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
Applicant’s amendment to the claims filed 07/15/2026 has been entered. Claims 1-12 are pending.
The amendment to claim 10 has been found sufficient to overcome the interpretation under 35 USC 112(f). The interpretation of this claim under 35 USC 112(f) is hereby withdrawn.
Regarding the rejection of claims 1, 2, 4, 5 and 10 under 35 USC 112(b), the amendments made to these claims are sufficient to overcome the rejection made in the previous Office action. The rejection of these claims under 35 USC 112(b) is hereby withdrawn.
Regarding the rejection of claims 11 and 12 under 35 USC 101, the amendments made to these claims are sufficient to overcome the rejection made in the previous Office action for being directed to non-statutory subject matter. However, claims 11 and 12 remain rejected under 35 USC 101 for the reasons discussed below.
Response to Arguments
Applicant's arguments filed 07/15/2026 have been fully considered but they are not persuasive.
Regarding the rejection of claims 1-10 under 35 USC 101 and the argument that a human mind is not equipped to determine a region of cells that have undergone necrosis because each cell has features of necrotic cells (page 8, paragraph 1 of Remarks filed 07/15/2026), the examiner respectfully disagrees. Claim 1 is simply directed to a general method of determining which cells have undergone necrosis. While the applicant points to paragraph [0004] of the instant application's specification, it is the position of the examiner that this paragraph is directed to a problem arising from a very specific instance (when cells are densely packed three-dimensionally). Additionally, applicant points to paragraph [0003] of the instant application's specification, which discloses that generally it is relatively easy to judge dead cells from living cells based on changes in appearance. There is nothing in claim 1 or it's dependent claims which differentiate it as being directed to a situation like the one described in paragraph [0004] rather than the situation described in paragraph [0003]. The method of claim 1 and its dependent claims is simply directed to "a region of cells that have undergone necrosis in an observation objective" and there are no further requirements as to the environment of these cells. Paragraphs [0007]-[0009] of the instant application explain the difficulties in determining a region of cell death and the type of cell death with high resolution using conventional methods such as fluorescent staining, and why refractive index distribution data is useful for non-invasive determination. However, claim 1 requires necrosis determination to be done with existing refractive index distribution data and does not require the refractive index distribution data to be acquired or used in a way that is not able to be done in the human mind. Rather, claim 1 only requires the refractive index distribution data to be used in determining if a cell is necrotic, which is able to be done in the human mind by determining a region and comparing the refractive index distribution data of the nucleus region to a threshold value.
Regarding the applicant’s argument that mental process grouping is not without limits, and the claim cannot be done practically in the human mind (page 9, paragraphs 1-2 of Remarks filed 07/15/2026), the examiner respectfully disagrees. As stated above, claim 1 does not require the refractive index distribution data to be calculated and instead only requires the refractive index distribution data to be used in determining if a cell is necrotic, which is able to be done in the human mind. While claim 7 requires a learning model, as explained in the Office action mailed 05/12/2026, the claim does no more than generally link the use of the abstract idea to a particular technological environment and it does not alter or affect how the process step of claim 1 is performed. Claim 7 is not directed to the development or training of the learning model and therefore does not merely involve an exception.
Regarding the rejection of amended claim 1 under 35 USC 103 and the argument that Hseih fails to determine a region that has undergone necrosis and the Office has merely found the features in the data (page 11 of Remarks filed 07/15/2026), the examiner respectfully disagrees. The method of Hseih is explicitly intended to identify and characterize cells which have undergone cell death using quantitative phase imaging (QPI) (title; page 1, paragraph 1; page 2, paragraph 4; 'Necrotic cells' - Fig. 3). Quantitative phase imaging is defined by a distribution in refractive index, therefore Hseih is using refractive index distribution data. Hseih further seeks to determine which cells have undergone necrosis (page 7, paragraph 2; an example of a necrotic cell is given in Fig. 5) based on if the cell data has features of a necrotic cell (page 8, paragraph 1 discloses data taken from the QPI measurements is used to determine if the cell has undergone necrosis or another type of cell death; Fig. 7 depicts this data). Further, one of the features used to determine the type of cell death is circularity, which indicates the degree of roundness of the area of the cell in question (Table 1; page 5, paragraph 2; page 8, paragraph 1; and Figs. 5 and 6 which depict a necrotic cell and a normal cell and their circularity). Paragraph [0016] of the instant application's specification describes the nucleus to be approximately a circular or spherical region and therefore analogous to the circularity measurement taught in Hseih as both are features determining a circular shaped region.
Regarding the argument that the purpose of Wang is not to determine a region of cells that have undergone necrosis (page 12, paragraphs 1-5 of Remarks filed 07/15/2026), the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Wang was not used to teach determining if a region of cells has undergone necrosis. Wang teaches a method in which a statistical dispersion of refractive index is used to describe cells (page 3, paragraph 2 discloses finding standard deviation of refractive index) and compares a ratio of the standard deviation to a threshold (page 7 discloses the threshold as cells that are not suspected of having a gene mutation; Fig. 5c depicts a ratio refractive index deviation of the genetically mutated cell compared to the ratio for a non-mutated cell). The motivation to use this as a feature in combination with Hseih being that the method described in Wang is simple and practical for investigating the internal structures of the cell (abstract), without needed extra information as Hseih already calculates a refractive index.
Specification
The disclosure is objected to because of the following informalities:
Paragraph [0008] recites “in an observation objectobservation object.” in the last two lines. This should read “in an observation object.”.
Paragraph [0009] recites “of an observation objectobservation object” in the line 2. This should read “in an observation object”.
Appropriate correction is required.
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 of matter, or any new and useful improvement thereof, may obtain a patent therefore, subject to the conditions and requirements of this title.
Claims 1-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1: Is the Claim to a Process, Machine, Manufacture or Composition of Matter?
Claims 1-10 recite a method and apparatus to perform the method for determining if cells have undergone necrosis based on a refractive index. Thus, these claims are to a process and apparatus, which are two of the statutory categories of inventions.
Step 2A: Prong One: Does the Claim Recite an Abstract Idea?
Claim 1 recites:
A method for determining a region of cells that have undergone necrosis in an observation object on a basis of refractive index distribution data of the observation object, the method comprising:
determining the region of cells that have undergone necrosis based on a fact that a region of each cell included in the refractive index distribution data has features of necrotic cells,
wherein the features of the necrotic cells include a feature of having a region equivalent to a nucleus and a feature in which statistical dispersion of refractive index of a nucleus is equal to or greater than a first threshold value (the examiner finds that the foregoing bolded elements recite a mental process as it can be practically performed in the human mind).
Step 2A: Prong Two: Does the Claim Recite Additional Elements that Integrate the Abstract Idea into a Practical application?
The claim does not recite any additional elements and thus the claim does not recite anything that integrates the abstract idea into a practical application.
Step 2B: Does the Claim Recite Additional Elements that Amount to Significantly More than the Abstract Idea?
The claim does not recite any additional elements and thus no element amounts to significantly more than the abstract idea.
Regarding claim 2, the same analysis as applied to claim 1 above applies, and the claim further merely recites an abstract idea of mental process because determining a region of the cell which has undergone necrosis based on a threshold value can be practically performed in the human mind.
Regarding claim 3, the same analysis as applied to claim 2 above applies, and the claim further does no more than generally link the use of the abstract idea to a particular technological environment or field of use because it is merely an incidental or token addition to the claim that does not alter or affect how the process step of claim 2 is performed.
Regarding claim 4, the same analysis as applied to claim 2 above applies, and the claim further merely recites an abstract idea of mental process because determining an approximately circular or approximately spherical region based on a threshold can be practically performed in the human mind.
Regarding claim 5, the same analysis as applied to claim 4 above applies, and the claim further does no more than generally link the use of the abstract idea to a particular technological environment or field of use because it is merely an incidental or token addition to the claim that does not alter or affect how the process step of claim 4 is performed.
Regarding claim 6, the same analysis as applied to claim 1 above applies, and the claim further does no more than generally link the use of the abstract idea to a particular technological environment or field of use because it is merely an incidental or token addition to the claim that does not alter or affect how the process step of claim 1 is performed.
Regarding claim 7, the same analysis as applied to claim 1 above applies, and the claim further does no more than generally link the use of the abstract idea to a particular technological environment or field of use because it is merely an incidental or token addition to the claim that does not alter or affect how the process step of claim 1 is performed.
Regarding claim 8, the same analysis as applied to claim 1 above applies, and the claim further does no more than recite insignificant extra-solution activity that does not alter or affect how the process step of claim 1 is performed.
Regarding claim 9, the same analysis as applied to claim 1 above applies, and the claim further does no more than recite insignificant extra-solution activity that does not alter or affect how the process step of claim 1 is performed.
Regarding claim 10, the same analysis as applied to claim 1 above applied, and the claim further recites the additional elements of a generic computer, which does not amount to significantly more than the mental process step of claim 1.
Claims 11 and 12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1: Is the Claim to a Process, Machine, Manufacture or Composition of Matter?
Claims 11 and 12 recite a non-transitory computer-readable storage medium to perform a method for determining if cells have undergone necrosis based on a refractive index. Thus, these claims are to a statutory category of invention.
Step 2A: Prong One: Does the Claim Recite an Abstract Idea?
Claim 11 recites:
A non-transitory computer-readable storage medium storing an information processing program for causing a computer to execute a determination step of determining a region of cells that have undergone necrosis in an observation object, by the method according to claim 1. (The examiner finds that the foregoing bolded elements recite a mental process as it can be practically performed in the human mind. As explained above in the 35 USC 101 rejection of claim 1, the method according to claim 1 has been found to be an abstract idea. A non-transitory computer-readable storage medium that performs a method found to be an abstract idea is also an abstract idea, as merely including instructions to implement an abstract idea on a computer does not integrate the abstract idea into a practical application).
Step 2A: Prong Two: Does the Claim Recite Additional Elements that Integrate the Abstract Idea into a Practical application?
The claim does not recite any additional elements and thus the claim does not recite anything that integrates the abstract idea into a practical application.
Step 2B: Does the Claim Recite Additional Elements that Amount to Significantly More than the Abstract Idea?
The claim does not recite any additional elements and thus no element amounts to significantly more than the abstract idea.
Regarding claim 12, the same analysis as applied to claim 11 above applies, and the claim does no more than recite insignificant extra-solution activity that does not alter or affect how the process step of claim 11 is performed.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Gorbenko ("Quantification of changes in cellular morphology during cell necrosis obtained from 3D refractive index distributions," Journal of physics, 2019, pp. 1-5) in view of Hsieh (Characterization and identification of cell death dynamics by quantitative phase imaging. J Biomed Opt. 2022 Apr;27(4):046502. doi: 10.1117/1.JBO.27.4.046502. PMID: 35484694; PMCID: PMC9047449) and Wang ("An insight into statistical refractive index properties of cell internal structure via low-coherence statistical amplitude microscopy:. Opt Express. 2010 Oct 11;18(21):21950-8. doi: 10.1364/OE.18.021950. PMID: 20941095; PMCID: PMC3408902.)
Regarding claim 1, Gorbenko teaches a method for determining a region of cells that have undergone necrosis (title; page 2, paragraphs 1 and 2) in an observation object on a basis of refractive index distribution data of the observation object (page 1, paragraph 2 discloses the method is performed using digital holographic tomography, which is a representation of the 3D refractive index), the method comprising:
determining the region of cells that have undergone necrosis based on a fact that a region of each cell included in the refractive index distribution data has features of necrotic cells (page 2, paragraphs 1-2 discloses finding a distribution of refractive index and using it to assess cell condition and if the cell died via necrosis; page 3, paragraph 1 further discloses distinguishing if a cell has undergone necrosis).
Gorbenko fails to teach the features of the necrotic cells include a feature of having a region equivalent to a nucleus and a feature in which statistical dispersion of refractive index of a nucleus is equal to or greater than a first threshold value.
However, in the same field of endeavor of investigating necrosis of cells, Hseih teaches a method of identifying cells which have undergone cell death (title; page 1, paragraph 1; page 2, paragraph 4) which includes identifying a circular region (Table 1 discloses circularity is a feature investigated; page 5, paragraph 2 further discloses circularity is a feature investigated and defines it as the degree of roundness of an area; page 8, paragraph 1 discloses how circularity compares for a necrotic versus non-necrotic region; and Figs. 5 and 6 which depict a necrotic cell and a normal cell and their circularity).
Gorbenko analyzes cell morphology to determine if a cell has undergone necrosis (abstract; page 1, paragraph 2; page 3, paragraph 2). Hseih discloses circularity describes cell morphology (page 5, paragraph 1) and provides a clear comparison for a cell that has undergone necrosis compared to a normal cell (see Figs. 5 and 6 which depict circularity of a necrotic cell and a normal cell). A person of ordinary skill in the art would find it obvious to use the well-known method of investigating circularity as taught in Hseih with the cell morphology analysis taught in Gorbenko and have a reasonable expectation of success in characterizing a necrotic cell. Thus, a person of ordinary skill in the art would find it obvious to combine the cell analysis method taught in Gorbenko with the use of circularity to determine cell necrosis taught in Hseih as it provides a clear identification of a cell that has undergone necrosis.
Gorbenko as modified by Hseih fails to teach a feature in which statistical dispersion of refractive index of a nucleus is equal to or greater than a first threshold value.
However, in the same field of endeavor of investigating cells, Wang teaches a method of investigated a statistical dispersion of a refractive index of a cell (page 3, paragraph 2 discloses finding standard deviation of refractive index) and comparing it to a threshold (page 7 discloses a ratio of standard deviation is compared to a non-modified cell. This is further depicted in Fig. 5c).
Gorbenko as modified by Hseih already calculates a refractive index. Wang discloses the method of investigating cells using the standard deviation is simple and practical for investigating the internal structures of the cell (abstract). Thus, a person of ordinary skill in the art would find it obvious to combine the cell analysis method taught in Gorbenko as modified by Hseih with the statistical dispersion investigation taught in Wang as it is a simple and practical method of investigating the internal structures of a cell.
Regarding claim 6, Gorbenko as modified by Hsieh and Wang teaches the invention as explained above in claim 1, and further teaches the refractive index distribution data is refractive index tomography data in a predetermined direction (Gorbenko: page 1, paragraph 2 discloses the method is performed using digital holographic tomography, which is a representation of the 3D refractive index; Fig. 1 shows this tomography in the z-direction).
Claims 1-5 and 7-12 are rejected under 35 U.S.C. 103 as being unpatentable over Hsieh (Characterization and identification of cell death dynamics by quantitative phase imaging. J Biomed Opt. 2022 Apr;27(4):046502. doi: 10.1117/1.JBO.27.4.046502. PMID: 35484694; PMCID: PMC9047449.) in view of Wang ("An insight into statistical refractive index properties of cell internal structure via low-coherence statistical amplitude microscopy:. Opt Express. 2010 Oct 11;18(21):21950-8. doi: 10.1364/OE.18.021950. PMID: 20941095; PMCID: PMC3408902.)
Regarding claim 1, Hsieh teaches a method for determining a region of cells that have undergone necrosis (page 2, paragraph 3 discloses determining if a cell is alive or dead and determining the type of death (apoptosis or necrosis)) in an observation object ('microincubator' - Fig. 1) on a basis of refractive index distribution data of the observation object (page 2, paragraph 2 discloses the method relies on quantitative phase imaging, which is the spatial distribution of the sample's refractive index), the method comprising:
determining the region of cells that have undergone necrosis (title; page 1, paragraph 1; page 2, paragraph 3) based on a fact that a region of each cell included in the refractive index distribution data has features of necrotic cells (Table 1 discloses the investigated features which were used to identify necrotic cells),
wherein the features of the necrotic cells include a feature of having a region equivalent to a nucleus (Table 1 discloses circularity is a feature investigated; page 5, paragraph 2 further discloses circularity is a feature investigated and defines it as the degree of roundness of an area; page 8, paragraph 1 discloses how circularity compares for a necrotic versus non-necrotic region; and Figs. 5 and 6 which depict a necrotic cell and a normal cell and their circularity).
Hseih fails to teach a feature in which statistical dispersion of refractive index of a nucleus is equal to or greater than a first threshold value.
However, in the same field of endeavor of investigating cells, Wang teaches a method of investigated a statistical dispersion of a refractive index of a cell (page 3, paragraph 2 discloses finding standard deviation of refractive index) and comparing it to a threshold (page 7 discloses a ratio of standard deviation is compared to a non-modified cell. This is further depicted in Fig. 5c).
Hseih already calculates a refractive index. Wang discloses the method of investigating cells using the standard deviation is simple and practical for investigating the internal structures of the cell (abstract). Thus, a person of ordinary skill in the art would find it obvious to combine the cell analysis method taught Hseih with the statistical dispersion investigation taught in Wang as it is a simple and practical method of investigating the internal structures of a cell.
Regarding claim 2, Hsieh as modified by Wang teaches the invention as explained above in claim 1, and further teaches the features of the necrotic cells further include a feature in which a statistic value of a refractive index of a whole cell (Hseih: page 5, paragraph 2 discloses the nuclear edge score quantifies the average amplitude the phase gradient, which is based on the refractive index, around the boundary of a nucleus) is equal to or less than a threshold value (Hseih: the nuclear edge region is determined based on the conditions disclosed in the last row of Table 1 on page 4, which include a threshold the features must be less than. If this value is above 0, then the cell is not necrotic).
Regarding claim 3, Hsieh as modified by Wang teaches the invention as explained above in claim 2, and further teaches the statistic value is an average value or a median value of the refractive index of the whole cell (Hsieh: page 5, paragraph 1 discloses a nuclear edge score, which defines a region equivalent to the nucleus and is based on an average amplitude of the phase gradient, which is based on the refractive index).
Regarding claim 4, Hsieh as modified by Wang teaches the invention as explained above in claim 2, and further teaches the region equivalent to the nucleus is an approximately circular or approximately spherical region and is a region in which a statistic value of refractive index is a value greater than the statistic value of refractive index of a whole cell (Hsieh: circularity is inherently calculated using a threshold method).
Regarding claim 5, Hsieh as modified by Wang teaches the invention as explained above in claim 4, and further teaches the statistic value of the refractive index of the whole cell is an average value or a median value of the refractive index of the whole cell (Hsieh: page 5, paragraph 1 discloses a nuclear edge score, which defines a region equivalent to the nucleus and is based on an average amplitude of the phase gradient of the cell, which is based on the refractive index).
Regarding claim 7, Hsieh as modified by Wang teaches the method as explained above in claim 1 and further teaches the determination of a region of cells that have undergone necrosis is carried out by inputting refractive index distribution data of an observation object into a learning model that has learned using training data including necrotic region data of a reference observation object and refractive index distribution data of the reference observation object corresponding to the necrotic region data, and a feature quantity utilized by the learning model includes a feature quantity corresponding to features of having a region equivalent to a nucleus (Hseih: Section 3.2, starting on page 9, details a learning model which is used to determine if a cell is dead, and if the cell death is due to apoptosis or necrosis based on parameters taken from the QPI measurements).
Regarding claim 8, Hsieh as modified by Wang teaches the method as explained above in claim 1 and further teaches a step of acquiring the refractive index distribution data of the observation object (Hseih: Sec. 2.1, starting on page 2 describes the QPI method).
Regarding claim 9, Hsieh as modified by Wang teaches the method as explained above in claim 1 and further teaches a method for evaluating quality of a cell cluster,
the observation object being a cell cluster (Hseih: Fig. 1b depicts a cluster of cells which have been observed),
the method further comprising:
a step of acquiring the refractive index distribution data of a cell cluster (Hseih: see section 2.1, beginning on page 2 which describes the QPI method).
Regarding claim 10, Hsieh as modified by Wang teaches the method of claim 1, and further teaches an apparatus for determining a region of cells that have undergone necrosis, the apparatus comprising:
a processor (Hseih: while a processor is not explicitly disclosed, it is the position of the examiner the corresponding calculations and figures shown in Hseih would have required a processor of some sort to be used) for acquiring refractive index distribution data of an observation object (Hseih: see section 2.1, beginning on page 2); and determining a region of cells that have undergone necrosis in the observation object (Hseih: Sec. 3.1, beginning on page 7 discloses the determination of necrotic cells).
Regarding claim 11, Hsieh as modified by Wang teaches the method according to claim 1, and further teaches a non-transitory computer-readable storage medium storing an information processing program for causing a computer to execute a determination step of determining a region of cells that have undergone necrosis in an observation object (Hseih: while a computer is not explicitly disclosed, Section 3.2, starting on page 9, details a learning model which determines cells that have undergone necrosis. It is the position of the examiner this would need to be done on a computer of some sort).
Regarding claim 12, Hsieh as modified by Wang teaches the invention as explained above in claim 11, and further teaches causing the computer to execute:
a data acquisition step of acquiring the refractive index distribution data of the observation object (Hseih: see section 3.2, beginning on page 2).
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 Alexandria Mendoza whose telephone number is (571)272-5282. The examiner can normally be reached Mon - Thur 11:00-8:00 ET.
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, Michelle Iacoletti can be reached at (571) 270-5789. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDRIA MENDOZA/ Examiner, Art Unit 2877
/MICHELLE M IACOLETTI/ Supervisory Patent Examiner, Art Unit 2877
