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 .
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Response to Amendment
The amendment filed on 1 October 2025 has been entered.
The amendment of claims 1, 6, 9, 12, 20, 22, 26, 28, 30, 32, 34, 36, 37, 39, 43, 47, 48, 49, 53, 55, 57, and 59 has been acknowledged.
Response to Arguments
Applicant’s arguments filed on 1 October 2025, with respect to the pending claims, have been fully considered but are moot because the arguments rely on newly added and/or amended claim limitations. The examiner has revised the rejections to match the new claim limitations.
Claim Rejections - 35 USC § 112
Claims 2-12, 14-15, 18-20, 22-26, 28, 30-31, and 52 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 2-12, 14-15, 18-20, 22-26, 28, and 30-31 recite “the system.” Claim 1 recites multiple systems (“processing system,” “sectioning system,” “staining system,” and “control system”) and it is unclear which system is being referred to in the dependent claims. For the purpose of further examination, the limitation “the system” in claims 2-12, 14-15, 18-20, 22-26, 28, and 30-31 has been interpreted as “the processing system” to distinguish from the other systems.
Claim 52 recites the limitation “a sample surface.” The limitation renders the claim indefinite because it is unclear whether a sample surface of claim 52 corresponds to the first, second, or new/different surface(s) (recited previously in claim 32). For the purpose of further examination, the limitation has been interpreted as “the first or second surface of the tissue sample.”
Claim Rejections - 35 USC § 103
Claim(s) 1-9, 11, 12, 14, 18-20, 22-24, 28, 30, 32-40, 44-50, 51, 54, 55, 57, and 58 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ragan (US 2012/0208184 A1), in view of Chafin et al. (US 2012/0214195 A1), hereinafter referred to as Ragan and Chafin, respectively.
Regarding claim 1, Ragan teaches a processing system for imaging a tissue sample comprising:
a sectioning system for sectioning a tissue sample in a fluid bath into a plurality of tissue sections, the sectioning system having an automated sectioning tool that cuts tissue sections from the sample in a sequence in response to control signals wherein removal of each tissue section exposes a cut surface of the tissue sample (Ragan Fig. 2A: see 64, microtome & 66, cutting tool; Ragan Fig. 9 & ¶¶0058: “the tissue sample is moved by the sample stage on which the bath is mounted …The flow liquid through the transfer tube is generated by a pump”; Ragan Fig. 2A: microtome 64; Ragan Fig. 4 & ¶¶0015: “sectioning tool”; Ragan ¶¶0009: “preferred embodiments of the inventions use an automated microtome integrated into a high speed TPM system”; Ragan ¶¶0037: “automated retrieval of tissue sections”);
a staining system operative to stain an exposed region of the tissue sample with a stain in sequence with a sectioning sequence performed by the sectioning system, wherein the stain enters an exposed cut surface after removing a section from the tissue sample to a depth in the sample (Ragan Fig. 1H: the tissue sample is cut on the surface to expose a region to be imaged; Ragan Fig. 2A: see 65, mouse brain tissue sections; Ragan ¶¶0011: “The present invention enables comparative analysis of image data … using IHC staining”; Ragan ¶¶0036: “staining the tissue sample”; Ragan ¶¶0049: “once the tissue has been sectioned, the tissue slice can often be much more easily stained with additional dyes”); and
a control system connected to the sectioning system and the staining system and that controls sequential staining and sectioning of the tissue sample to provide a plurality of stained tissue sections, the control system communicating the control signals to the sectioning system to control a cutting depth for cutting a section of each sequentially exposed cut surface of the tissue sample (Ragan Figs. 2A, 4 & ¶¶0009, ¶¶0015, ¶¶0037: discussed above teaches an automated microtome system connected to the entire system comprising a processor 42 – ¶¶0009 teaches adjusting to a desired depth depending on when the sample is being imaged vs sectioned; Ragan Fig. 2A: see 40, imaging and processing system; 42, processor; 65 tissue sample sections imaged sequentially; Ragan ¶¶0010: “allowing a larger image to be constructed from a series of overlapping 3D volumes” Ragan ¶¶0114: “series of sections was exposed”; Ragan Figs. 15-16; Ragan Fig. 1H & ¶¶0032: “Imaging below the cut depth in the second region 11 enables more precise registration in the formation of 3D images of whole organs or deep tissue samples as the overlapping region 17 extends below the cut depth 15. This enables registration of the first image region (17 and 18) with the second region 11 which also includes overlap region 17”).
However, Ragan does not appear to explicitly teach that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region.
Pertaining to the same field of endeavor, Chafin teaches that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region (The claim states that the transport rate is the rate at which the dye enters the exposed surface of the tissue sample, i.e., diffusion rate of the dye into the tissue. Chafin ¶¶0013: “The speed and methods used for raising the temperatures are so designed that optimal preservation of post-translation modification signals is achieved”; Chafin ¶¶0017: “This protocol differs from the prior art by separating the fixation process into a first process step that permits diffusion of fixative solution into a tissue sample but minimizes cross-linking, and a second process step that increases the rate of cross-linking, during the time periods typically used for fixing a tissue sample in disclosed working embodiments”; Chafin ¶¶0088: “The second step is to subject the tissue sample to fixative composition at a second, higher temperature to allow cross-linking to occur at as fast a rate as possible without compromising the tissue characteristics, such as antigenicity and morphology. Each of these processing steps is discussed in more detail below”; Chafin ¶¶0097: “As the temperature increases, the rate of cross-linking increases. And this first processing step attempts to balance the beneficial properties associated with substantially complete diffusion of fixative composition throughout the entire cross section of the tissue sample while minimizing the effects associated with initializing cross-linking. However, diffusion also increases with increasing temperature, and so for a given sample, it has been found that maximizing the rate of diffusion while minimizing any deleterious effects associated with increased cross-linking rate appears to increase benefits” – the increased temperature increases the transport/diffusion rate and reduces the time by using the fastest rate possible).
Ragan and Chafin are considered to be analogous art because they are directed to tissue staining. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and system for imaging and processing tissue (as taught by Ragan) to increase the transport rate during the staining period only (as taught by Chafin) because the combination increases the cross-linking rate of the dye while minimizing any deleterious effects (Chafin ¶¶0097).
Regarding claim 2, Ragan, in view of Chafin, teaches the system of claim 1, further comprising an imaging system that is configured to use one or more of multiphoton, confocal, optical coherence tomography, second harmonic generation, third harmonic generation, coherent anti-Stokes Raman, photoacoustic, or Raman imaging techniques (Note that only one of the alternative limitations is required by the claim language. Ragan ¶¶0009: “two-photon 3D tissue image cytometer … using multiphoton excitation”; Ragan ¶¶0115: “Once the brain tissue has been IHC stained, it can be reimaged by a variety of method including wide field, multiphoton and confocal microscopy”).
Regarding claim 3, Ragan, in view of Chafin, teaches the system of claim 2, wherein the imaging system images the exposed region of the tissue sample and/or a subsurface region of the tissue sample (Note that only one of the alternative limitations is required by the claim language. Ragan Fig. 1H: Imaging plane 14 and maximum imaging depth 16 are below the tissue surface that has been cut with a microtome & Ragan ¶¶0032: “Imaging below the cut depth”; Ragan claim 1 further teaches that the tissue is sectioned to expose a first and second region of the tissue).
Regarding claim 4, Ragan, in view of Chafin, teaches the system of claim 1, wherein the sectioning system is configured to sequentially cut sections from the tissue sample to sequentially expose deeper regions of the tissue sample (Ragan Fig. 1H: microtome cut plane 12, Ragan Fig. 2A: cutting tool 66 & microtome 64; Ragan ¶¶0009: “preferred embodiments of the inventions use an automated microtome integrated into a high speed TPM system”; Ragan ¶¶0037: “the system integrates a vibrating blade microtome into the high speed whole mount tissue scanner”; Ragan ¶¶0040: “Preferred embodiments use a standard cryostat or microtome to section frozen or paraffin embedded tissue”).
Regarding claim 5, Ragan, in view of Chafin, teaches system of claim 4, further comprising an imaging system that images the sequentially cut sections from the tissue sample (Ragan Fig. 1H, 15-16 & ¶¶0045: “sequential cutting of 254 sections”).
Regarding claim 6, Ragan, in view of Chafin, teaches the system of claim 4, wherein the sequentially cut sections have a thickness of 50 microns or less (Ragan pg. 4, Table: “Section Thickness 10-100 µm”).
Regarding claim 7, Ragan, in view of Chafin, teaches the system of claim 2, wherein the control system further comprises a memory to store image received from the imaging system (Ragan Abstract: “processing three-dimensional data that is collected to create a three-dimensional image of the region of interest”; Ragan ¶¶0035: “The images of the tissue, both before and after sectioning, can be stored in memory 46”).
Regarding claim 8, Ragan, in view of Chafin, teaches the system of claim 7, wherein the control system is configured to generate a three-dimensional representation of the tissue sample using the images stored in the memory (Ragan Abstract & ¶¶0035 discussed above).
Regarding claim 9, Ragan, in view of Chafin, teaches the system of claim 1, wherein the stain is delivered to the tissue sample with a detergent (Ragan ¶¶0114: “The free-floating sections were washed in phosphate-buffered saline (PBS) containing 0.3% Triton-X, and then 1-in-5 series of sections was exposed for 30 mins to PBS Triton solution containing 3% normal rabbit serum” – Triton-X is a detergent).
Regarding claim 11, Ragan, in view of Chafin, teaches the system of claim 1, wherein the staining system includes a motorized stage to move the tissue sample, agitate the stain, or both (Note that only one of the alternative limitations is required by the claim language. Ragan Fig. 2A: x-y-z motorized stage 62).
Regarding claim 12, Ragan, in view of Chafin, teaches the system of claim 1, wherein the staining system includes at least one of a fluid pump, a stirrer and a fan to provide agitation by circulating the stain in a fluid bath containing the tissue sample (Ragan Fig. 9 & ¶¶0058: “the tissue sample is moved by the sample stage on which the bath is mounted …The flow liquid through the transfer tube is generated by a pump”; Ragan ¶¶0081: “The liquid is stirred briefly and then injected into the animal through the same cannula the perfusion and fixation was performed”).
Regarding claim 14, Ragan, in view of Chafin, teaches the system of claim 1, wherein the staining system includes a heating element in contact with the fluid bath, the fluid bath in thermal contact with the stain (Ragan Fig. 9 & ¶¶0058 as discussed above teaches a water bath; Ragan ¶¶0080: “All perfusion solutions are warmed to 37°C in a water bath prior to use”).
Regarding claim 18, Ragan, in view of Chafin, teaches the system of claim 1, wherein the sectioning system includes a vibrating blade, a microtome, or a cryostat (Note that only one of the alternative limitations is required by the claim language. Ragan ¶¶0037: “the system integrates a vibrating blade microtome into the high speed whole mount tissue scanner to allow automated retrieval of tissue sections for later processing such as immunohistochemistry (IHC) staining of the sectioned tissue slices”).
Regarding claim 19, Ragan, in view of Chafin, teaches the system of claim 2, further comprising a robotic device to move the tissue sample among the staining system, imaging system, and sectioning system (Ragan Fig. 4B: flexure arm 210 & ¶¶0042: “motion control requires two separate functional units: a force generating unit, such as motor 204, to actuate the motion and a bearing unit, such as flexure arm 210 on which a blade holder assembly 208 is mounted, the arm 210 being attached to platform 212. This operates to constrain the motion to the desired trajectory”).
Regarding claim 20, Ragan, in view of Chafin, teaches the system of claim 1 further comprising a staining system device configured to increase the transport rate of the stain into the tissue sample, the control system being connected to the staining system device to control the transport rate (Ragan Figs. 2A, 4 & ¶¶0009, ¶¶0015, ¶¶0037: discussed above teaches an automated microtome system connected to the entire system comprising a processor 42, processing system 72 (where the tissue is processed), and transport system 68; Chafin ¶¶0013, ¶¶0017, ¶¶0088, ¶¶0097 discussed above).
Regarding claim 22, Ragan, in view of Chafin, teaches the system of claim 1, wherein the control system is programmed with a software module to select one or more staining system devices to control the transport rate of a stain into a sample (Ragan Fig. 2A: teaches the system comprising a programmable control system, see Ragan ¶¶0035: “The processor 42 can be programmed with software that operates the system components”; Ragan Figs. 2A, 4 & ¶¶0009, ¶¶0015, ¶¶0037: discussed above teaches an automated microtome system connected to the entire system comprising a processor 42; Chafin ¶¶0013, ¶¶0017, ¶¶0088, ¶¶0097 discussed above).
Regarding claim 23, Ragan, in view of Chafin, teaches the system of claim 1 wherein the system controls a steric property of the tissue sample (Ragan ¶¶0048: “due to the large size of antibodies used in IHC staining and their subsequent slow diffusion and steric hindrance within the tissue”).
Regarding claim 24, Ragan, in view of Chafin, teaches the system of claim 1 wherein the control system has a memory that stores sample processing parameters including stored sectioning parameters and stored imaging parameters for a plurality of imaging modes of one or more imaging devices (Ragan Abstract: “determining volumetric imaging parameters”; Ragan Fig. 5: tissue sectioning parameters; Ragan Fig. 6: imaging parameters 504; Ragan Fig. 8: 714, image processing parameters; Ragan ¶¶0035: “stored in memory 46”).
Regarding claim 28, Ragan, in view of Chafin, teaches the system of claim 1 further comprising a sample stage that controls movement of the tissue sample to be processed and wherein the control system is programmed to independently control processing parameters for a plurality of tissue sections (Ragan Fig. 2A: x-y-z motorized stage 62; Ragan Abstract: “determining volumetric imaging parameters”; Ragan Fig. 5: tissue sectioning parameters; Ragan Fig. 6: imaging parameters 504; Ragan Fig. 8: 714, image processing parameters).
Regarding claim 30, Ragan, in view of Chafin, teaches the system of claim 28 wherein the sample stage is operative to move the plurality of samples between one or more imaging stations, one or more sectioning stations, one or more staining stations and one or more transport rate control stations (Ragan Fig. 2A: x-y-z motorized stage 62 – the stage moves in x, y, and z directions; Ragan 2A & ¶¶0035 further teaches that the system comprises a transport system which moves the tissue sections).
Regarding claim 32, Ragan teaches a method of producing sequentially stained tissue sections from a tissue sample (Ragan Fig. 8 & ¶¶0055: “loaded sequentially into computer memory”), comprising:
staining a first surface of the tissue sample with a stain to a depth within tissue sample (Ragan ¶¶0011: “The present invention enables comparative analysis of image data … using IHC staining”; Ragan ¶¶0036: “staining the tissue sample”; Ragan Figs. 1H & 2A);
removing a first section of the tissue sample to expose a second surface of the tissue sample with a sectioning device connected to a control system (Ragan Fig. 1H: the tissue sample is cut on the surface to expose a region to be imaged; Ragan ¶¶0032: “Imaging below the cut depth”; also see Ragan claim 1: teaches that the tissue is sectioned to expose a first and second regions of the tissue);
staining the second surface of the tissue sample (Ragan Fig. 2A: 65 – the sample has multiple slices, in sequential surfaces);
removing a second section of the tissue sample with the stained second surface (Ragan Fig. 3: sample hand-over; Ragan ¶¶00114: “series of sections”; also see Ragan Figs. 15-16); and
in response to the control system, iterating the staining and removing steps to provide a plurality of stained tissue sections (Ragan Fig. 3 & 6: the processes are iterative, see 506-514; Ragan ¶¶0038: “re-staining the tissue with other dyes”; Ragan ¶¶0049: “By staining or re-staining the tissue after it has been sliced, it is possible to use both a far wider range of dyes and more homogenous staining, and generate more types of contrast to identify various tissue constituents”).
However, Ragan does not appear to explicitly teach that a transport rate of the stain is increased to reduce a staining time period.
Pertaining to the same field of endeavor, Chafin teaches that the transport rate of the stain is increased to reduce a staining time period (Chafin ¶¶0013, ¶¶0017, ¶¶0088, ¶¶0097 discussed above).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and system for imaging and processing tissue (as taught by Ragan) to increase the transport rate during the staining period only (as taught by Chafin) because the combination increases the cross-linking rate of the dye while minimizing any deleterious effects and reducing the time (Chafin ¶¶0097).
Regarding claim 33, Ragan, in view of Chafin, teaches the method of claim 32, further comprising imaging the tissue sample after staining and before sectioning and saving the images in a memory or storage device (Ragan ¶¶0011: “The present invention enables comparative analysis of image data using images obtained both before and after sectioning”; Ragan ¶¶0051: “the imaging process can be followed by selective IHC/FISH staining of individual sections of interest”).
Regarding claim 34, Ragan, in view of Chafin, teaches the method of claim 32, further comprising agitating the stain while it is in contact with the tissue sample to increase the rate of transport of the stain within the tissue sample (Ragan Fig. 2A: x-y-z motorized stage 62; Ragan ¶¶0081: “The liquid is stirred briefly”; Chafin ¶¶0013, ¶¶0017, ¶¶0088, ¶¶0097 discussed above).
Regarding claim 35, Ragan, in view of Chafin, teaches the method of claim 34, wherein agitating the stain includes translating a motorized stage (Ragan Fig. 2A: x-y-z motorized stage 62).
Regarding claim 36, Ragan, in view of Chafin, teaches the method of claim 34, wherein agitating the stain includes circulating a staining solution through a pump (Ragan Fig. 9 & ¶¶0058: “the tissue sample is moved by the sample stage on which the bath is mounted …The flow liquid through the transfer tube is generated by a pump”).
Regarding claim 37, Ragan, in view of Chafin, teaches the method of claim 36, wherein agitating the stain includes using a stirrer or a fan to move the staining solution (Ragan ¶¶0081: “The liquid is stirred briefly and then injected into the animal through the same cannula the perfusion and fixation was performed”).
Regarding claim 38, Ragan, in view of Chafin, teaches the method of claim 32, wherein the stain comprises a detergent or a protease (Ragan ¶¶0114: “The free-floating sections were washed in phosphate-buffered saline (PBS) containing 0.3% Triton-X, and then 1-in-5 series of sections was exposed for 30 mins to PBS Triton solution containing 3% normal rabbit serum” – Triton-X is a detergent).
Regarding claim 39, Ragan, in view of Chafin, teaches the method of claim 32, further comprising changing a temperature of the stain while the stain is in contact with the tissue sample (Ragan ¶¶0080: “All perfusion solutions are warmed to 37°C in a water bath prior to use”).
Regarding claim 40, Ragan, in view of Chafin, teaches the method of claim 39, wherein changing the temperature of the stain includes placing the stain in thermal contact with a heated water bath (Ragan ¶¶0080 discussed above).
Regarding claim 44, Ragan, in view of Chafin, teaches the method of claim 32, further comprising staining the second surface of the tissue sample with a different stain than was used on the first surface of the tissue sample (Ragan ¶¶0049: “small molecule stains such as DAPI or Hoescht 33442. Other important dyes include dyes used in standard H&E” – H&E includes two different stains, hematoxylin and eosin. Eosin is applied after hematoxylin).
Regarding claim 45, Ragan, in view of Chafin, teaches the method of claim 32, wherein the stain includes one or more of antibodies, nanobodies, dyes, aptamers, nucleic acid probes, fluorescent peptide probes, nanoparticles quantum dots, or photoacoustic probes (Ragan ¶¶0049 discussed above teaches DAPI, Hoescht 33442, and H&E).
Regarding claim 46, Ragan, in view of Chafin, teaches the method of claim 32, wherein the stain includes DAPI or anti-NeuN-alexafluor488 (Ragan ¶¶0049 discussed above teaches DAPI).
Claim 47 is rejected using the same rationale as applied to claim 20 discussed above.
Regarding claim 48, Ragan, in view of Chafin, teaches the method of claim 47, wherein the control system is connected to the staining system device to communicate control signals to change the transport rate (Ragan Figs. 2A, 4 & ¶¶0009, ¶¶0015, ¶¶0037: discussed above teaches an automated microtome system connected to the entire system comprising a processor 42, processing system 72 (where the tissue is processed), and transport system 68; Chafin ¶¶0013, ¶¶0017, ¶¶0088, ¶¶0097 discussed above; also see Ragan Fig. 9: the tissue section 808 is subjected to flow 810).
Claim 49 is rejected using the same rationale as applied to claim 22 discussed above.
Claim 50 is rejected using the same rationale as applied to claim 23 discussed above.
Claim 51 is rejected using the same rationale as applied to claim 24 discussed above.
Regarding claim 54, Ragan, in view of Chafin, teaches the method of claim 32 wherein the control system has stored sectioning parameters and stored imaging parameters for a plurality of imaging modes (Ragan Abstract: “determining volumetric imaging parameters”; Ragan Fig. 5: tissue sectioning parameters; Ragan Fig. 6: imaging parameters 504; Ragan Fig. 8: 714, image processing parameters; Ragan ¶¶0035: “stored in memory 46”).
Regarding claim 55, Ragan, in view of Chafin, teaches the method of claim 32 further comprising controlling movement of the tissue sample to be processed using a sample stage wherein the control system is programmed to independently control processing parameters for different tissue samples (Ragan Fig. 2A: x-y-z motorized stage 62; Ragan Abstract: “determining volumetric imaging parameters”; Ragan Fig. 5: tissue sectioning parameters; Ragan Fig. 6: imaging parameters 504; Ragan Fig. 8: 714, image processing parameters).
Regarding claim 57, Ragan, in view of Chafin, teaches the method of claim 55 wherein the sample stage is operative to move the plurality of samples between one or more imaging stations, one or more sectioning stations, one or more staining stations and one or more transport rate control stations (Ragan Fig. 2A: x-y-z motorized stage 62 – the stage moves in x, y, and z directions; Ragan 2A & ¶¶0035 further teaches that the system comprises a transport system which moves the tissue sections).
Regarding claim 58, Ragan, in view of Chafin, teaches the method of claim 32, further comprising moving at least one of the tissue sample and a tissue section with a robotic arm (Ragan Fig. 4B: flexure arm 210 & ¶¶0042: “motion control requires two separate functional units: a force generating unit, such as motor 204, to actuate the motion and a bearing unit, such as flexure arm 210 on which a blade holder assembly 208 is mounted, the arm 210 being attached to platform 212. This operates to constrain the motion to the desired trajectory”).
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ragan (US 2012/0208184 A1), in view of Chafin et al. (US 2012/0214195 A1), and further in view of Carrigan et al. (U.S. PGPub No. 2015/0276563), hereinafter referred to as Ragan, Chafin, and Carrigan, respectively.
Regarding claim 10, Ragan teaches the system of claim 1, wherein a staining kit is used (Ragan ¶¶0049: “small molecule stains such as DAPI or Hoescht 33442. Other important dyes include dyes used in standard H&E”; Ragan ¶¶0089: “stained with a cyanine-5-conjugated mouse anti-EF5 (1/50) antibody … Cy5 fluorescence, representing hypoxic regions will be imaged with 665 to 695 nm emission filters”; Ragan ¶¶0112: “we use the Vectastain ABC-kit. In the last staining step, the reaction is visualized with a 3-3' diaminobenzidine tetrahydrochloride (DAB)”).
However, Ragan does not appear to explicitly teach that the stain includes a protease.
Pertaining to the same field of endeavor, Carrigan teaches that the stain includes a protease (Carrigan ¶¶0045: “a serial section of the same sample specifically stained with DAB”; Carrigan ¶¶0055: “Cell conditioning may further include applying a protease reagent. Illustratively, a protease treatment may involve the step of contacting a protease solution to a biological sample. The protease treatment, as with cell conditioning, is intended to increase the expression of target antigens and/or nucleic acids.”).
Ragan and Carrigan are considered to be analogous art because they are directed to tissue analysis. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and system for imaging and processing tissue (as taught by Ragan) to use a protease (as taught by Carrigan) because the combination increases the expression of target antigens and/or nucleic acids (Carrigan ¶¶0055).
Claim(s) 15, 41, 42, and 43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ragan (US 2012/0208184 A1), in view of Chafin et al. (US 2012/0214195 A1), and further in view of Aceto et al. (U.S. PGPub No. 2016/0264973), hereinafter referred to as Ragan, Chafin, and Aceto, respectively.
Regarding claim 15, Ragan teaches the system of claim 1, but does not appear to explicitly teach that the staining system includes at least one of a sonicator, an electrophoresis and a microwave to retrieve antigens.
Pertaining to the same field of endeavor, Aceto teaches that the staining system includes at least one of a sonicator, an electrophoresis and a microwave to retrieve antigens (Aceto ¶¶0046: “Methods to measure gene expression products associated with the marker genes described herein are well known to a skilled artisan. Such methods to measure gene expression products, e.g., protein level, include ELISA (enzyme linked immunosorbent assay), western blot, and immunoprecipitation, immunofluorescence using detection reagents such as an antibody or protein binding agents” – western blot requires the sample to be run on a gel electrophoresis; Aceto ¶¶0049: “the assay can be a Western blot analysis. Alternatively, proteins can be separated by two-dimensional gel electrophoresis systems”; Aceto ¶¶0074: “Exemplary methods for treating a test sample include, but are not limited to, centrifugation, filtration, sonication, homogenization, heating, freezing and thawing, and combinations thereof”).
Ragan and Aceto are considered to be analogous art because they are directed to tissue analysis. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and system for imaging and processing tissue (as taught by Ragan) to sonicate the sample and apply electrophoresis (as taught by Aceto) because the combination allows undesired impurities to be removed by agitating and separating particles within the sample and allows the gene expression of the tissue sample to be measured (Aceto ¶¶0046).
Claims 41-43 are rejected using the same rationale as applied to claim 15 discussed above.
Claim(s) 25 and 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ragan (US 2012/0208184 A1), in view of Chafin et al. (US 2012/0214195 A1), and further in view of Kram et al. (U.S. PGPub No. 2008/0102006), hereinafter referred to as Ragan, Chafin, and Kram, respectively.
Regarding claim 25, Ragan teaches the system of claim 24 but does not appear to explicitly teach that the sample processing parameters control a selection of a stain to be delivered to a sample surface and an amount of the stain to be delivered.
Pertaining to the same field of endeavor, Kram teaches that the sample processing parameters control a selection of a stain to be delivered to a sample surface and an amount of the stain to be delivered (Kram ¶¶0067: “control unit 914 can have stored in memory alternate sets of commands to enable staining protocols for use with alternate platen configurations. Or, control unit 914 can include a graphical user interface that allows a user to create a protocol for any particular staining procedure and/or platen configuration”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and system for imaging and processing tissue (as taught by Ragan) to use a control system that can store staining protocols (as taught by Kram) because the combination allows the user to customize the parameters for any particular staining procedures (Kram ¶¶0067).
Claim 52 is rejected using the same rationale as applied to claim 25 discussed above.
Double Patenting
Claim(s) 1, 2, 3, 5, 6, 7, 9, 32, and 39 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-25 of U.S. Patent No. 8,771,978, in view of Chafin et al. (US 2012/0214195 A1), hereinafter referred to as the patent and Chafin, respectively.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the application and the patent are directed to tissue sample imaging methods and systems comprising an imaging system, sectioning system, and staining system, wherein the tissue samples are sectioned in layers (~10-100 micron thickness), imaged with OCT, multiphoton imaging, coherent anti-stokes Raman spectroscopy, or second harmonic generation, and stained using IHC. Both inventions form a 3D image of the tissue sample.
However, the patent does not appear to explicitly teach that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region.
Pertaining to the same field of endeavor, Chafin teaches that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region (Chafin ¶¶0013, ¶¶0017, ¶¶0088, ¶¶0097 discussed above).
The patent and Chafin are considered to be analogous art because they are directed to tissue staining. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and system for imaging and processing tissue (as taught by the patent) to increase the transport rate during the staining period only (as taught by Chafin) because the combination increases the cross-linking rate of the dye while minimizing any deleterious effects (Chafin ¶¶0097).
Claim(s) 1, 2, 3, 5, 7, 9, 32, and 39 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-27 of U.S. Patent No. 9,983,134, in view of Chafin et al. (US 2012/0214195 A1), hereinafter referred to as the patent and Chafin, respectively.
Although the claims at issue are not identical, they are not patentably distinct from each other because both are directed to tissue sample imaging methods and systems comprising an imaging system, sectioning system, and staining system, wherein the tissue samples are sectioned in layers (~10-100 micron thickness), imaged with OCT, multiphoton imaging, coherent anti-stokes Raman spectroscopy, or second harmonic generation, and stained using IHC. Both inventions form a 3D image of the tissue sample.
However, the patent does not appear to explicitly teach that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region.
Pertaining to the same field of endeavor, Chafin teaches that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region (Chafin ¶¶0013, ¶¶0017, ¶¶0088, ¶¶0097 discussed above).
The patent and Chafin are considered to be analogous art because they are directed to tissue staining. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and system for imaging and processing tissue (as taught by the patent) to increase the transport rate during the staining period only (as taught by Chafin) because the combination increases the cross-linking rate of the dye while minimizing any deleterious effects (Chafin ¶¶0097).
Claim(s) 1-5, 7, 9, 11, 28, 29, 30, 32, and 55 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-27 of U.S. Patent No. 7,372,985, in view of Chafin et al. (US 2012/0214195 A1), hereinafter referred to as the patent and Chafin, respectively.
Although the claims at issue are not identical, they are not patentably distinct from each other because both are directed to tissue sample imaging methods and systems comprising an imaging system, sectioning system, and staining system, wherein the tissue samples are imaged with OCT, multiphoton imaging, coherent anti-stokes Raman spectroscopy, or second harmonic generation, moved on the imaging stage, and stained using IHC. Both inventions form a 3D image of the tissue sample.
However, the patent does not appear to explicitly teach that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region.
Pertaining to the same field of endeavor, Chafin teaches that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region (Chafin ¶¶0013, ¶¶0017, ¶¶0088, ¶¶0097 discussed above).
The patent and Chafin are considered to be analogous art because they are directed to tissue staining. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and system for imaging and processing tissue (as taught by the patent) to increase the transport rate during the staining period only (as taught by Chafin) because the combination increases the cross-linking rate of the dye while minimizing any deleterious effects (Chafin ¶¶0097).
Claim(s) 1-5, 7, 9, 12, 32, and 34 is/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-48 of U.S. Patent No. 10,908,087, in view of Chafin et al. (US 2012/0214195 A1), hereinafter referred to as the patent and Chafin, respectively.
Although the claims at issue are not identical, they are not patentably distinct from each other because both are directed to tissue sample imaging methods and systems comprising an imaging system, sectioning system, and staining system, wherein the tissue samples are imaged with OCT, multiphoton imaging, coherent anti-stokes Raman spectroscopy, or second harmonic generation, moved/transported, subjected to flow, and stained using IHC. Both inventions form a 3D image of the tissue sample.
However, the patent does not appear to explicitly teach that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region.
Pertaining to the same field of endeavor, Chafin teaches that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region (Chafin ¶¶0013, ¶¶0017, ¶¶0088, ¶¶0097 discussed above).
The patent and Chafin are considered to be analogous art because they are directed to tissue staining. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and system for imaging and processing tissue (as taught by the patent) to increase the transport rate during the staining period only (as taught by Chafin) because the combination increases the cross-linking rate of the dye while minimizing any deleterious effects (Chafin ¶¶0097).
Claims 20, 22, 30, 47, 48, 49, and 57 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-27 of U.S. Patent No. 11,519,832, in view of Chafin et al. (US 2012/0214195 A1), hereinafter referred to as the patent and Chafin, respectively.
Although the claims at issue are not identical, they are not patentably distinct from each other because both are directed to tissue sample imaging methods and systems comprising an imaging system, sectioning system, and staining system, wherein the tissue samples are sectioned in layers (~10-100 micron thickness), imaged with OCT, multiphoton imaging, coherent anti-stokes Raman spectroscopy, or second harmonic generation, and stained using IHC. Both inventions form a 3D image of the tissue sample.
However, the patent does not appear to explicitly teach that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region.
Pertaining to the same field of endeavor, Chafin teaches that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region (Chafin ¶¶0013, ¶¶0017, ¶¶0088, ¶¶0097 discussed above).
The patent and Chafin are considered to be analogous art because they are directed to tissue staining. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and system for imaging and processing tissue (as taught by the patent) to increase the transport rate during the staining period only (as taught by Chafin) because the combination increases the cross-linking rate of the dye while minimizing any deleterious effects (Chafin ¶¶0097).
1-12, 14-15, 18-20, 22-26, 28, 30, 32-55, and 57-58 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-36 of U.S. Patent No. 10,788,403, in view of Chafin et al. (US 2012/0214195 A1), hereinafter referred to as the patent and Chafin, respectively.
Although the claims at issue are not identical, they are not patentably distinct from each other because both are directed to tissue sample imaging methods and systems comprising an imaging system, sectioning system, and staining system, wherein the tissue samples are sectioned in layers (~10-100 micron thickness), imaged with OCT, multiphoton imaging, coherent anti-stokes Raman spectroscopy, or second harmonic generation, and stained using IHC. Both inventions form a 3D image of the tissue sample and comprising a diffusion device that controls the diffusion rate.
However, the patent does not appear to explicitly teach that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region.
Pertaining to the same field of endeavor, Chafin teaches that the sample has a transport rate for the tissue sample, wherein the transport rate is increased during a staining period of the exposed region (Chafin ¶¶0013, ¶¶0017, ¶¶0088, ¶¶0097 discussed above).
The patent and Chafin are considered to be analogous art because they are directed to tissue staining. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method and system for imaging and processing tissue (as taught by the patent) to increase the transport rate during the staining period only (as taught by Chafin) because the combination increases the cross-linking rate of the dye while minimizing any deleterious effects (Chafin ¶¶0097).
Allowable Subject Matter
Claims 26 and 31 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Claims 53 and 59 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
Regarding claims 26 and 53, the prior art of record teaches that it was known at the time the application was filed to use the system and method of claims 24 and 51.
The prior art (US 2006/0194261 A1, hereinafter Kim) further teaches that the sample processing parameters include control parameters of a diffusion device including selection of a diffusion rate adjustment mode (Kim ¶¶0134: “The flow characteristics of the system were measured using varying flow rates of upper perfusion with fluorescein visible dye in basic solution (pH=9) … The data were collected using the xzt mode of the microscope with the injection loop switched to ‘inject’ mode at the onset of data acquisition … the sample injection loop and syringe pump system provided improved sample injection integrity and flow stability relative to the gravity feed system. However, non-uniform flow characteristics of the open chamber coupled with the varying liquid bead size in contact with the objective lens resulted in irreproducible sample injection times as a function of flow rate”).
However the prior art does not appear to teach or suggest that the selected mode operating parameters include duration of mode operation in addition to the selection of a transport rate adjustment mode.
Regarding claims 31 and 59, the prior art of record teaches that it was known at the time the application was filed to use the system and method of claims 24 and 51.
However, the prior art, alone or in combination, does not appear to teach or suggest that the processing parameters are calibrated so that the timing sequence between sequential staining, imaging, and sectioning operations is correlated to generate images of regions of the tissue sample at selected depths within each region of the sample.
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.
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/Soo Shin/Primary Examiner, Art Unit 2667 571-272-9753
soo.shin@uspto.gov