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 .
Claim Objections
Claims 21, 24, and 25 are objected to because of the following informalities:
Each claim should separate the various statements of the claim (particularly the “wherein” clauses) by a line indentation as set forth by 37 CFR 1.75(i).
Appropriate correction is required.
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 4-5 and 25-26 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.
Claims 4 and 5 each recites the limitation "the sample" in lines 1-2 of each claim. There is insufficient antecedent basis for this limitation in the claim. What sample is being referred to here? Is it the reference sample, the test sample, or both? Clarification is required.
For purposes of examination, the examiner will consider “the sample” to be the test sample.
As for claim 25, the claim recites, recites that the average test spectrum is in the first cluster is the first distance between the average test spectrum and the first cluster is shorter than a second distance between the average test spectrum and the second cluster, and it also recites that the average test spectrum is in the first cluster is a first distance between the average test spectrum and the first cluster is longer than a second distance between the average test spectrum and the second cluster. This makes the claim indefinite for two reasons. First, how can the average test spectrum be in the first cluster if it is both closer to the first cluster than the second cluster and further from the first cluster than the second cluster? This is contradictory. Additionally, the use of “a first distance” and “a second distance” in lines 5 and 6 of the claim after that phrase is used in lines 2 and 3 of the claim is unclear, as it is not clear whether the second instance of the first and second distance are supposed to be the same first and second distance or different first and second distances.
It appears as though the wherein statement in lines 4-6 of the claim should read that the average test spectrum is in the second cluster if the first distance between the average test spectrum and the first cluster is longer than the second distance between the average test spectrum and the second cluster.
Claim 26 recites the limitation "the first distance between the average test FTIR spectrum and the first cluster" in lines 1-2 of the claim. There is insufficient antecedent basis for this limitation in the claim.
Claim 26 recites the limitation "the second distance between the average test FTIR spectrum and the second cluster" in lines 3-4 of the claim. There is insufficient antecedent basis for this limitation in the claim.
For both of the above statements, claim 26 depends on claim 1; however, claim 1 does not provide antecedent basis for “a first distance” or “a second distance”. While for prior art purposes the claim will be treated as if it depends on claim 1, it appears as though, given the subject matter, claim 26 is best dependent on claim 25, not claim 26.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 11-16, 21, 23, 25, 26, and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grunert et al (WO 2021/037866).
Regarding claim 1, Grunert discloses a method for determining a state of a test subject comprising generating a plurality of reference Fourier transform infrared spectroscopy (FTIR) spectra (see step c) in the short description of the invention on page 2, which states that at least one reference spectrum is obtained from at least one reference sample using FTIR as found in step b)) for each of a plurality of reference samples (the last paragraph of claim 3 defines a reference sample as a sample for comparison), wherein the plurality of reference samples comprises a plurality of first reference samples obtained from first reference subjects known to be in a first state and a plurality of second reference samples obtained from reference subjects known to be a second state (see the third paragraph of page 4 – “In the first case, the method relies on differences (or similarities) between individual subjects with different physiological and/or pathological states”; see also the fifth paragraph of that pages, stating that the reference sample is related, or preassigned, to a certain clinical parameter, which would be equivalent to a first or second state); determining an average reference FTIR spectrum of the plurality of reference FTIR spectra for each of the plurality of reference samples (as the reference spectra are obtained in the same manner as the test spectra as found on page 2, steps b) and c), the determination of average reference FTIR spectra is disclosed by the “sample preparation and FTIR spectroscopy” section on pages 11-12, which states that 32 interferograms are obtained and averaged with background subtraction); generating a plurality of test FTIR spectra for a test sample obtained from a test subject (see step b found on page 2; see also the “sample preparation and FTIR spectroscopy” section on pages 11-12, which states that a plurality of test spectra of the test sample are obtained), wherein one or more characteristics of the test subject and the reference subjects are matched (see page 4, paragraph 3, “the method relies on . . . similarities . . . between individual subjects”); determining an average test FTIR spectrum of the plurality of test FTIR spectra for the test sample (the determination of average reference FTIR spectra is disclosed by the “sample preparation and FTIR spectroscopy” section on pages 11-12, which states that 32 interferograms are obtained and averaged with background subtraction), clustering the average reference FTIR spectra of the plurality of reference samples and the average test FTIR spectrum into a first cluster and a second cluster corresponding to the first state and the second state, respectively (this clustering for computing the similarity value is done via one of the methods set forth in paragraphs 1 and 2 of page 8, with further details in the “Unsupervised and supervised chemometrics” section on pages 12-13, with, for example, principal component analysis being a known technique for clustering closely related data points); and determining the test subject is in the first state or the second state based on whether the average test FTIR spectrum is in the first cluster or the second cluster (see step d) on page 2, where a clinical parameter is assigned to the analysis sample based on the similarity value).
As for claim 11, Grunert discloses that the generation of the generation of the FTIR spectra is performed at room temperature or -80°C (the samples are thawed as per “Sample preparation and FTIR spectroscopy” on pages 11-12; thawing would imply room temperature; Grunert also suggests, in “Sample collection and preparation” on page 11, -80°C).
As for claim 12, Grunert discloses that the first state is non-responsiveness to a treatment of a disease, and wherein the second state is responsiveness to the treatment of the disease (as Grunert teaches that the disclosed method of analyzing a peritoneal dialysis analysis sample is to provide clinicians with better tools to monitor/mange a dialysis regime and/or to predict the dialysis outcome, it follows that a first state would include non-responsiveness to treatment and the second state would include responsiveness to treatment in order to ascertain whether or not the dialysis is working or will fail).
As for claim 13, Grunert discloses that the one or more characteristics of the test subject and the reference subjects that are matched include patient age (see page 15 between Table 1 and Table 2).
As for claim 14, Grunert discloses that the second reference subjects have no symptoms (see Example 3 on page 20, “a control group of 22 PDE samples taken from patients without acute peritonitis”).
As for claim 15, Grunert discloses that the plurality of reference FTIR spectra, the average reference FTIR spectra, the plurality of test FTIR spectra, and the average test FTIR spectra comprise second derivative absorbance spectra (see “Spectral preprocessing and analysis” on page 12, “Raw absorbance spectra were preprocessed for the whole spectral range . . . by second derivatives of the original spectra . . .”).
As for claim 16, Grunert discloses, on the first paragraph of page 6, the claimed ranges of the reference and test spectra.
As for claim 21, Grunert discloses pre-processing the plurality of reference FTIR spectra for each of the plurality of samples and the plurality of test FTIR spectra to generate a plurality of pre-processed, reference FTIR spectra for each of the plurality of samples and the plurality of pre-processed, test FTIR spectra, wherein determining the average reference FTIR spectrum of the plurality of reference FTIR spectra for each of the plurality of reference samples comprises determining an average reference FTIR spectrum of the plurality of pre-processed, reference FTIR spectra for each of the plurality of reference samples, and wherein determining the average test FTIR spectrum comprises determining the average test FTIR spectrum of the plurality of pre-processed, test FTIR spectra, optionally wherein pre-processing comprises smoothing, baseline correction, spectral contrast optimization, and/or vector normalization (see paragraphs 3-5 of page 6, which discloses preprocessing both the sample and the reference spectra, and paragraph 5 discloses the optional limitation of vector normalization).
As for claim 23, Grunert discloses that the clustering comprises unsupervised clustering such as Principal Component Analysis (see page 8, paragraphs 2 and 3).
As for claim 25, Grunert discloses, in the best understanding of the examiner, that the average test FTIR spectrum is in the first cluster if a first distance between the average test FTIR spectrum and the first cluster is shorter than a second distance between the average test FTIR spectrum and the second cluster, and wherein the average test FTIR spectrum is in the second cluster if a first distance between the average test FTIR spectrum and the first cluster is longer than a second distance between the average test FTIR spectrum and the second cluster (see the last paragraph of page 12 into page 13, “The linear method of discriminant analysis is applied when the difference between the two classes is expressed by a linear function, whereas the Mahalanobis method (MDA) uses ellipses to define the distances”).
As for claim 26, Grunert discloses that the first distance between the average test FTIR spectrum and the first cluster comprises the first distance between the average test FTIR spectrum and k-nearest neighbors of the first cluster, and wherein the second distance between the average test FTIR spectrum and the second cluster comprises the second distance between the average test FTIR spectrum and k-nearest neighbor of the second cluster (see page 8, paragraph 1, as the description of a k-nearest neighbors algorithm as an example of the claimed clustering step from claim 1 would lead to the claimed limitation being met).
Regarding claim 31, Grunert discloses a system for determining a state of a test subject comprising non-transitory memory (inherent) configured to store executable instructions (inherent as will be seen by the disclosed steps performed below) and an average reference Fourier transform infrared spectroscopy (FTIR) spectrum of a plurality of reference FTIR spectra for each of a plurality of reference samples (see the second full paragraph of page 7, which states that the at least one reference spectrum is stored as sets of data, for the generation of the average spectrum, see step c) in the short description of the invention on page 2, which states that at least one reference spectrum is obtained from at least one reference sample using FTIR as found in step b), and as the reference spectra are obtained in the same manner as the test spectra as found on page 2, steps b) and c), the determination of average reference FTIR spectra is disclosed by the “sample preparation and FTIR spectroscopy” section on pages 11-12, which states that 32 interferograms are obtained and averaged with background subtraction), wherein the plurality of reference samples comprises a plurality of first reference samples obtained from first reference subjects known to be in a first state and a plurality of second reference samples obtained from reference subjects known to be a second state (see the third paragraph of page 4 – “In the first case, the method relies on differences (or similarities) between individual subjects with different physiological and/or pathological states”; see also the fifth paragraph of that pages, stating that the reference sample is related, or preassigned, to a certain clinical parameter, which would be equivalent to a first or second state); and a hardware processor (inherent as per the discussion of a machine learning model in the first paragraph of page 8) in communication with the non-transitory memory, the hardware processor programmed by the executable instructions to perform generating a plurality of test FTIR spectra for a test sample obtained from a test subject (see step b found on page 2; see also the “sample preparation and FTIR spectroscopy” section on pages 11-12, which states that a plurality of test spectra of the test sample are obtained), wherein one or more characteristics of the test subject and the reference subjects are matched (see page 4, paragraph 3, “the method relies on . . . similarities . . . between individual subjects”); determining an average test FTIR spectrum of the plurality of test FTIR spectra for the test sample (the determination of average reference FTIR spectra is disclosed by the “sample preparation and FTIR spectroscopy” section on pages 11-12, which states that 32 interferograms are obtained and averaged with background subtraction); clustering the average reference FTIR spectra of the plurality of reference samples into a first cluster and a second cluster corresponding to the first state and the second state, respectively, in a reduced dimensionality space (this clustering for computing the similarity value is done via one of the methods set forth in paragraphs 1 and 2 of page 8, with further details in the “Unsupervised and supervised chemometrics” section on pages 12-13, with, for example, principal component analysis being a known technique for clustering closely related data points in a reduced dimensionality space); and determining the test subject is in the first state or the second state based on a first distance between the average test FTIR spectrum and the first cluster and a second distance between the average test FTIR spectrum and the second cluster (see step d) on page 2, where a clinical parameter is assigned to the analysis sample based on the similarity value, while the state is determined based on the distance between the clusters as disclosed by the last paragraph of page 12 into page 13, “The linear method of discriminant analysis is applied when the difference between the two classes is expressed by a linear function, whereas the Mahalanobis method (MDA) uses ellipses to define the distances”).
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.
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 3-5 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Grunert et al (WO 2021/037866) in view of Sahu et al (“Characteristic Absorbance of Nucleic Acids in the Mid-IR Region as Possible Common Biomarkers for Diagnosis of Malignancy”).
As for claim 3, Grunert discloses the claimed invention as set forth above regarding claim 1, but fails to disclose that the reference and test samples comprise about 100 cells to about 1000 cells. As taught by Grunert above regarding claim 1, the sample measurement and reference measurements are performed in the same manner.
Sahu discloses a method where FTIR is used to analyze tissue samples for disease diagnosis (see abstract). In the FTIR Microspectroscopy section on page 631, Sahu teaches the measurement of about 100 cells.
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have the samples comprise between 100 and 1000 cells in the method of Grunert as taught by Sahu, the motivation being that Sahu teaches that it is known in the art that an area of about 100 cells is enough of a biopsy in order to perform analysis via FTIR (see FTIR Microspectroscopy, Col. 2, page 631).
As for claim 4, Grunert discloses the claimed invention as set forth above regarding claim 1, but fails to disclose that the sample comprises a tissue sample, wherein the tissue sample is about 10 µm thick.
Sahu discloses a method where FTIR is used to analyze tissue samples for disease diagnosis (see abstract). In the sample preparation section (see Col. 2 of page 630), Sahu discloses that the sample is a tissue, with a thickness of 10 µm.
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to use the method of Grunert to measure samples that are tissues that are about 10 µm as taught by Sahu, the motivation being that the skilled artisan would recognize that tissues from human samples can be analyzed for disease, while the claimed thickness is appropriate to keep the tissues thin enough for IR measurements (see Col. 2 of page 630 in the sample preparation section).
As for claim 5, Grunert discloses the claimed invention as set forth above regarding claim 1, but fails to disclose that the sample comprises surrogate cells such as fibroblasts.
Sahu discloses a method where FTIR is used to analyze tissue samples for disease diagnosis (see abstract). In the sample preparation section (see Col. 1 of page 631), Sahu discloses that the sample includes surrogate cells such as fibroblasts.
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to substitute the sample being measured in Grunert with fibroblasts as per Sahu, the motivation being that surrogate cells such as fibroblasts are able to be manipulated so that comparative measurements can be made (see sections b and c of the sample preparation section in Col. 1, page 631; see also the results in Fig. 4).
As for claim 17, Grunert discloses the claimed invention as set forth above regarding claim 1, but fails to disclose plurality of reference and test spectra are generated from cytoplasm of cells. As taught by Grunert above regarding claim 1, the sample measurement and reference measurements are performed in the same manner.
Sahu discloses a method where FTIR is used to analyze tissue samples for disease diagnosis (see abstract). Sahu discloses on Col. 1 of page 636 that the cytoplasm of cells can be used to generate the FTIR spectra.
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to use the cytoplasm of cells to generate the FTIR spectra in the method of Grunert as taught by Sahu, the motivation being that “cytoplasmic RNA plays a pivotal roles in neoplastic samples and can contribute significantly to the overall nucleic acid signal in normal and abnormal samples. However, the decrease in cytoplasm and increased nuclear volume would also increase the DNA signals compared to the RNA signals. Thus, it is expected that the RNA/DNA ratio would be affected during carcinogenesis” (see Col. 1, page 636 of Sahu).
Claims 7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Grunert et al (WO 2021/037866) in view of Meade et al (2023/0026291).
As for claim 7, Grunert discloses the claimed invention as set forth above regarding claim 1, but fails to disclose that the plurality of reference samples and the test sample comprise fixed cells on slides.
Meade discloses a method where FTIR is used to analyze tissue samples to test for cancer recurrence (see paragraphs 0014-0018 and 0021). Meade discloses that the sample is tissue (which will include cells) that are fixed on slides (see paragraph 0128).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to place the samples of Grunert on slides as taught by Meade, the motivation being that one having ordinary skill in the art would know to place samples on slides to hold the sample in place in order to perform microscopy or microspectroscopy as taught by paragraph 0128 of Meade.
For the below claim, due to the use of “and/or” after the plurality of “wherein” clauses in the claim, the examiner is interpreting all of the “wherein” clauses to be claimed in the alternative, so only one clause needs to be met in order to render unpatentable the entire claim.
As for claim 9, in a continuation of the rejection of claim 7, Meade discloses mounting the cells on calcium fluoride slides; the examiner notes that calcium fluoride is known in the art as an excellent choice for FTIR analysis.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Grunert et al (WO 2021/037866) in view of Shalek et al (2024/0150453).
For the below claim, due to the use of “and/or” after the plurality of “wherein” clauses in the claim, the examiner is interpreting all of the “wherein” clauses to be claimed in the alternative, so only one clause needs to be met in order to render unpatentable the entire claim.
As for claim 24, Grunert discloses the claimed invention as set forth above regarding claim 1, but fails to disclose a Silhouette score of the test sample being determined to be in the first state or the second state is about 0.4 to 0.9.
Shalek is considered analogous art to Grunert as Shalek is concerned with detecting treatment naïve cell states to predict the response of a subject having disease to treatment. Shalek shows that cells that are grouped by clustering have a resolution set by an optimized silhouette score (see paragraphs 0029 and 0030, for example), with an iterative tiered clustering approach used to optimize that score and stop when a specific granularity is reached (see paragraph 0139). Additionally, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or working ranges (here, a score of between 0.4 and 0.9) involves only routine skill in the art. In re Aller, 105 USPQ 233; the specific granularity of Shalek can be seen to meet the claimed silhouette score as a result.
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have a silhouette score of the test sample being determined to be in the first state or the second state in Grunert to be between 0.4 and 0.9 as suggested by Shalek, the motivation being that the skilled artisan would know that the higher a silhouette score is when performing clustering, the more accurate and better grouped that clustering is.
Allowable Subject Matter
Claim 19 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form 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 to claim 19, the prior art of record, taken either alone or in combination, fails to disclose or render obvious the further limitation of claim 17, comprising segmenting the plurality of reference FTIR spectra for each of the plurality of reference samples and the plurality of test FTIR spectra to determine reference FTIR spectra of the plurality of reference FTIR spectra for each of the plurality of reference samples and test FTIR spectra of the plurality FTIR spectra generated from cytoplasm of cells, wherein the segmenting is based on integrated absorbance frequencies between 1670-1630 cm-1, in combination with the rest of the limitations of the above claim.
While the combination of Grunert and Sahu discloses measuring spectra that is generated from the cytoplasm of cells, this combination fails to disclose the claimed segmenting of the reference and test spectra at the specific integrated absorbance frequencies set forth by the instant claim.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. US Pat. 6,620,621 to Cohenford et al. teaches a method for detecting cellular abnormalities using FTIR spectroscopy (see title) where the identification of samples is based on establishing a reference using a representative set of spectra of normal and/or diseased specimens (see abstract). US 2019/0041324 to Foreman et al. teaches a method for identifying or sorting cells according to the FTIR spectrum each cell produces which allows for improved screening of samples that may include cancerous or precancerous cells or other disease states (see abstract).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Michael A. Lyons whose telephone number is (571)272-2420. The examiner can normally be reached Monday - Friday.
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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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/Michael A Lyons/Primary Examiner, Art Unit 2877 January 7, 2026