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 .
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on June 18, 2024, November 20, 2024, February 27, 2025, April 15, 2025, August 19, 2025, August 27, 2025 and November 5, 2025 meet the requirements of 37 CFR 1.97 and 1.98 and therefore have been considered by the examiner and placed in the file.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation (BRI) using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The BRI of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification.
In the following, some of the terms in the claims have been given BRIs in light of the specification. These BRIs are used for purposes of searching for prior art and examining the claims, but cannot be incorporated into the claims. Should Applicant believe that different interpretations are appropriate, Applicant should point to the portions of the specification that clearly support a different interpretation.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 62 is 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 62, which depends from claim 55, recites the limitation "said property", but the term “property” is not recited in claim 55 or earlier in claim 62. Therefore, there is insufficient antecedent basis for this limitation. In addition, because it is unclear what “property” the claim is referring to, the meaning of the claim cannot be ascertained. Some of the language recited in claim 62 is used in paras. [0003] and [0007] of the present specification, but the meaning of the claim is impossible to determine from the claim language or from what appear to be corresponding portions of the specification.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 55-57, 59-61, 63-67, 69, 70 and 72-74 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WIPO Publication No. WO 2019/199579 A1 to Wang et al. (hereinafter referred to as “Wang”).
Regarding claim 55, Wang discloses a method, comprising:
(a) receiving a plurality of images of a sample comprising an amplicon with a barcode molecule associated therewith (para. [0004], the in situ tissue samples have amplicons fixed thereto that comprise barcode sequences; para. [0099]-[00113] discuss different imaging modalities that are suitable for obtaining images of the samples: “[t]he methods disclosed include imaging the one or more hydrogel-embedded amplicons using any of a number of different types of microscopy, e.g., confocal microscopy, two- photon microscopy, light-field microscopy, intact tissue expansion microscopy, and/or CLARITY™-optimized light sheet microscopy (COLM)”; para. [0058] discusses adding the barcode to the sample during the amplification process that generates the amplicon);
(b) measuring a multi-channel fluorescent signal of said barcode molecule for each image of said plurality of images, to thereby yield a plurality of multi-channel fluorescent signals (para. [00150] discusses a multi-channel measurement of optical signals (i.e., at least four color channels) and paras. [0087] and [00114]-[00115] are examples of portions of Wang that discuss that the signals that are detected are fluorescent signals);
(c) computer processing said plurality of multi-channel fluorescent signals to identify said barcode molecule (para. [0058] discusses identifying the barcode sequence of the amplicon to thereby identify the target nucleic acid of the amplicon; paras. [00124]-[00128] discuss the processor unit that performs the method); and
(d) upon identifying said barcode molecule, identifying said amplicon (para. [0058] discusses identifying the barcode sequence of the amplicon to thereby identify the target nucleic acid of the amplicon).
Regarding claim 56, Wang discloses that step (c) of claim 55 comprises for each image of said plurality of images, determining an identity of said barcode molecule by
(i) determining a signal in a channel of said multi-channel fluorescent signal,
(ii) using said signal to determine a portion of an identity of said barcode molecule, and
(iii) repeating (i) and (ii) for each other image of said plurality of images, thereby determining a sequence of said barcode molecule (paras. [00147]-[00171] disclose that during the experiment the process of determining the barcode sequence was an iterative process of acquiring image signals, measuring the acquired image signals, registering the images, and processing the registered images until the entire barcode sequence has been identified).
Regarding claim 57, Wang discloses using a machine learning algorithm to perform a segmentation process that processes the fluorescent signals to identify the barcode molecule (para. [00186]).
Regarding claim 59, the claim recites that the plurality of images is acquired over a time period of at least 3 days. The present specification makes no reference to image acquisition occurring over any particular time period, much less over a time period of at least 3 days. Para. [0179] of the present specification describes the final results of the method being obtained in 3 or 4 days, but the method involves steps in addition to the image acquisition step. For these reasons, the BRI for this limitation is that it means that the result obtained in step (d) of claim 1 is the result of performing the method over a period of time of at least 3 days. Wang discloses this limitation (para. [00129]: “”[e]xamples of advantages of the methods described herein include efficiency, where it takes merely 3 or 4 days to obtain final data from a raw sample….”).
Regarding claim 60, Wang discloses that the signal is a fluorescent wavelength or a fluorescent intensity (paras. [0087] and [00114]-[00115] are examples of portions of Wang that discuss that the signals that are detected are fluorescent signals; fluorescent signals having both fluorescent wavelengths and fluorescent intensity, as is known in the art).
Regarding claim 61, Wang discloses determining a copy number of nucleic acid molecules in the amplicon (para. [0035: “[f]or example the methods can be used to detect copy number variants, e.g. in a cancer cell population in which a target nucleic acid is present at different abundance in the genome of cells in the population”).
Regarding claim 63, Wang discloses that the sample is an in situ sample (para. [0004]: “[t]he present disclosure provides a method for in situ gene sequencing of a target nucleic acid in a cell in an intact tissue….”).
Regarding claim 64, Wang discloses that the in situ sample is an in situ tissue sample (para. [0004]: “[t]he present disclosure provides a method for in situ gene sequencing of a target nucleic acid in a cell in an intact tissue….”).
Regarding claim 65, Wang discloses that each image of the plurality of images uses a different channel of said multi-channel fluorescent signal (paras. [00149]-[00151] disclose that in the four-color-channel experimental setup, each fluorescent image uses a different color channel where the images are represented by respective dots (each dot corresponding to a 7-pixel diameter channel)).
Regarding claim 66, the BRI for the term “applying configuration parameters”, based on para. [0003] of the present specification, is that it means applying one or more of an encoding scheme, a codebook, image acquisition parameters, and sample metadata. Wang discloses this limitation (para. [00151] discusses converting the barcode codebook color space based on 2-base encoding; see also para. [00173] discussing applying 2-base encoding for error correction; see also para. [00182] discussing applying I-base encoding).
Regarding claim 67, under MPEP 2111.04, Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed. In addition, when a claim requires selection of an element from a list of alternatives, the prior art teaches the element if one of the alternatives is taught by the prior art. See, e.g., Fresenius USA, Inc. v. Baxter Int’l, Inc., 582 F.3d 1288, 1298, 92 USPQ2d 1163, 1171 (Fed. Cir. 2009). The BRI for the claim limitation “configuration parameters comprise an encoding scheme, a codebook, image acquisition parameters, or sample metadata” is that the claim requires any one or more of the listed items. Wang expressly discloses at least the encoding scheme list item and the codebook list item (para. [00151] discusses converting the barcode codebook color space based on 2-base encoding; see also para. [00173] discussing applying 2-base encoding for error correction; see also para. [00182] discussing applying I-base encoding).
Regarding claim 69, Wang discloses prior to receiving the plurality of images of the sample comprising the amplicon with the barcode molecule associated therewith, registering said plurality of images (para. [00149], under the image registration heading, registering the plurality of images is discussed, which occurs prior to receiving and processing the images to identify the barcode molecule).
Regardinjg claim 70, Wang discloses that the identifying step comprises sequencing because the barcode comprises a sequence (para. [0058]) that is decoded via a sequencing process to identify the barcode sequence (paras. [00147]-[00171] discuss imaging and sequencing processes that are performed to identify the barcode molecule).
Regarding claim 72, for the reasons stated above in the rejection of claim 67, the BRI for this claim is that the claim requires any one or more of the recited alternatives. (Wang discloses that the plurality of images further comprises morphological information, para. [0079], “the improved sequencing-by-ligation method herein includes operating at room temperature for best preservation of tissue morphology with low background noise and error reduction”; paras. [0032], [0044], [0085], [00134] and [00136] disclose that the plurality of images comprises sequential readout amplicon data).
Regarding claim 73, Wang discloses that prior to receiving and processing the images of the samples comprising the amplicons with barcode molecules, a cell segmentation process is performed that segments the sample into a plurality of images of single cells of the sample (paras. [00152]-[00153] discuss 2D cell segmentation of the images followed by single-cell processing of the segmented image data).
Regarding claim 74, Wang discloses that the segmenting includes semi-manual segmenting of the plurality of images (para. [00152] discloses that the 2D cell segmenting of the image data is semi-manually performed based on the maximum intensity projection of the DAPI channel following the final round of sequencing).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 58 is rejected under 35 U.S.C. 103 as being unpatentable over Wang in view of U.S. Publ. Appl. No. 2022/0084629 A1 to Shah (hereinafter referred to as “Shah”).
Regarding claim 58, Wang does not explicitly disclose using a machine learning algorithm to perform the image registration process. Shah, in the same field of endeavor, discloses using a machine learning algorithm to perform a variety of tasks including image registration (Shah, para. [0190]). It would have been obvious to one of ordinary skill in the art, before the effective filing date of the present disclosure, to substitute the image registration machine learning algorithm of Shah for the registration algorithm of Wang. One of ordinary skill in the art would have been motivated to make the modification to take advantage of the well-known benefits of using machine learning algorithms in image processing/analysis applications to improve the robustness of the registration algorithm, thereby reducing barcode decoding and identification errors as taught by Shah. The modification could have been made by one of ordinary skill in the art before the effective filing date of the present disclosure with a reasonable expectation of success because making the modification merely involves combining prior art elements according to known methods to yield predictable results (modifying and/or replacing software executed by the processor of Wang that performs image registration).
Claim 68 is rejected under 35 U.S.C. 103 as being unpatentable over Wang in view of U.S. Publ. Appl. No. 2024/0254545 A1 to Wang et al. (hereinafter referred to as “Wang 2”) and further in view of U.S. Publ. Appl. No. 2023/0238078 A1 to Gonzalez Lozano et al. (hereinafter referred to as “Lozano”).
Claim 68 recites performing several preprocesses that are well known in the art. Merging of overlapping fields of view of images is performed as a normal part of the image registration process. Wang discloses performing an image registration process during which overlapping fields of view of the images are merged in order to register and align the image data (paras. [00149]-[00152]). Wang also discloses performing preprocessing filtering to remove optical aberrations in cases where a fluorescence microscope is used for image acquisition (para. [00106]). Although Wang does not explicitly disclose using deconvolution and background subtraction, these preprocesses are commonly used in the art.
Wang 2, in the same field of endeavor, discloses performing deconvolution of image data as a preprocess to the amplicon decoding process (para. [0326]).
Lozano, also in the same field of endeavor, discloses performing background subtraction by subtracting at the minimum local intensity gradient from the image data. The minimum local intensity gradient corresponds to background (para. [0396]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the present disclosure, to apply the preprocesses of deconvolution and background subtraction as taught by Wang 2 and Lozano, respectively, in conjunction with the merging and filtering preprocesses disclosed in Wang. One of ordinary skill in the art would have been motivated to make the modification to reduce optical distortion and remove noise in the image data that can lead to errors in barcode decoding and amplicon identification. The modification could have been made by one of ordinary skill in the art before the effective filing date of the present disclosure with a reasonable expectation of success because making the modification merely involves combining prior art elements according to known methods to yield predictable results (employing known preprocesses in combination with one another to reduce or eliminate barcode decoding and amplicon identification errors).
Claim 71 is rejected under 35 U.S.C. 103 as being unpatentable over Wang in view of Lozano.
Wang does not explicitly disclose that the computer processing is performed on a cloud. Lozano discloses using a cloud computing system to process image data sets comprising molecular measurement data of a biological sample (paras. [0482]-[0483]). It would have been obvious to one of ordinary skill in the art, before the effective filing date of the present disclosure, to use a cloud computing system as the computing system of Wang to enable the computer processing of Wang to be performed in the cloud as taught by Lozano. A person of ordinary skill in the art would have been motivated to make the modification to take advantage cloud-based resources such as data centers that employ processors equipped with artificial intelligence (AI). The modification could have been made by one of ordinary skill in the art before the effective filing date of the present disclosure with a reasonable expectation of success because making the modification merely involves combining prior art elements according to known methods to yield predictable results (moving on-premises operations to a cloud-based data center).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANIEL J SANTOS whose telephone number is (571)272-2867. The examiner can normally be reached M-F 9-5.
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/DANIEL JOSEPH SANTOS/Examiner, Art Unit 2667
/MATTHEW C BELLA/Supervisory Patent Examiner, Art Unit 2667