims are or only exemplary. See MPEP § 2173.05(d).
Claims 113, 117, 120, 125-127 recite “administering a cardiovascular drug, surgical intervention, optionally revascularization surgery, or amputation of the effected limb or a portion thereof based on the elevated level of FABP3”. The language of the claim causes a confusion that it is unclear if revascularization surgery, amputation of the effected limb or a portion thereof” are options of surgical intervention; or only “revascularization surgery” is an option of surgical intervention and “or amputation of the effected limb or a portion thereof” is one of the main choice of the treating. The term “optionally” renders the claim indefinite because it is not clear if the applicant wants to claim “revascularization surgery” or “revascularization surgery, or amputation of the effected limb or a portion thereof” as a surgical intervention. See MPEP § 2173.05(h).
The term “substantially” in claims 114, 117-118, 121, and 126 are relative terms which renders the claim indefinite. These term 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, for instant, it is not known how to define the levels of markers in the patient is a substantially normal level. It is unclear if a substantially normal level is difference from a normal level.
Regarding claim 115, the term “optionally” in line 2 renders the claim indefinite because the claim lists all the potential concurrent conditions as optional, thus it is not clear which condition needs to be selected. See MPEP § 2173.05(h).
Regarding claim 117, the phrase "for example" in line 9 renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are positive limitations of the claims are or only exemplary. See MPEP § 2173.05(d).
Regarding claim 119, the term “optionally” in line 2 renders the claim indefinite because the claim lists all the potential concurrent conditions as optional, thus it is not clear which condition needs to be selected. See MPEP § 2173.05(h).
Regarding claim 122, the term “optionally” in line 2 renders the claim indefinite because the claim lists all the potential concurrent conditions as optional, thus it is not clear which condition needs to be selected. See MPEP § 2173.05(h).
All dependent claims are also rejected based on their dependency of the defected parent claims.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 124 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 124 depends on claim 120. Claim 120 has been amended to comprise the method of treating a subject with PAD. Claim 124 recites “treating the subject based upon the outcome of the method”. The treatment recited in claim 24 is generic and does not further limit the treatment recited in claim 120. Thus, claim 124 is improper dependent form for failing to further limit the treating of the claim 120.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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) 113-116, 120-122, 124-125, and 127-131 is/are rejected under 35 U.S.C. 103 as being unpatentable over Otaki et al. (Heart-type fatty acid binding protein and high-sensitivity troponin T are myocardial damage markers that could predict adverse clinical outcomes in patients with peripheral artery disease, BBA Clin. 2015 Jun 18:4:35-41, IDS filed 03/24/2023) as evidenced by Vergnes et al. (Heart-type Fatty Acid-binding Protein Is Essential for Efficient Brown Adipose Tissue Fatty Acid Oxidation and Cold Tolerance, J Biol Chem. 2010 Nov 1;286(1):380–390, PTO-892 dated 05/09/25), in view of Hennion et al. (Diagnosis and Treatment of Peripheral Arterial Disease, 2013).
For claims 113, 125 and 127, Otaki teaches a method for diagnosing or staging peripheral artery disease (PAD), such as non-symptomatic (stage 0), mild (stage 1), moderate (stage 2), severe (stage 3), early chronically threatened limb ischemia (CTLI)(stage 4) or advanced CTLI (stage 5 or 6) PAD in a subject, the method comprising detecting the level of fatty acid-binding protein 3 (FABP3) in the subject; wherein an elevated level of FABP3 is indicative of PAD in the subject; wherein optionally the elevated level of FABP3 in the subject is determined by comparing the detected level of FABP3 to a control level of FABP3, optionally the control level is a predetermined value obtained from one or a pool of non- PAD patients or healthy patients, as recited in claim 113.
(Otaki teaches a method to predict adverse clinical outcomes in patients with peripheral artery disease _ PAD (see Otaki Abstract). The method comprises measuring the level of myocardial damage markers Heart-type fatty acid-binding protein (H-FABP) in serum sample of patients who were admitted to hospital for the treatment of PAD (see Otaki Abstract). As evidenced by Vergnes, H-FABP is FABP3 (see Vergnes Abstract).
The result shows that H-FABP was higher in patients with major adverse cardiovascular and cerebrovascular events (MACCEs) compared to those without this condition (see Otaki Abstract, see page 37 section 3.2, see Table 1, Figure 1 and 2). The adverse events include the development of critical limb ischemia (CLI) (see Otaki page 36 section 2.5). CLI is also known as chronic limb threatening ischemia (CTLI) as noted in the instant specification page 10.
The teaching of Otaki shows the increased level of FABP3 in PAD patients compared to the general population. Also, the level of FABP3 in patients with CTLI (i.e., severe PAD) is higher than that in patients without CTLI (i.e., mild to moderate PAD) (see Otaki page 39 col.1 par.2). The result of Otaki supports for the use of FABP3 in predicting if the PAD patients are developing severe events (see Otaki Abstract and Discussion). The result of Otaki implies that the level of FABP3 can be used to distinguish mild to moderate PAD patients (patients without CLI) from severe PAD patients (patients with CLI) (see Otaki page 37 sections 3.2-3.3 and Figs.2-3), which means the increased level of FABP3 can be used for staging PAD.
Moreover, from Otaki’s teaching, it would have been obvious to use this method for the purpose of diagnosing a patient with PAD because Otaki teaches that there is an increased level of FABP3 in patient with PAD compared to that in the general population which may comprise non-PAD patients or healthy patients (see Otaki page 38 section 4.1).)
The teaching of Otaki above also encompasses the method of diagnosing PAD in a subject as recited in claim 125.
The teaching of Otaki above also encompasses the method of predicting whether a subject with PAD is likely to progress to CTLI as recited in claim 127 because the PAD patients with higher level of FABP3 are more likely to develop CTLI later (see Otaki Abstract, see page 37 section 3.2, see Table 1, Figure 1 and 2).
Otaki does not teach “administering a cardiovascular drug, surgical intervention, optionally revascularization surgery, or amputation of the effected limb or a portion thereof based on the elevated level of FABP3” as recited in claims 113, 125 and 127.
Hennion teaches that PAD represents a significant systemic atherosclerotic burden and should be considered equivalent to coronary heart disease when assessing overall cardiovascular risk (see Hennion page 308 Treatment). Management of PAD includes: administering a cardiovascular drug (e.g., statin therapy, aspirin, antiplatelet therapy) (see Hennion page 307 Sort: Key recommendations for practice, and page 308 Treatment), surgical intervention (e.g., surgical revascularization) (see Hennion page 309 Surgical Referral), amputation of the effected limb or a portion thereof (see Hennion Fig.1 and page 309 Prognosis par.1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of diagnosing or staging PAD taught by Otaki and the method of treating PAD taught by Hennion for the benefit of improving health outcomes, e.g., prevent cardiovascular events (Hennion page 307 Sort: Key recommendations for practice), improving claudication symptoms, reducing the risk of myocardial infarction, stroke, or vascular death in asymptomatic patients with moderate to severe PAD (see Hennion page 309 Medication), or arterial reconstructing in patients with CLI (see Hennion page 309 Surgical referral).
For claim 114, Otaki as evidenced by Vergnes, and Hennion teach the method of claim 113. Otaki teaches wherein the method further comprises detecting the level of at least one additional biomarker, wherein the at least one additional biomarker comprises the other of FABP3 and/or FABP4, high sensitivity troponin, Tnl, TnT, and/or creatinine, wherein a substantially normal level of high sensitivity troponin, Tnl, TnT and/or creatinine in the subject is further indicative of PAD in the subject.
(Otaki further teaches that the method comprises detecting the level of hsTnT and creatinine in the subject (see Abstract, see page 37 section 3.2, see Table 1, Figure 1 and 2). Otaki, in Table 1, shows that the level of hsTnT in an All patients group, which are patients with PAD including event free and MACCE), is 1.07 pg/mL. The levels of hsTnT in an Event free group and in a MACCE group are 1.0 pg/mL and 1.25 pg/mL respectively (see Otaki Table 1). In page 39, section 4.2, Otaki teaches that the abnormal cut-off value for hsTnT is 1.2 pg/mL (0.016 ng/mL). Based on the cut-off value, Otaki teaches that the level of an additional biomarker hsTnT is substantially normal in the subject with PAD because the level of hsTnT in the subject with PAD is about the cut-off value.)
For claim 115, Otaki as evidenced by Vergnes, and Hennion teach the method of claims 113. Otaki further teaches that patients with PAD will have higher risk of developing MACCEs if they have a concurrent condition such as kidney dysfunction (see page 37 par.1: teaching that age, previous cerebrovascular disease, previous IHD, CLI, CKD, and BNP were also related to MACCEs, see Table 2: showing the hazard ratio of having MACCEs in chronic kidney disease (CKD) group is 1.97). Both H-FABP and hsTnT were found to be independent predictors of MACCEs after adjusting for CLI, previous IHD, and CKD (H-FABP, hazard ratio, 2.75; 95% confidence interval, 1.94–3.87; P < 0.0001 and hsTnT, hazard ratio, 2.14; 95% confidence interval, 1.42–3.23; P = 0.0003; Fig. 3B).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to adjust the level of FABP3 for the concurrent condition when diagnose or stage PAD in a subject because the concurrent condition is a confounding factor which also increases the risk of developing MACCEs in PAD (see Otaki, Abstract page 37 par.1 and Table 2, teaches that the concurrent conditions, such as CKD or diabetes, increase the risk of developing MACCEs in PAD patient). After adjusting for the concurrent condition, the increasing level of FABP3 was found to be an independent predictor of severe PAD (see page 37 col.2 par.1).
For claim 116, Otaki as evidenced by Vergnes, and Hennion teach the method of claim 113. Otaki further teaches the method comprising assessing the ABI of the subject (see Table 1).
Hennion teaches that the ankle-brachial index (ABI) can be used to screen for and diagnose PAD in the primary care setting because it is inexpensive and efficient method (see Hennion page 307 col.1 par.2). A low ABI is an independent predictor of future cardiovascular events and a low ABI was 92.7% specific for predicting incident coronary heart disease (see Hennion page 309 Prognosis).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the ABI of the subject in the method of detecting levels of FABP3 as taught by Otaki because ABI is the inexpensive and efficient screening test for PAD and is an independent predictor of future cardiovascular events as taught by Hennion.
For claims 120-121, and 124, Otaki as evidenced by Vergnes, and Hennion teach the method of claim 113. The method comprising detecting the level of fatty acid-binding protein 3 (FABP3), wherein the extent of elevation of FABP3 is correlated with the likelihood of the subject progressing to CTLI, wherein the extent of elevation of FABP3 in the subject is determined by comparing the detected level of FABP3 to a control level of FABP3 (see discussion in claim 113). Briefly, Otaki measures the level of FABP3 and hsTnT on PAD patients. The results of Otaki show that the level of FABP3 and hsTnT can be indicative of progression to CLI in the PAD patient as discussed above, in other words, there is a relationship between the level of FABP3 and hsTnT, and the worsening PAD severity (see Otaki Table 1, see Figures 1A and 2A, see page 38 col.2 par.2). H-FABP and hsTnT were found to be higher in patients with critical limb ischemia (CLI) compared to those without this condition (see Abstract, Figures 1A and 2A, page 39 col.1 par.2).
Therefore, the teaching of Otaki anticipates the increased level of FABP3 in PAD patients compared to the general population, and the level of FABP3 in severe PAD (e.g., CLI) is higher than that in not severe PAD.
This also means that if the extent of elevation of FABP3 in the subject is correlated with the likelihood of the subject progressing to CTLI because the level of FABP3 is still higher in that subject compared to that in a control group.
The PAD patient may not have clinical and/or biochemical evidence of myocardial ischemia and/or free of clinical and/or biochemical evidence of kidney dysfunction and/or free of clinical and/or biochemical evidence of acute stroke and/or muscle toxicity (see Otaki page 36 par.1: teaching that the exclusion criteria of the present study were acute coronary syndrome within the 3 months preceding admission, estimated glomerular filtration rate less than 30 mL/min/1.72 m2, and malignant disease).
Otaki further teaches the method comprising assessing the ABI of the subject (see Table 1).
Otaki does not teach “administering a cardiovascular drug, surgical intervention, optionally revascularization surgery, or amputation of the effected limb or a portion thereof based on the elevated level of FABP3” as recited in claim.
Hennion teaches that PAD represents a significant systemic atherosclerotic burden and should be considered equivalent to coronary heart disease when assessing overall cardiovascular risk (see Hennion page 308 Treatment). Management of PAD includes: administering a cardiovascular drug (e.g., statin therapy, aspirin, antiplatelet therapy) (see Hennion page 307 Sort: Key recommendations for practice, and page 308 Treatment), surgical intervention (e.g., surgical revascularization) (see Hennion page 309 Surgical Referral), amputation of the effected limb or a portion thereof (see Hennion Fig.1 and page 309 Prognosis par.1).
Hennion teaches that the ankle-brachial index (ABI) can be used to screen for and diagnose PAD in the primary care setting because it is inexpensive and efficient method (see Hennion page 307 col.1 par.2). A low ABI is an independent predictor of future cardiovascular events and a low ABI was 92.7% specific for predicting incident coronary heart disease (see Hennion page 309 Prognosis).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of diagnosing or staging PAD taught by Otaki and the method of treating PAD taught by Hennion for the benefit of improving health outcomes, e.g., prevent cardiovascular events (Hennion page 307 Sort: Key recommendations for practice), improving claudication symptoms, reducing the risk of myocardial infarction, stroke, or vascular death in asymptomatic patients with moderate to severe PAD (see Hennion page 309 Medication), or arterial reconstructing in patients with CLI (see Hennion page 309 Surgical referral).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the ABI of the subject in the method of detecting level of FABP3 as taught by Otaki because ABI is the inexpensive and efficient screening test for PAD and is an independent predictor of future cardiovascular events as taught by Hennion.
For claim 122, Otaki as evidenced by Vergnes, and Hennion teach the method of claims 113. Otaki further teaches that patients with PAD will have higher risk of developing MACCEs if they have a concurrent condition such as kidney dysfunction (see page 37 par.1: teaching that age, previous cerebrovascular disease, previous IHD, CLI, CKD, and BNP were also related to MACCEs, see Table 2: showing the hazard ratio of having MACCEs in chronic kidney disease (CKD) group is 1.97). Both H-FABP and hsTnT were found to be independent predictors of MACCEs after adjusting for CLI, previous IHD, and CKD (H-FABP, hazard ratio, 2.75; 95% confidence interval, 1.94–3.87; P < 0.0001 and hsTnT, hazard ratio, 2.14; 95% confidence interval, 1.42–3.23; P = 0.0003; Fig. 3B).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to adjust the level of FABP3 for the concurrent condition when diagnose or stage PAD in a subject because the concurrent condition is a confounding factor which also increases the risk of developing MACCEs in PAD (see Otaki, Abstract page 37 par.1 and Table 2, teaches that the concurrent conditions, such as CKD or diabetes, increase the risk of developing MACCEs in PAD patient). After adjusting for the concurrent condition, the increasing level of FABP3 was found to be an independent predictor of severe PAD (see page 37 col.2 par.1).
Regarding claims 128-130, Otaki as evidenced by Vergnes, and Hennion teach the method of claims 113. Otaki teaches that the subject of the study comprises male, or person without diabetes (see Table 1: showing that the subject can be male, and there is 2% of patient is not diabetes). Otaki does not teach the subject is from general population.
However, it would have been obvious to use the Otaki’s method for the purpose of screening a subject with high risk of severe PAD in a general population since it is necessary to define a subject with PAD or with high risk of severe PAD to put them into a treatment as early as possible to improve their quality of life and function. This motivation comes from Otaki, who suggests that H-FABP and hsTnT showed significantly improved abilities to predict MACCEs in patients with PAD (see page 38 col.2 par.2), and Hennion who teaches patients with PAD should be treated to improve health outcomes (e.g., prevent cardiovascular events (Hennion page 307 Sort: Key recommendations for practice), improve claudication symptoms, reduce the risk of myocardial infarction, stroke, or vascular death in asymptomatic patients with moderate to severe PAD (see Hennion page 309 Medication), or arterial reconstruct in patients with CLI (see Hennion page 309 Surgical referral)).
Regarding claim 131, Otaki as evidenced by Vergnes, and Hennion teach the method of claims 113. Otaki teaches the PAD patient may not have clinical and/or biochemical evidence of myocardial ischemia and/or free of clinical and/or biochemical evidence of kidney dysfunction and/or free of clinical and/or biochemical evidence of acute stroke and/or muscle toxicity (see Otaki page 36 par.1: teaching that the exclusion criteria of the present study were acute coronary syndrome within the 3 months preceding admission, estimated glomerular filtration rate less than 30 mL/min/1.72 m2, and malignant disease).
Claim(s) 117-119, 126 and 132 is/are rejected under 35 U.S.C. 103 as being unpatentable over Otaki et al. as evidenced by Vergnes et al., in view of Hennion, and Thukkani et al. (Endovascular Intervention for Peripheral Artery Disease, Circ Res. 2015 April 24; 116(9): 1599–1613, PTO-892 dated 09/26/25).
Regarding claims 117-118, and 126, Otaki as evidenced by Vergnes in view of Hennion teaches the method of diagnosing or staging PAD, including asymptomatic PAD (stage 0), mild PAD (stage 1), moderate PAD (stage 2), severe PAD (stage 3), early CTLI (stage 4) or advanced CTLI (stages 5-6). See discussion in claim 113. The method comprises detecting the level of fatty acid-binding protein 3 (FABP3), and at least one additional biomarker high sensitivity troponin (see Otaki Abstract).
Otaki measures the level of FABP3 and hsTnT on PAD patients before endovascular therapy (EVT). The results of Otaki show that the levels of FABP3 and hsTnT can be indicative of progression to CTLI in the PAD patient as discussed above, in other words, there is a relationship between the levels of FABP3 and hsTnT, and the worsening PAD severity (see Otaki Table 1, see Figures 1A and 2A, see page 38 col.2 par.2). H-FABP and hsTnT were found to be higher in patients with critical limb ischemia (CLI) compared to those without this condition (see Abstract, Figures 1A and 2A, page 39 col.1 par.2).
Otaki shows that event free patients have a mean level of FABP3 ~1.4 ng/mL, MACCE patients have a mean level of FABP3 ~ 1.87, and a general population has a mean level of FABP3 ~ 1.25 ng/mL (see Otaki Table 1, page 38 col.2 section 4.1, Figure 1A). Thus, Otaki supports a substantially normal level of FABP3 is found in the subject without CLI (see Figures 1A and 2A). Otaki shows that event free patients have a mean level of hsTnT ~1 pg/mL, MACCE patients have a mean level of hsTnT ~1.25 pg/mL, and a control has a mean level of hsTnT ~ 1.07 ng/mL (see Table 1, Figure 2A)
Otaki teaches the substantially normal level of FABP3 or the reduction in the elevated level of FABP3 is determined by comparing the detected level of FABP3 to a control level of FABP3, wherein the control level of FABP3 is a predetermined value obtained from one or a pool of non-PAD patients or healthy patients (see Abstract, teaching that serum H-FABP and hsTnT were measured in all patients before EVT; see page 38 col.2 section 4.1, teaching the control level of FABP3 is measured on general population).
However, Otaki does not explicitly teach that a substantially normal level of FABP3 or a reduction in an elevated level of FABP3 is indicative of arterial revascularization in the subject as recited in claims 117-118 and 126. Otaki does not teach “administering a cardiovascular drug, surgical intervention, optionally revascularization surgery, or amputation of the effected limb or a portion thereof based on the elevated level of FABP3” as recited in claims 117-118 and 126.
Hennion teaches that PAD represents a significant systemic atherosclerotic burden and should be considered equivalent to coronary heart disease when assessing overall cardiovascular risk (see Hennion page 308 Treatment). Management of PAD includes: administering a cardiovascular drug (e.g., statin therapy, aspirin, antiplatelet therapy) (see Hennion page 307 Sort: Key recommendations for practice, and page 308 Treatment), surgical intervention (e.g., surgical revascularization) (see Hennion page 309 Surgical Referral), amputation of the effected limb or a portion thereof (see Hennion Fig.1 and page 309 Prognosis par.1).
Thukkani teaches that endovascular therapies during the past decade is an option for treating peripheral vascular disease (see Abstract). In general, most endovascular operators aim to re-establish in-line flow to the ischemic zone with a priority given to revascularization of the dominant vessel (see page 10 par.3). Revascularization is typically considered in patients with PAD who have developed any 1 of 3 distinct clinical presentations: (1) lifestyle-limiting claudication no longer responsive to conservative therapy (IC); (2) critical limb ischemia (CLI); or (3) acute limb ischemia (ALI) (page 3 par.3). The timing and need for revascularization are broadly related to the 3 main clinical presentations of claudication, critical limb ischemia, and acute limb ischemia. Critical limb ischemia and acute limb ischemia threaten the limb and require more urgent revascularization. Patients receiving endovascular procedures need a structured surveillance plan for follow-up care. This includes intensive treatment of cardiovascular risk factors to prevent myocardial infarction and stroke, which are the main causes of death. See Abstract.
The combined teaching of Otaki and Thukkani implies that the substantially normal level of FABP3 is indicative of arterial revascularization in the subjects because those subjects do not develop CLI as taught by Otaki, so they do not need for revascularization treatment as taught by Thukkani. Accordingly, the method of Otaki can be able to assess revascularization in a subject with peripheral artery disease (PAD) because it can predict which subject is at risk of developing CLI who is in need for revascularization as taught by Thukkani.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of diagnosing or staging PAD taught by Otaki and the method of treating PAD taught by Hennion for the benefit of improving health outcomes, e.g., prevent cardiovascular events (Hennion page 307 Sort: Key recommendations for practice), improving claudication symptoms, reducing the risk of myocardial infarction, stroke, or vascular death in asymptomatic patients with moderate to severe PAD (see Hennion page 309 Medication), or arterial reconstructing in patients with CLI (see Hennion page 309 Surgical referral).
It would have been obvious to use the method of Otaki for the purpose of assessing the effectiveness of revascularization in a subject with PAD by detecting the level of FABP3 and optionally hsTnT because Otaki teaches that there is a relationship between the level of FABP3 and the worsening PAD severity, e.g., developing CLI, who requires more urgent revascularization as taught by Thukkani. Since the increasing levels of FABP3 and hsTnT are found in the patient with CLI whereas the reducing level of FABP3 is found in the patient who is not having CLI (Otaki Figures 1A and 2A), FABP3 can also be used for assessing the effectiveness of revascularization in the patient because the reduction in an elevated level of FABP3 can be indicative of patients without CLI, which means the vascularization is effective in preventing the progressive of PAD.
A person of ordinary skill in the art would have been motivated to assess the effectiveness of revascularization in the subject with PAD to change the treatment method because some patients are likely to benefit from medical therapy comparable with surgical intervention or vice versa (Thukkani page 2 par.2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method taught by Otaki and the method of treating PAD taught by Thukkani for the benefit of improving quality of life and function e.g., prevent cardiovascular events (Thukkani Abstract, page 2 par.4).
One having an ordinary skill in the art would have had a reasonable expectation of success in combining Otaki and Thukkani because Otaki is directed to a method of diagnosing PAD and Thukkani is directed to a method of treating PAD to improve quality of life and function for PAD patients.
For claim 119, Otaki as evidenced by Vergnes in view of Hennion and Thukkani teach the method of claim 117. Otaki further teaches that patients with PAD will have higher risk of developing MACCEs if they have a concurrent condition such as kidney dysfunction (see page 37 par.1: teaching that age, previous cerebrovascular disease, previous IHD, CLI, CKD, and BNP were also related to MACCEs, see Table 2: showing the hazard ratio of having MACCEs in chronic kidney disease (CKD) group is 1.97). Both H-FABP and hsTnT were found to be independent predictors of MACCEs after adjusting for CLI, previous IHD, and CKD (H-FABP, hazard ratio, 2.75; 95% confidence interval, 1.94–3.87; P < 0.0001 and hsTnT, hazard ratio, 2.14; 95% confidence interval, 1.42–3.23; P = 0.0003; Fig. 3B).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to adjust the level of FABP3 for the concurrent condition when diagnose or stage PAD in a subject because the concurrent condition is a confounding factor which also increases the risk of developing MACCEs in PAD (see Otaki, Abstract page 37 par.1 and Table 2, teaches that the concurrent conditions, such as CKD or diabetes, increase the risk of developing MACCEs in PAD patient). After adjusting for the concurrent condition, the increasing level of FABP3 was found to be an independent predictor of severe PAD (see page 37 col.2 par.1).
Regarding claim 132, Otaki as evidenced by Vergnes in view of Hennion and Thukkani teach the method of claims 117. Otaki teaches the PAD patient may not have clinical and/or biochemical evidence of myocardial ischemia and/or free of clinical and/or biochemical evidence of kidney dysfunction and/or free of clinical and/or biochemical evidence of acute stroke and/or muscle toxicity (see Otaki page 36 par.1: teaching that the exclusion criteria of the present study were acute coronary syndrome within the 3 months preceding admission, estimated glomerular filtration rate less than 30 mL/min/1.72 m2, and malignant disease).
Response to Arguments
Applicant's arguments filed 01/22/2026 have been fully considered but they are not persuasive.
Applicant argues that Otaki discloses that FABP3 and hsTnT were predictors of major adverse cardiovascular and cerebrovascular events in patients that had PAD. Otaki does not teach or suggest that FABP can be used to diagnose PAD, but it can be used to predict other Cardiovascular events in patients that already have PAD.
Examiner respectfully disagrees. The claim recites a method for diagnosing or staging PAD from stage 0 to stage 6 of PAD by detecting the elevated level of FABP3 in the subject. The teaching of Otaki at least encompasses the method for staging PAD because Otaki uses the levels of H-FABP (alternative name of FABP3 as evidenced by Vergnes) and an addition marker hsTnT for predicting adverse clinical outcomes in patients which the adverse clinical outcomes comprise critical limb ischemia _ CLI, which is equivalent to stage 4 or 5 or 6. Otaki shows that the level of H-FABP in the patients with PAD is greater than that in the general population (see page 38 section 4.1), and the level of H-FABP is higher in patients with CLI compared to those without this condition (see Abstract, see page 37 section 3.2, see Table 1, Figure 1 and 2), thereby showing the elevated level of FABP3 in patients with PAD is correlated to the severity of PAD. Otaki also shows that the level of hsTnT (an additional biomarker) is higher in patients with CLI compared to those without this condition (see Abstract, see page 37 section 3.2, see Table 1, Figure 1 and 2).
Moreover, from Otaki’s teaching, it would have been obvious to use the method of Otaki for diagnosing PAD because Otaki teaches that the level of H-FABP in patient with PAD is higher compared to the level of H-FABP in the general population (see page 38 section 4.1). In other words, if a subject has an increased level of H-FABP compared to that in general population, it is more likely that the subject has PAD.
Applicant argues that Otaki only discusses FABP3 and therefore does not teach or suggest that FABP4 is a standalone biomarker for PAD.
Examiner respectfully disagrees. While Examiner withdrew the restriction requirement for groups of inventions, the species election is still maintained. Since Applicant elected the species FABP3, the argument is moot because Examiner did not examine the non-elected FABP4 species.
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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHAU N.B. TRAN whose telephone number is (571)272-3663. The examiner can normally be reached Mon-Fri 8:30-6:30 CT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy L Nguyen can be reached at 571-272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHAU N.B. TRAN/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 March 30, 2026