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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 8, 2025 has been entered.
Claims 1, 3-22, 24 and 25 remain pending. Applicant amended claims 1, 3, 7-11, 15, 16, 20, 24 and 25.
Response to Arguments
Despite the amendment and Applicant’s remarks, the outstanding 35 U.S.C. 112(b) rejection of claims 1 and 22 is maintained. The rejection has been updated to further elaborate the nature of the rejection and why Applicant’s remarks are not persuasive.
Regarding the prior art rejections, Applicant’s arguments have been fully considered but most of them are moot. The Office action includes a new ground rejection, which is set forth below. Regarding the arguments that remain pertinent, they have been fully considered but they are not persuasive.
Applicant argues that the claims are patentable over the combination of Becker and Bergo because Bergo uses a 3-D microarray plate having a plurality of microwells to concentrate analytes, which prohibits measurement of proliferation capability. Remarks 18. The argument is not persuasive because the rejection is not suggesting bodily incorporation of Bergo’s microwells into the method of Becker. Rather, the disclosure of Bergo relied upon is limited to its disclosure pertaining to using MALDI mass spectrometry to analyze animal cells, which Applicant previously argued is not technically obvious based on the disclosure of Becker.
As for Applicant’s arguments that Bergo does not teach determining degree of growth/proliferation of animal cells or the use of spatially resolved MALDI MS (Remarks 18), the arguments are also not persuasive. As indicated in the new ground of rejection set forth below, the combination of Becker and Bergo would arrive at a method comprising the steps taught by Becker (e.g. determining growth/proliferation using spatially resolved MALDI MS) except that the mass spectrometric sample would comprise animal cells (e.g. tumor cells) and the analytical sample would comprise a factor that is potentially cytotoxic to said animal cells (e.g. chemotherapeutic agent). In other words, the determination of degree of growth/proliferation of cells and the use of spatially resolved MALDI MS need not be taught by Bergo because the steps are taught by Becker. As discussed above, the disclosure of Bergo relied upon is limited to its disclosure pertaining to using MALDI mass spectrometry to analyze animal cells.
Applicant also argues that Becker’s deficiency (i.e. Becker does not disclose analysis of animal cells) is not cured by Bergo. Remarks 19. The argument is not persuasive. Bergo explicitly teaches analysis of animal cells using MALDI-TOF MS (see [0214] and [0221]-[0222]). Thus, the combination of Becker and Bergo, along with the motivation provided by Yen, would arrive at analyzing animal cells using the methodology taught by Becker.
Applicant also argues that Becker does not teach the use of spatially resolved mass spectrometry because “the location of the laser shots are not precisely defined, but generally directed across a defined grid”, and “Becker merely notes the number of successful shots but does not correlate the number of successful shots to the surface area and does not determine the degree of coverage.” Remarks 19-20. Notwithstanding the fact that Becker explicitly discloses the words “spatial resolution” in the context of “MALDI-TOF MS methods” in [0099], the argument is not persuasive because Applicant’s argument is based on speculation and misinterpretation/misrepresentation of Becker’s disclosure. Specifically, regarding Applicant’s assertion that the area of the “grid” taught by Becker is “quantitatively unknown”, this is mere speculation and contrary to the disclosure of Becker. Becker explicitly discloses that the grid is “precisely defined” (see [0099]), meaning it is constant and predetermined/known, and hence the number of “successful shots” within this “precisely defined” grid conveys degree of coverage within the grid, which is sufficient to anticipate the limitations in question. Even in Applicant’s example posited in Remarks 19-20, 10 successful shots would convey higher degree of coverage than 3 shots within the same defined grid. Regarding Applicant’s reference to [0098] of Becker, the disclosure is unrelated to the disclosure of [0099] relied upon in the rejection. Becker explicitly discloses that the “spatial resolution” “MALDI-TOF MS method[s]” disclosed in [0099] is “another possible version” relative to the disclosure of [0098]. Consequently, Applicant’s reference to [0098] appears irrelevant to the issue of whether Becker discloses spatial resolution mass spectrometer.
Claim Objections
Claims 22 and 24 are objected to because of the following informalities:
In claim 22, the limitation “a proliferation capability” in the third evaluation step should be changed to “the proliferation capability”.
In claim 24, the limitation “a transition point” should be changed to “the transition point”.
Appropriate corrections are required.
Claim Rejections - 35 USC § 112
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3-20, 22 and 24 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Despite Applicant’s remarks (see Remarks 12), the rejection of claims 1 and 22 is maintained due to the recitation of “and/or” preceding the third evaluation step A. Contrary to Applicant’s remarks that the “and/or” conveys that the claimed method has two possibilities (perform evaluation steps 1, 2 and 4; and perform evaluation steps 1, 2, 3 and 4), the recitation of “and/or” conveys additional possibilities (perform evaluation steps 1, 3 and 4; and perform evaluation steps 3 and 4), and some of these possibilities are impossible without performing the missing steps. Based on Applicant’s remarks (see Remarks 12), the intent of the claims appears to be that the third evaluation step, and only the third evaluation step, is optional. If that is the intent, then, the limitation “and/or” should be changed to “optionally”. The recitation of “optionally” unequivocally conveys that the method has two possibilities, the possibilities discussed by Applicant on page 12 of the Remarks.
While the claims will be interpreted according to Applicant’s remarks, the claims must be amended as suggested.
Claims not explicitly rejected are rejected due to their dependency.
Claim Rejections - 35 USC § 103
Claims 1, 3-5, 9-15, 17-22, 24 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Becker et al. (“Becker”) (US 2020/0291446 A1) in view of Yen-Maguire et al. (“Yen”) (US 5,242,806) and Bergo (US 2014/0323330 A1).
With respect to claim 1, Becker discloses a method for determining effects of an analytical sample (e.g. antibiotics) on microbial cells (see abstract and [0057]), the method comprising the following steps:
-a sample provision step comprising providing a mass spectrometric sample comprising the microbial cells, culture medium, and the analytical sample on at least one sample spot of a mass spectrometric sample support (see steps a and b of claim 1);
-a cultivation step comprising incubating the mass spectrometric sample in a cultivation device (see step c of claim 1);
-a liquid removal step comprising removing residual liquid of the mass spectrometric sample from the at least one sample spot (see step d of claim 1);
-a measuring step comprising recording spatially resolved mass spectra at a plurality of measuring positions in at least one partial area of the at least one sample spot by means of a spatial resolution mass spectrometer (see [0099] and step f of claim 1),
-a first evaluation step comprising analyzing each spatially resolved mass spectrum for a presence of a cell-specific mass spectrometric signature of the microbial cells and assigning a cell presence value (“successful shot”) to each measuring position (see [0099]);
-a second evaluation step comprising determining the degree of coverage by the microbial cells for the at least one partial area from the cell presence values (see [0099] disclosing comparing cell presence values with a control sample and mapping the cell presence values within a defined spatial grid); and
-a fourth evaluation step comprising deriving the effects of the analytical sample on the cells from the determined degree of coverage of the second evaluation step (see step g of claims 1 and 6).
The method taught by Becker differs from the claimed invention in that Becker does not disclose that the method uses animal cells as the mass spectrometric sample. Instead, the method is intended to study the cytotoxic effects of certain antibiotics on bacteria (i.e. non-animal cells). However, it is well-known in the art to study the cytotoxic effects of external factors (e.g. chemotherapeutic agents) on animal cells (e.g. tumor cells) (see abstract of Yen), and Bergo discloses a method of performing cytotoxicity assays on animal cells using MALDI mass spectrometry (see [0214] and [0221]-[0222]). In light of the disclosure of Yen and Bergo, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed cytotoxicity testing on animal cells using the methodology taught by Becker for the purpose of determining the effects of chemotherapeutic agents on tumor cells. If the modification is made, then the method would comprise the same steps, except that the mass spectrometric sample would comprise animal cells (e.g. tumor cells) and the analytical sample would comprise a factor (e.g. chemotherapeutic agent) that is potentially cytotoxic to said animal cells.
With respect to claim 3, as discussed above, the combination of Becker, Yen and Bergo teaches a method for determining cytotoxic effects of an analytical sample (chemotherapeutic agent) on animal cells (tumor cells). In addition to the steps discussed above, Becker further discloses that the at least one partial area comprises a first partial area, and a second partial area from which a reference data set is obtained, wherein the reference data set comprises mass spectra that do not originate from the cells (see [0013]). Furthermore, the method comprises recording mass spectra of the second partial area, determining a cell expansion distance of each partial area from a reference point to a transition point (see claim 8 and [0099] disclosing mapping “successful” shots within a defined spatial grid), comparing the cell expansion distances of the two partial areas, and deriving the effects of the analytical sample based on the difference in cell expansion distances (see claim 8).
With respect to claim 4, the cells would be organ/tissue-specific cells (see [0222] of Bergo and lines 6-10, col. 8 of Yen), meaning the cells would be adherently growing cells.
With respect to claim 5, the plurality of measuring positions in the at least one partial area of the at least one sample spot are distributed spatially in such a way that the determined degree of coverage is representative of the at least one partial area (see [0099] disclosing use of a spatial grid that represents the at least one partial area).
With respect to claim 9, the mass spectrometric sample is provided in the sample provision step by applying the cells in suspended form to the at least one sample spot (see claim 14 of Becker).
With respect to claim 10, as discussed above (see rejection of claim 9), the cells are provided in suspended form to the at least one sample spot in the sample provision step. The method further comprises a washing step in which the cells are washed on the at least one sample support using washing liquids (see [0022]), and subsequently removing residual washing liquids (see [0072]).
With respect to claims 11 and 15, as discussed above, the analytical sample of the modified method would comprise an isolated cytotoxic factor in the form of a chemotherapeutic agent.
With respect to claims 12-14, the animal cells in the modified method would be tumor samples taken from a human (see lines 6-10, col. 8 of Yen).
With respect to claim 17, Becker discloses a step of determining a concentration-dependent cytotoxic effect of the analytical sample by providing different concentrations of the analytical sample respectively on different sample spots (see [0014]). Based on the disclosure, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have studied the cytotoxic effects of the chemotherapeutic agent at various concentrations to determine a threshold concentration level that is considered effective for treating cancer.
With respect to claim 18, the spatial resolution mass spectrometer taught by Becker is a MALDI-ToF mass spectrometer (see [0099]).
With respect to claim 19, claim is directed to subject matter that is optional. Consequently, prior at need not teach claim 19 to reject the claim.
With respect to claim 20, as discussed above, the data processing unit is configured to perform all of the evaluation steps, including deriving a proliferation capability and/or a migration capability of the cells from the determined cell expansion distance (see Fig. 4B of Becker illustrating range of growth). Furthermore, the method comprises an intermediate evaluation step of comparing the cell expansion distance of at least one reference sample with the cell expansion distance of the mass spectrometric sample to derive the effects in the fourth evaluation step (see claim 8).
With respect to claims 22 and 24, the method uses a mass spectrometer with a data processing unit for evaluating mass spectra (see [0076]-[0077]). Based on the disclosure, it would have been obvious, if not evident, to configure the data processing unit to carry out the evaluation steps of the method.
With respect to claim 21, the method taught by Becker is achieved using a system comprising the spatial resolution mass spectrometer, a sample support (see claim 1), and a data processing unit for controlling the spectrometer and performing the evaluation steps (see [0076]-[0077] disclosing software that performs evaluation of the mass spectra).
With respect to claim 25, as discussed above, the method taught by Becker is performed using a data processing unit, the method comprising determining the degree of coverage by using the presence of at least one cell-specific mass spectrometric signature (see [0099]).
Allowable Subject Matter
Claims 6-8 and 16 would be allowable if they are amended to overcome the 35 U.S.C. 112(b) rejections set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
As discussed above, the combination of Becker, Yen and Bergo teaches a method for determining cytotoxic effects of an analytical sample (chemotherapeutic agent) on animal cells (tumor cells). However, the combination does disclose adding a cytotoxic factor-neutralizing factor to the mass spectrometric sample. Given that the purpose of the modified method would be to study the cytotoxic effects of an analytical sample on animal cells, there is no motivation to further add to the mass spectrometric sample something that would impact the cytotoxic effects of the analytical sample (i.e. a neutralizing factor), as recited in claims 6-8 and 16.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL S HYUN whose telephone number is (571)272-8559. The examiner can normally be reached M-F 8:30-5:00.
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/PAUL S HYUN/Primary Examiner, Art Unit 1796