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
The examiner for this Application has changed. Please direct all future correspondence to Patent Examiner, Katriel B Kasayan, AU 1634. Additional contact information can be found at the end of this paper.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to papers filed August 18, 2025. Currently, claims 1, 10, 16-19, 28-38 are currently pending. Claims 1, 10, 16 and 19 have been amended, claims 2-9, 11-15, and 20-27 are canceled and claims 28-38 are newly added by Applicants’ amendment filed on 08/18/2025. It is noted that claim 1, 10, 29 and 34 are independent claims.
Therefore, claims 1, 10, 16-19 and 28-38 are under examination to which the following grounds of rejection are applicable.
Priority
The present application is a continuation-in-part of Patent No. 15/967,719 filed May 1, 2018 (now US Patent PAT 11169145) , which claims priority to US Provisional Application 62/492,447 filed May 1, 2017.
Therefore, the earliest possible priority for the instant application is May 1, 2017.
Response to Arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 101
In view of Applicants’ amendments filed on August 18, 2025, the rejection regarding claims 10-14 and 17-27 under 35 U.S.C. §101 because the claimed invention is directed to an abstract idea without significantly more, has been withdrawn.
Applicants’ amended claim 10 such that it states “identifying the subject as having an elevated level of circulating FAS enzyme content as compared to a control; and treating the identified subject with a vasodilator” to overcome the rejection.
Claim Rejections - 35 USC § 103
In view of Applicants’ amendments filed on August 18, 2025, the rejection of claims 2, 11, 21 and 23 under 35 U.S.C §103 as rendered obvious by Muraca (Published: 2012. Cited in IDS filed 1/12/2023. US Publication: 201210165218. WIPO: WO2013188605) in view of De Silva (Published: 2019. Atherosclerosis, 287, 38–45) has been withdrawn, and is moot as the rejection is drawn to canceled claims.
In view of Applicants’ amendments filed on August 18, 2025, the rejection of claims 5, 7 , and 14 under 35 U.S.C §103 as rendered obvious by Muraca (Published: 2012. Cited in IDS filed 1/12/2023. US Publication: 201210165218. WIPO: WO2013188605) in view of Gibbons et al. (Cited in IDS filed 1/12/2023. Seminars in Vascular Surgery, 25, 2, p.p. 89-92) has been withdrawn, and is moot as the rejection is drawn to canceled claims.
In view of Applicants’ amendments filed on August 18, 2025, the rejection of claim 9 under 35 U.S.C §103 as rendered obvious by Muraca (Published: 2012. Cited in IDS filed 1/12/2023. US Publication: 201210165218. WIPO: WO2013188605) in view of Schnieder et al. (Cited in IDS filed 1/12/2023. The Journal of Biological Chemistry, 285, 30, p.p. 23398-23409.) has been withdrawn, and is moot as the rejection is drawn to canceled claims.
In view of Applicants’ amendments filed on August 18, 2025, the rejection of claims 10 and 17-19 under 35 U.S.C §103 as rendered obvious by Muraca (Published: 2012. Cited in IDS filed 1/12/2023. US Publication: 201210165218. WIPO: WO2013188605) has been withdrawn.
Applicants’ arguments are moot in view of the withdrawn rejections. A response to any argument pertaining to a new or maintained rejection can be found below.
Maintained Objections/Rejections in Response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 103
Claim 1 remains rejected under 35 U.S.C. 102(a)(1) as being anticipated by Muraca (WO2013188605; 12 January 2023 IDS Document).
This is a modified rejection necessitated by Applicants’ amendments to the claims in the
response filed August 18, 2025.
Regarding claim 1, Muraca teaches a method for detecting a level of Fatty Acid Synthase (FASN) enzyme comprising, providing a serum or plasma (para 0017, “The present invention provides a method of predicting whether a subject afflicted with metabolic syndrome will develop heart failure comprising obtaining a biologic sample from the subject, determining the level of one or more biomarkers selected from the group consisting of FASN… in said biologic sample and stratifying the subjects as likely to develop heart failure based on the expression level of said one or more biomarkers.”; para 0018, “In a further embodiment, the biologic sample obtained is selected from the group consisting of blood, peripheral blood mononuclear cells (PBMC), isolated blood cells, serum and plasma”), detecting a level of FAS enzyme content using an ELISA (para 0011, “The present invention provides a method for predicting the incidence of metabolic syndrome in a subject comprising determining the level of FASN or FASN in combination with USP2A in a sample obtained from the subject and stratifying the subject as likely to develop metabolic syndrome based on the level of FASN or FASN in combination with USP2A where the detection rate of either FASN or FASN…”; para 0018, “In another embodiment, protein expression levels are measured by immunoassay. In a further embodiment, the immunoassay is an enzyme-linked immunosorbent assay (ELISA). In another embodiment, the expression level of two biomarkers is determined.”; para 0136, “In one embodiment, a technique for use in the present invention to detect the amount of a biomarker (including, but not limited to FASN, USP2A, GSΤΩ1, SOD2, KCNE2 or BNP) in circulating cells is the sandwich ELISA, in which highly specific monoclonal antibodies are used to detect sample antigen.”).
In relation to the recitation of “the serum or plasma derived from the cardiovascular tissue of the subject”, Muraca discloses detecting a level of Fatty Acid Synthase (FASN) enzyme comprising, providing a serum or plasma. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections, wherein the prior art discloses subject matter which there is reason to believe naturally includes functions that are newly cited or is identical to a product instantly claimed. In such a situation, the burden is shifted to the Applicants to “prove that subject matter shown to be in the prior art does not possess characteristic relied on” (205 USPQ 594, second column, first full paragraph).
Response to Applicant arguments as they apply to the rejection of the claims under 35 U.S.C. 102 as
being unpatentable over Muraca et al.
Beginning on page 8 of the Remarks filed on August 18, 2025, Applicants essentially argue the following:
Applicant submits that Muraca is completely silent as to a method of detecting a level of circulating FAS enzyme content specifically in serum or plasma derived from the cardiovascular tissue of a subject.
Accordingly, Applicant submits that Muraca fails to teach each and every element of claim 1.
In response to that argument, it has been fully considered but deemed not persuasive for the following reasons:
Regarding claims 1) and 2), the phrase “serum or plasma derived from cardiovascular tissue” does not clearly define a structural or procedural distinction over the serum samples disclosed by Muraca in paragraph [0018]. Further, the claim is indefinite as serum and plasma are isolated from blood and not cardiovascular tissue, absent to any evidence to the contrary. As such, it is unclear whether the amended language requires serum or plasma to be obtained from blood associated with cardiovascular tissue, serum or plasma obtained by subjects suffering from cardiovascular disease, etc. Furthermore, the recitation of the serum or plasma derived from the cardiovascular tissue of the subject” is similar to a product-by-process claims. M.P.E.P. § 2113 reads, “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps.”
The use of 35 U.S.C. §§ 102 and 103 rejections for product-by-process claims has been approved by the courts. “[T]he lack of physical description in a product-by-process claim makes determination of the patentability of the claim more difficult, since in spite of the fact that the claim may recite only process limitations, it is the patentability of the product claimed and not of the recited process steps which must be established. We are therefore of the opinion that when the prior art discloses a product which reasonably appears to be either identical with or only slightly different than a product claimed in a product-by-process claim, a rejection based alternatively on either section 102 or section 103 of the statute is eminently fair and acceptable. As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
Thus, Muraca teaches an embodiment of detecting FAS enzyme from serum or plasma using an ELISA. Therefore, the amendment does not persuasively distinguish the claimed invention from Muraca.
New Grounds Objections/Rejections necessitated by Applicants’ amendments to the claims in the
response filed August 18, 2025.
Claim Rejections - 35 USC § 112(b)
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, 10, 16-19, 28, 31 , 36 and 37 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 claims 1, and 28, the claims are indefinite in its recitation of the phrase “serum or plasma derived from cardiovascular tissue”, as serum and plasma are derived from blood rather than tissue. Further, the claims do not provide sufficient clarity as to what constitutes a serum or plasma sample derived from the cardiovascular tissue of a subject. It is unclear the nature and number of steps required to obtain a "derivative" of a cardiovascular tissue. The term implies a number of different steps that may or may not result in a change in the functional characteristics of a serum or plasma sample from the source that it is "derived from".
Claim 1 is indefinite in its recitation of “the cardiovascular tissue” in line 1. There is not proper antecedent bases for the recitation of “the cardiovascular tissue”.
Regarding claim 31, it is indefinite in its recitation of the phrase “low-density lipoprotein (LDL) fractions derived from arterial plaque”. Claim 31 is vague and indefinite because they recite the phrase "derived from" and the metes and bounds of how LDL fractions can be "derived from" the claimed arterial plaque and still meet the intended limitation of the claims are not clear. Without a clear statement of the process by which the starting material is derivatized, it is not possible to know the metes and bounds of a "derivative" because any given starting material can have many divergent derivatives depending on the process of derivatization. This rejection could be overcome by substituting "isolated" for "derived" in the claim.
Claims 18 and 37 are indefinite because it is unclear how an elevated first level of circulating FAS enzyme content compared to a second level can simultaneously indicate both foot wound healing and foot wound progression, as these two processes appear to be opposites. Moreover, claim 18 and 37 are indefinite because it is unclear how an elevated first level of circulating FAS enzyme content compared to a second level relates to the circulating FAS enzyme content as compared to a control of independent claims 1 and 34. As such, the metes and bounds of the claims are indefinite.
For the purpose of a compact prosecution the term “derived” recited in claim 31 has been interpreted as “obtained or isolated from”.
Claims 16-19 and 28 are indefinite insofar as they depend on claim 10. Claim 38 is indefinite insofar as it depends on claim 37.
Claim Rejections - 35 USC § 103
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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 10, and 16-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Muraca (WO2013188605; 12 January 2023 IDS Document) as applied to claim 1, in view of De Francis (Wound Journal, 12, 250-253; 12 January 2023 IDS Document) and De Silva (Published: 2019. Atherosclerosis, 287, 38–45)
With regard to claim 1, the teachings of Muraca render obvious the claimed methodology, as iterated above in the 102 rejection the content of which is incorporated in claim 1. Moreover, Muraca teaches screening for heart failure or a metabolic syndrome (para 0019, “The invention relates to compositions, methods and assays for detecting, screening for, or diagnosing conditions including, but not limited to metabolic syndrome, heart failure, insulin resistance and/or insulin sensitivity, staging or stratifying subjects; and determining the progression of, regression of and/or survival from metabolic syndrome.”; para 0020, “As used herein, the term "metabolic syndrome" or "MS" refers to a group of risk factors that occur together and increase an individual's risk for coronary artery disease, heart failure (HF) [also referred to herein as congestive heart failure (CHF)], stroke, and Type 2 diabetes”). Further, Muraca teaches measuring levels of FAS enzyme (para 0049, “In doing so, the present invention provides methods, algorithms and other clinical tools to augment traditional diagnostic, prognostic and/or therapeutic paradigms. Combination approaches using one or more biomarkers in the determination of the value of one or more clinical management parameters also are envisioned. For example methods of this invention that measure FASN…”). Muraca also teaches using normal tissues as controls (para 0084, “Clinical information also includes information such as age, sex, medical history, treatment history, symptoms, family history, recurrence (yes/no), etc. Samples of normal tissue of different types (e.g., tissue, serum, etc) as well as samples of non-metabolic syndrome or non-diabetic can be used as controls.”) and comparing the expression profiles from samples to a control (para 0098, “The expression profiles of the samples are then compared to the profile of a control cell. If the sample expression patterns are consistent with the expression pattern for recurrence of metabolic syndrome and/or heart failure then (in the absence of countervailing medical considerations) the patient is treated as one would treat a relapse patient. If the sample expression patterns are consistent with the expression pattern from the normal/control cell then the patient is diagnosed negative for the syndrome.”). Muraca teaches that levels of FAS enzyme can be optimize in samples of peripheral blood “optimized set of genes that could include some genes that are expressed in peripheral blood as well as in diseased tissue.” (para [0096]) and clinical management of metabolic syndrome and type 2 diabetes (para [0070])
However, Muraca does not explicitly teach the circulating FAS enzyme content level in the subject is elevated compared to a control as recited in claim 10.
De Silva teaches comparing a subject with elevated Fatty Acid Synthase (FAS) enzyme to controls (pp. 40, col 2, “Additionally, patients with CAS had higher cFAS enzyme activity compared to controls… Patients with diabetes had significantly higher cFAS enzyme activity compared to patients with no diabetes (p < 0.05) and control patients (p < 0.01; Fig. 1C).”)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the diagnosis step in Muraca's treatment according to the method of De Silva to compare the circulating FAS enzyme content levels that may be upregulated to a control sample to determine an appropriate treatment regimen.
However, Muraca and De Silva are silent on treating the identified subject comprising upregulated levels of FAS enzyme content with a vasodilator.
De Francis teaches that cilostazol (vasodilator) has been used to prevent peripheral vascular events and slows the onset of foot ulcers (Abstract, “Cilostazol appears to have a lowering effect on MMP‐9 levels and this may suggest a beneficial effect in order to prevent or retard the onset of foot ulcer in diabetic patients.”; pp. 251, col 1, “cilostazol administration in diabetic patients with peripheral vascular disease and intermittent claudication seems to be effective not only in improving walking distances but also in preventing foot ulceration”). Further, De Francis teaches that diabetes is commonly associated with high risk of foot ulceration (pp. 250, “diabetes mellitus II is associated with a high incidence of peripheral vascular disease and a high risk of foot ulceration and consequent amputation that affects not only the quality of life but also represents an important factor related to mortality rate in diabetic patients.” )
It would have been obvious to modify the treatment method of Muraca, to further comprise administering in cases of upregulated FAS enzyme content level a vasodilator, cilostazol, to slow the progression of diabetic foot ulcers in diabetic patients with peripheral vascular disease. There would have been reasonable expectations of success absent any evidence of unexpected results.
Regarding claim 16, the combined teachings of De Francis and Muraca render obvious the claimed method of claims 1 and 10. Moreover, De Francis teaches that the vasodilator is cilostazol (Abstract, “Cilostazol appears to have a lowering effect on MMP‐9 levels and this may suggest a beneficial effect in order to prevent or retard the onset of foot ulcer in diabetic patients.”; pp. 251, col 1, “cilostazol administration in diabetic patients with peripheral vascular disease and intermittent claudication seems to be effective not only in improving walking distances but also in preventing foot ulceration”).
Regarding claim 17 and 18, the combined teachings of De Francis and Muraca render obvious the claimed method of claims 1 and 10. Moreover, Muraca teaches that the FAS enzyme is measured one or more times (para 0067, “In one embodiment of the invention, FASN expression is measured relative to the expression of one or more additional genes and/or at one or more different biopsy sites or at a different blood or serum draw time. Comparisons of gene expression within the site and/or at a different time allow conclusions to be drawn about the status of a site or the subject and whether a condition such as (but not limited to) any of the features of metabolic syndrome require further monitoring or clinical management.”).
Regarding claim 19, the combined teachings of De Francis and Muraca render obvious the claimed method of claims 1, 10 and 17. Moreover, Muraca teaches clinical management parameters addressed by the present invention include degree of regression, responsiveness to treatment, effectiveness of treatment (para 0045, “clinical management parameters addressed by the present invention include, but are not limited to, survival in years, disease related death, early or late response to insulin and resistance, degree of regression, responsiveness to treatment, effectiveness of treatment, the likelihood of progression of a condition on to a more severe disease such as one or more cancers, blood pressure, body mass index (BMI), levels of insulin, blood sugar, triglycerides, HDL, LDL, C-reactive protein, as well as biomarker status such as levels of FASN, USP2A, GSΤΩ1, SOD2, KCNE2, BNP or other genes or a SNP of FASN, GSΤΩ1, SOD2, KCNE2, BNP or USP2A, or any metabolic related gene.”)
***
Claim(s) 1 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Muraca (WO2013188605; 12 January 2023 IDS Document) in view of De Francis (Wound Journal, 12, 250-253; 12 January 2023 IDS Document), as applied to claim 1 above, and in further view of Teuper et al. (Published: 2002. Ultracentrifugal separation of VLDL, LDL and HDL. Animal Models of Diabetic Complications Consortium AMDCC Protocol) and Schneider et al. (Schneider et. al., Macrophage Fatty-acid Synthase Deficiency Decreases Diet-induced Atherosclerosis, 2010, The Journal of Biological Chemistry, 285(30), 23398-23409; 12 January 2023 IDS Document).
With regard to claim 1, the teachings of Muraca and De Francis render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 1. Moreover, Muraca teaches that LDL (lipoprotein) is a clinically relevant parameter for metabolic system, (para 0012, “The methods of predicting the incidence of metabolic syndrome may further comprise measuring one or more clinical management parameter such as, but not limited to, blood pressure, body mass index (BMI), levels of insulin, blood sugar, triglycerides, HDL, LDL and C-reactive protein.”).
However, Muraca and De Francis do not explicitly teach fractioning the serum or plasma to obtain lipoproteins.
Teuper teaches a method for centrifuging blood plasma to obtain lipid fractions such as LDL (pp. 1, “This protocol is used to isolate the various lipid fractions from blood plasma using ultracentrifugation. The actual measured concentrations are performed separately once the isolations are complete.”; pp. 2, step 12, “Measure cholesterol, triglycerides or phospholipids concentrations in the lipoprotein fractions using their respective protocols.”).
It would have been obvious for a skilled artisan to modify the detection method of Muraca and fractionate blood plasma to obtain lipid fractions such as LDL using the known method from Teupser to screen for individuals with metabolic syndrome. The incorporation of Teupser applies merely a known fractionation technique that would have achieved predictable results.
The combined teachings of De Frances, Muraca, and Teupser fail to teach evaluating FAS enzyme levels within the lipoprotein fractions.
Schneider discloses teaches atherosclerosis accelerates vascular fatty acid synthesis and the plaque appears to be the predominant site of synthesis (Schneider, Pg. 23398 Col. 2, 2nd passage). Schneider further teaches in the FASKOM knockout model, uptake of fluorescently labeled oxidized LDL was decreased significantly as compared with wild type cells (Pg. 23404 Col 2 ).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Muraca's method to include the correlation of increased FAS levels to increased levels of LDL (lipoprotein) deposited in arterial plaque, because Schneider suggests determination of such mechanisms involved in the progression of atherosclerotic lesions as many patients whose initial presentation of atherosclerosis is myocardial infarction or sudden death were not previously identified by conventional risk measures (Schneider Pg. 23398, Col. 2,[1]).
***
Claim(s) 29-31, and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Muraca (WO2013188605; 12 January 2023 IDS Document) in view of, and in further view of Teuper et al. (Published: 2002. Ultracentrifugal separation of VLDL, LDL and HDL. Animal Models of Diabetic Complications Consortium AMDCC Protocol) and Schneider et al. (Schneider et. al., Macrophage Fatty-acid Synthase Deficiency Decreases Diet-induced Atherosclerosis, 2010, The Journal of Biological Chemistry, 285(30), 23398-23409; 12 January 2023 IDS Document).
Regarding claim 29, Muraca teaches a method for detecting a level of Fatty Acid Synthase (FAS) enzyme comprising, providing a serum or plasma (para 0017, “The present invention provides a method of predicting whether a subject afflicted with metabolic syndrome will develop heart failure comprising obtaining a biologic sample from the subject, determining the level of one or more biomarkers selected from the group consisting of FASN… in said biologic sample and stratifying the subjects as likely to develop heart failure based on the expression level of said one or more biomarkers.”; para 0018, “In a further embodiment, the biologic sample obtained is selected from the group consisting of blood, peripheral blood mononuclear cells (PBMC), isolated blood cells, serum and plasma”), detecting a level of FAS enzyme content using an ELISA (para 0011, “The present invention provides a method for predicting the incidence of metabolic syndrome in a subject comprising determining the level of FASN or FASN in combination with USP2A in a sample obtained from the subject and stratifying the subject as likely to develop metabolic syndrome based on the level of FASN or FASN in combination with USP2A where the detection rate of either FASN or FASN…”; para 0018, “In another embodiment, protein expression levels are measured by immunoassay. In a further embodiment, the immunoassay is an enzyme-linked immunosorbent assay (ELISA). In another embodiment, the expression level of two biomarkers is determined.”; para 0136, “In one embodiment, a technique for use in the present invention to detect the amount of a biomarker (including, but not limited to FASN, USP2A, GSΤΩ1, SOD2, KCNE2 or BNP) in circulating cells is the sandwich ELISA, in which highly specific monoclonal antibodies are used to detect sample antigen.”).
However, Muraca does not explicitly teach fractioning the serum or plasma to obtain lipoproteins.
Teuper teaches a method for centrifuging blood plasma to obtain lipid fractions such as LDL (pp. 1, “This protocol is used to isolate the various lipid fractions from blood plasma using ultracentrifugation. The actual measured concentrations are performed separately once the isolations are complete.”; pp. 2, step 12, “Measure cholesterol, triglycerides or phospholipids concentrations in the lipoprotein fractions using their respective protocols.”).
It would have been obvious for a skilled artisan to modify the detection method of Muraca and fractionate blood plasma to obtain lipoproteins using the known method from Teupser to screen for individuals with metabolic syndrome. The incorporation of Teupser applies merely a known fractionation technique that would have achieved predictable results.
However, the combined teachings of Muraca, and Teupser fail to teach evaluating FAS enzyme levels within the lipoprotein fractions.
Schneider discloses teaches atherosclerosis accelerates vascular fatty acid synthesis and the plaque appears to be the predominant site of synthesis (Schneider, Pg. 23398 Col. 2, 2nd passage). Schneider further teaches in the FASKOM knockout model, uptake of fluorescently labeled oxidized LDL was decreased significantly as compared with wild type cells (Pg. 23404 Col 2 ).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Muraca's method to include the correlation of increased FAS levels to increased levels of LDL (lipoprotein) deposited in arterial plaque, because Schneider suggests determination of such mechanisms involved in the progression of atherosclerotic lesions as many patients whose initial presentation of atherosclerosis is myocardial infarction or sudden death were not previously identified by conventional risk measures (Schneider Pg. 23398, Col. 2,[1]).
Regarding claim 30, the combined teachings of Muraca, Teupser, and Schnieder render obvious the claimed methodology of claim 29. Moreover, Teupser teaches that the lipoprotein include low-density lipoprotein (LDL) (pp. 2, “Using a rinsed Hamilton syringe remove the bottom 60 µl from tube B and transfer to the same Eppendorf tube labeled LDL in step 9 above (To recover any LDL contaminating the VLDL preparation after the first ultracentrifugation spin)”).
Regarding claim 31, the combined teachings of Muraca, Teupser, and Schnieder render obvious the claimed methodology of claim 29. Moreover, Schnieder teaches that the lipoproteins are derived from arterial plaque (Schneider, Pg. 23398 Col. 2, 2nd passage; Pg. 23404 Col 2).
Regarding claim 33, the combined teachings of Muraca, Teupser, and Schnieder render obvious the claimed methodology of claim 29. Moreover, Muraca teaches measuring levels of FAS enzyme using an ELISA (para 0136, “In one embodiment, a technique for use in the present invention to detect the amount of a biomarker (including, but not limited to FASN, USP2A, GSΤΩ1, SOD2, KCNE2 or BNP) in circulating cells is the sandwich ELISA, in which highly specific monoclonal antibodies are used to detect sample antigen.”).
***
Claim(s) 29, 32, 34-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Muraca (WO2013188605; 12 January 2023 IDS Document) in view of De Silva (Published: 2019. Atherosclerosis, 287, 38–45) and Teuper et al. (Published: 2002. Ultracentrifugal separation of VLDL, LDL and HDL. Animal Models of Diabetic Complications Consortium AMDCC Protocol) and Schneider et al. (Schneider et. al., Macrophage Fatty-acid Synthase Deficiency Decreases Diet-induced Atherosclerosis, 2010, The Journal of Biological Chemistry, 285(30), 23398-23409; 12 January 2023 IDS Document), and in further view of De Francis (Wound Journal, 12, 250-253; 12 January 2023 IDS Document).
With regard to claim 29, the combined teachings of Muraca, Teupser, and Schnieder render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 29.
Moreover, Muraca teaches screening for heart failure or a metabolic syndrome (para 0019, “The invention relates to compositions, methods and assays for detecting, screening for, or diagnosing conditions including, but not limited to metabolic syndrome, heart failure, insulin resistance and/or insulin sensitivity, staging or stratifying subjects; and determining the progression of, regression of and/or survival from metabolic syndrome.”; para 0020, “As used herein, the term "metabolic syndrome" or "MS" refers to a group of risk factors that occur together and increase an individual's risk for coronary artery disease, heart failure (HF) [also referred to herein as congestive heart failure (CHF)], stroke, and Type 2 diabetes”). Further, Muraca teaches measuring levels of FAS enzyme (para 0049, “In doing so, the present invention provides methods, algorithms and other clinical tools to augment traditional diagnostic, prognostic and/or therapeutic paradigms. Combination approaches using one or more biomarkers in the determination of the value of one or more clinical management parameters also are envisioned. For example methods of this invention that measure FASN…”). Muraca also teaches using normal tissues as controls (para 0084, “Clinical information also includes information such as age, sex, medical history, treatment history, symptoms, family history, recurrence (yes/no), etc. Samples of normal tissue of different types (e.g., tissue, serum, etc) as well as samples of non-metabolic syndrome or non-diabetic can be used as controls.”) and comparing the expression profiles from samples to a control (para 0098, “The expression profiles of the samples are then compared to the profile of a control cell. If the sample expression patterns are consistent with the expression pattern for recurrence of metabolic syndrome and/or heart failure then (in the absence of countervailing medical considerations) the patient is treated as one would treat a relapse patient. If the sample expression patterns are consistent with the expression pattern from the normal/control cell then the patient is diagnosed negative for the syndrome.”).
However, Muraca does not explicitly teach the circulating FAS enzyme content level in the subject is elevated compared to a control.
De Silva teaches comparing a subject with elevated Fatty Acid Synthase (FAS) enzyme to controls (pp. 40, col 2, “Additionally, patients with CAS had higher cFAS enzyme activity compared to controls… Patients with diabetes had significantly higher cFAS enzyme activity compared to patients with no diabetes (p < 0.05) and control patients (p < 0.01; Fig. 1C).”) It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the diagnosis step in Muraca's treatment method according to the method of De Silva to compare the circulating FAS enzyme content levels to a control sample to determine an appropriate treatment regimen.
However, Muraca is silent on treating the identified subject with a vasodilator.
De Francis teaches that cilostazol (vasodilator) has been used to prevent peripheral vascular events and slows the onset of foot ulcers (Abstract, “Cilostazol appears to have a lowering effect on MMP‐9 levels and this may suggest a beneficial effect in order to prevent or retard the onset of foot ulcer in diabetic patients.”; pp. 251, col 1, “cilostazol administration in diabetic patients with peripheral vascular disease and intermittent claudication seems to be effective not only in improving walking distances but also in preventing foot ulceration”).
It would have been obvious to modify the treatment method of Muraca, to further comprise administering in cases of upregulated FAS enzyme content level a vasodilator, cilostazol, to slow the progression of diabetic foot ulcers in diabetic patients with peripheral vascular disease. There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results absent any evidence of unexpected results.
Regarding claim 34, the combined teachings of Muraca, Teupser, and Schnieder and De Francis render obvious the claimed methodology of claim 29. Further, Muraca describes the method of measuring a level of FAS enzyme from serum or plasma (para 0017,-0018). Moreover, De Francis teaches that vasodilator (Abstract, “Cilostazol appears to have a lowering effect on MMP‐9 levels and this may suggest a beneficial effect in order to prevent or retard the onset of foot ulcer in diabetic patients.”; pp. 251, col 1, “cilostazol administration in diabetic patients with peripheral vascular disease and intermittent claudication seems to be effective not only in improving walking distances but also in preventing foot ulceration”).
Regarding claim 35, the combined teachings of De Francis and Muraca render obvious the claimed method of claims 29 and 34. Moreover, De Francis teaches that the vasodilator is cilostazol (Abstract, “Cilostazol appears to have a lowering effect on MMP‐9 levels and this may suggest a beneficial effect in order to prevent or retard the onset of foot ulcer in diabetic patients.”; pp. 251, col 1, “cilostazol administration in diabetic patients with peripheral vascular disease and intermittent claudication seems to be effective not only in improving walking distances but also in preventing foot ulceration”).
Regarding claim 36, the combined teachings of De Francis and Muraca render obvious the claimed method of claims 29 and 34. Moreover, Muraca teaches that the FAS enzyme is measured one or more times (para 0067, “In one embodiment of the invention, FASN expression is measured relative to the expression of one or more additional genes and/or at one or more different biopsy sites or at a different blood or serum draw time. Comparisons of gene expression within the site and/or at a different time allow conclusions to be drawn about the status of a site or the subject and whether a condition such as (but not limited to) any of the features of metabolic syndrome require further monitoring or clinical management.”).
Regarding claim 37 and 38, the combined teachings of De Francis and Muraca render obvious the claimed method of claims 29 and 34. Moreover, Muraca teaches clinical management parameters addressed by the present invention include degree of regression, responsiveness to treatment, effectiveness of treatment (para 0045, “clinical management parameters addressed by the present invention include, but are not limited to, survival in years, disease related death, early or late response to insulin and resistance, degree of regression, responsiveness to treatment, effectiveness of treatment, the likelihood of progression of a condition on to a more severe disease such as one or more cancers, blood pressure, body mass index (BMI), levels of insulin, blood sugar, triglycerides, HDL, LDL, C-reactive protein, as well as biomarker status such as levels of FASN, USP2A, GSΤΩ1, SOD2, KCNE2, BNP or other genes or a SNP of FASN, GSΤΩ1, SOD2, KCNE2, BNP or USP2A, or any metabolic related gene.”).
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KATRIEL BARCELLANO KASAYAN/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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