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
Applicant’s arguments with respect to claim(s) 1-4,6-9,11,15-18,20-29, 31-41,43,45-57, 59-63, 65-72 and 74-76 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant argues
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Examiner’s Response:
The Examiner disagrees. Physical Objects in a tissue sample as well as edges/corners of coverslip; and or slides read on physical position markers.
Klaiman clearly discloses generating a standard stained and washed target image from a sample that is stained using CycleGan, identical to Applicant’s specification. Klaiman also discusses tiling (forming patches) and combining the resultant tiles. Klaiman explicitly discloses with or without a wash step. The Examiner agrees that Kaiman doesn’t explicitly disclose “fast-staining” and spacers, such as water or glycerol, which regulated spacing between two plates. Fast-staining of an image sample, such as crystal violet or Gram Stain, and spacers are notoriously well known, conventional and routine in research microscopy. Additionally slides with graticules (grid markings) are also well-known, conventional and routine. The Specification does not appear to disclose which combination of elements, Applicant believes is novel.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 4, 6, 16, 46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 4 recites “4. (Currently Amended) The method of claim 1, wherein the machine learning algorithm is trained using a training data set that comprises at least one image of the at least three including the plurality of physical position markers and the stained sample that is stained in under a first set of staining conditions, and at least one image of the sample stained sample that is stained in under a second set of staining conditions.” The Examiner is unable to find support for this limitation.
Claim 6, 16, 46 is rejected under similar grounds as claim 4.
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 1-11 and 13-76are 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 1 preamble states “without a wash step”. Amended limitation (d) states “without performing the wash step…”. Amended limitation (g)(ii) states “(ii) images of samples stained and washed by the standard staining procedure”.
There are multiple issues
The preamble states “without a wash step”, yet the images in step (g) have been washed. This is an inconsistency.
Limitation (d) “the wash step” references a step that is not ever run.
The Examiner recommends removing without a wash step in the preamble, in step d, replacing “the wash step” with “any wash step”.
Claim 1 recites “wherein the target image has an image quality corresponding to an image of a sample stained and washed by a standard staining procedure; “ and “(ii) images of samples stained and washed by the standard staining procedure”. The Specification does not detail what is a “standard staining procedure” and what is not a “standard staining procedure”. Additionally the Specification does not provide any metric what constitutes an “image quality corresponding to an image of sample stained and washed by a standard staining procedure”. Thereby rendering the claim indefinite.
Furthermore, no working examples on network architecture other than CycleGan and pix2pix, which would further elaborate on the current scope of the claim.
Claim 2 recites “a first image that is suitable for machine-learning transformation…” The Specification fails to set bounds on what constitutes “suitable for machine learning transformation …”
Claim 4 recites “the sample stained …”. This limitation lacks antecedent basis. Claim 1 has a plurality of samples in the training data.
Claims 17 and 47 appear to recite the same limitations as recited in the independent claim (35 USC 112(d)), It is not clear how they further narrow the claims which they depend upon.
Claims 2-11 and 13-76are rejected as dependent upon a rejected claim.
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.
Claim(s) 1-6, 10, 13-22, 30, 32-34, 42, 44-51, 56-61, 64-76 is/are rejected under 35 U.S.C. 103 as being unpatentable over Klaiman(PGPub 2021/00005308) in view of in view of Ergezen (PGPub 2019/0344260).
Klaiman discloses 1. (Currently Amended) A method of staining and imaging a sample without a wash step, comprising:
(a) providing a sample holder comprising a first plate and a second plate that are movable relative to each other into different configurations comprising an open configuration and a closed configuration, wherein at least one of the first plate and the second plate comprises a plurality of physical position markers having predetermined distances therebetween; (Klaiman, paragraph 160, “slide-mounted tissue”, while a coverslip isn’t explicitly disclosed it is considered essential for most standard biological observations for purposes of prevention of contamination, flattening the sample, preventing evaporation1)
(b) depositing the sample and a staining reagent on the first plate, on the second plate, or between the first plate and the second plate; (Klaiman, Paragraph 7-11, “ [0009] a digital image of the tissue sample whose pixel intensity values correlate with the amount of a non-biomarker specific stain (e.g. hematoxylin, H&E, or the like); or [0010] a digital image of the tissue sample whose pixel intensity values correlate with the amount of a first biomarker specific stain, the first biomarker-specific stain adapted to selectively stain a first biomarker contained in the tissue sample; or [0011] a digital image of the tissue sample wherein pixel intensity values of some pixels correlate with the strength of a non-biomarker specific stain (e.g. hematoxylin or H&E or the like) and wherein pixel intensity values of other pixels correlate with the strength of one or more first biomarker specific stains (e.g. Ki67 specific stain).”)
(c) moving the first plate and the second plate to the closed configuration to sandwich the sample and the staining reagent between the first plate and the second plate, wherein the sample and the staining reagent form a thin layer (Klaiman, Paragraph 7-11, “ [0009] a digital image of the tissue sample whose pixel intensity values correlate with the amount of a non-biomarker specific stain (e.g. hematoxylin, H&E, or the like); or [0010] a digital image of the tissue sample whose pixel intensity values correlate with the amount of a first biomarker specific stain, the first biomarker-specific stain adapted to selectively stain a first biomarker contained in the tissue sample; or [0011] a digital image of the tissue sample wherein pixel intensity values of some pixels correlate with the strength of a non-biomarker specific stain (e.g. hematoxylin or H&E or the like) and wherein pixel intensity values of other pixels correlate with the strength of one or more first biomarker specific stains (e.g. Ki67 specific stain).”)
But doesn’t fairly disclose “having a plate-to-plate distance regulated by spacers, and wherein the staining reagent stains the sample during a staining time of 60 seconds or less to obtain a stained sample;”
Ergezen discloses “having a plate-to-plate distance regulated by spacers, and wherein the staining reagent stains the sample during a staining time of 60 seconds or less to obtain a stained sample;” (Ergezen, “[0171] In some embodiments, the spacers can be mounted onto platform 1760A in an adjustable manner such that the gap thickness and shape can be adjusted as desired. For example, spacers 1770A-D can be mounted to platform 1760A using a mechanism that controls the length of each spacer that protrudes above the surface of platform 1760A, e.g., using shims, pin-sets with different lengths, and/or platforms with different thicknesses/shapes.”)(Ergezen, paragraph 185, “[0185] System 1 can be programmed to repeat these staining and evacuation phases after a delay (e.g., a delay of between 3 seconds and 10 seconds, such as a five second delay), following the first staining phase”)
It would have been obvious to a person having ordinary skill in the art before the time of the effective filing date of the claimed invention of the instant application to use a spacer such as the one disclosed by Ergezen between the plates of Klaiman.
The suggestion/motivation for doing so would have been preventing compression, controlling sample thickness as well as creating a sealed chamber.
Further, one skilled in the art could have combined the elements as described above by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results.
Therefore, it would have been obvious to combine Klaiman with Ergezen to obtain the invention as specified above.
(d) without performing the wash step that would remove at least a portion of the staining reagent from the sample, capturing a first image of the stained sample while the sample remains between the first plate and the second plate in the closed configuration; (Klaiman, “[0012] The method further comprises providing a trained machine learning logic—MLL. The MLL is a machine learning logic having been trained to (explicitly or implicitly) identify tissue regions predicted to comprise a second biomarker. The method further comprises inputting the received acquired image into the MLL and automatically transforming, by the MLL, the acquired image into an output image. The output image highlights tissue regions predicted to comprise the second biomarker. For example, the MLL may be provided as a software product stored on a portable or non-portable data storage device, e.g. a DVD or USB stick or a hard disk drive or may be downloaded via a network, e.g. the Internet or an intranet of a laboratory. Likewise, the MLL may be provided by training an untrained version of the MLL.
[0013] Typically, the MLL has been trained on training images depicting tissue samples that have the same or a similar type as the tissue sample depicted in the acquired image. Typically, the tissue samples depicted in the training images have been stained with the same stain and with the same or similar staining protocol like the tissue sample depicted in the acquired image.”, since the acquired image has the same or similar type of image as the training images and the training images comprises stained samples without wash, the first image can be a stained sample without a wash)
(f) generating, by a machine learning algorithm, a target image of the stained sample from the plurality of image patches of the first image, wherein the target image has an image quality corresponding to an image of a sample stained and washed by a standard staining procedure; and(Klaiman, “[0012] The method further comprises providing a trained machine learning logic—MLL. The MLL is a machine learning logic having been trained to (explicitly or implicitly) identify tissue regions predicted to comprise a second biomarker. The method further comprises inputting the received acquired image into the MLL and automatically transforming, by the MLL, the acquired image into an output image. The output image highlights tissue regions predicted to comprise the second biomarker. For example, the MLL may be provided as a software product stored on a portable or non-portable data storage device, e.g. a DVD or USB stick or a hard disk drive or may be downloaded via a network, e.g. the Internet or an intranet of a laboratory. Likewise, the MLL may be provided by training an untrained version of the MLL.
[0013] Typically, the MLL has been trained on training images depicting tissue samples that have the same or a similar type as the tissue sample depicted in the acquired image. Typically, the tissue samples depicted in the training images have been stained with the same stain and with the same or similar staining protocol like the tissue sample depicted in the acquired image.”, since the acquired image has the same or similar type of image as the training images and the training images comprises stained samples without wash, the first image can be a stained sample without a wash)
wherein the machine learning algorithm is trained using a training data set comprising (i) images of samples stained for 60 seconds or less and imaged without the wash step and (ii) images of samples stained and washed by the standard staining procedure. (Klaiman, paragraph 68,78-79, “[0078] In case the pixel intensities of the first training images are of an image type whose pixel intensities are indicative of the non-biomarker specific stain or of the first biomarker-specific stain, the generation of the training data set may comprise washing the training tissue samples for removing the non-biomarker specific stain or the first biomarker-specific stain. The generation of the training data set may further comprise staining the training tissue samples with the non-biomarker-specific stain or with the first biomarker specific stain before the first training images are acquired. In case the pixel intensities of the first training images are of an image type whose pixel intensities are indicative of the non-biomarker specific stain or of the first biomarker-specific stain, washing the training tissue samples for removing the non-biomarker specific stain or the first biomarker-specific stain. Thus, it is possible to stain, wash, and re-stain the sample as described for the machine-learning approach A. However, the washing steps are optional here, as it would also be possible to use images of other samples having been stained with one or more biomarker specific second stains as the second training images.”)
(e) segmenting the first image into a plurality of image patches using the plurality of physical position markers, wherein at least one of the image patches is defined by four corners corresponding to four of the physical position markers having predetermined distances therebetween; (g) stitching transformed image patches generated by the machine learning algorithm to form the target image, (Klaiman, paragraph 162, “ Then the image acquisition system acquires images of the entire tissue sample or microarray or acquires images of parts (tiles) of the samples. Using commercially available software, the computer then can generate a composite image of the entire tissue sample or microarray.”)
Klaiman in view of Ergezen discloses 2. (Currently Amended) A kit for performing the method of claim 1, comprising: (a) a sample holder comprising a first plate and a second plate that face each other in a closed configuration and are separated by a spacer-regulated plate-to-plate distance, wherein one or both of the first plate and the second plate comprise a plurality of physical position markers having predetermined distances therebetween; and (b) a staining reagent aving a concentration awash- step after a staining time of 60 seconds or less, staining of the sample is visible in a first image that is suitable for machine-learning transformation into a target image corresponding to an image of a sample stained and washed by a standard staining procedure. (see claim 1, the sample holder is inherently disclosed whether it is a persons hard, table, or microscope tray; placed spacers inherently have a predetermined distance between them based on where they are placed)
Klaiman in view of Ergezen discloses 3. (Currently Amended) A system for staining and imaging a sample, comprising: (a) the kit of claim 2; (b) an imager configured to capture a first image of the stained sample between the first plate and the second plate; without the wash step; and (c) [[a]]one or more non-transitory computer-readable storage media storing a instructions that, when executed, cause one or more processors to segment the first image into image patches using the plurality of physical position markers, transform the image patches using a machine learning algorithm, and stitch transformed image patches to generate a target image aving an image quality corresponding to an image of [[the]] a sample stained and washed by a standard staining procedure, wherein the machine learning algorithm is trained using a training data set omprising (i) images of samples stained for 60 seconds or less and imaged without [[a]]the wash step and (ii) images of[[the]]samples stained and washed by the standard staining procedure. (see claim 1 & 2)
Klaiman in view of Ergezen discloses 4. (Currently Amended) The method of claim 1, wherein the machine learning algorithm is trained using a training data set that comprises at least one image of the at least three including the plurality of physical position markers and the stained sample that is stained in under a first set of staining conditions, and at least one image of the sample stained sample that is stained in under a second set of staining conditions.(see claim 1)
Klaiman in view of Ergezen discloses 5. (Currently Amended) The kit of claim 2, wherein one or both of the first and second plates comprise at least three position markers, wherein each pair of the at least three position markers has a predetermined distance between them. (Klaiman, where a slide has 4 corners (position markers) where the distance between two pairs of coordinate points are equal and parallel)
Klaiman in view of Ergezen discloses 6. (Currently Amended) The system of claim 3, wherein the including the plurality of physical position markers and the stained sample under a first set of staining conditions, and at least one image of the sample stained under a second set of staining conditions. (Klaiman, paragraph 7, “one or more biomarker stains”)
Klaiman discloses 10. (Currently Amended) The method of claim 1, wherein the two first and second plates are movable relative to each other.(see claim 1)
Klaiman discloses 13. (Currently Amended) The method, kit and system of claim 1 wherein the sample is a tissue.(Klaiman, Abstract)
Klaiman discloses 14. (Currently Amended) The method of claim 1, wherein the machine learning algorithm employs Cycle GAN. (Klaiman, paragraph 79, “[0080] An example for a suitable cyclic GAN network architecture is described by Jun-Yan Zhu, Taesung Park, Phillip Isola, and Alexei A. Efros in “Unpaired Image-to-Image Translation using Cycle-Consistent Adversarial Networks”, (24 Nov. 2017). The document can be downloaded via the Cornell University Library https://arxiv.org/abs/1703.10593).”
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* Examiner Note: The J.Zhu paper is one of the seminal works in generative models and computer vision and is one of the most cited papers in this field, therefore a POSITA would recognize this paper as Cycle GAN)
Klaiman discloses 15. (Currently Amended) The method of claim 1, wherein the machine learning algorithm employs GAN based pixel-to-pixel transform.(see claim 14)
Klaiman discloses 16. (Currently Amended) The method of claim 1, wherein the ]]including the plurality of physical position markers and the stained sample under a first set of staining conditions, and at least one image of the sample stained nder a second set of staining conditions. (see claim 4)
Klaiman discloses 17. (Currently Amended) The method of claim 1, wherein employs at least four position markers are at least.(see claim 5)
Klaiman discloses 18. (Currently Amended) The method of claim 1, wherein the machine learning algorithm employs the physical position markers [[that]] have a geometry and/or [[a]] an inter- marker distance between the position markers in in an x-direction different from [[that ]]an inter- marker distance in a y-direction which is orthogonal to the x-direction. (see claim 5)
Klaiman discloses 19. (Currently Amended) The method of claim 1, wherein the sample comprises bodily fluid selected from the group consisting of amniotic fluid, aqueous humour, vitreous humour, blood, breast milk, cerebrospinal fluid (CSF), cerumen (earwax), chyle, chime, endolymph, perilymph, feces, breath, gastric acid, gastric juice, lymph, mucus, pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, exhaled breath condensates, sebum, semen, sputum, sweat, synovial fluid, tears, vomit, urine, and any combination thereof. (Klaiman, paragraph 125)
Klaiman discloses 20. (Currently Amended) The method of claim 1, wherein the staining reagent comprises H&E staining, immunohistochemical staining, immuno- fluorescence staining, in situ hybridization staining, or any combination of thereof.(Klaiman, paragraph 87)
Klaiman discloses 21. (Currently Amended) The method of claim 1 wherein the staining reagent comprises a dry staining reagent coated on the surface of at least one of the plates. (Klaiman, paragraph 38, eosin)
Klaiman discloses 22. (Currently Amended) The method of claim 1 wherein the staining reagent is a dry staining reagent coated on the surface of at least one of the plates, and wherein the staining solution is a transfer liquid that transfer the dry stain agent into the sample. (Klaiman, paragraph 38, H&E stain)
Klaiman discloses 30. (New) The kit of claim 2, wherein the first and second plates are movable relative to each other.(see claim 10)
Klaiman discloses 32. (New) The kit of claim 2, wherein the staining reagent comprises the agent for H&E staining, immunohistochemical staining, immuno-fluorescence staining, in situ hybridization staining, or any combination of thereof. (Klaiman, paragraph 87)
Klaiman discloses 33. (New) The kit of claim 2, wherein the staining reagent comprises a dry staining reagent coated on the surface of at least one of the plates. (Klaiman, paragraph 38)
Klaiman discloses 34. (New) The kit of claim 2, wherein the kit further comprises a transfer liquid between the sample and the second plate; wherein the staining reagent comprises a dry staining reagent coated on the surface of at least one of the plates, and wherein the transfer liquid transfers the dry staining reagent to the sample. (Klaiman, paragraph 38)
Klaiman discloses 42. (New) The system of claim 3, wherein the first and second plates are movable relative to each other. (see claim 10)
Klaiman discloses 44. (New) The system of claim 3, wherein the machine learning algorithm employs Cycle GAN.(see claim 14)
Klaiman discloses 45. (New) The system of claim 3, wherein the machine learning algorithm employs GAN based pixel-to-pixel transform. (see claim 14)
Klaiman discloses 46. (Currently Amended) The system of claim 3, wherein the including the atplurality of physical position markers and the stained sample under a first set of staining conditions, and at least one image of the sample stained under a second set of staining conditions. (see claim 4)
Klaiman discloses 47. (New) The system of claim 3, wherein the machine learning algorithm employs at least four position markers. (see claim 4)
Klaiman discloses 48. (Currently Amended) The system of claim 3, wherein the physical position markers have a geometry and/or [[a]]aninter-marker distance in an x-direction different from [[that]] an inter-marker distance in ay-direction (claim 18)
Klaiman discloses 49. (New) The system of claim 3, wherein the staining reagent comprise the agent for H&E staining, immunohistochemical staining, immuno-fluorescence staining, in situ hybridization staining, or any combination of thereof. (see paragraph 38)
Klaiman discloses 50. (New) The system of claim 3, wherein the staining reagent is a dry staining reagent coated on the surface of at least one of the plates. (see paragraph 38)
Klaiman discloses 51. (New) The system of claim 3, wherein the system further comprises a transfer liquid between the sample and the second plate; wherein the staining reagent is a dry staining reagent coated on the surface of at least one of the plates, and wherein the transfer liquid transfers the dry staining reagent into the sample. (see paragraph 38)
Klaiman discloses 56. (New) The method of claim 1, wherein the target image is for cytopathology.(Klaiman, paragraph 47)
Klaiman discloses 57. (New) The method of claim 1, wherein the target image is for pathology. (Klaiman, paragraph 47)
Klaiman discloses 58. (New) The method of claim 1, wherein the sample is a biopsy sample. (Klaiman, paragraph 47)
Klaiman discloses 59. (New) The method of claim 1, wherein the staining reagent is a staining liquid that drops on the tissue, one plate, both plate, or any combination thereof. (Klaiman, paragraph 38, eosin)
Klaiman discloses 60. (New) The method of claim 1, wherein the staining reagent is a H&E staining solution and is dropped on the sample or on the plate. (Klaiman, paragraph 38, eosin)
Klaiman discloses 61. (New) The method of claim 1, wherein the target image comprises diagnosing cancer, infectious diseases, or other inflammatory conditions. (Klaiman, paragraph 43)
Klaiman discloses 64. (New) The method of claim 1, wherein the sample is a tissue smear.(Klaiman, paragraph 6)
Klaiman discloses 65. (New) The method of claim 1, wherein the staining reagent comprises permeabilizing agents capable of permeabilizing cells in the tissue sample that contain the target analyte.(Klaiman, paragraph 38, H&E, PAS, Trichrome, GMS)
Claims 66-73 are anticipated by paragraph 38 of Klaiman
Klaiman discloses 74. (New) The method of claim 1, wherein the sample contains or is suspected of containing a target analyte, and wherein the staining reagent comprises detection agents that specifically label the target analyte in the sample. (Klaiman, paragraph 22)
Klaiman discloses 75. (New) The method of claim 73, wherein the target analyte comprises a protein, nucleic acid, peptide, amino acid, or cell. (Klaiman, paragraph 22)
Klaiman discloses 76. (New) The method of claim 73, wherein the target analyte comprises biological molecule. (Klaiman, paragraph 22)
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.
Claim(s) 7-9, 11, 23-26, 27-29, 31, 35,36-41, 43, 52-55 is/are rejected under 35 U.S.C. 103 as being unpatentable over Klaiman in view of Ergezen (PGPub 2019/0344260).
Klaiman discloses 7. (Currently Amended) The method of claim 1
But doesn’t fairly disclose “further comprising spacers that regulate the distance between the first plate and the second plate.”
Ergezen discloses “further comprising spacers that regulate the distance between the first plate and the second plate.” (Ergezen, “[0171] In some embodiments, the spacers can be mounted onto platform 1760A in an adjustable manner such that the gap thickness and shape can be adjusted as desired. For example, spacers 1770A-D can be mounted to platform 1760A using a mechanism that controls the length of each spacer that protrudes above the surface of platform 1760A, e.g., using shims, pin-sets with different lengths, and/or platforms with different thicknesses/shapes.”)
It would have been obvious to a person having ordinary skill in the art before the time of the effective filing date of the claimed invention of the instant application to use a spacer such as the one disclosed by Ergezen between the plates of Klaiman.
The suggestion/motivation for doing so would have been preventing compression, controlling sample thickness as well as creating a sealed chamber.
Further, one skilled in the art could have combined the elements as described above by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results.
Therefore, it would have been obvious to combine Klaiman with Ergezen to obtain the invention as specified in claim 7.
Klaiman in view of Ergezen discloses 8. (Currently Amended) The method of claim 7, wherein the spacing between the two plates or the height of the spacers is selected between 0.5 um to 30 um. Klaiman in view of Ergezen disclose an adjustable size spacer but fails to explicitly disclose the range of sizes. However, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to make prior art spacers with claimed dimension because it has been held that changes in size, shape, and proportion are considered routine expedients for one having ordinary skill in the art. MPEP 2144.04 IV A and B.
Klaiman in view of Ergezen discloses 9. (Currently Amended) The method claim 7, wherein the spacing between the two [[plate]] plates or the height of the spacers is 10 um. Klaiman in view of Ergezen disclose an adjustable size spacer but fails to explicitly disclose the range of sizes. However, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to make prior art spacers with claimed dimension because it has been held that changes in size, shape, and proportion are considered routine expedients for one having ordinary skill in the art. MPEP 2144.04 IV A and B.
Klaiman in view of Ergezen discloses 11. (Currently Amended) The method of claim 7, wherein the spacing between the two plates or the spacer height is selected to have a stain saturation time of 5 sec, 10 sec, 20 sec, 30 sec, 60 sec, or a range between any two of the values. Klaiman in view of Ergezen disclose saturating a sample with a stain but fails to explicitly disclose the range of sizes. However, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to make prior art spacers with claimed dimension because it has been held that changes in size, shape, and proportion are considered routine expedients for one having ordinary skill in the art. MPEP 2144.04 IV A and B.
Klaiman in view of Ergezen discloses 23. (Currently Amended) The method of claim 7, wherein the spacers are position markers. (where the edges/corners of the spacers are the position markers)
Klaiman in view of Ergezen discloses 24. (Currently Amended) The method of claim 7, wherein the inter-spacer-distance between neighboring spacers or between neighboring position markers is in the range of 50 m to 120 m. Klaiman in view of Ergezen disclose spacers, where the edges/corners of the spacers can be considered as markers but fails to explicitly disclose the range of sizes. However, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to make prior art spacers with claimed dimension because it has been held that changes in size, shape, and proportion are considered routine expedients for one having ordinary skill in the art. MPEP 2144.04 IV A and B.
Klaiman in view of Ergezen discloses 25. (Currently Amended) The method of claim 7,wherein one or both of the first and second plates are flexible,(see claim 1) But doesn’t disclose “wherein the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range of 60 to 750 GPa-pm; and wherein the fourth power of the inter-spacer-distance (ISD) divided by the thickness of the flexible plate (h) and the Young's modulus (E) of the flexible plate, ISD4/(hE), is equal to or less than 106 um3/GPa.”
Applicant has not disclosed that “wherein the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range of 60 to 750 GPa-pm; and wherein the fourth power of the inter-spacer-distance (ISD) divided by the thickness of the flexible plate (h) and the Young's modulus (E) of the flexible plate, ISD4/(hE), is equal to or less than 106 um3/GPa.” Is used for a particular purpose or solves a stated problem. One of ordinary skill in the art, furthermore, would have expected Applicant’s invention to perform equally well with any flexibility.
Klaiman in view of Ergezen discloses 26. (Currently Amended) The method of claim 7,wherein one or both of the first and second plates are flexible; wherein the spacer height is selected in the range of 0.5 to 50 pm,(see claim 24) the [[IDS]] ISD is 100 pm [[um]] or less, the fourth power of the inter-spacer-distance ([[IDS]]ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD4/(hE))(ISD^I'/(hE)) is 5x105pm3/GPa5x10^5 um^3/GPa or less; the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range of 60 to 750 GPa-pmGPa um. Applicant has not disclosed that “wherein the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range of 60 to 750 GPa-pm; and wherein the fourth power of the inter-spacer-distance (ISD) divided by the thickness of the flexible plate (h) and the Young's modulus (E) of the flexible plate, ISD4/(hE), is equal to or less than 106 um3/GPa.” Is used for a particular purpose or solves a stated problem. One of ordinary skill in the art, furthermore, would have expected Applicant’s invention to perform equally well with any flexibility.
Klaiman discloses 27. (New) The kit of claim 2, wherein one or both of the first and second plates comprises the spacers that regulate the distance between the first plate and the second plate. (see claim 7)
Klaiman in view of Ergezen discloses 28. (New) The kit of claim 27, wherein the spacing between the two plates or the height of the spacers is selected between 0.5 pm to 30 pm. (see claim 8)
Klaiman in view of Ergezen discloses 29. (New) The kit of claim 27, wherein the spacing between the two plates or the height of the spacers is 10 pm. (see claim 8)
Klaiman in view of Ergezen discloses 31. (New) The kit of claim 27, wherein the spacing between the two plates or the spacer height is selected to have a stain saturation time of 5 sec, 10 sec, 20 sec, 30 sec, 60 sec, or a range between any two of the values. (see claim 11)
Klaiman in view of Ergezen discloses 35. (New) The kit of claim 27, wherein the spacers are position markers. (see claim 23)
Klaiman in view of Ergezen discloses 36. (New) The kit of claim 27, wherein the inter-spacer-distance between neighboring spacers or between neighboring position markers is in the range of 50 m to 120 km. (see claim 24)
Klaiman in view of Ergezen discloses 37. (New) The kit of claim 27, wherein one or both of the first and second plates are flexible; and wherein the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range of 60 to 750 GPa-pm; wherein the fourth power of the inter-spacer- distance (ISD) divided by the thickness of the flexible plate (h) and the Young's modulus (E) of the flexible plate, ISD4/(hE), is equal to or less than 106 m3/GPa. (see claim 25)
Klaiman in view of Ergezen discloses 38. (New) The kit of claim 27, wherein one or both of the first and second plates are flexible; wherein the spacer height is selected in the range of 0.5 to 50 pm, the ISD is 100 pm or less, the fourth power of the inter-spacer-distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD4/(hE)) is 5x105pm3/GPa or less; the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range of 60 to 750 GPa-pm. (see claim 25)
Klaiman in view of Ergezen discloses 39. (New) The system of claim 3, wherein one or both of the first and second plates comprises the spacers that regulate the distance between the first plate and the second plate. (see claim 7)
Klaiman in view of Ergezen discloses 40. (New) The system of claim 39, wherein the spacing between the two plates or the height of the spacers is selected between 0.5 pm to 30 pm. (see claim 8)
Klaiman in view of Ergezen discloses 41. (New) The system of claim 39, wherein the spacing between the two plates or the height of the spacers is 10 pm. (see claim 8)
Klaiman discloses 43. (New) The system of claim 3, wherein the spacing between the two plates or the spacer height is selected to have a stain saturation time of 5 sec, 10 sec, 20 sec, 30 sec, 60 sec, or a range between any two of the values. (see claim 10)
Klaiman in view of Ergezen discloses 52. (New) The system of claim 39, wherein the spacers are position markers. (see claim 23)
Klaiman in view of Ergezen discloses 53. (New) The system of claim 39, wherein the inter distance between neighboring spacers or between neighboring position markers is in the range of 50 m to 120 m. (see claim 24)
Klaiman in view of Ergezen discloses 54. (New) The system of claim 39, wherein one or both of the first and second plates are flexible; and wherein the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range of 60 to 750 GPa-pm; wherein the fourth power of the inter- spacer-distance (ISD) divided by the thickness of the flexible plate (h) and the Young's modulus (E) of the flexible plate, ISD4/(hE), is equal to or less than 106 m3/GPa. (see claim 25)
Klaiman in view of Ergezen discloses 55. (New) The system of claim 39, wherein one or both of the first and second plates are flexible; wherein the spacer height is selected in the range of 0.5 to 50 pm, the ISD is 100 pm or less, the fourth power of the inter-spacer-distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD4/(hE)) is 5x105pm3/GPa or less; the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range of 60 to 750 GPa-pm. (see claim 25)
Claim(s) 62-63 is/are rejected under 35 U.S.C. 103 as being unpatentable over Klaiman in view of Ergezen in view ofトポル，エリック(JP2014523533), hereafter referred to as Toporu.
Klaiman in view of Ergezen discloses 62. (New) The method of claim 1 BUT fails to disclose wherein the target image comprises measuring the ratio of the area of a cell to the area of the nucleus of the cell. Toporu discloses wherein the target image comprises measuring the ratio of the area of a cell to the area of the nucleus of the cell ( Toporu, “ The terms “control” or “standard” are used interchangeably. Average CEC standards for comparison to CEC isolated from individuals with cardiovascular disorders are compared. In some embodiments, the control is CEC or multiple CECs obtained from healthy individuals. In some embodiments, the control is a CEC or a plurality of CECs obtained from an individual having or having a subject's cardiovascular disorder. In some embodiments, the control is a CEC or multiple CECs. In some embodiments, the control is a CEC or measurement related to CEC (e.g., cell area, cell shape, nucleus area, nucleus shape, number of nuclei, or ratio of cell area to nucleus area). Or the concentration of CEC in the blood). In some embodiments, the control or standard is an average CEC measurement derived from measurements obtained from multiple individuals.”)
It would have been obvious to a person having ordinary skill in the art before the time of the effective filing date of the claimed invention of the instant application to calculate the ratio as shown by Toporu after generating the image of Klaiman.
The suggestion/motivation for doing so would have been to use the image to determine cardiovascular disorders.
Further, one skilled in the art could have combined the elements as described above by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results.
Therefore, it would have been obvious to combine Klaiman in view of Tomoru to obtain the invention as specified in claim 62.
Klaiman discloses 63. (New) The method of claim 1 BUT fails to disclose wherein the target image comprises measuring the ratio of the area of a cell to the area of the nucleus of the cell, and wherein the ratio is used to screen a smoker or a non-smoker. Toporu discloses wherein the target image comprises measuring the ratio of the area of a cell to the area of the nucleus of the cell, and wherein the ratio is used to screen a smoker or a non-smoker ( Toporu, see claim 62 and “In order to compare CEC levels and morphology with those obtained from STEMI patients, healthy controls were taken from a normal blood donor program at The Scripts Research Institute. All healthy controls were between 18 and 35 years old and were considered free of any chronic disability by self-report. Blood for confirmation of CEC in healthy random age matched samples was obtained via venipuncture. A randomly selected sample of age-matched controls that denied the presence of any acute disease or condition via self-report was included as part of the analysis of the CEC form of the study. Smoking status, obesity, family history of cardiovascular disorders, or acute fever disease were not used as exclusive criteria. Individuals with existing vascular disease who have recently undergone an open endarterectomy with a patient with non-ST-segment elevation myocardial infarction (NSTEMI) also serve the sole purpose of morphological characterization of CEC Adopted. The criteria for MI in a group of NSTEMI were symptoms consistent with MI, serological evidence of myocardial necrosis as measured by high levels of myocardial troponin and CK-MB, and angiographic evidence of obstructive coronary artery disease Included.”)
It would have been obvious to a person having ordinary skill in the art before the time of the effective filing date of the claimed invention of the instant application to calculate the ratio as shown by Toporu after generating the image of Klaiman.
The suggestion/motivation for doing so would have been to use the image to determine cardiovascular disorders.
Further, one skilled in the art could have combined the elements as described above by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results.
Therefore, it would have been obvious to combine Klaiman in view of Toporu to obtain the invention as specified in claim 63.
Conclusion
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 GANDHI THIRUGNANAM whose telephone number is (571)270-3261. The examiner can normally be reached M-F 8:30-5PM.
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/GANDHI THIRUGNANAM/ Primary Examiner, Art Unit 2672
1 8th grade biology class; as well as What Are The Functions Of Glass Slide & Cover Slips? https://www.sciencing.com/functions-glass-slide-cover-slips-6680506/
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