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 the 18/604429 filed 06/25/2024.
This application has been examined as part of the PBA program.
Claims 1, 4-10, 12, 14-16, 19, 22, 25-26, 28, 30-31, 34-36 are pending and have been fully examined.
Claims 2-3, 11, 13, 17-18, 20-21, 27, 29 & 32-33 are cancelled.
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, 4-10, 12, 14-16, 19, 22, 25-26, 28, 30-31, 34-36 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 Claim 1, step a) it is unclear if multiple internal standards are added, or just one which “corresponds to each of the multiple analytes.” Correction is required to make this clear.
With respect to Claim 1, step b), the sample comprising a carbonyl group is contacted with a reagent which has a carbonyl reactive group and a masking group, however it is claimed that the carbonyl group is “derivatized,” “with the masking group,” and not with the carbonyl reactive group, or a combination of both carbonyl group and masking group. It would seem the carbonyl reactive group is what reacts with the carbonyl group and derivatizes it. Therefore, the claim is unclear as to what is meant and correction is required.
Further with respect to Claim 1, in the first wherein paragraph after steps a)-d), the paragraphs states comparing to “an external calibration.” It is unclear with respect to this if applicant means an external calibration curve or a reagent or compound of some kind. This is confusing and correction is required.
Further with respect to Claim 1, in the first wherein paragraph after steps a)-d), “the signal obtained for the known amount of the stable isotope labelled analogue,” “the signal,” “the known amount,” and “the stable isotope labelled analogue,” all fail to have proper antecedent basis as none of these terms were referred to priorly in the claims and therefore it is unclear what applicant is referred back to with “the.” Correction is required.
Further with respect to Claim 1, in the second paragraph after steps a)-d), “the external calibration curve,” fails to have proper antecedent basis and “external calibration curve,” was not mentioned priorly to this in the claims. Correction is required.
With respect to Claim 4, it contains some claim limitations which seem to be required, but some are optional, however all are claimed as possibilities for the claimed cell culture. Therefore, the claim is unclear as to what is required.
With respect to Claim 8, “nominal,” is a relative term and different people would take it to mean different things, so it is confusing in the claims. Further, claim 8 is confusing as it claims “ the most abundant isotopologue of one of the multiple analytes,’ and therefore the internal standard does not have to have the same “nominal,” relationship with all of the claimed internal standard isotopologues.
With respect to Claim 12, it claims “comprise or consists,” which is unclear since comprise and consist has distinctly different meaning in U.S. patent law and therefore it is unclear what applicant intends as the scope.
Regarding claims 16 & 18, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
With respect to Claim 25, it refers back to Claim 1, however Claim 1 does not mention “the full scan accurate mass high resolution mass spectrometry,” so in Claim 25 it fails to have proper antecedent basis.
Further for Claim 25, it contains a broad limitation of “at least 50 to not more than about 800 m/z,” and then a narrow optional limitation of “optionally,” “about 100 to about 500 m/z.” With respect to this, it is unclear what applicant intends as the scope of the claim.
With respect to Claim 26, it is unclear what is meant by “or better,” as “better,” is a relative term and would mean different things to different people.
With respect to Claim 28, it is unclear what the “orders of magnitude,” are with respect to.
With respect to Claims 30 and 25, it is unclear what “full,” scan is and “accurate,” as both of these are relative terms which would mean different things to different people, and they are not defined by the claims.
With respect to Claims 31 & 34, step (c ) claims optional repeating of steps that already involve repeating. Therefore, it is unclear what repeating of repeating is, and unclear if it is really optional or not. Further, it is unclear if the step after the optional step (c ) is also optional as it reads as so, and then since Claim 35 depends on this , it is unclear if 34 is optional as well. Further for Claims 34-35 , it is unclear if the concentration is required to change or not or if the “in response,” only happens if there is a concentration change.
Further with respect to Claim 34, “optimising,” is a relative term that would mean different things to different people and that is not defined by the claims and therefore is unclear.
With respect to Claim 35, it is unclear if applicant is trying to further limit the claim by adding the optional limitation or not.
Claims 4-10, 12, 14-16, 19, 22, 25-26, 28, 30-31, 34-36 are also rejected by virtue of their dependency on an unclear claim.
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 1, 8-9, 12, 14, 22, 25-26, 28, 30-31, 34-35 are rejected under U.S.C. 103 as being obvious by DENG PAN in Quantitative profiling of carbonyl metabolites directly in crude biological extracts using chemoselective tagging and nanoESI- FTMS (as cited on IDS dated 06/25/2024) in view of KASSIS in US 20230137741.
With respect to Claims 1 & 30, DENG PAN teaches of a method of profiling of carbonyl metabolite in biological abstracts by chemoselective tagging and nanoESI-FTMS (title).
DENG PAN teaches that the analysis is of hydrophilic and hydrophobic carbonyl-containing metabolites directly in biological samples:
by simultaneous derivatization of stable and labile carbonylated metabolites using N-[2(aminooxy)ethyl]-N, N-dimethyI-1-dodecylammonium (QDA) (has both a reactive and a masking group) to derivatize the analytes and ¹³CD₃ isotope labeled QDA, and also the internal standard;
suitability of this method for determining ¹³C labeled isotopologues of carbonyl metabolites in ¹³C₆⁻ glucose-based stable isotope-resolved metabolomic (SIRM) studies (PG 311, 315, Fig.3) which can be monoisotopic (Page 319, column 1, paragraph 1).
and further of subjecting the sample to chromatography separation, and then detecting and analyzing and quantifying the metabolites by ultra-high resolution (UHR) mass spectrometry (MS) (Thermo Fusion: resolution = 370 000 at m/z = 400, mass accuracy < 0.5ppm) to determine all possible isotopologues(abstract);
the use of know amounts of internal standards (Figure 3 description, Page 314 column 1, paragraph 1, column 2, paragraph 1, page 211, column 2, paragraph 1);
method validation (e.g. upper limit of quantification) use of M+0 QDA peak pairs (PG 313, 314, 319, 320, Fig.6,7); and
of using various metabolites (PG 318, 319, Table 2), liquid chromatography (e.g. C4) UHR mass spectrometry (PG 320) (abstract).
DENG PAN teaches of using a cell culture and sampling the cell culture medium which is from a human mammal and of derivatization and extraction of it and derivatization with acetone D6-QDA/QDA (Page 313,2.2).
DENG PAN further teaches of constructing and using external calibration curves for all of the stock solutions for all of the analytes (Page 314, column 1, 2nd to last paragraph). DENG PAN further teaches of normalizing the signals to the internal standards and external calibrations (Page 314, column, paragraph 1, Figure 2).
DENG PAN even further teaches of detecting the isotopic distributions and abundances of the isotopologues (Page 317, column 1, paragraph 1, Figure 5) and of using the most abundant for the signal (Figure 7 description).
If it is unclear that DENG PAN teaches of using the claimed internal standards for isotopologues, KASSIS is used to remedy.
KASSIS teaches of methods for quantifying a sample using internal standards (abstract, paragraph 0014, 0065-0068), wherein they are placed with a laboratory sample from a cell culture (paragraph 0070, 0109), which is measured for metabolites like butyric acid (paragraph 0127). KASSIS further teaches of the internal standards being specific to each metabolite and being deuterium labeled (paragraph 0240).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use the internal standards such as deuterium labeled standards of the detected compounds as is done in KASSIS in the method of DENG PAN due to the advantage this offers in being able to distinguish mass difference (KASSIS, paragraph 0237).
With respect to Claim 8, DENG PAN teaches of using internal standards (Figure 3 description, Page 314 column 1, paragraph 1, column 2, paragraph 1, page 211, column 2, paragraph 1). Due to the clarity issues with the claim, this can be interpreted as the internal standard having at least two nominal mass units more than the most abundant isotopologue of one of the multiple analytes.
With respect to Claim 9, DENG PAN teaches of using internal standards (Figure 3 description, Page 314 column 1, paragraph 1, column 2, paragraph 1, page 211, column 2, paragraph 1). DENG PAN further teaches of using doubly charged di-QDA and of using Carbon 13 labels (Page 319, column 1, paragraph 1 and paragraph 2).
With respect to Claim 12, DENG PAN teaches of the solutions comprising formic acid (Page 313, 2.3) of using valerate (Table 2).
With respect to Claim 14, DENG PAN teaches of using the metabolites as shown above, but do not call out the use of amino acid standard analytes as claimed.
If it is unclear that DENG PAN teaches of using the claimed internal standards for isotopologues, KASSIS is used to remedy.
KASSIS teaches of methods for quantifying a sample using internal standards (abstract, paragraph 0014, 0065-0068), wherein they are placed with a laboratory sample from a cell culture (paragraph 0070, 0109), which is measured for metabolites like butyric acid (paragraph 0127). KASSIS further teaches of the internal standards being specific to each metabolite and being deuterium labeled (paragraph 0240).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use the internal standards such as deuterium labeled standards of the detected compounds as is done in KASSIS in the method of DENG PAN due to the advantage this offers in being able to distinguish mass difference (KASSIS, paragraph 0237).
With respect to Claim 22, DENG PAN teaches of subjecting the sample to chromatography separation, and then detecting and analyzing and quantifying the metabolites by ultra-high resolution (UHR) mass spectrometry (MS) (Thermo Fusion: resolution = 370 000 at m/z = 400, mass accuracy < 0.5ppm) to determine all possible isotopologues(abstract).
With respect to Claim 25, DENG PAN teaches of performing a full scan, so that includes the claimed range (Figure 6 description).
With respect to Claim 26, DENG PAN teaches of the resolution being less than 50000, which includes the claimed range (Page 312, column 2, paragraph 1, Figure 7 description).
With respect to Claim 28, DENG PAN teaches of the dynamic range being 1000 fold, which reads on the claimed range (Page 316, column 1m last paragraph).
With respect to Claims 31 & 34, DENG PAN teaches of making multiple time point measurements, with multiple analytes, so repeating the method (Figure 3).
With respect to Claim 35, DENG PAN teaches there being a change in concentration for the metabolites across timepoints (See Figure 3).
Claims 4-7, 10, 36 are rejected under U.S.C. 103 as being obvious by DENG PAN in Quantitative profiling of carbonyl metabolites directly in crude biological extracts using chemoselective tagging and nanoESI- FTMS (as cited on IDS dated 06/25/2024) in view of KASSIS in US 20230137741 and further in view of HILLER in US 20170107552.
With respect to Claim 4, DENG PAN teaches of using a cell culture and sampling the cell culture medium which is from a human mammal and of derivatization and extraction of it and derivatization with acetone D6-QDA/QDA (Page 313,2.2). KASSIS also teaches of the invention as shown above.
DENG PAN does not teach of using Chinese Hamster Ovary cell culture.
HILLER is used to remedy this and teaches of using Chinese hamster ovary cells (paragraph 0115). 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 Chinese hamster ovary cells as is done in HILLER in the method of DENG PAN and KASSIS since it has been shown to have advantage as a susceptible cell culture (paragraph 0115).
With respect to Claim 5, DENG PAN teaches of using a cell culture and sampling the cell culture medium which is from a human mammal and of derivatization and extraction of it and derivatization with acetone D6-QDA/QDA (Page 313,2.2). KASSIS also teaches of the invention as shown above.
DENG PAN does not teach of using online cell culture sampling.
HILLER teaches of a method of cell culture in which optimization of cell culture conditions are used (paragraph 0002), and also online measurement methods for the cell culture are performed (paragraph 0030, 0292).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to perform online cell culture sampling as is done in HILLER in the method of DENG PAN and KASSIS due to the advantage this gives for automated analysis (HILLER, paragraph 0030).
With respect to Claim 6, DENG PAN teaches of using a cell culture and sampling the cell culture medium which is from a human mammal and of derivatization and extraction of it and derivatization with acetone D6-QDA/QDA and quantifying being completed within about 4 hours from sampling (Page 313,2.2). KASSIS also teaches of the invention as shown above.
DENG PAN and KASSIS does not teach of using online cell culture sampling.
HILLER teaches of a method of cell culture in which optimization of cell culture conditions are used (paragraph 0002), and also online measurement methods for the cell culture are performed (paragraph 0030, 0292). HILLER further teaches of measuring/sampling every 30 minutes to daily, which includes the claimed range (paragraph 0028).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to perform online cell culture sampling as is done in HILLER in the method of DENG PAN and KASSIS due to the advantage this gives for automated analysis (HILLER, paragraph 0030).
With respect to Claim 7, DENG PAN teaches of using a cell culture and sampling the cell culture medium which is from a human mammal and of derivatization and extraction of it and derivatization with acetone D6-QDA/QDA and quantifying being completed within about 2 hours from sampling (Page 313,2.2). KASSIS also teaches of the invention as shown above.
DENG PAN and KASSIS does not teach of using online cell culture sampling.
HILLER teaches of a method of cell culture in which optimization of cell culture conditions are used (paragraph 0002), and also online measurement methods for the cell culture are performed (paragraph 0030, 0292). HILLER further teaches of measuring/sampling every 30 minutes to daily, which includes the claimed range (paragraph 0028).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to perform online cell culture sampling as is done in HILLER in the method of DENG PAN and KASSIS due to the advantage this gives for automated analysis (HILLER, paragraph 0030).
With respect to Claim 10, DENG PAN teaches of using the metabolites as shown above. KASSIS also teaches of the invention as shown above. They do not call out using amino acid metabolites.
HILLER is used to remedy this and teaches of using amino acid metabolites in the cell culture (abstract).
It would have been obvious to one of ordinary skill in the art to detect amino acid metabolites as is done in HILLER in the method of DENG PAN and KASSIS due to the fact that amino acid metabolites have been shown to inhibit the growth of cells in the cell culture medium (paragraph 00245).
With respect to Claim 36, DENG PAN teaches of using a cell culture and sampling the cell culture medium which is from a human mammal and of derivatization and extraction of it and derivatization with acetone D6-QDA/QDA and quantifying being completed within about 2 hours from sampling (Page 313,2.2). KASSIS teaches of the invention as shown above.
DENG PAN and KASSIS does not teach of changing a parameter of the cell culture sampling as claimed.
HILLER teaches of a method of cell culture in which optimization of cell culture conditions are used (paragraph 0002), and also online measurement methods for the cell culture are performed (paragraph 0030, 0292). HILLER further teaches of adjusting the temperature and pH of the cell culture (paragraph 0281).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to optimize the cell culture as is done in HILLER and KASSIS in the method of DENG PAN due to the advantage this gives for commercial production (HILLER, paragraph 0002).
Claims 15-16, 19 are rejected under U.S.C. 103 as being obvious by DENG PAN in Quantitative profiling of carbonyl metabolites directly in crude biological extracts using chemoselective tagging and nanoESI- FTMS (as cited on IDS dated 06/25/2024) in view of KASSIS in US 20230137741 and further in view of BARTA in US 20010039287.
With respect to Claim 15, DENG PAN and KASSIS teaches of the invention as shown above. They do not teach of activating a carbonyl group as claimed.
BARTA teaches of a method wherein carbonyls are activated. BARTA further teaches of using ethylcarbodiimide hydrochloride (paragraph 0268, 0322, 0326) and also benzylhydroxylamine (paragraph 0349, 0352, 0530). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to activate the carbonyl and mask it as is done in BARTA in the method of DENG PAN and KASSIS due to the advantage activated compounds shown for reactions/reactivity with other compounds (paragraph 0326).
With respect to Claim 16, DENG PAN teaches of the invention as shown above. They do not teach of activating a carbonyl group as claimed.
BARTA teaches of a method wherein carbonyls are activated. BARTA further teaches of using ethylcarbodiimide hydrochloride (paragraph 0268, 0322, 0326) and also benzylhydroxylamine (paragraph 0349, 0352, 0530). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to activate the carbonyl and mask it as is done in BARTA in the method of DENG PAN due to the advantage activated compounds shown for reactions/reactivity with other compounds (paragraph 0326).
With respect to Claim 19, DENG PAN and KASSIS teaches of the invention as shown above. They do not teach of activating a carbonyl group as claimed.
BARTA teaches of a method wherein carbonyls are activated. BARTA further teaches of using ethylcarbodiimide hydrochloride (paragraph 0268, 0322, 0326) and also benzylhydroxylamine (paragraph 0349, 0352, 0530). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to activate the carbonyl and mask it as is done in BARTA in the method of DENG PAN abd KASSIS due to the advantage activated compounds shown for reactions/reactivity with other compounds (paragraph 0326).
Conclusion
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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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
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