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
Summary
This is the Non-Final Office Action based on application 18/315445 election response dated 05/11/2026.
Claims 2-7, 9-11, 13-15, 19-20, 22-24, 26, 30-31, 39, 41, 43, 45-46, 69-71, 73-87 & 91-92 are elected and have been fully considered.
Claims 1, 8, 12, 16-18, 21, 25, 27-29, 32-38, 40, 42, 44, 47-61, 67-68, 72, 88-90 & 94 are cancelled.
Claims 62-66 & 93 are withdrawn from prosecution.
Election/Restrictions
Applicant’s election without traverse of Claims 2-7, 9-11, 13-15, 19-20, 22-24, 26, 30-31, 39, 41, 43, 45-46, 69-71 & 91-92 in the reply filed on 05/11/2026 is acknowledged.
Claims 62-66 & 93 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/11/2026.
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 91-92 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.
With respect to Claims 91-92, they fail to have proper antecedent basis as “FXN replacement therapy,” was not mentioned in the claim chain of claims 91-92 are dependent on, and “the,” is used before it, so it is unclear what applicant is referring back to. It is assumed applicant intends to use “a,” FRAXN replacement instead.
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 ofmatter, or any new and useful improvement thereof, may obtain a patent therefor, subject to theconditions and requirements of this title.
Claims 2-7, 9-11, 13-15, 19-20, 22-24, 26, 30-31, 39, 41, 43 & 45-46 are rejected under 35 U.S.C. 101 because they directed to non-statutory subject matter.
*It is noted that independent Claim 69 and claims which depend therefrom were also evaluated, however this claim and the claims that depend therefrom are clearly drawn towards detection by mass spectrometry and not “evaluating,” or “monitoring,” which as shown below are abstract ideas.
Through 101, inquiry:
Inquiry: Are the claims directed to a statutory category of invention?
Yes, independent Claims 2 & 46 and all claims depending therefrom are drawn towards a statutory category (a method).
Step 2A, Prong 1: Do the claims involve a Judicial Exception?
Yes.
The invention of instant claim 2 and those that depend therefrom is/are drawn towards a method for “evaluating,” efficacy of a therapy, specifically frataxin replacement therapy. “Evaluating,” is a mental process which is an abstract idea.
The invention of instant claim 46 and those that depend therefrom is/are drawn towards a method for “monitoring,” treatment, specifically frataxin replacement therapy. “Monitoring,” is a mental process which is an abstract idea.
Both claims also include a “comparing,” step too, which is also a mental process, which is an abstract idea. Claim 2 also includes “determining efficacy,” which again is an abstract idea.
These are abstract idea judicial exceptions. See USPTO subject matter eligibility example 43 as carries somewhat similar analysis to Claim 1 of that example.
Also, see MPEP 2106.03 & 2106.04.
Step 2A, Prong 2: Has the abstract idea been integrated into a particular practical application?
For Claims 2 & 46, the answer is no.
In addition to the abstract ideas mentioned above, the following steps are required for Claims 2 and/or 46:
Determining (a first) frataxin replacement lipid profile… (following administration of a therapy, though a positive administration step of the therapy is not claimed)
Determining a second frataxin replacement lipid profile…
The claimed “Determining,” steps could be read as abstract ideas, however as claimed seem to be detection steps. Even if they are detection steps, as claimed they are just used as data-gathering to perform the judicial exception. Therefore, they are insignificant extra-solution activity and therefore do not practically apply the judicial exceptions. MPEP 2106.05 (g).
Therefore, nothing in Claims 2 or 46 which practically applies the judicial exceptions.
Step 2B: Do the claims recite any elements which are significantly more than the natural correlation or abstract idea?
For Claims 2 & 46, the answer is no.
In addition to the abstract ideas mentioned above, the following steps are required for Claims 2 and/or 46:
Determining (a first) frataxin replacement lipid profile… (following administration of a therapy, though a positive administration step of the therapy is not claimed)
Determining a second frataxin replacement lipid profile.
Determining the levels of biomarkers, specifically the lipid profile claimed, even by mass spectrometry, which isn’t claimed until the dependent claims is well understood, routine and conventional (WURC) in the art. Therefore, there is nothing claimed which requires the claimed biomarkers to be derivatized or processed in any way which is not WURC, and further no unconventional way of performing a comparison nor an unconventional treatment nor is specific and unconventional detection claimed. See MPEP 2106.05 (a) & MPEP 2106.05 (d).
That detection as claimed is WURC in the art is evidenced by… HALBERT in US 20130287772, who teaches of detection of biomarkers including lipids for theranostic purposes (abstract, paragraph 0179, 0263) for neurological conditions like ataxia (paragraph 0944).
The dependent claims are reviewed for additional limitations dependent on the independent claim above.
Claim 3-5 specify the label for the reference profile and specifies what kind of patient the reference is from. This is still part of the abstract idea, comparison and therefore does not practically apply at step 2 A/2 nor does it add significantly more at step 2B.
Claims 6-7, 9-11, 13-15, 19-20, 22-23 specify what the FSLM biomarkers are further. However, they are still just the biomarkers and as claimed data is gathered from them to make use of the judicial exception. Therefore, this does not practically apply at step 2 A/2 nor does it add significantly more at step 2B.
Claims 24, 26 & 30-31 specify what the FSLM biomarkers are and if they are increased or decreased and when therapy is considered to be effective. As shown above for Claims 2 & 46--- all the claimed parts involved in this are either an abstract idea itself, or not practically applying nor adding significantly more. That is maintained for these claims as they do not add any further along a line which would change these things.
Claim 39 specify that the lipid profile is determined by mass spectrometry. Determining the levels of biomarkers, specifically the lipid profile claimed, even by mass spectrometry, does nothing to practically apply at step 2A/s and also well understood, routine and conventional (WURC) in the art. Therefore, there is nothing claimed which requires the claimed biomarkers to be derivatized or processed in any way which is not WURC, and further no unconventional way of performing a comparison nor an unconventional treatment nor is specific and unconventional detection claimed, so this does not add significantly more at step 2B. See MPEP 2106.05 (a) & MPEP 2106.05 (d).
Claims 41 specifies that the subject the analysis is performed on has the condition of Friedreich’s Ataxia. In these claims this is merely specifying what the data pull is done from. Therefore, does not practically apply at step 2 A/2 nor does it add significantly more at step 2B.
Claims 43 & 45 specifies that the same is a body sample, such as plasma or buccal or hair follicle. In these claims this is merely specifying what the data pull is done from. Therefore, does not practically apply at step 2 A/2 nor does it add significantly more at step 2B.
*Claims 69-71, 73-87 & 91-92 are not rejected under 101 as shown above.
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 non-obviousness.
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 2-7, 9-11, 13-15, 19-20, 22-24, 26, 30-31, 39, 41, 43, 45-46, 69-71, 73-87 & 91-92 are rejected under 35 U.S.C. 103 as being unpatentable by FOREST in Comprehensive and Reproducible Untargeted Lipidomic Workflow Using LC-QTOF Validated to Human Plasma Analysis in view of BETTOUN in WO 2020223576 and in further view of NAVARRO in Altered lipid metabolism in a Drosophila model of Friedreich’s ataxia (all as cited on IDS dated 01/11/2024).
With respect to Claim 2, FOREST teaches of a method of high-resolution liquid chromatography-mass spectrometry (LC-MS)-based lipidomic workflow.
More specifically, FOREST teaches of detecting phosphatidylcholines, cholesterol/steryl esters (CE’s), diacylglycerols (Figure 4 description, Page 3659, column 2, last paragraph, Table 1). FOREST further teaches of making and taking multiple sample measurements, so there is a first sample/profile and a second sample or profile, and of comparison to a reference compound for the lipid profile (Page 3659, column 1, paragraph 2, lines 26-28). They further teach that the method can be applied to things such as “biomarker discovery (Abstract) and of comparison to a reference compound for the lipid profile (Page 3659, column 1, paragraph 2, lines 26-28) and the method can be used for thing such mechanisms for determining targets of therapy or treatment (Page 3657, column 1, paragraph 1, lines 5-9 & Page 3661, column 1, paragraph 1).
FOREST does not specifically teach of evaluation of frataxin replacement therapy.
BETTOUN is used to remedy this. BETTOUN further teaches of providing a set of markers, also referred to herein as FXN-sensitive genomic markers (or FSGMs), the respective expression levels of which are positively or negatively correlated to frataxin (FXN) levels in a cell. Therefore, these FSGMs can be used to determine, evaluate, and/or monitor the effectiveness/efficacy of FXN replacement therapy in a subject (abstract). BETTOUN teaches that a condition called Friedreich’s Ataxia (FRDA) is the most common inherited ataxia in humans and results from a deficiency of the mitochondrial protein frataxin (FXN) (Page 1, last paragraph).
It would have been obvious to one to one of ordinary skill in the art before the effective filing date of the instant invention to evaluate the efficacy of frataxin therapy as is done in BETTOUN using the method/biomarkers of FORREST, due to the need in the art for a reliable and efficient assay to measure response and effectiveness of frataxin replacement (background of the art).
Again, as shown above- BETTOUN teaches that a condition called Friedreich’s Ataxia (FRDA) is the most common inherited ataxia in humans and results from a deficiency of the mitochondrial protein frataxin (FXN) (Page 1, last paragraph).
FOREST and BETTOUN do not teach of the claimed lipids being frataxin sensitive or frataxin related.
NAVARRO is used to remedy this and more specifically teaches of lipid metabolism being altered in Friedreich’s ataxia (which has been shown to be related to frataxin above) (titles and abstract). More specifically, NAVARRO teaches that a lipid analysis of frataxin interference is performed and that fatty acids, triacylglycerides, and phosphatidylcholines are detected (Figure 2 description).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to monitor the lipids as done in NAVARRO in the methods of FOREST and BETTOUN due to the advantage that these offer in detecting ataxia since it has been shown that loss of frataxin and increased fatty acid accumulation are related (NAVARRO, Page 2832, column 1, first column, paragraph 2 & abstract). The examiner notes that no administration of frataxin replacement therapy is actually required within the boundaries of the claim.
With respect to Claim 3, FOREST and BETTOUN teach of the invention as shown above. They do not teach of a baseline lipid profile. NAVARRO is used to remedy this and teaches of using controls/making baseline measurements of those controls. NAVARRO also teaches of frataxin deficient subjects. (Figure 1 & Figure 2 and associated description). NAVARRO also teaches of frataxin deficient subjects. It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to compare the lipids to a baseline or control as is done in NAVARRO in the method of FOREST and BETTOUN since this shows advantage for determinations of if the biomarkers are increased or decreased with respect to normal state (Figure 1 & 2 description).
With respect to Claim 4, FOREST and BETTOUN teach of the invention as shown above. They do not teach of a baseline lipid profile. NAVARRO is used to remedy this and teaches of using controls/making baseline measurements of those controls- wherein the control is not administered frataxin replacement therapy (Figure 1 & Figure 2 and associated description). NAVARRO also teaches of frataxin deficient subjects. See reason for combination from Claim 3.
With respect to Claim 5, FOREST and BETTOUN teach of the invention as shown above. They do not teach of a baseline lipid profile. NAVARRO is used to remedy this and teaches of using controls/making baseline measurements of those controls- wherein the control is not administered frataxin replacement therapy (Figure 1 & Figure 2 and associated description). NAVARRO also teaches of frataxin deficient subjects. See reason for combination from Claim 3.
With respect to Claim 6, FOREST teaches of the above and further of identifying 116 triacyl glycerols (Table 1). FOREST specifically teaches on the Supplmental Excel filed indicated under Table 1 description that the triacylgylcerols (TGS) detected all contain 7 or less unsaturations and the triglyceride molecules contain less than 56 carbons as claimed (See Table 1 Supplemental Excel file).
With respect to Claim 7, FOREST teaches of the above and further of identifying 116 triacyl glycerols (Table 1). FOREST specifically teaches on the Supplmental Excel filed indicated under Table 1 description that the triacylgylcerols (TGS) detected all contain 7 or less unsaturations and the triglyceride molecules contain less than 56 carbons as claimed (See Table 1 Supplemental Excel file). FOREST does not call out that the detected triglycerides are any of the exact claimed ones, but they would be included I the 116 ones detected.
With respect to Claim 9, FOREST teaches of detecting diacylglycerophosphocholines (Table 1, column 2) which are ether phosphoplipids (Figure 1) and also of detecting (PCO-)(Page 3665, column 2, paragraph 2 & Table 3).
With respect to Claim 10, FOREST teaches of detecting diacylglycerophosphocholines (Table 1, column 2) which are ether phosphoplipids (Figure 1) and also of detecting (PCO-)(Page 3665, column 2, paragraph 2 & Table 3).
With respect to Claim 11, FOREST teaches of detecting diacylglycerophosphocholines (Table 1, column 2) which are ether phosphoplipids (Figure 1) and also of detecting (PCO-)(Page 3665, column 2, paragraph 2 & Table 3). FOREST further teaches of detecting PC(O-16:0/18:2) along with others claimed (See Table 1 Supplemental Excel file.)
With respect to Claim 13, FOREST teaches of detecting PEO-‘s, and specifically PE(O-16:0/20:4) and PE(O-18:0/20:4) (See Table 1 Supplemental Excel file).
With respect to Claim 14, FOREST and BETTOUN teach of the invention as shown above. They do not teach call out the detection of phosphatidycholines. NAVARRO is used to remedy this and more specifically teaches of lipid metabolism being altered in Friedreich’s ataxia (which has been shown to be related to frataxin above) (titles and abstract). More specifically, NAVARRO teaches that a lipid analysis of frataxin interference is performed and that fatty acids, triacylglycerides, and phosphatidylcholines are detected (Figure 2 description). See reason for combination from Claim 1.
With respect to Claim 15, FOREST teaches of using PC 16:0, 22:6, 18:0, 22:3, 18:2, 20:4, (Page 3660. column 2, paragraph 2) and also specifically of PC (18:2, 18:2) (Figure 4 on graph).
With respect to Claim 19, FOREST teaches of monitoring CE’s (cholesterol esters) for acyl side chains including C20:5 (See Figure 5, volcano plots).
With respect to Claim 20, FOREST teaches of monitoring CE’s (cholesterol esters) for acyl side chains including C20:5 (See Figure 5, volcano plots).
With respect to Claim 22, FOREST teaches of detecting di- glycerides/ols and of specifically the side chains C18:2, C20:5, C22:4, C22:6 and 22:5 and 18:1(Page 3666, column 1, paragraph 1 & Page 3665, column 2, paragraph 2, table 2 and Figure 2).
With respect to Claim 23, FOREST teaches of detecting di- glycerides/ols and of specifically the side chains C18:2, C20:5, C22:4, C22:6 and 22:5 and 18:1(Page 3666, column 1, paragraph 1 & Page 3665, column 2, paragraph 2, table 2 and Figure 2).
With respect to Claim 39, FOREST and BETTOUN teach of the invention as shown above. They do not teach of detecting the claimed lipids by mass spectrometry. NAVARRO is used to remedy this and teaches of detection by mass spectrometry (Page 2829, column 2, paragraph 3). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use mass spectrometry to detect lipids as is done in NAVARRO in the method of FOREST and BETTOUN due to the advantage this shows in determining the lipidic composition and the increase or decrease of these lipids in comparison to a control (Page 2829, column 2, paragraph 3 & Fig 1 & 2 description).
With respect to Claim 24, FOREST teaches of the detection of (PCO-)(Page 3665, column 2, paragraph 2 & Table 3). FOREST further teaches of detecting PC(O-16:0/18:2) along with others claimed (See Table 1 Supplemental Excel file.)
FOREST and BETTOUN do not teach of the claimed lipids being frataxin sensitive or frataxin related.
NAVARRO is used to remedy this and more specifically teaches of lipid metabolism being altered in Friedreich’s ataxia (which has been shown to be related to frataxin above) and of detecting an increase in the lipids (titles and abstract). More specifically, NAVARRO teaches that a lipid analysis of frataxin interference is performed and that fatty acids, triacylglycerides, and phosphatidylcholines are detected (Figure 2 description).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to monitor the lipids as done in NAVARRO in the methods of FOREST and BETTOUN due to the advantage that these offer in detecting ataxia since it has been shown that loss of frataxin and increased fatty acid accumulation are related (NAVARRO, Page 2832, column 1, first column, paragraph 2 & abstract).
With respect to Claim 26, FOREST teaches the above including detection of PC (16:0_22:4) and PC (18:2_18:3) (See Supplemental Excel sheet) in addition to other claimed lipids. FOREST does not teach of monitoring if therapy is effective.
NAVARRO is used to remedy this and more specifically teaches of lipid metabolism being altered in Friedreich’s ataxia (which has been shown to be related to frataxin above) and of detecting an increase in the lipids and that a frataxin decrease leads to an increase in lipid accumulation (so decrease if frataxin increases) (titles and abstract). More specifically, NAVARRO teaches that a lipid analysis of frataxin interference is performed and that fatty acids, triacylglycerides, and phosphatidylcholines are detected (Figure 2 description).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to monitor the lipids as done in NAVARRO in the methods of FOREST and BETTOUN due to the advantage that these offer in detecting ataxia since it has been shown that loss of frataxin and increased fatty acid accumulation are related (NAVARRO, Page 2832, column 1, first column, paragraph 2 & abstract).
With respect to Claim 30, FOREST teaches the above including detection of PC (16:0_22:4) and PC (18:2_18:3) (See Supplemental Excel sheet) in addition to other claimed lipids. FOREST does not teach of monitoring if therapy is effective.
NAVARRO is used to remedy this and more specifically teaches of lipid metabolism being altered in Friedreich’s ataxia (which has been shown to be related to frataxin above) and of detecting an increase in the lipids and that a frataxin decrease leads to an increase in lipid accumulation (so decrease if frataxin increases) (titles and abstract). More specifically, NAVARRO teaches that a lipid analysis of frataxin interference is performed and that fatty acids, triacylglycerides, and phosphatidylcholines are detected (Figure 2 description).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to monitor the lipids as done in NAVARRO in the methods of FOREST and BETTOUN due to the advantage that these offer in detecting ataxia since it has been shown that loss of frataxin and increased fatty acid accumulation are related (NAVARRO, Page 2832, column 1, first column, paragraph 2 & abstract).
With respect to Claim 31, FOREST teaches the above including detection of PC (16:0_22:4) and PC (18:2_18:3) and PC (18:1_20:3) (See Supplemental Excel sheet) in addition to other claimed lipids. FOREST does not teach of monitoring if therapy is effective.
NAVARRO is used to remedy this and more specifically teaches of lipid metabolism being altered in Friedreich’s ataxia (which has been shown to be related to frataxin above) and of detecting an increase in the lipids and that a frataxin decrease leads to an increase in lipid accumulation (so decrease if frataxin increases) (titles and abstract). More specifically, NAVARRO teaches that a lipid analysis of frataxin interference is performed and that fatty acids, triacylglycerides, and phosphatidylcholines are detected (Figure 2 description).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to monitor the lipids as done in NAVARRO in the methods of FOREST and BETTOUN due to the advantage that these offer in detecting ataxia since it has been shown that loss of frataxin and increased fatty acid accumulation are related (NAVARRO, Page 2832, column 1, first column, paragraph 2 & abstract).
With respect to Claim 41, FOREST teaches of the invention as shown above, but does not teach of Friedrich’s ataxia. BETTOUN however does teach of this (Page 1, last paragraph). NAVARRO also teaches of this and of detection of the claimed lipids for the claimed ataxia (abstract). See reasons for combination from Claim 2.
With respect to Claim 43, FOREST teaches of using a blood sample (Page 3658, column 2, line 5).
With respect to Claim 45, FOREST teaches of using a blood sample (Page 3658, column 2, line 5).
With respect to Claim 46, FOREST teaches of a method of high-resolution liquid chromatography-mass spectrometry (LC-MS)-based lipidomic workflow.
More specifically, FOREST teaches of detecting phosphatidylcholines, cholesterol/steryl esters (CE’s), diacylglycerols (Figure 4 description, Page 3659, column 2, last paragraph, Table 1). FOREST further teaches of making and taking multiple sample measurements, so there is a first sample/profile and a second sample or profile, and of comparison to a reference compound for the lipid profile (Page 3659, column 1, paragraph 2, lines 26-28). They further teach that the method can be applied to things such as “biomarker discovery (Abstract) and of comparison to a reference compound for the lipid profile (Page 3659, column 1, paragraph 2, lines 26-28) and the method can be used for thing such mechanisms for determining targets of therapy or treatment (Page 3657, column 1, paragraph 1, lines 5-9 & Page 3661, column 1, paragraph 1).
FOREST does not specifically teach of evaluation of frataxin replacement therapy.
BETTOUN is used to remedy this. BETTOUN further teaches of providing a set of markers, also referred to herein as FXN-sensitive genomic markers (or FSGMs), the respective expression levels of which are positively or negatively correlated to frataxin (FXN) levels in a cell. Therefore, these FSGMs can be used to determine, evaluate, and/or monitor the effectiveness/efficacy of FXN replacement therapy in a subject (abstract). BETTOUN teaches that a condition called Friedreich’s Ataxia (FRDA) is the most common inherited ataxia in humans and results from a deficiency of the mitochondrial protein frataxin (FXN) (Page 1, last paragraph).
It would have been obvious to one to one of ordinary skill in the art before the effective filing date of the instant invention to evaluate the efficacy of frataxin therapy as is done in BETTOUN using the method/biomarkers of FORREST, due to the need in the art for a reliable and efficient assay to measure response and effectiveness of frataxin replacement (background of the art).
Again, as shown above- BETTOUN teaches that a condition called Friedreich’s Ataxia (FRDA) is the most common inherited ataxia in humans and results from a deficiency of the mitochondrial protein frataxin (FXN) (Page 1, last paragraph).
FOREST and BETTOUN do not teach of the claimed lipids being frataxin sensitive or frataxin related.
NAVARRO is used to remedy this and more specifically teaches of lipid metabolism being altered in Friedreich’s ataxia (which has been shown to be related to frataxin above) (titles and abstract). More specifically, NAVARRO teaches that a lipid analysis of frataxin interference is performed and that fatty acids, triacylglycerides, and phosphatidylcholines are detected (Figure 2 description).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to monitor the lipids as done in NAVARRO in the methods of FOREST and BETTOUN due to the advantage that these offer in detecting ataxia since it has been shown that loss of frataxin and increased fatty acid accumulation are related (NAVARRO, Page 2832, column 1, first column, paragraph 2 & abstract). The examiner notes that no administration of frataxin replacement therapy is actually required within the boundaries of the claim.
With respect to Claim 69, FOREST teaches of a method of high-resolution liquid chromatography-mass spectrometry (LC-MS)-based lipidomic workflow.
More specifically, FOREST teaches of detecting one or more phosphatidylcholines, cholesterol/steryl esters (CE’s), diacylglycerols (Figure 4 description, Page 3659, column 2, last paragraph, Table 1). FOREST further teaches of making and taking multiple sample measurements, so there is a first sample/profile and a second sample or profile, and of comparison to a reference compound for the lipid profile (Page 3659, column 1, paragraph 2, lines 26-28). They further teach that the method can be applied to things such as “biomarker discovery (Abstract) and of comparison to a reference compound for the lipid profile (Page 3659, column 1, paragraph 2, lines 26-28) and the method can be used for thing such mechanisms for determining targets of therapy or treatment (Page 3657, column 1, paragraph 1, lines 5-9 & Page 3661, column 1, paragraph 1).
FOREST does not specifically teach of evaluation of frataxin replacement therapy or that the subject which the biomarkers are detected from are “frataxin deficient”.
BETTOUN is used to remedy this. BETTOUN further teaches of providing a set of markers, also referred to herein as FXN-sensitive genomic markers (or FSGMs), the respective expression levels of which are positively or negatively correlated to frataxin (FXN) levels in a cell. Therefore, these FSGMs can be used to determine, evaluate, and/or monitor the effectiveness/efficacy of FXN replacement therapy in a subject (abstract). BETTOUN teaches that a condition called Friedreich’s Ataxia (FRDA) is the most common inherited ataxia in humans and results from a deficiency of the mitochondrial protein frataxin (FXN) (Page 1, last paragraph).
It would have been obvious to one to one of ordinary skill in the art before the effective filing date of the instant invention to evaluate fraxtaxin deficiency as is done in BETTOUN using the method/biomarkers of FORREST, due to the need in the art for a reliable and efficient assay to measure response and effectiveness of frataxin replacement in patients who are frataxin deficient or have Fredriech’s ataxia (background of the art).
Again, as shown above- BETTOUN teaches that a condition called Friedreich’s Ataxia (FRDA) is the most common inherited ataxia in humans and results from a deficiency of the mitochondrial protein frataxin (FXN) (Page 1, last paragraph).
FOREST and BETTOUN do not teach of the claimed lipids being frataxin sensitive or frataxin related.
NAVARRO is used to remedy this and more specifically teaches of lipid metabolism being altered in Friedreich’s ataxia (which has been shown to be related to frataxin above) (titles and abstract). More specifically, NAVARRO teaches that a lipid analysis of frataxin interference is performed and that fatty acids, triacylglycerides, and phosphatidylcholines are detected (Figure 2 description).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to monitor the lipids in relation to frataxin as done in NAVARRO in the methods of FOREST and BETTOUN due to the advantage that these offer in detecting ataxia since it has been shown that loss of frataxin and increased fatty acid accumulation are related (NAVARRO, Page 2832, column 1, first column, paragraph 2 & abstract).
With respect to Claim 70, FOREST teaches of the above, but does not specifically teach of evaluation for or of using/treating with frataxin replacement therapy.
BETTOUN is used to remedy this. BETTOUN further teaches of providing a set of markers, also referred to herein as FXN-sensitive genomic markers (or FSGMs), the respective expression levels of which are positively or negatively correlated to frataxin (FXN) levels in a cell. Further, BETTOUN teaches of using FSGMs can be used to determine, evaluate, and/or monitor the effectiveness/efficacy of FXN replacement therapy in a subject (abstract). BETTOUN teaches that a condition called Friedreich’s Ataxia (FRDA) is the most common inherited ataxia in humans and results from a deficiency of the mitochondrial protein frataxin (FXN) (Page 1, last paragraph).
It would have been obvious to one to one of ordinary skill in the art before the effective filing date of the instant invention to evaluate the efficacy of frataxin therapy as is done in BETTOUN using the method/biomarkers of FORREST, due to the need in the art for a reliable and efficient assay to measure response and effectiveness of frataxin replacement (background of the art).
With respect to Claim 71, FOREST teaches of the above, but does not specifically teach of evaluation for or of using/treating with frataxin replacement therapy of a frataxin deficient subject.
BETTOUN is used to remedy this. BETTOUN further teaches of providing a set of markers, also referred to herein as FXN-sensitive genomic markers (or FSGMs), the respective expression levels of which are positively or negatively correlated to frataxin (FXN) levels in a cell. Further, BEEOUN teaches of using FSGMs can be used to determine, evaluate, and/or monitor the effectiveness/efficacy of FXN replacement therapy in a subject (abstract), specifically in a frataxin deficient subject (Page 2, last paragraph). See reason for combination from Claim 70.
With respect to Claim 73, FOREST teaches of the above and further of identifying 116 triacyl glycerols (Table 1). FOREST specifically teaches on the Supplmental Excel filed indicated under Table 1 description that the triacylgylcerols (TGS) detected all contain 7 or less unsaturations and the triglyceride molecules contain less than 56 carbons as claimed (See Table 1 Supplemental Excel file).
With respect to Claim 74, FOREST teaches of the above and further of identifying 116 triacyl glycerols (Table 1). FOREST specifically teaches on the Supplmental Excel filed indicated under Table 1 description that the triacylgylcerols (TGS) detected all contain 7 or less unsaturations and the triglyceride molecules contain less than 56 carbons as claimed (See Table 1 Supplemental Excel file). FOREST does not call out that the detected triglycerides are any of the exact claimed ones, but they would be included in the 116 ones detected.
With respect to Claim 75, FOREST teaches of detecting diacylglycerophosphocholines (Table 1, column 2) which are ether phosphoplipids (Figure 1) and also of detecting (PCO-)(Page 3665, column 2, paragraph 2 & Table 3).
With respect to Claim 76, FOREST teaches of detecting diacylglycerophosphocholines (Table 1, column 2) which are ether phosphoplipids (Figure 1) and also of detecting (PCO-)(Page 3665, column 2, paragraph 2 & Table 3).
With respect to Claim 77, FOREST teaches of detecting diacylglycerophosphocholines (Table 1, column 2) which are ether phosphoplipids (Figure 1) and also of detecting (PCO-)(Page 3665, column 2, paragraph 2 & Table 3). FOREST further teaches of detecting PC(O-16:0/18:2) along with others claimed (See Table 1 Supplemental Excel file.)
With respect to Claim 78, FOREST teaches of detecting PEO-‘s, and specifically PE(O-16:0/20:4) and PE(O-18:0/20:4) (See Table 1 Supplemental Excel file).
With respect to Claim 79, FOREST and BETTOUN teach of the invention as shown above. They do not teach call out the detection of phosphatidycholines. NAVARRO is used to remedy this and more specifically teaches of lipid metabolism being altered in Friedreich’s ataxia (which has been shown to be related to frataxin above) (titles and abstract). More specifically, NAVARRO teaches that a lipid analysis of frataxin interference is performed and that fatty acids, triacylglycerides, and phosphatidylcholines are detected (Figure 2 description). See reason for combination from Claim 1.
With respect to Claim 80, FOREST teaches of using PC 16:0, 22:6, 18:0, 22:3, 18:2, 20:4, (Page 3660. column 2, paragraph 2) and also specifically of PC (18:2, 18:2) (Figure 4 on graph).
With respect to Claim 81, FOREST teaches of monitoring CE’s (cholesterol esters) for acyl side chains including C20:5 (See Figure 5, volcano plots).
With respect to Claim 82, FOREST teaches of monitoring CE’s (cholesterol esters) for acyl side chains including C20:5 (See Figure 5, volcano plots).
With respect to Claim 83, FOREST teaches of detecting di- glycerides/ols and of specifically the side chains C18:2, C20:5, C22:4, C22:6 and 22:5 and 18:1(Page 3666, column 1, paragraph 1 & Page 3665, column 2, paragraph 2, table 2 and Figure 2). FOREST also teaches of detecting DG DG(18:1/18:2) (Supplemental Excel Sheet).
With respect to Claim 84, FOREST teaches of detecting di- glycerides/ols and of specifically the side chains C18:2, C20:5, C22:4, C22:6 and 22:5 and 18:1(Page 3666, column 1, paragraph 1 & Page 3665, column 2, paragraph 2, table 2 and Figure 2). FOREST also teaches of detecting DG DG(18:1/18:2) (Supplemental Excel Sheet).
With respect to Claim 85, FOREST and BETTOUN teach of the invention as shown above. They do not teach of detecting the claimed lipids by mass spectrometry. NAVARRO is used to remedy this and teaches of detection by mass spectrometry (Page 2829, column 2, paragraph 3). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use mass spectrometry to detect lipids as is done in NAVARRO in the method of FOREST and BETTOUN due to the advantage this shows in determining the lipidic composition and the increase or decrease of these lipids in comparison to a control (Page 2829, column 2, paragraph 3 & Fig 1 & 2 description).
With respect to Claim 86, FOREST teaches of the invention as shown above, but does not teach of Friedrich’s ataxia. BETTOUN however does teach of this (Page 1, last paragraph). NAVARRO also teaches of this and of detection of the claimed lipids for the claimed ataxia (abstract). See reasons for combination from Claim 2.
With respect to Claim 87, FOREST teaches of using a blood sample (Page 3658, column 2, line 5).
With respect to Claim 91, BETTOUN teaches of administration of FXN fusion protein (Figure 4 and Figure 7 and associated descriptions).
With respect to Claim 92, BETTOUN teaches of a fusion protein sequence having the sequence claimed for SEQ ID NO:12 of MYGRKKRRQRRRGGMWTLGRRAVAGLLASPSPAQAQTLTRVPRPAELAP LCGRRGLRTDIDATCTPRRASSNQRGLNQIWNVKKQSVYLMNLRKSGTL GHPGSLDETTYERLAEETLDSLAEFFEDLADKPYTFEDYDVSFGSGVLT VKLGGDLGTYVINKQTPNKQIWLSSPSSGPKRYDWTGKNWVYSHDGVSL HELLAAELTKALKTKLDLSSLAYSGKDA (Page 57, Seq ID NO 12 is 100% match).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
HALBERT in US 20130287772, who teaches of detection of biomarkers including lipids for theranostic purposes (abstract, paragraph 0179, 0263) for neurological conditions like ataxia (paragraph 0944).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA M FRITCHMAN whose telephone number is (303)297-4344. The examiner can normally be reached 9:30-4:30 MT Monday-Friday.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758
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