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 .
Claims 1-23 are pending in this application.
Election/Restrictions
Applicant's election with traverse of Group I (Claims 1-18) in the reply filed on 05/12/2026 is acknowledged. The traversal is on the ground(s) that the sub-division of the samples of Knebel would allegedly be contrary to the teachings of the reference and the ordinary artisan would not have found obvious doing so. Applicant alleges that the reference images living whole biological samples and division of a larger sample would not result in discrete living specimens. Applicant argues that “sphericity” is not a result effective variable as Li merely describes that sphericity is a shape parameter (Remarks, Pg. 2, Lines 10-25 and Pg. 3, Lines 1-12). This is not found to be persuasive because division of a larger biological sample (such as a tissue culture sample) into smaller samples of the same living tissue or cells thereof would still result in discrete, living specimens which are just smaller than the original sample.
As discussed in the prior action, one of ordinary skill in the art would recognize that the sphericity and volume of a sample is a result-effective optimizable variable. Li et al. teaches that "sphericity" is a parameter which can be applied to non-spherical shapes (Pg. 97, Abstract and Pg. 98, Table 1) while volume is dependent on the size or amount of space a sample occupies. This is motivation for someone of ordinary skill in the art to practice or test the sample sphericity and volume widely to find those that are functional or optimal to provide a suitable sample for imaging which then would be inclusive or cover the instantly claimed values. Claims 19-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 05/12/2026.
Claims 1-18 were examined on their merits.
The requirement is still deemed proper and is therefore made FINAL.
Specification
The use of the term CULTREX™, MATRIGEL™ and JELLAGEL™ which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 17-18 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.
Claim 17 recites the limitation "a composite image". There is insufficient antecedent basis for this limitation in the claim as forming a composite image is never positively recited in the preceding claims. Claim 18 is rejected as being dependent upon rejected Claim 17 and for failing to remedy the lack of antecedence.
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.
Claims 1, 2, 3, 4 and 7 are rejected under 35 U.S.C. § 103 as being unpatentable over Knebel et al. (US 2016/0153892 A1), cited in the IDS, in view of Li et al. (2012), of record.
Knebel et al. teaches embedding a plurality of samples into a discrete entity/sub-holders (embedding medium) and imaging the embedded samples (Fig. 2-3 and Pg. 6, Paragraphs [0079]-[0083]);
and wherein the samples may be biological samples (Pg. 2, Paragraph [0020]), and reading on Claims 1,
wherein the embedding medium may be an agarose polymer hydrogel (Pg. 6, Paragraph [0081]), and reading on Claim 2;
wherein each of the sub-holders can be cylindrical or cube shaped and the samples are ovoid in shape (Figs. 2-3);
and wherein the embedding medium (discrete entity) is a liquid (Pg. 6, Paragraph [0079]), and reading on Claim 4.
The teachings of Knebel et al. were discussed above.
Knebel et al. did not teach wherein a biological sample is divided to attain the plurality of samples, as required by Claim 1;
wherein the sub-holders are spherical or spheroidal in shape, as required by Claim 3;
or wherein each of the samples have a cuboid shape, as required by Claim 7.
It would have been obvious to those of ordinary skill in the art to modify the method of Knebel et al. of embedding and imaging multiple discrete samples to provide the plurality of samples by dividing a single initial biological sample because there are only a finite number of ways to attain a plurality of samples, either sub-dividing a larger sample or providing a plurality of separate unique samples. Those of ordinary skill in the art would have been motivated to make this modification in order to obtain multiple sub-samples from a larger whole which can then easily be imaged. There would have been a reasonable expectation of success in making this modification because Knebel et al. teaches embedding and imaging multiple samples and those samples can only be obtained in a few ways.
While the Knebel reference does not specifically teach the limitations of Claim 1, that each sample part has a sphericity of at least 0.4 and has a volume in the range of 1000 µm³ to 27 mm³, one of ordinary skill in the art would recognize that the sphericity and volume of a sample is a result-effective optimizable variable.
Li et al. teaches that "sphericity" is a parameter which can be applied to non-spherical shapes (Pg. 97, Abstract and Pg. 98, Table 1) while volume is dependent on the size or amount of space a sample occupies. This is motivation for someone of ordinary skill in the art to practice or test the sample sphericity and volume widely to find those that are functional or optimal to provide a suitable sample for imaging which then would be inclusive or cover the instantly claimed values. Absent any teaching of criticality by the Applicant concerning the sphericity and volume of a sample, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B). Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain a desired size and shaped sample. There would have been a reasonable expectation of success in making these modifications because the Knebel reference is drawn to the embedding and imaging of biological samples and Li et al. teaches these samples will have an intrinsic sphericity as well as volume.
With regard to Claims 3 and 7, it would have been further obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Knebel et al. and Li et al. of embedding and imaging multiple discrete ovoid samples into cylindrical or cuboid sub-holders because changing the shape of an element is prima facie obvious in the absence of evidence that the claimed shape is critical. See the MPEP at 2144.04, IV. B.
Those of ordinary skill in the art would have been motivated to make this modification in order to prepare a sample and sub-holder having the artisan desired shape. There would have been a reasonable expectation of success in making this modification because the Knebel already teaches that the sub-holders can be different shapes and the samples have a certain shape, therefore the alteration thereof could be reasonably expected to be performed in the absence of any evidence to the contrary.
Claims 1, 2, 3, 4, 5, 6 and 7 are rejected under 35 U.S.C. § 103 as being unpatentable over Knebel et al. (US 2016/0153892 A1), cited in the IDS, in view of Li et al. (2012), of record, as applied to Claims 1, 2, 3, 4 and 7 above, and further in view of Loboda (US 2016/0194590 A1).
The teachings of Knebel et al. and Li et al. were discussed above.
Neither reference taught a method wherein the sample is divided into a plurality of samples by a rotating cutter knife wheel, as required by Claims 5 and 6.
Loboda teaches that biological material/tissue can be separated into discrete areas by cutting the tissue into sections (Pg. 6, Paragraphs [0060]-[0061]) and,
wherein in certain applications it may be desirable to focus analysis on one or more specific areas of a tissue or cell smear or to target individual cells from a cell sample applied as a thin layer. Moreover, a user may also want to obtain an optical or other image of the tissue or a cell smear or the cells spreads over the carrier prior to the analysis by imaging mass cytometry or imaging mass spectrometry, in order, for example, to correlate the mass cytometry or mass spectrometry results with cellular or morphological structure. Also, by taking the optical image one will be able to record an image over a large area quickly and then identify the areas of interest that require in-depth characterization by imaging mass cytometry or imaging mass spectrometry”.
and,
“In certain embodiments, cutting a tissue sample into subsections involves laser cutting or mechanical cutting. In certain embodiments it is desirable to make mechanical cuts by operating a rotating cutting wheel with multiple cutting zones along the circumference”.
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Knebel et al. and Li et al. of embedding and imaging multiple subdivided biological samples with the method of Loboda of cutting a biological sample into subsections by cutting with a rotating cutting wheel because the multiple biological samples of Knebel are not limited solely to whole samples and Loboda provides a specific means for dividing a biological sample to obtain multiple biological samples.
Those of ordinary skill in the art would have been motivated to make this modification because Loboda teaches the technique is applicable when it is desired to focus analysis on one or more specific areas of a tissue or cell smear or to target individual cells from a cell sample applied as a thin layer. There would have been a reasonable expectation of success in making this modification because all of the references are reasonably drawn to the same field of endeavor, that is, the analysis of biological samples.
Claims 1, 2, 3, 4, 7 and 8-10 are rejected under 35 U.S.C. § 103 as being unpatentable over Knebel et al. (US 2016/0153892 A1), cited in the IDS, in view of Li et al. (2012), of record, as applied to Claims 1, 2, 3, 4 and 7 above, and further in view of Fuchs (WO 2014/172530 A1).
The teachings of Knebel et al. and Li et al. were discussed above.
Neither reference taught a method wherein images of the embedded samples are assembled into a composite image, as required by Claim 8;
wherein the assembling comprises stitching the images of the embedded parts to generate the composite image, as required by Claim 9;
or wherein the assembling comprises combining the images based on location information of each embedded sample part within the sample, as required by Claim 10.
Fuchs teaches a simple and reliable method for generating a composite image from multiple adjacent sub-images by stitching the sub-images together to form a composite image in the image processing operation is performed using an optical pattern that is generated by means of a pattern means. The pattern provides adequate optical information, so that the position of the sub-images in relation to each other can be reliably determined by means of the properties of the pattern, such as its location in the sub-images (Pg. 2, Lines 9-16);
wherein the sample can be a biological sample (Pg. 4, Lines 30-32).
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Knebel et al. and Li et al. of embedding and imaging multiple subdivided biological samples with the method of Fuchs of forming a composite image from multiple sub-images because this would allow the imaging of the sub-divided samples as well as the whole sample from which they were derived. Those of ordinary skill in the art would have been motivated to make this modification because this would provide an image of both the whole and the parts of the imaged biological sample. There would have been a reasonable expectation of success in making this modification because at least the Knebel and Fuchs references are reasonably drawn to the same field of endeavor, that is, the image analysis of biological samples.
Claims 1, 2, 3, 4, 7, 12, 13, 14 and 15 are rejected under 35 U.S.C. § 103 as being unpatentable over Knebel et al. (US 2016/0153892 A1), cited in the IDS, in view of Li et al. (2012), of record, as applied to Claims 1, 2, 3, 4 and 7 above, and further in view of Seppo et al. (US 2015/0050650 A1).
The teachings of Knebel et al. and Li et al. were discussed above.
Neither reference taught a method wherein at least one sample part
contained by the respective discrete entity is analyzed by molecular biology
techniques comprising at least one of in particular, proteomic, metabolomic, transcriptomic and/or genomic analysis, as required by Claim 12;
wherein analysis data generated by the molecular biology techniques, comprising at least one of proteomic, metabolomic, transcriptomic and/or genomic analysis, is superimposed on the on a composite image at the location of the respective sample part within the sample, as required by Claim 13;
wherein each sample part comprises a marker, as required by Claim 14;
or wherein the marker is associated with location information, as required by Claim 15.
Seppo et al. teaches a method wherein an image is generated of a region of interest in a biological sample treated with a first protocol and a second image of the region after treatment with a second protocol and the immunofluorescent detection of a target protein or at least one target nucleic sequence (Pg. 20, Claim 1);
and wherein a composite image is generated including at least the regions of interest from the first and second images and wherein generating of the composite image comprises registering locations of selected signals (markers) obtained during the generation of the first image with locations of selected signals obtained during the generation of the second image (Pg. 20, Claims 25-26).
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Knebel et al. and Li et al. of embedding and imaging multiple subdivided biological samples with the method of Seppo et al. of forming a composite image of proteomic and/or genomic data which is correlated with the location of detected signals (e.g. superimposed) because this would allow the protein and/or genomic data images to be correlated with the location within the sample that the signals were obtained. Those of ordinary skill in the art would have been motivated to make this modification because this would provide a composite image of both the presence and location of protein and/or genomic signals in the sub-samples. There would have been a reasonable expectation of success in making this modification because at least the Knebel and Seppo references are reasonably drawn to the same field of endeavor, that is, the image analysis of biological samples.
Claims 1, 2, 3, 4, 7, 12, 13, 14, 15, 16, 17 and 18 are rejected under 35 U.S.C. § 103 as being unpatentable over Knebel et al. (US 2016/0153892 A1), cited in the IDS, in view of Li et al. (2012), of record, and Seppo et al. (US 2015/0050650 A1), as applied to Claims 1, 2, 3, 4, 7, 12, 13, 14 and 15 above, and further in view of Alexander et al. (US 2020/0011775 A1).
The teachings of Knebel et al., Li et al. and Seppo et al. were discussed above.
None of the above references taught a method wherein at least one of the sample part contained by the respective discrete entity is dissociated into a plurality of
single cells that are individually analyzed by molecular biology techniques, comprising at least one of microscopic, cytometric, proteomic, transcriptomic, metabolomic and/or genomic analysis, as required by Claim 16;
wherein single cell analysis data generated by the molecular biology techniques, comprising at least one of microscopic, cytometric, proteomic, transcriptomic, metabolomic and/or genomic analysis, is superimposed on a composite image of the embedded sample parts at a location of the respective single cell within the sample, as required by Claim 17;
or wherein the location of the respective single cell within the sample is determined by tracking the origin of the respective single cell from one of the sample parts and by correlating levels of molecular markers determined in the respective sample part with levels of molecular markers determined in the respective single cell, as required by Claim 18.
Alexander et al. teaches wherein a biological sample is dissociated into discrete/individual cellular particles which may be cells (Pg. 1, Paragraph [0004]) and wherein the cellular particles are assayed for an RNA (genomic) biomarker or a protein (proteomic) biomarker (Pg. 1, Paragraph [0008]) and wherein flow cytometry analysis may be used to analyze the genomics or proteomics of a specific cell population (Pg. 16, Paragraph [0163]).
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Knebel et al., Li et al. and Seppo et al. of embedding and imaging multiple subdivided biological samples and
forming a composite image of proteomic and/or genomic data which is correlated with the location of detected signals (e.g. superimposed) with the method of Alexander et al. of dissociating a biological sample into individual cells and analyzing the individual cells genomics and/or proteomics cytometrically because this would allow the individual cell proteomic and/or genomic data and images to be correlated with the location within the sample that the signals were obtained. Those of ordinary skill in the art would have been motivated to make this modification because this would provide a composite image of both the presence and location of proteomic and/or genomic signals in the sub-samples correlated with individual cell proteomic and/or genetic signals. There would have been a reasonable expectation of success in making this modification because the Knebel, Seppo and Alexander references are reasonably drawn to the same field of endeavor, that is, the analysis of biological samples.
It would have been further obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Knebel et al., Li et al., Seppo et al. and Alexander et al. of embedding and imaging multiple subdivided biological samples and determining marker locations therein, dissociating a biological sample into individual cells and analyzing the individual cells cytometrically and forming a composite image of proteomic and/or genomic data which is correlated with the location of detected signals (e.g. superimposed) with the superimposition of the obtained genomic and/or proteomic data on the composite image and tracking cell location by correlating measured biomarkers in single cells with the measured biomarkers in the sample whole because this would allow the artisan to determine the cells position in the sample and visually correlate that data to measured biomarkers in the cell and adjacent and non-adjacent cells. Those of ordinary skill in the art would have been motivated to make this modification because this would provide a composite image of both the presence and location of proteomic and/or genomic signals in the sub-samples correlated with individual cell proteomic and/or genetic signals. There would have been a reasonable expectation of success in making this modification because the Knebel, Seppo and Alexander references are reasonably drawn to the same field of endeavor, that is, the analysis of biological samples.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/ Examiner, Art Unit 1653 06/01/2026
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