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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/04/2025 has been entered.
Response to Amendment
The Amendment filed 08/04/2025 has been entered. Claims 1, 3-8, 10-12 remain pending in the application. Claims 1, 4, and 11 have been amended. Claim 9 has been cancelled, and claim 2 is previous cancelled.
Status of Objections and Rejections
All objections to the claims are withdrawn in view of Applicant's amendment.
All rejections under 35 USC 101 are withdrawn in view of Applicant's amendment.
All rejections under 35 USC 103 are withdrawn in view of Applicant's amendment.
New grounds of rejection under 35 U.S.C. 103 are necessitated by the amendments.
New grounds of rejection under 35 U.S.C. 112(b) are necessitated by the amendments.
Response to Arguments
Applicant’s arguments see pages 4-6, filed 08/04/2025, with respect to the rejections of claims 1, 3-4, 6-11 under 35 U.S.C. 103 are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Claim Interpretation
The claims recite a treatment method, however, the disclosure is directed to a diagnostic/prognostic method and does not name, describe, or claim any specific treatment. The disclosure only claims that metabolite-based prognosis can be used to inform or adapt a clinician’s subsequent treatment ([0008][0027]), but the content of that treatment is outside the scope of the invention. The Examiner interprets the claims and disclosure as a diagnostic/prognostic method intended to help clinicians decide how to treat a non-healing wound, but they do not identify or describe any actual treatment modality.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-8, 10-12 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 11, it is unclear whether the administration of treatment is a ratio of carnitine to ceramide and/or ceramide derivate that is lower than a reference value in a sample taken from the mammal or whether before the treatment the mammal already naturally has a ratio of carnitine to ceramide lower than a reference value in a sample taken from the mammal. The Examiner interprets the limitation to be the latter.
Claims 5-8, 10, and 12 are rejected based on dependence of rejected claims 1 and 11.
Regarding claim 4, lines 1-2 recite “said reference value has been determined in mammals who healed,” however claim 1, from which claim 4 depends, claims the reference value to be from a sample taken from the mammal to which treatment is administered. It is unclear how the reference value can both be obtained from a healed mammal and a mammal requiring treatment. Applicant may correct this by correcting claim 1, lines 5-6, to state “a reference value in a sample taken from a mammal different than the mammal to be administered treatment”.
Regarding claim 12, lines 5-6 recite the phrase “preferably”. The term “preferably” renders the claim indefinite because it introduces subjective or relative terminology that fails to clearly define the metes and bounds of the invention. The scope of the broad ranges is uncertain in view of the “preferably” language, as it suggests an unstated distinction in operative conditions without clearly defining the boundaries of the claimed invention. See MPEP 2173.05 (b).
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3-6, 8 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Burslem (US 2004/0038292 A1) in view of Kamlage (EP 3502699A1; 06-26-2019; See attached English translation).
Regarding claim 1, Burslem teaches a method of treating a non-healing or chronic ulcer in a mammal (A method for treatment of a disease or disorder characterised by an impaired healing response, such as chronic dermal ulcers; claim 14) comprising administering treatment to the non-healing or chronic ulcer in a mammal (administering to a mammal in need of such treatment a therapeutically effective amount of an agonist or activator of a protein; claim 14) with a ratio of carnitine enzyme to ceramide and/or ceramide derivate enzyme lower than a reference value in a sample taken from the mammal (Emphasis Added)(The mammal is characterized by having an impaired healing response by collecting a tissue sample, measuring carnitine and ceramide enzymatic levels and comparing them to unwounded control tissue; See claim 19 and cluster data Table 1)(Claims 14 and 19 are interpreted as including but not limited to the cited clusters because Burslem presents these gene clusters as exemplary indicators of wound status rather than an exclusive set, permitting other biomarkers, such as ceramide and carnitine enzymes, to fall within the same conceptual framework of assessing and treating impaired wound healing)(The cluster data of Table 1 of pages 147, 174, 361, and 575 shows that ceramide glucosyltransferase, is a measured biomarker from both wounded mammal tissue and healthy mammal tissue (See values from columns WT30 min, WT3 hours, and WT 12 hours compared to WT control), and pages 83, 270, 457 show that carnitine acetyltransferase/cds is a measured biomarker from both wounded mammal tissue and a healthy mammal tissue. The numeric values presented in the tables illustrate that carnitine and ceramide naturally exist in mammals in relative quantities which could naturally be expressed as ratios and readily fall below an arbitrarily selected reference value. For example carnitine at 407.9 of page 83, line 24 divided by ceramide at -21.7 of page 174 line 11 creates a ratio that is less than a reference value of 115.4 of ceramide in WT control samples or even a reference value of infinity)(The Examiner interprets a reference value to be derived from any source using any method. The instant specification states that the reference value is obtained from a ratio of ceramide to carnitine in healthy mammals ([0040]; US 20220334137 A1; Fig.2). Application may correct the claim to state as such)(The claim does not explicitly recite a step of calculating the ratio nor a step of comparing the ratio to a reference value; therefore, under broadest reasonable interpretation, the Examiner understands that the mammal naturally exhibits a ratio of carnitine to ceramide in relation to a reference value of infinity).
Burslem fails to teach carnitine and ceramide molecules, but instead teaches the enzyme of each.
Kamlage teaches carnitine and ceramide molecules (“determining in a sample of said subject the value of (i) at least one biomarker of the categories carnitines…and (ii) a first and a second sphingolipid,” wherein “the first sphingolipid and the second sphingolipid are from the same subclass, preferably both are ceramides” where “the value of a biomarker is a ratio or another value derived from the amount of more than one biomarker,” and “whereby values found in a sample to be investigated which are higher than (or depending on the marker lower than) the threshold”; [0001][[0036][0018][0047]).
Kamlage is considered to be analogous to the claimed invention because it is in the same field of endeavor for lesion treatment based on carnitine-dependent regulation of ceramide biosynthesis ([0045][0015][0017])(Kamlage teaches treatment of pancreatic cancer symptoms which include abdominal cystic lesions). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the biomarker list taught by modified Burslem by substituting the analysis of carnitine acetyltransferase/cds and ceramide glucosyltransferase with carnitine and ceramide metabolites since both measurements serve the same purpose of predicting whether a mammal exhibits an impaired wound healing response, yielding the predictable result of a mammal’s wound-healing status (See MPEP 2143(B, E)). Burslem already implicates the ceramide and carnitines metabolic pathways through its disclosure of the associated enzymes. Substituting direct measurement of carnitine and ceramide molecules is a predictable modification, especially in view of Kamlage, which teaches that carnitine and ceramide metabolite levels are altered in abdominal cystic lesions and therefore serve as diagnostically relevant biomarkers. One of ordinary skill in the art would reasonable extend Kamlage’s metabolite findings to ulcer-based diagnostics since both abdominal cystic lesions and ulcers are conditions represented by localized pathological tissue injury driven by similar cellular process, apoptosis and inflammatory signaling (Kamlage, [0007]).
Regarding claim 3, Modified Burslem teaches the method according to claim 1, wherein said reference value is 40 (the ratio of carnitine at 407.9 of page 83, line 24 divided by ceramide at -21.7 of page 174 line 11 of Burslem would create a negative value that is still below an arbitrary reference value of 40; see page 262, second to last row, column 4)(The Examiner interprets a reference value of 40 to be derived from any source using any method. The instant specification states that the reference value is obtained from a ratio of ceramide to carnitine in healthy mammals ([0040]; US 20220334137 A1; Fig.2). Application may correct the claim to state as such).
Regarding claim 4, Modified Burslem teaches the method according to claim 1, wherein said reference value has been determined in mammals who healed (“comparing the mRNA expression level
detected in the test subject with the mRNA expression level of the or each gene a control subject with a normal wound healing response; wherein a difference in mRNA expression levels of one or more of said genes indicates that the test subject has an impaired wound healing response”; Burslem claim 19)(The reference value of 115.4 is in WT control column of Table 1 on page 174, line 11 of Burslem .
Regarding claim 5, Modified Burslem teaches the method according to claim 1, wherein the ceramide is Cer d18:1/24:0 (Cer d18:1,C24:0; Kamlage, page 11; Table 1), Cer d18:1/24:1, Cer d18:1/23:0, Cer d18:2/23:0, Cer d18:1/22:0, and/or Cer d18:2/22:0.
Regarding claim 6, Modified Burslem teaches the method according to claim 1.
Modified Burslem fails to teach the ceramide derivative is a ceramide-1-phosphate, or a sphingomyelin.
Modified Burslem instead teaches sphingomyelin phosphodiesterase 1 (page 17, line 9 from the bottom), and sphingomyelinase (page 526, line 6).
Kamlage teaches the ceramide derivative is sphingomyelin (sphingomyelins as biomarkers; [0023]).
Kamlage is considered to be analogous to the claimed invention because it is in the same field of endeavor for lesion treatment based on carnitine-dependent regulation of ceramide biosynthesis ([0045][0015][0017])(Kamlage teaches treatment of pancreatic cancer symptoms which include abdominal cystic lesions). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have tried to have modified the biomarker list taught by Burslem in view of Kamlage by substituting the analysis of ceramide glucosyltransferase with sphingomyelin since there are only a finite number of ceramide derivates expressed in mammals as they relate to wound healing and both measurements would serve the same purpose of predicting whether a mammal exhibits an impaired wound healing response (See MPEP 2143(B, E)). Burslem already implicates the ceramide metabolic pathway through its disclosure of ceramide glucosyltransferase as well as related enzymatic sphingolipid components such as sphingosine phosphate lyase (page 384, last line), sphingomyelin phosphodiesterase 1 (page 17, line 9 from the bottom), and sphingomyelinase (page 499, line 6). Substituting direct measurement of sphingomyelin is a predictable modification, especially in view of Kamlage, which teaches that specific ceramide precursors, including sphingomyelin, are altered in abdominal cystic lesions and therefore serve as diagnostically relevant biomarkers. One of ordinary skill in the art would reasonable extend Kamlage’s metabolite findings to ulcer-based diagnostics since both abdominal cystic lesions and ulcers are conditions represented by localized pathological tissue injury driven by similar cellular process, apoptosis and inflammatory signaling (Kamlage, [0007]).
Regarding claim 8, Modified Burslem teaches the method according to claim 6, wherein the ceramide is SM d 18:1/23:0 (Sphingomyelin (d18:1,C23:0); Kamlage, page 47; line 43).
Regarding claim 10, Modified Burslem teaches the method according to claim 1.
Modified Burslem fails to teach the sample is chosen among: blood, serum, urine and ulcer fluids.
Modified Burslem instead teaches “taking a tissue sample” (claim 19).
Kamlage teaches the sample is chosen among: blood (a sample of a body fluid, preferably, blood; [0043]), serum, urine and ulcer fluids.
Kamlage is considered to be analogous to the claimed invention because it is in the same field of endeavor for lesion treatment based on carnitine-dependent regulation of ceramide biosynthesis ([0045][0015][0017])(Kamlage teaches treatment of pancreatic cancer symptoms which include abdominal cystic lesions). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the tissue sample taught by Burslem in view of Kamlage with the blood sample taught by Kamlage since the two sample types are known equivalents which would yield the same predictable result of metabolite analysis (See MPEP 2143(I)(B)).
Regarding claim 11, Burslem teaches a method of treating a non-healing or chronic ulcer in a mammal (A method for treatment of a disease or disorder characterised by an impaired healing response, such as chronic dermal ulcers; claim 14) comprising administering treatment to the non-healing or chronic ulcer in a mammal (administering to a mammal in need of such treatment a therapeutically effective amount of an agonist or activator of a protein; claim 14) with a level of at least one enzyme in a sample from the mammal (Emphasis added)(See enzymes of Table 1)(The Examiner interprets the limitation as the mammal having at least one metabolite and not the treatment to be at least one metabolite), wherein:
- at least carnitine is lower than a reference value
- at least one ceramide and/or one ceramide derivative enzyme is higher than a reference value (Emphasis added)
(The mammal is characterized by having an impaired healing response by collecting a tissue sample, measuring ceramide enzymatic levels and comparing it to unwounded control tissue; See claim 19 and cluster data Table 1)(Claims 14 and 19 are interpreted as including but not limited to the cited clusters because Burslem presents these gene clusters as exemplary indicators of wound status rather than an exclusive set, permitting other biomarkers, such as ceramide enzymes, to fall within the same conceptual framework of assessing and treating impaired wound healing)(The cluster data of Table 1 of page 548 shows that ceramide glucosyltransferase is a measured biomarker from both wounded mammal tissue and a healthy mammal tissue pages (See values from columns WT30 min, WT3 hours, and WT 12 hours compared to WT control). The numeric values presented in the table illustrate that ceramide enzyme can readily exist above an arbitrarily selected reference value. For example ceramide at 238.1 of page 548, row 19, is higher than a reference value of 140.1 of the WT control sample)(The Examiner interprets a reference value to be derived from any source using any method. The instant specification states that the reference value is obtained from a ratio of ceramide to carnitine in healthy mammals ([0040]; US 20220334137 A1; Fig.2). Application may correct the claim to state as such)(The claim does not explicitly recite a step of comparing the ceramide level to a reference value; therefore, under broadest reasonable interpretation, the Examiner understands that the mammal naturally exhibits a ceramide level higher than a reference value including negative infinity), and/or
- at least one phosphatidylethanolamine is higher than a reference value
Burslem fails to teach a ceramide metabolite, but instead teaches the ceramide enzyme.
Kamlage teaches ceramide metabolites (“determining in a sample of said subject the value of (i) at least one biomarker of the categories…a first and a second sphingolipid,” wherein “the first sphingolipid and the second sphingolipid are from the same subclass, preferably both are ceramides”; [0001][[0036]).
Kamlage is considered to be analogous to the claimed invention because it is in the same field of endeavor for lesion treatment based on regulation of ceramide biosynthesis ([0045][0015][0017])(Kamlage teaches treatment of pancreatic cancer symptoms which include abdominal cystic lesions). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modified the biomarker list taught by modified Burslem by substituting the analysis of ceramide glucosyltransferase with a ceramide metabolite since both measurements serve the same purpose of predicting whether a mammal exhibits an impaired wound healing response, yielding the predictable result of a mammal’s wound-healing status (See MPEP 2143(B, E)). Burslem already implicates the ceramide metabolic pathways through its disclosure of the associated enzyme. Substituting direct measurement of ceramide molecules is a predictable modification, especially in view of Kamlage, which teaches that ceramide metabolite levels are altered in abdominal cystic lesions and therefore serve as diagnostically relevant biomarkers. One of ordinary skill in the art would reasonable extend Kamlage’s metabolite findings to ulcer-based diagnostics since both abdominal cystic lesions and ulcers are conditions represented by localized pathological tissue injury driven by similar cellular process, apoptosis and inflammatory signaling (Kamlage, [0007]).
Regarding claim 12, Modified Burslem teaches the method according to claim 11, wherein
- the ceramide is Cer d18:1/24:0 (Kamlage, Cer d18:1,C24:0; page 11; Table 1), Cer d18:1/24:1, Cer d18:1/23:0, Cer d18:2/23:0, Cer d18:1/22:0, and/or Cer d18:2/22:0, and/or
- the ceramide derivative is:
* a ceramide-1-phosphate, preferably CerP d18:1/18:0, and/or
* a sphingomyelin, preferably SM d18:1/23:0, and/or
- the phosphatidylethanolamine is PE 18:4/22:6.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Burslem (US 2004/0038292 A1) in view of Kamlage (EP 3502699A1; 06-26-2019; See attached English translation), as applied to claim 6 above, and in further view of Wijesinghe (“Ceramide kinase is required for a normal eicosanoid response and the subsequent orderly migration of fibroblasts”; 2014).
Regarding claim 7, Modified Burslem teaches the method according to claim 6.
Modified Burslem fails to teach the ceramide-1-phosphate is CerP d18:1/18:0.
Wijesinghe teaches CerP d18:1/18:0 (d18:1/18:0 C1P; page 1301; column 2, Results, line 12).
Wijesinghe is considered to be analogous to the claimed invention because it is in the same field of endeavor for wound healing assays using ceramide derivates in mammalian species. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the ceramide taught by Burslem in view of Kamlage with the ceramide derivative (CerP d18:1/18:0) taught by Wijesinghe since there are only a finite number of identified, predictable ways for the synthesis of ceramide, and a ceramide-1-phosphate precursor can act as an equivalent biomarker for wound healing (See MPEP 2143(I)(B)) and MPEP 2143(I)(E)). Choosing CerP d18:18:0 as the representative metabolite for assessing or modulating treatment would have been an obvious selection of a known, biologically dominant species within the cermide-1-phosphate class, motivated by its documented correlation with wound-healing efficacy and fibroblast behavior (Wijesinghe, Abstract; page 1299; column 1, paragraph 1).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Sonis, 2001 (instant PTO-892), teaches the treatment of oral mucositis, a type of ulcer, by administering carnitine.
Park et al., 2000 (instant PTO-892) teaches ceramide exhibits therapeutic effects for ulcer healing.
Ishikawa et al., 2016 (filing date)(instant PTO-892) teaches using a ratio of ceramides to analyze the status of skin lesions.
Weber et al., 2012 (instant PTO-892) teaches xerosis treatment using formulation containing both carnitine and ceramide.
Uehara et al., 2002 (instant PTO-892) measures ceramide in samples after administering a treatment that inhibits ceramide production.
No claims are allowed.
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/V.S./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758
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