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 Arguments
The amendments to claims 21, 24, and 25 made in the June 16, 2026 amendment are sufficient to overcome the claim objections made to those claims in the previous Office action mailed January 16, 2026. These objections are hereby withdrawn. Upon further consideration, however, new objections are made to claims 19 and 31 to clear up claim language. These objections can be found below.
The amendments to claims 4, 5, 25, and 26 made in the June 16, 2026 amendment are sufficient to overcome the rejections of these claims made under 35 USC 112(b). These rejections are hereby withdrawn.
The amendment to claim 1 is sufficient to overcome the 35 USC 102 rejection of that claim and certain dependent claims as being anticipated by Grunert et al (WO 2021/037866). However, a new ground of rejection is made under 35 USC 103 using a combination of Grunert, the newly discovered reference “Potential of infrared microscopy to differentiate between dementia with Lewy bodies and Alzheimer’s diseases using peripheral blood samples and machine learning algorithms” by Salman et al, and the previously used reference “Characteristic Absorbance of Nucleic Acids in the Mid-IR Region as Possible Common Biomarkers for Diagnosis of Malignancy” by Sahu et al which was used in combination with Grunert to reject at least original claim 5 in the previous Office action.
Regarding the comments made about Sahu on page 11 of the remarks, the examiner does not find them persuasive. First, the claim only requires “surrogate cells obtained from a test subject”. There is no requirement that these cells be skin cells as found in paragraph 0066. That paragraph does not give a special definition of skin cells as surrogate cells in order to limit the surrogate cells in the claim to be skin cells. Indeed, paragraph 0066 states that prediction can use other accessible cell types such as buccal cells. That being said, MPEP 2111 states that reading a claim in light of the specification is a quite different thing from reading limitations of the specification into a claim to thereby narrow the scope of the claim. See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997). Also, as in MPEP 2111.01, "Though understanding the claim language may be aided by explanations contained in the written description, it is important not to import into a claim limitations that are not part of the claim. For example, a particular embodiment appearing in the written description may not be read into a claim when the claim language is broader than the embodiment." Superguide Corp. v. DirecTV Enterprises, Inc., 358 F.3d 870, 875, 69 USPQ2d 1865, 1868 (Fed. Cir. 2004). As a result, there is no requirement that the surrogate cells found in claim 1 be skin cells as in paragraph 0066.
Additionally, the argument that there would be no motivation to combine Sahu’s cancer biopsy sample to arrive at neurological disease determination is not persuasive. Applicant argues that paragraph 0004 of the specification states “at the time of effective filing, ‘there is currently no method or biomarker’ to predict neurodegenerative disease”. However, this argument is not persuasive for a couple of reasons. First, the claims are drawn to determining a neurological disease, not predicting a neurological disease. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e that there is no method or biomarker to predict neurodegenerative disease) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Second, if applicant is attempting to show that the claimed method produces unexpected results as a way to show the claimed invention is not obvious over the prior art, evidence must be provided to show such results (see MPEP 716.02). Finally, the examiner notes that Sahu is being relied upon only for the benefits of using surrogate cells such as fibroblasts in comparative measurements. As will be shown below, the Salman reference is being used to show that FTIR can indeed be used to differentiate between different types of neurological diseases, and the prior art generally shows that FTIR can be used to ascertain multiple types of diseases ranging from cancer to cardiovascular disease to neurological disease (see claims 27 and 29 of WO 2018/112460 to Farokhzad et al, as an example).
Claim Objections
Claims 19 and 31 are objected to because of the following informalities:
As for claim 19, in line 5 of the claim, the phrase “of the plurality FTIR spectra” should be amended to read “of the plurality of FTIR spectra”.
As for claim 31, in lines 14-15 of the claim, the phrase “of the plurality FTIR spectra” should be amended to read “of the plurality of FTIR spectra”.
Appropriate correction is required.
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 1, 3-5, 11-17, 23, 23, 25, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Grunert et al (WO 2021/037866) in view of Salman et al et al (“Potential of infrared microscopy to differentiate between dementia with Lewy bodies and Alzheimer’s diseases using peripheral blood samples and machine learning algorithms”) and in further of Sahu et al (“Characteristic Absorbance of Nucleic Acids in the Mid-IR Region as Possible Common Biomarkers for Diagnosis of Malignancy”).
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).
Grunert fails to disclose that the method is for determining a neurological disease state of a test subject by having the first and second state be with respect to a neurological disease in a test subject, and that the test sample comprises surrogate cells.
Regarding determining a neurological disease state of a test subject, Salman discloses using mid-infrared spectroscopy (such as FTIR – see section 2.2) in combination with machine learning for the determination of neurological disease. Salman looks to identify two different neurological disease states – Alzheimer’s disease and dementia with Lewy bodies (see the significance section of the abstract) in combination with a control group (see the approach section of the abstract along with section 2.1). These two different neurological disease states would be considered the first and second state found in the instant claim. As stated above, these samples are all tested using FTIR and their spectra are compared via machine learning (see sections 2.2 and 2.3).
Regarding the surrogate cells, 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.
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 FTIR based method of Grunert to determine a neurological disease state of a test subject using reference spectra that come from a first state and a second state with respect to a neurological disease in a test subject as taught by Salman, and to substitute the sample being measured in Grunert with fibroblasts as per Sahu, the motivation being that Salman shows the applicability of FTIR in being able to accurately identify and differentiate between different types of neurological diseases in a noninvasive manner in order to avoid misdiagnosis of, for example, Alzheimer’s disease or dementia with Lewy bodies or vice versa in order to provide better treatment options, particularly in the early stages of the diseases (see Salman abstract, particularly the significance, aim, results, and conclusions sections), while Sahu teaches that surrogate cells such as fibroblasts have the benefit of being 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 3, Grunert, Salman, and Sahu discloses the claimed invention as set forth above regarding claim 1, but the combination discussed therein 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, 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, Salman, and Sahu discloses the claimed invention as set forth above regarding claim 1, but the combination discussed therein fails to disclose that the test 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 measure samples that are tissues that are about 10 µm, 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, Sahu (see Col. 1 of page 631) discloses that the surrogate cells are fibroblasts.
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, the combination of Grunert and Salman, through Grunert, discloses that the first state is non-responsiveness to a treatment of the neurological disease, and wherein the second state is responsiveness to the treatment of the neurological 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).
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 17, Grunert, Salman, and Sahu discloses the claimed invention as set forth above regarding claim 1, but the combination disclosed therein 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, 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” (see Col. 1, page 636 of Sahu).
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 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, or wherein the average test FTIR spectrum is in the second cluster if the first distance between the average test FTIR spectrum and the first cluster is longer than the 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 a 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 a 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).
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 Salman et al et al (“Potential of infrared microscopy to differentiate between dementia with Lewy bodies and Alzheimer’s diseases using peripheral blood samples and machine learning algorithms”) and Sahu et al (“Characteristic Absorbance of Nucleic Acids in the Mid-IR Region as Possible Common Biomarkers for Diagnosis of Malignancy”) and in further view of Meade et al (2023/0026291).
As for claim 7, the combination of Grunert, Salman, and Sahu 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, Salman, and Sahu 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 Salman et al et al (“Potential of infrared microscopy to differentiate between dementia with Lewy bodies and Alzheimer’s diseases using peripheral blood samples and machine learning algorithms”) and Sahu et al (“Characteristic Absorbance of Nucleic Acids in the Mid-IR Region as Possible Common Biomarkers for Diagnosis of Malignancy”) and in further 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, the combination of Grunert, Salman, and Sahu 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, Salman, and Sahu 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.
Claim 31 is allowed in view of the prior art.
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.
As to claim 31, the prior art of record, taken either alone or in combination, fails to disclose or render obvious a system for determining a state of a test subject, the system comprising, among other essential features, a hardware processor in communication with the non-transitory memory that performs, among other functions, segmenting the plurality of test FTIR spectra to determine test FTIR spectra of the plurality of 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.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. “FTIR Spectroscopy – A Potential Tool to Identify Metabolic Changes in Dementia Patients” by Correia et al. discloses using FTIR to analyze AD biomarkers using multivariate analysis of spectral data to improve early Alzheimer’s Disease diagnosis and treatment (see abstract).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 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 July 29, 2026
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