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 .
Response to Amendment
The amendment filed on July 26, 2026 is acknowledged. Claims 1, 3-22, 24 and 25 remain pending. Applicant amended claims 1, 22 and 24 to obviate various outstanding issues*. The outstanding objections and the rejection of claim 1 under 35 U.S.C. 112(b) have been withdrawn in light of the amendment. The rejection of claim 22 under 35 U.S.C. 112(b) is maintained because the amendment did not address the rejection.
*Claim 7, despite being identified as “previously presented”, is not verbatim identical to the previous version of itself (see last line of claim 7). The claim will be examined based on its status indicator. Applicant is required to correct either the status indicator or the claim such that they correspond. Applicant is advised in general to review ALL of the claims to ensure proper status of the claims.
Response to Arguments
Applicant's arguments directed to the patentability of the claims have been fully considered but they are not persuasive.
Applicant argues that independent claims 1, 3 and 21 are patentable over the combination of Becker et al. (“Becker”) Yen-Maguire et al. (“Yen”) and Bergo because the combination “does not disclose, teach, or suggest the use of spatial resolution mass spectrometry to measure expansion/growth of animal cells as a function of degree of coverage of on sample spot, or using the degree of coverage to derive the proliferation capability of the cells”. Remarks 12. To support the argument, Applicant submitted a 37 CFR 1.132 Declaration to challenge the interpretation of [0099] of Becker set forth in the Office action. Remarks 13. According to Applicant, [0099] of Becker does not disclose spatial resolution mass spectrometry as the location of the laser shots are not precisely determined. Id. Rather, Becker uses standard MALDI-ToF-MS to note the number of successful shots across a grid, and does not correlate individual shots to specific locations on the grid, and hence it does not determine the degree of coverage from the number of successful shots. Id; Declaration 14 and 17-20.
The argument is not persuasive because Applicant’s argument is not commensurate with the scope of the claims.
Regarding Becker’s use of standard MALDI-ToF-MS, contrary to Applicant’s argument, the limitation “spatial resolution mass spectrometer” intends to encompass MALDI-ToF mass spectrometer (see claim 18). Consequently, Applicant’s argument that the claims are patentable over the combination because Becker utilizes standard MALDI-ToF-MS and not a “spatial resolution spectrometer” is not persuasive.
As for Applicant’s argument that Becker only notes the number of successful shots across the grid instead of correlating successful shots to specific locations on the grid (Remarks 13-14), contrary to the implication of Applicant’s argument, the claims do not require spectra resembling a map that conveys laser shots to locations of the measuring positions. Instead, the claims merely require recording mass spectra at a plurality of measuring positions within an area, and subsequently assigning a cell presence value to each measuring position. This is taught by Becker. Becker fires laser shots (e.g. 1000 shots) “distributed over defined areas” and each “successful shot” is recorded (see [0099]). In other words, Becker teaches recording a mass spectra at a plurality of measuring positions within an area, and assigning a cell presence value to each measuring position where cells are detected. Arguendo, even if Becker teaches a simple ratio of successful shots to total number of shots, given that the shots were “distributed over defined areas”, the ratio constitutes a “spatially resolved” mass spectra wherein the “successful shots” convey coverage of the at least one partial area by cells and the total number of shots convey the size of the at least one partial area (i.e. more successful shots=more cell growth/proliferation within the at least one partial area). This is evidenced by Becker explicitly disclosing that this method is directed to a “spatial resolution” algorithm (see [0099]).
Regarding Applicant’s arguments directed to the secondary art Bergo (Remarks 15), Bergo is relied upon for its teaching that mass spectrometry can be used to obtain mass spectra of animal cells, as Applicant previously argued that it would not have been obvious to image animal cells using the method of Becker because animal cells have different morphology relative to microbial cells. Consequently, whether Bergo uses mass spectra to determine growth/proliferation of cells, or whether Bergo utilizes a microwell to perform its method, is not applicable to the motivation for combining Becker and Bergo.
Regarding Applicant’s arguments directed to the secondary art Yen (Remarks 15-16), Yen is relied upon for the motivation of applying the method taught by Becker to animal cells. Consequently, the specifics of Yen’s method that are central to Applicant’s arguments with respect to Yen (see Remarks 15-16) are not applicable to the motivation for combining Becker and Yen. The combination of Becker and Yen would still rely on the method steps taught by Becker, the modification being the analytical sample comprising animal cells instead of microbial cells.
For the foregoing reasons, the outstanding 35 U.S.C. 103 rejection is maintained.
Claim Objections
Claim 10 is objected to because of the following informalities:
In claim 10, the limitation “the at least one sample support” should be changed to “the sample support”. There is no antecedent basis for “at least one sample support”
Appropriate correction is 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.
Claim 22 is 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), claim 22 was not amended to obviate the outstanding rejection. Consequently, the rejection of claim 22 is maintained. Specifically, the recitation of “and/or” preceding the third evaluation step renders the claim indefinite because it is unclear to which step(s) the “and/or” applies. Based on Applicant’s remarks in previous communications, 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”.
While the claim will be interpreted according to Applicant’s remarks, the claim must be amended as suggested.
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 (US 2020/0291446 A1) in view of 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 are objected to as being dependent on a rejected claim, but they would be allowable if they are rewritten as independent claims including 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 not 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
THIS ACTION IS MADE FINAL. 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.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Luan Van can be reached at 571-272-8521. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PAUL S HYUN/Primary Examiner, Art Unit 1796
Prosecution Insights