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 Final Office Action based on application 16/575909 response filed 09/26/2025.
Claims 1, 3-4,7, & 29-44 have been examined and fully considered.
Claims 29-44 are newly added.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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, 3-4, 7 & 29-44 are rejected under 35 U.S.C. 103 as being obvious over HERMANN in US 20190300920 in view of HANSEN in US 10705100 in view of Lipids Maps Mass Spectrometry Chapters (from here on out referred to as LIPIDS) and further in view of MCKENNA in US 20120328594.
With respect to Claim 1, 37, & 41 HERMANN teaches of a method for production of and use of stable isotope labeled lipids and their use as internal standards for mass spectrometry methods (abstract).
HERMANN more specifically teaches that the mass spectrometry methods can involve identifying and quantifying lipids in a mixture comprising classes of lipids and wherein the classes of lipids can include phosphatidylethanolamines, phosphatidylglycerols, and phosphatidylinositols (Table 7).
HERMANN teaches that the stable isotope lipid standards are made from lipid extraction of processed yeast cells (paragraph 0223-0224) and that after the extraction the sample is enriched with isotopes and then mass spectrometry is performed in multiple reaction mode (MRM) is performed (paragraph 0245, 0246, 0252-0265).
HERMANN even further teaches of that the stable isotope labeled lipids can comprise five or more stable isotope lipids (paragraph 0109), and that these stable isotope lipids can be combined with the sample and used as internal standards (paragraph 0001). Further, HERMANN teaches that this stable isotopic labeled (lipid) can be used as an internal standard which is added to the sample to be analyzed at the beginning of sample preparation, in defined known concentrations (paragraph 0002). So—in the case that the lipid stable isotopic lipid standards contain five or more stable isotope lipids--- 5 defined known concentrations of the lipids are added (paragraph 0002).
The signals of both the stable isotope lipid standards (5 of them) and the corresponding analyte/s in the sample are simultaneously detected and they are correlated to a calibration curve established with the same concentration of the internal standards (which have the 5 lipid stable isotopic standards) and different known concentrations of the corresponding analyte. This allows for one to quantitate the amount of analyte contained in the sample (paragraph 0002).
HERMANN doesn’t specifically teach of measuring the lipids themselves by MRM, nor of providing a “library,” for MRM transitions within the classes of lipids in the mixture.
LIPIDS et al. is used to remedy this. LIPIDS et al. teach of methods for detecting lipids through mass spectrometry (Title page, and Table of contents). LIPIDS et al. further teach of synthesizing and using 18 deuterium labeled internal standards (Page labeled 2, first paragraph & Introduction on Page 2 & Page 3, 2.2) to detect triglycerols/ides, and further of measuring a biological sample that has multiple classes of lipids in it including phosphatidylcholines, phosphatidylinosiltols (Page 31, paragraph 3, line 9) and even further of analysis of sphingolipids (Page 28, last paragraph & Figure 4.6)(Page 351, abstract, line 3).
LIPIDS teaches of measuring the lipids and introducing the sample matrix into an LC to separate the lipids into discrete bands (Page 101, Figure 14.8, 14.7).
LIPIDS et al. further teach of comparing of the measured samples to a calibration curve generated from the internal standards (Page 5, 3.1.3 & 3.1.4). LIPIDS et al. further teach that the lipid extracts are analyzed to find changes from normal sources to show the status of a biological condition such as a disease (Page 25, paragraph 1).
Even further, LIPIDS teaches of measuring the lipids using MRM mode (Page 63, 2.5, line 3) and even further that a library or MRM transitions is used (Page 74, 3.1 MRM transition selection, line 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to measure or compare to a library of MRM transitions to detect a class or classes of lipids as is done in LIPIDS in the method of HERMANN due to the advantage this offers for calculating the presence or concentration of unknown lipids (Page labeled as 11, 4.2, paragraph 1) and further to make the internal standard as chemically and structurally similar to the target analyte as possible(Page 64, last paragraph).
HERMANN and LIPIDS do not teach of precipitating proteins/ the separation of specifically discrete bands from the sample matrix.
MCKENNA is used to remedy this. MCKENNA further teaches of a method for detecting lipid and/or protein biomarkers (abstract). MCKENNA further teaches of the sample being in a sample matrix (paragraph 0244), and of assaying for lipids by spiking the samples with an internal standard (which has three odd chain analogs of the lipids CE 15:1, CE 170:0, and LY 17:0)), then precipitating the proteins by adding MeOH/CHC13 and then centrifuging the samples and then of analyzing the analyte (lipids) by mass spec and HPLC and by comparison to a calibration curve (paragraph 0324). MCKENNA further teaches of the separation (paragraph 0276) wherein binding indicates the discrete classes/detection. MCKENNA further teaches that that the peak area ratios of analyte/internal standard) are calculated and converted to absolute analytes concentrations using the calibration curves (paragraph 0324) (this reads on the claimed quantifying the separated lipids based on a comparison between the detector response and known concentrations of the standards.)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to separate/precipitate proteins from a sample when wanting to measure lipids due to the advantage this offers in separating the desired analyte in the supernatant to make for easier analysis (MCKENNA, paragraph 0324).
HERMANN and LIPIDS do not call out that the sample and lipids are associated with a medical condition. MCKENNA is used to remedy this.
MCKENNA is used to remedy this. MCKENNA further teaches of a method for detecting lipid and/or protein biomarkers and using the biomarkers to detect if the individual will develop the medical condition diabetes (abstract). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to detect diabetes as is done in MCKENNA in the methods of HERMANN and LIPIDS due to the need in the art for better methods of testing diabetes (MCKENNA, paragraph 0021).
With respect to Claim 3, HERMANN al. teach of MRM detection in both positive and negative ion mode (paragraph 0246, 0248). LIPIDS teaches of monitoring in positive and negative ion mode (Page 104, Page 354, lines 14-15 & Page 31, second paragraph).
With respect to Claim 4 & 18, LIPIDS et al. teach of normalization of neutral loss data for the different groups of fatty acyl groups. It would have been obvious to detect such groups do to the advantage this has for sample identification (Page labeled as 11, 4.2, paragraph 1).
With respect to Claim 7, LIPIDS et al. teach of using HPLC for extraction and of using isopropanol for the extraction/purification/precipitation of the lipids (Page 3, 2.3 & Page 33, 5.4, Page 152, 5., paragraph 2), of using a vortex and centrifuge which would cool the sample and take place for 5 plus minutes or so and cooling with nitrogen (Page 5, 3.1.4).
With respect to Claim 29, HERMANN teaches that the mixture can comprise LPC, PC, and SM and that the SIL standards are deuterated versions of these (paragraph 0099), (paragraph 0067). MCKENNA teaches of using spingomyelins (paragraph 0117).
With respect to Claim 30, HERMANN teaches that the mixture can comprise ceramides, hexosylceramides and sphingolipids (which include sphingomyelins) and that the SIL standards are deuterated versions of these (paragraph 0099), (paragraph 0067). MCKENNA teaches of using spingomyelins (paragraph 0117).
With respect to Claim 31, HERMANN teaches that the mixture can comprise LPC, PC, and SM and that the SIL standards are deuterated versions of these (paragraph 0099), (paragraph 0067). HERMANN teaches that the mixture can comprise ceramides, hexosylceramides and sphingolipids (which include sphingomyelins) and that the SIL standards are deuterated versions of these (paragraph 0099), (paragraph 0067). HERMANN further teaches of using radyl phospholipids (Page 25, last paragraph). MCKENNA teaches of using spingomyelins (paragraph 0117).
With respect to Claim 32, HERMANN teaches that the mixture can comprise LPC, PC, and SM and that the SIL standards are deuterated versions of these (paragraph 0099), (paragraph 0067). HERMANN teaches that the mixture can comprise ceramides, hexosylceramides and sphingolipids (which include sphingomyelins) and that the SIL standards are deuterated versions of these (paragraph 0099), (paragraph 0067). HERMANN further teaches of using radyl phospholipids (Page 25, last paragraph). MCKENNA teaches of using spingomyelins (paragraph 0117).
With respect to Claim 33, MCKENNA teaches of the sample being human plasma (paragraph 0033).
With respect to Claim 34, LIPIDS teaches that the library also includes MS conditions for obtaining the transitions (See Table 3.1 with retention times and limit of detection and recovery).
With respect to Claim 35, LIPIDS teaches that the library also includes MS conditions for obtaining the transitions (See Table 3.1 with retention times and limit of detection and recovery).
With respect to Claim 36, HERMANN teaches of the SIL including deuterated lipid standards (paragraph 0067). LIPIDS also teaches of using 18 different deuterium labeled internal standards (Page 2, first paragraph).
With respect to Claim 38, MCKENNA teaches of the sample being human plasma (paragraph 0033).
With respect to Claim 39, LIPIDS teaches that the library also includes LC conditions for obtaining the transitions (See Table 3.1 with retention times and limit of detection and recovery).
With respect to Claim 40, LIPIDS teaches that the library also includes MS conditions for obtaining the transitions (See Table 3.1 with retention times and limit of detection and recovery).
With respect to Claim 42, MCKENNA teaches of the sample being human plasma (paragraph 0033).
With respect to Claim 43, LIPIDS teaches that the library also includes LC conditions for obtaining the transitions (See Table 3.1 with retention times and limit of detection and recovery).
With respect to Claim 44, LIPIDS teaches that the library also includes MS conditions for obtaining the transitions (See Table 3.1 with retention times and limit of detection and recovery).
Response to Arguments
Applicant’s arguments with respect to claim(s) have been considered but are moot because the new ground of rejection does not rely on the combination of references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
All claims remain rejected.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maris Kessel can be reached on 571-270-7698. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/REBECCA M FRITCHMAN/
Primary Examiner, Art Unit 1758