DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/04/2025 has been entered.
Priority
The present application was filed as a proper National stage (371) entry of PCT application No. PCT/EP2016/076130, filed 10/28/2016, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/247,609, filed 10/28/2015.
Claim status
Claims 1-16 and 19-40 are pending in the application. Claims 1-15 and 25-39 are withdrawn, claims 16, 20, and 40 are amended and claims 17 and 18 are cancelled. Claims 16, 19-24 and 40 are examined below.
Withdraw rejections/objections
The objection to the specification has been withdrawn due to the amendment of the specification.
The rejection of claim 40 under 35 U.S.C. §112(b) has been withdrawn due to the amendment of the claim.
The rejection of claim 20 under 35 U.S.C. §112(d) has been withdrawn due to the amendment of the claim.
Claim Interpretation
Claim term “mid-infrared” has been interpreted in view of its plain meaning in the art, namely 4,000-400 cm-1 (2.5-25 mm). See, e.g., Petrich et al. (doi: 10.1081/ASR-100106156), IDS entered on 5/10/2018) on page 184.
The reference characters recited in the claims ((220), (221), (211), and (231)) have not been considered to affect the scope of the claims. See MPEP 08.01(m).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 16, 19-20, and 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Baunoch et al. (US 2001/0055799 A1, see PTO-892, 04/24/2024) in view of Mazur (2011 Analytical Chemistry, see PTO-892, 04/24/2024), Smith (US 2004/0253649 A1, see PTO-892, 04/24/2024), and Lasch et al. (2003, Analytical Chemistry).
Regarding claims 16 and 40, Baunoch teaches a method of automatically reprocessing a specimen (tissue sample) for microscopic examination, involving fixation of the specimen and preparation of the embedded specimen from the fixed specimen and reprocessing the specimen if there is inadequate fixation (classify fixation state; performing remedial tissue processes if the sample is determined to be inadequately fixed; Baunoch, Abstract, lines 1-9). Baunoch further teaches that the specimen can be a cell, cell suspension, tissue section, or tissue specimen (Baunoch, page 1, paragraph [0007], lines 1-3). Baunoch further teaches that fixation of the specimen involves a fixing agent, such as formalin and an infiltrating medium, such as paraffin wax (Baunoch, page 1, paragraph [0006], lines 1-11; [0043]; Fig. 5). Baunoch further teaches that traditionally if a specimen is not properly processed, such as being inadequately fixed, there are two options: obtain another specimen or reprocess the specimen ((c1) additional fixation; (c2) rejection and obtaining a new sample; Baunoch, page 1, paragraph [0007], lines 6-13).
Baunoch’s methods address this problem of improper specimen processing in an automated manner, with specimen re-processing, including re-fixation, as in claim 16 (c1). The operator can determine if the specimen has been processed properly, and if needed, can reprocess the specimen with a fixing agent (refixing/ additional fixation). See especially [0045], [0058], and Fig. 6A, second page, particularly steps 108 and 110).
Baunoch further teaches that after reprocessing, nuclei from specimen are prepared for DNA analysis using a fluorescent compound (labeling a fixed cellular sample; performing a labeling process on the acceptably fixed tissue sample; Baunoch, page 1, paragraph [0008], lines 6-10). It is noted that the above steps by Baunoch read on a classification “algorithm” in the absence of a specific or limiting definition for this term, and consistent with the plain meaning of this term as referring to a process or set of rules to be followed1, insofar as Baunoch instructs that one would determine specimen processing quality and then decide whether to reprocess the sample or not (e.g., by refixing).
Baunoch differs from the claimed invention in that although Baunoch teaches determining if a sample is adequately fixed, Baunoch is silent as to the technique used for determining the status of fixation. While Baunoch teaches determining that a sample has inadequate fixation or is otherwise not properly processed and needs to be reprocessed, the reference fails to specifically teach determining fixation quality (e.g., that the sample is over-fixed or under-fixed) using mid-infrared spectroscopy. More particularly, Baunoch fails to teach identifying a fixation signature in a mid-infrared spectroscopy spectrum of the fixed cellular sample (test spectrum), applying a classification or quantification algorithm to the fixation signature in the test spectrum to determine the fixation state of the fixed cellular sample, classified as under-fixed, over-fixed, or acceptably fixed. Baunoch further fails to teach a trained classification algorithm, which is trained using one or more reference MIR spectra. Baunoch further fails to teach that the trained classification algorithm is one of a trained unsupervised or trained supervised classification algorithm, or a trained quantification algorithm (claim 40).
Mazur teaches infrared spectroscopy (spectral cytopathology) used to interrogate biochemical components of cellular samples. Mazur further teaches studying the effects of fixation protocols (different fixative solutions, varying fixation exposure times) and further teaches that fixative and duration or sample storage contribute to minor spectral changes (Mazur, entire selection, page 1259, see Abstract). Mazur further teaches studying the effects of fixation such as by SurePath or buffered formalin solution (Mazur, page 1259, 4th paragraph, lines 1-3). Mazur further teaches applying mean spectra, second-derivative spectra (fixation signature), and PCA plots (classification algorithm). Mazur further teaches that principal component analysis of the data is able to distinguish very small spectral changes, for example cells fixed by different methods (Mazur, page 1263, lines 1-5).
Mazur further teaches that that fixation methods do not cause strong changes in spectral patterns (Mazur, page 1262, paragraph 6, lines 12-13), although some spectral signatures could be distinguished with different fixation methods (Figs. 4-5, pages 1262-1263) or with varying exposure times (Fig. 7A, page 1264). Mazur further teaches that certain methods of fixation may be acceptable in spectral cytopathology, but unacceptable in classical cytology (Mazur, page 1259, 3rd paragraph, lines 7-9). Mazur further teaches that infrared spectroscopy is an ideal technique for diagnostics since it is a label-free method which requires minimal sample preparation and since it is nondestructive, cells can be stained following standard protocols subsequent to infrared data acquisition (Mazur, page 1259, see 2nd paragraph). In summary, Mazur indicates that chemical changes produced by fixation can be investigated using infrared spectroscopy. Further, although Mazur refers to “infrared” generally and does not specify “mid-infrared,” Mazur investigated the spectral region from 1800-1000 cm-1 which is within the mid-IR range (4,000-400 cm-1; see “Claim Interpretation” above). Mazur at Figs. 4-8.
Smith teaches that fixation preserves tissue architecture, cell cytology, and their antigens. Smith further teaches that under-fixation can cause false-positive staining, and over-fixation can cause antigen ‘denaturation’, changing its 3D structure (Smith, page 33-34, see paragraph [0298]).
Lasch teaches applying Fourier transform infrared spectroscopy and advanced methods of pattern analysis to identify biochemical alterations in serum (Lasch, page 6673, 4th paragraph, lines 1-4). Lasch further teaches a trained classification algorithm (claim 40) using infrared spectra of bovine sera from BSE-positive, healthy controls and animals suffering from viral or bacterial infections (Lasch, page 6673, Abstract, lines 11-15). Lasch further teaches infrared absorbance spectra in the mid-infrared range (Lasch, page 6676, see Figure 1). Lasch further teaches classification accuracies of up to 93.5% (Lasch, page 6677, last paragraph, lines 5-6).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have used the method of Mazur of identifying a fixation signature in mid-infrared spectroscopy in the method of Baunoch, because of the teaching of Mazur, that the method can detect very small spectral changes for example caused by differences in fixation and further because it is label free and nondestructive and the samples can be stained following standard protocols subsequent to infrared data acquisition. It would have further been obvious to use mid-infrared spectroscopy, because it was known to detect small changes caused by differences in fixation and because of the teaching of Smith that over-fixation can cause denaturation of the antigen.
One of ordinary skill in the art would have been motivated to incorporate the known technique of Mazur of using mid-IR spectroscopy to investigate chemical changes associated with fixation into the methods of Baunoch as this would assist with the goal of Baunoch of providing means of automated sample reprocessing as necessary depending on the determined quality of the sample processing. That is, the ordinary artisan would have found it obvious to investigate fixed samples using mid-IR rather than (or as a supplement to) the operator having to manually determine sample processing quality.
It would have further been obvious to apply the classification algorithm of Lasch in the method of Mazur, of investigating spectral signatures of different fixation methods or varying exposure times, because of the teaching of Lasch the combination of infrared spectroscopy and the classification algorithm results in accuracies of up to 93.5% in classifying different samples.
The ordinary artisan would have a reasonable expectation of success in applying the algorithm of Lasch to the data of Baunoch, because Lasch, as in Baunoch collects mid-infrared spectroscopy data and classifies three different samples.
Regarding claim 19, Baunoch and the cited art above teach a method substantially as claimed.
Baunoch does not teach a difference in the fixation signature is a change in amplitude and/or peak position between 1615 cm-1 and 1640 cm-1 in a second derivative spectrum.
Mazur teaches Infrared spectroscopy used to interrogate biochemical components of cellular samples and multivariate statistical methods such as principal component analysis to analyze and diagnose spectra. Mazur further teaches studying the effects of fixation protocols and further teaches that fixative and duration of sample storage contribute to minor spectral changes (Mazur, page 1259, see Abstract). Mazur further teaches that the largest differences between two fixatives, comprising formalin, can be seen in the amide I shoulder at 1635 cm-1 (Mazur, page 1264, 3rd paragraph, lines 2-3 and page 1262, Figure 4, arrow). Mazur further teaches that in general, second-derivative spectra are more sensitive toward the detection of small spectral changes (Mazur, page 1262, lines 7-9).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Baunoch to interrogate changes in amplitude at 1635 cm-1 (between 1615 cm-1 and 1640 cm-1), because of the teaching of Mazur that that is where the largest effect of fixation can be seen. It would have further been obvious to assess the second derivative spectrum, because of the teaching of Mazur that in general these spectra are more sensitive toward the detection of small spectral changes and because the changes measured due to different fixatives are small.
The ordinary artisan would have a reasonable expectation of success, because Mazur as well as the prior art above teaches the measurement of the effect of fixation on formalin treated tissue.
Regarding claim 20, Baunoch and the cited art above teach a method substantially as claimed.
Baunoch fails to teach a difference in the fixation signature is a change in amplitude and/or peak position between 1615 cm-1 and 1640 cm-1 in a principal component plot.
Mazur teaches Infrared spectroscopy used to interrogate biochemical components of cellular samples and multivariate statistical methods such as principal component analysis to analyze and diagnose spectra. Mazur further teaches studying the effects of fixation protocols and further teaches that fixative and duration of sample storage contribute to minor spectral changes (Mazur, page 1259, see Abstract). Mazur further teaches that the largest differences between two fixatives, comprising formalin, can be seen in the amide I shoulder at 1635 cm-1 (Mazur, page 1264, 3rd paragraph, lines 2-3 and page 1262, Figure 4, arrow). Mazur further teaches that principal component plots depict individual, rather than averaged cell spectra to allow an assessment of the variability of spectra and the magnitude of spectral changes in each of the experiments (Mazur, page 1261, 2nd column, lines 8-11).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have interrogated changes in amplitude at 1635 cm-1 (between 1615 cm-1 and 1640 cm-1), because of the teaching of Mazur that that is where the largest effect of fixation can be seen, as discussed previously above. It would have further been obvious to use principal component analysis, because of the teaching of Mazur that the individual plots depict individual, rather than averaged cell spectra to allow an assessment of the variability of spectra and the magnitude of spectral changes.
The ordinary artisan would have a reasonable expectation of success, because Mazur as well as the prior art above teaches the measurement of the effect of fixation on formalin treated tissue.
Claims 21, 23, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Baunoch et al. in view of Mazur, Smith, and Lasch as applied to claim 16 above, and further in view of Bird et al. (US 2001/0055799A1, see PTO-892, 04/24/2024).
Regarding claim 21, Baunoch and the prior art above teaches a method substantially as claimed.
Baunoch teaches that the data is acquired using an imaging infrared spectrometer.
Baunoch fails to teach that the test spectrum is obtained by quantum cascade laser based microscopy.
Bird teaches analyzing biological specimens by infrared spectral imaging to provide a medical diagnosis (Bird, see Abstract). Bird further teaches that the sample sections were cut from formalin fixed paraffin embedded cell blocks (Bird, page 51, paragraph [0194], line 1). Bird further teaches that the infrared data acquisition may be carried out with tunable laser-based imaging instruments, such as Fourier transform infrared imaging microspectrometers or quantum cascade devices (Bird, page 25, paragraph [0108], lines 1-3).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have used a quantum cascade laser to acquire the data as a simple substitution of one art-recognized data acquisition method over another, both known for acquiring mid-infrared spectroscopy data in formalin fixed, paraffin-embedded samples.
The ordinarily skilled artisan would have been motivated to do so, because both methods perform the same function in substantially the same way and produce substantially the same result of detecting mid-infrared spectra in formalin fixed, paraffin embedded samples.
The ordinary artisan would have a reasonable expectation of success, because both Baunoch and Bird acquire the same type of data from the same type of sample, namely infrared spectra from formalin fixed, paraffin embedded tissue.
Regarding claims 23 and 24, Baunoch and the prior art above teaches a method substantially as claimed.
Baunoch teaches that tissue sections are formalin fixed and paraffin-embedded (Baunoch, page 1, paragraph [00063-11], lines 5-6).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Baunoch, Mazur, Smith SJ, Lasch, and Bird as applied to claim 21 above, and further in view of Kröger et al. 2014 Journal of Biomedical Optics, see PTO-892, 04/24/2024.
Regarding claim 22, Baunoch and the cited art above teach a method substantially as claimed.
Bird does not teach that the test spectrum is obtained in 30 minutes or less.
Kröger teaches quantum cascade laser-based hyperspectral imaging of biological tissue (Kröger, see title). Kröger further teaches rapid image acquisition of an unstained tissue section within 5 min with diffraction limited spatial resolution and further teaches that this reduces acquisition time by more than one or three orders of magnitude compared to standard Fourier transform infrared imaging or mapping (Kröger, see Abstract). Kröger further teaches that data acquisition using Fourier transform infrared mapping can take up to several days, which limits the practical use of the technique (Kröger, page 1, 2nd paragraph, lines 5-10). Kröger further teaches that the sample is perfusion fixed in 4% paraformaldehyde and paraffin-embedded (Kröger, page 2, ‘2.1 Sample Preparation”, lines 1-3).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Baunoch and the cited art above with the method of Kröger in order to obtain a test spectrum in 5 minutes, because of the teaching of Kröger that long acquisition times limit the practical application of infrared spectroscopy.
The ordinary artisan would have a reasonable expectation of success, because the sample examined was a formaldehyde fixed paraffin embedded specimen, as where the specimen of the prior art.
Response to Arguments
Applicant's arguments filed 02/04/2025 have been fully considered but they are not persuasive. Applicant argues starting on page 8 regarding the rejection under 35 U.S.C. §103 that the references as combined do not teach all the limitations of the claimed invention, particularly applicant argues that for example it does not provide for a trained classification algorithm that is trained using a plurality of reference MIR spectra derived from a plurality of fixed training tissue samples, wherein each of the plurality of fixed training tissue samples have been fixed with a chemical fixative and wherein at least two of the fixed training tissue samples of the plurality of fixed training tissue samples have different known fixation quality states. In detail applicant argues that Baunoch is directed to a system that automatically reprocesses tissue samples for microscopic examination and that the apparatus of Baunoch is designed to automatically reprocess a specimen from an infiltrating medium to an aqueous fluid. Applicant argues that Baunoch does not disclose or suggest applying a trained classification algorithm to identify a fixation signature in a test MIR spectrum and does not disclose or suggest the utilization of a trained classification algorithm that is trained using a plurality of reference MIR spectra derived from a plurality of fixed training tissue samples. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Baunoch is not relied on to teach a trained classification algorithm to identify a fixation signature in a test MIR spectrum that is trained using a plurality of reference MIR spectra derived from a plurality of fixed training tissue samples. Baunoch is relied on to teach a method of labeling a fixed test tissue sample and applying an algorithm to identify improper processing of specimen for example those with inadequate fixation. Therefore the argument is not persuasive.
Applicant further argues starting on page 10 that Mazur, Smith, or Lasch cure the deficiency of Baunoch. Applicant argues that Mazur is directed to fixation induced changes in samples prepared with different methods of fixation such as formalin or a mixture of alcohols or rapid drying, but does not disclose a trained classification algorithm. However, Mazur teaches spectral changes between different modes of fixation and by altering the length of time in fixation. Mazur further teaches a fixation signature and a classification algorithm that allows for distinction of varying exposure times. As such Mazur indicates that chemical changes produced by fixation can be investigated using infrared spectroscopy. Mazur is not relied on to teach a trained classification algorithm. Similarly, Smith is also not relied on to teach a trained classification algorithm for use in identifying the fixation state of a sample. Therefore the argument is not persuasive.
Applicant further argues that Lasch does not disclose or suggest a trained classification algorithm that is trained using a plurality of reference MIR spectra derived from a plurality of fixed training tissue samples, wherein each of the plurality of fixed training tissue samples that have different known fixation quality states. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Lasch is relied on to teach a trained classification algorithm using infrared spectra trained on multiple control groups. As explained previously in detail above, it would have been obvious to one having ordinary skill in the art to apply a trained classification algorithm as taught by Lasch to the method of Baunoch in view of Mazur which uses mid-infrared spectroscopy to investigate chemical changes associated with fixation. Mazur teaching the use of infrared spectroscopy to interrogate biochemical components of cellular samples for example changes spectral changes due to the duration of fixation using SurePath or buffered formalin solution. As such, Mazur teaches tissue samples with different known fixation quality states and Lasch teaches a trained fixation algorithm that would be obvious to have applied to Baunoch in view of Mazur. Therefore the argument is not persuasive.
Regarding the argument starting on page 11 that Lasch teaches serum samples and not tissue samples, see as discussed previously in detail above, Lasch is not relied on to teach the sample type, but rather is relied on to teach the trained classification algorithm applied to the method of Baunoch in view of Mazur. Baunoch teaches that the specimen is a tissue sample. Therefore the argument is not persuasive.
Applicant further argues that Lasch teaches bovine samples that are not fixed and therefore cannot meet the claim reciting “one or more fixed training samples have been fixed with a chemical fixative” and that Lasch does not describe any step where the bovine serum is incubated with a chemical fixative and therefore Lasch cannot disclose or suggest the training of a classification algorithm as required by claim 16 and therefore the combined references would not disclose or suggest all of the limitations of the claimed invention. As explained previously in detail above, the sample type is taught by Baunoch in view of Mazur, Lasch teaches a trained classification algorithm that would be obvious to have been applied to the method of Baunoch in view of Mazur. Baunoch teaches a method of automatically reprocessing a specimen, which can be a tissue sample, for microscopic examination, comprising reprocessing the specimen if there is inadequate fixation. Mazur teaches using infrared spectroscopy to study the effect of fixation protocols such as samples with differing fixation times and an algorithm to detect spectral changes for examples between samples fixed by different methods. As such, Baunoch in view of Mazur teaches tissue samples incubated with a chemical fixative that are analyzed using an algorithm and teaches that different sample types can be differentiated based on the fixation protocol. Lasch teaches that a trained classification algorithm has very high classification accuracies which is desirable when determining which samples should be reprocessed in the method of Baunoch. As such the combination of the art does teach all elements of the claim. Therefore the argument is not persuasive.
Applicant further argues that the rejection of the remaining claims should also be withdrawn based on the arguments on pages 8-11. However, the arguments are not persuasive and the rejection is maintained.
For the reasons mentioned above, the arguments are not persuasive.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEFANIE J KIRWIN whose telephone number is (571)272-6574. The examiner can normally be reached Monday - Friday 7.30 - 4 pm.
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1600
1 See, e.g., definition of algorithm at https://www.merriam-webster.com/dictionary/algorithm: “broadly: a step-by-step procedure for solving a problem.”
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