Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/13/26 has been entered.
Response to Arguments
Applicant’s arguments in light of the amendments, filed 07/13/26, with respect to the rejection(s) of claim(s) under 35 USC 112 and 35 USC 102 have been fully considered and are partially persuasive in light of the amendments. Therefore, some of the rejections under 35 USC 112 have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of 35 USC 112 with respect to enablement and written description and the previous rejection under 35 USC 102 in view of Sakai stands.
The applicant argues that Sakai fails to disclose a receiver system having a plurality of detector modules each having a plurality of detector channels with a plurality of photodetectors in a row forming a detector chain. It should be noted that part of the limitation “near a transparent block” is not limiting since the transparent block is an environmental description, not part of the claimed receiver system. Sakai, Col.11, l 6-11, does in fact disclose a receiver system (“detecting sub-system”) having a plurality of detector modules (“image pick up elements” in the plurality form) each having a plurality of detector channels (“having different reception wavelength ranges”). A CCD or CMOS are generally known to be in a row of some sort (sometimes two dimensional, sometimes one dimensional, but generically a row).
For these reasons, the rejections are presented as follows.
Claim Rejections - 35 USC § 112
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 10, 12-14, 19, 21-26, 28, and 29 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.
With respect to claim 10, the limitation “generating a reference matrix of spectral signatures” from single stained controls lacks written description. The specification states that single stained controls “separately generate spectral profiles or signatures” and that those controls are used to “generate… an initial reference matrix for the spectral flow cytometer.” However, it does not describe how measured control events are converted into matrix entries, whether each column is a raw mean spectrum, a background subtracted spectrum, or a normalized signature, dimensions of the matrix relative to the N detectors and M fluorochromes, and treatment of unstained/autofluorescence controls. Equation 3 and the accompanying column/row explanation are given only for the initial spillover matrix [S] of a conventional cytometer, not for the spectral reference matrix. “Generating a reference matrix” is only shown as a functional result, not as a process step.
With respect to the limitation “a receiver system each having a plurality of detector modules” is not disclosed in the specification. The specification does disclose as provided by the applicant “linear 16-channel compact wavelength detection module 600” in P.0076-80. But there is no mention of a “receiver system” with a plurality of those detection modules. Correction is required.
With respect to the limitation “generating an unmixed sample event vector for the spectral flow cytometer by using the reference matrix and the measured sample event vector” is broader than the disclosed species. The specification’s spectral teaching is measured vector U has a matrix relationship with unmixed vector V; a least squares algorithm is used; after unmixing, spectral spillover is an identity matrix that may be fine adjusted with a delta matrix. The claimed genus that any use of a reference matrix and measured vector matrix results in an unmixed vector is overly broad and does not have evidence of possession of that full genus.
With respect to claim 28 and 29, the limitation “the plurality of detector modules each have eight/sixteen or more detector channels with eight/sixteen or more photodetectors in a row forming the detector chain” is not disclosed. The specification discloses having 8 channels or having 16 channels. The specification also discloses that many channels can be used together, but not “in a row forming the detector chain”. The unlimited part of the phrase “or more” is not supported in the original disclosure. The application’s own specification discloses the negative limit of adding an unbounded number that results in image quality degradation with a long chain. Correction is required.
Claims 10, 12-14, 19, 21-26, 28, and 29 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is lacking for the full scope of “generating a reference matrix of spectral signatures” and “generating an unmixed sample event vector by using the reference matrix and the measured sample event vector.” The generating and unmixing steps are purely functional. Any algorithm that turns single-stain data into “a reference matrix” and any algorithm that “uses” that matrix with a measured vector fall within the claim. (Breadth of claim) However, MPEP 2161.01 discloses that algorithms must be disclosed. The specification gives a worked structure for conventional spillover matrix [S] (Equation 3) and a fast recompensation algorithm for adjusting an already obtained matrix. For the reference matrix, it gives only the instruction to run single stains and then apply a least square algorithm to an unspecified matrix equation. (Presence of working examples/direction). The equation itself is not set out. Spectral unmixing is known in the art, but the claim is not limited to know least squares unmixing. Using the specification alone, a skilled person would have to supply the missing least model, control processing, and a solver. That is undue experimentation to the extent the claim is not limited to ordinary least squares unmixing as is commonly practiced. Implementing a well known unmixing from single-stain spectra may be routine. But implementing the claim’s full functional scope, including an undefined matrix construction and undefined “use” are not.
All claims dependent on the above noted claims fail to further clarify and support the limitation of a delta function and a compensated spillover matrix and thereby are rejected likewise.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 10, 12, 19, and 22 are rejected under 35 U.S.C. 102 as being anticipated by Sakai U.S. Patent 8,581,210.
With respect to claim 10, Sakai discloses a fluorescence intensity computing method comprising:
With a plurality of runs of single stained compensation controls individually run through the spectral flow cytometer, generating a reference matrix of spectral signatures, wherein each single stained compensation control is respectively associated with a plurality of antibody capture beads single stained with a differing fluorochrome (Figure 3, step (A), Col.6, l 4-6, l 38-40, Figure 4, wavelength distribution coefficients of fluorochrome n, Col.5, l 35-37)
Wherein the spectral flow cytometer includes a receiver system having a plurality of detector modules each having a plurality of detector channels with a plurality of photodetectors in a row forming a detector chain near a transparent block to receive and detect fluorescent light emitted by the fluorochromes excited by laser light (Col.11, receiver system = detecting sub-system, plurality of detector modules = image pick up elements, plurality of detector channels = having different reception wavelength ranges, plurality of photodetectors = MPT, CCD, CMOS commonly have a plurality of sensor elements in each one)
Through the spectral flow cytometer, running a sample with a plurality of differing cells and conjugated antibodies with the plurality of fluorochromes attached thereto (Figure 3, step (B), Col.2, l 55-60, Col.5, l 35-37)
Generating a measured sample event vector, representing a mixture of differing cells, by measuring fluorescence of the plurality of differing cells with attached fluorochromes passing through the spectral flow cytometer (Figure 4, Measured Fluorescence Intensities PMT1-PMT5, Col.5, l 35-37)
Generating an unmixed sample event vector for the spectral flow cytometer by using the reference matrix and the measured sample event vector to facilitate identification and quantity of types of differing cells within the sample (Figure 3, step (C), Figure 4, unmixed sample event vector = FL1-FL5 True Fluorescence Intensities, Col.2, l 65-Col.3, l 4)
It should be noted “near a transparent block” is not positively limiting on the claimed receiver system but rather an indication of environmental factors.
With respect to claim 12, 19, and 22, Sakai discloses all of the limitations as applied to claim 10 above. In addition, Sakai discloses:
12- The unmixed sample even vector equals the measured sample event vector linearly multiplied times the reference matrix (Figure 4, Col.1, l 67- Col.2, l 5)
19- the measured sample event vector includes N values, and wherein the unmixed sample event vector has M values (Figure 4, both have 5)
22- Each single stained compensation control separately generates a differing spectral signature from respective various luminescence emitted by fluorochromes excited by the laser light (Figure 3, (A))
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 13, 14, 21, 23, 24, 25, 26, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Sakai U.S. Patent 8,581,210.
With respect to claims 13 and 23, Sakai discloses all of the limitations as applied to claim 10 above.
In addition, Sakai discloses:
The number of variables in both the unmixed sample event vector and the measured sample event vector is dependent upon the number of detectors and fluorochromes (Col.3, l 26-46, Col.6, l 31-67, Figure 2, claim 3, unmixed sample event vector = True Fluorescence Intensities FLx, measured sample event vector = Measured Fluorescence Intensities PMTx)
However, Sakai fails to disclose the number of variables in the unmixed sample event vector is less than a number of variables in the measured sample event vector or that the spectral flow cytometer has at least N detectors to measure M fluorochromes where M is less than N.
The situation described in the claim is when there are more detectors than fluorochromes. It would have been obvious to one of ordinary skill in the art at the time of the invention to include more detectors than fluorochromes because it is well known in the art that you need more knowns than unknowns to solve equations. In this case, the number of detectors will result in a number of known spectrum while solving for the different combinations of fluorochromes in the sample. Having a greater number of detectors will allow for easier math but also more information about the particles so that a clearer approximation can be determined for matching the spectral responses to the fluorochromes.
With respect to claim 14, Sakai discloses all of the limitations as applied to claims 10 and 13 above. In addition, Sakai discloses:
Solving for the unmixed sample event vector comprises using a least square algorithm on the measured sample even vector and the reference matrix (Col.8, l 51- Col.9, l 6)
With respect to claim 21, Sakai discloses all of the limitations as applied to claim 10 above. In addition, Sakai discloses:
Each of the single stained compensation controls includes one of: FITC, PE, ECD, PC5, PC7 (Col.2, l 5-10)
However, Sakai fails to disclose the single stained compensation controls include PerCP, PE-Cy7, APC-Cy7, or APC.
These are all well known fluorescent labels and it would have been obvious to one of ordinary skill in the art at the time of the invention for one of ordinary skill in the art to select from any of the known options based on the source wavelengths and detector’s spectral ranges.
With respect to claims 24, 25, 26, and 27, Sakai discloses all of the limitations as applied to claim 23 above. However, Sakai fails to disclose a specific value of N beyond 5.
It would have been obvious to one of ordinary skill in the art at the time of the invention to select the number of photodetectors, N, based upon the number of wavelengths desired to be detected. The greater variety of fluorochromes will require a greater number of detectors that can catch their responses. Additionally, the more detectors used, the smaller the range they can be focused upon which will minimize the noise. Selecting the exact number will be within ordinary skill in the art as the cost of extra detectors is balanced with the noise level and range of fluorochromes.
With respect to claims 28 and 29, Sakai discloses all of the limitations as applied to claim 10 above. However, Sakai discloses the plurality of detector modules having 5 detector channels with 5 photodetectors forming the detector chain. Sakai does not disclose either 8 or more or 16 or more channels and detectors.
It would have been obvious to one of ordinary skill in the art at the time of filing to scale Sakai’s plurality of banded detectors to 16. Having a greater number of spectral samples is a predictable count change and it has been held finding an optimum value of a result effective variable (result effective variable here being the number of spectral channels collected) involves only routine skill in the art. The specific numbers, 16 and 8, don’t seem to solve any particular problems.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA CAROLE BRYANT whose telephone number is (571)272-9787. The examiner can normally be reached on M-F, 12-4 pm.
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/REBECCA C BRYANT/Examiner, Art Unit 2877
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