DETAILED ACTION
Status of the Claims
Claims 2-21 are currently pending and are examined herein.
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 statement(s) (IDS) submitted on 08/30/2023, 11/14/2023, 02/08/2024, 05/03/2024, 08/14/2024, 11/13/2024, 02/24/2025, and 05/20/2025 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the examiner.
Objection to the Abstract
Applicant is reminded of the proper language, content, and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words. It is important that the abstract not exceed 150 words in length since the space provided for the abstract on the computer tape used by the printer is limited. The form and legal phraseology often used in patent claims, such as "means" and "said," should be avoided. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. In certain patents, particularly those for compounds and compositions, wherein the process for making and/or the use thereof are not obvious, the abstract should set forth a process for making and/or use thereof. If the new technical disclosure involves modifications or alternatives, the abstract should mention by way of example the preferred modification or alternative.
The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
Where applicable, the abstract should include the following:
(1) if a machine or apparatus, its organization and operation;
(2) if an article, its method of making;
(3) if a chemical compound, its identity and use;
(4) if a mixture, its ingredients;
(5) if a process, the steps.
The abstract of the disclosure is objected to because it does not relate enough information about the disclosed invention(s) needed to "…disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details”, as per MPEP 608.01(b). Applicant is instructed to amend the abstract accordingly.
Claim Rejections – 35 U.S.C. 103
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 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.
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.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Fodor et al., So et al., and Barany et al.
Claims 2, 6-13, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Fodor et al. (WO 2016/138496 A1, cited in IDS of 08/30/2023) in view of So et al. (WO 2017/019456 A2, cited in IDS of 08/30/2023) and further in view of Barany et al. (U.S. PGPub 2016/0319334 A1).
Regarding claim 2, Fodor discloses a method of determining a surgical margin of a tissue to be resected in a subject (e.g., using spatial barcodes to characterize the surface of a tissue sample in determining the boundaries of tumors, such as for resections as per para [075] and/or [0288]) comprising contacting a tissue section obtained from the subject with a plurality of spatial barcode probes (e.g., as per para [0006], [0010], [0061]-[0068], and/or [0093]-[0115]), wherein the tissue section is on a substrate (e.g., spatially analyzing tissue samples attached to a substrate as per para [0191]).
However, it is noted that Fodor is silent regarding the limitations that the spatial barcodes or labels comprise a plurality of first and second probes that hybridize to nucleic acids of the tissue, ligating said first and second probes to one another, wherein the second probe further comprises a capture domain to hybridize to capture probes immobilized on an array, and wherein the ligated probes are released from the tissue and captured on the array for spatial analysis, as set forth in claim 2.
So discloses methods of in situ hybridization of a plurality of first and second probes (e.g., probes 920 and 925 as shown in Fig. 9 of So) to a subject-derived, mounted tissue section (e.g., as per para [0125]-[0126]), followed by generating ligation products (e.g., 950 as shown in Fig. 9) that are released and captured to probes of an array (e.g., as shown in Fig. 9 and/or [0182]-[0183]), wherein the capture probes of the array comprise spatial barcodes to identify their locations (e.g., 130 as per Fig. 9 and para [0141]-[0142]).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to utilize a first and second probe as per So in the tissue mapping of Fodor. One of ordinary skill in the art would have been motivated to do so since the use of two probes increases specificity and reduces signal from non-specific binding of a single probe.
However, it is noted that So performs isothermal amplification after generating the ligation products and then captures these amplification products to the spatial array, rather than directly capturing the ligation products without amplification, as set forth in claim 2.
Barany discloses methods of generating adjacent ligation probe products, releasing/denaturing them, followed by capture to a capture array (e.g., as per para [0071]-[0072], [0089]).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to release/denature the probes as per Barany in the tissue mapping method as per Fodor and So. One of ordinary skill in the art would have been motivated to do so since doing so would reduce the time for processing and possibly reduce diffusion that might result from an additional amplification step.
One of ordinary skill in the art would have had a reasonable expectation of success as of the application’s effective filing date in combining the teachings of the prior art references to arrive at the invention as presently claimed since all three references were in the same field of endeavor and used established molecular biology techniques that were within reach of the skilled artisan.
Regarding the limitation in claim 2 of (f) comparing the presence of the ligation product at the location in the tissue section to presence of the ligation product at one or more different locations in the tissue section, and determining the surgical margin of the tissue to be resected from the subject based on the comparison, it would have been obvious to compare the presence of the reporters for selected tumor-associated sequences in the tissue and use that comparison to outline a surgical margin and help identify the extent of tissued needing to be removed, as per the combined references.
Regarding claim 6, So discloses the above, wherein the array is on a second substrate, and wherein the method further comprises aligning the substrate with the second substrate comprising an array, such that at least a portion of the tissue section is aligned with at least a portion of the array (e.g., as per para [0226]-[0227]).
Regarding claim 7, Fodor discloses the above, wherein the tissue is an infected tissue, a necrotic tissue, a diseased tissue, or a tissue comprising a tumor (e.g., as per para [0239]).
Regarding claim 8, Fodor discloses the above, wherein the infected tissue is infected by a bacterium, a virus, a fungus, a parasite, and/or a protozoan (e.g., as per para [0240]).
Regarding claim 9, Fodor discloses the above, wherein the subject is a human suspected of or diagnosed as having a cancer (e.g., as per para [0239]).
Regarding claim 10, Barany discloses the above, wherein the first probe and the second probe are substantially complementary to adjacent sequences of the nucleic acid (e.g., adjacent probe binding sites as per para [0071]).
Regarding claims 11-12, So discloses the above, where the first probe and the second probe hybridize to sequences that are not adjacent to each other on the nucleic acid and wherein the first probe is extended with a DNA polymerase, thereby (i) filling in a gap between the first probe and the second probe and (ii) generating an extended first probe (e.g., polymerase-mediated gap filling as per So in Fig. 9).
Regarding claim 13, Barany discloses the above, wherein the generating the ligation product comprises ligating the first probe to the second probe using T4 DNA ligase (e.g., Barany para [0102] and/or Fodor para [0197]).
Regarding claim 20, the tissue section was obtained from the subject (e.g., as per taught by Fodor in para [0239] and/or by So in para [0125]).
Fodor et al., So et al., Barany et al., and Imler et al
Claims 2, 4-13, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Fodor et al. (WO 2016/138496 A1, cited in IDS of 08/30/2023) in view of So et al. (WO 2017/019456 A2, cited in IDS of 08/30/2023) and further in view of Barany et al. (U.S. PGPub 2016/0319334 A1) and further in view of Imler et al. (U.S. PGPub 2018/0237864 A1, cited in IDS of 08/30/2023).
Fodor in view of So and further in view of Barany is relied on as above, however, the references are silent as to the limitations of wherein the presence of the nucleic acid at the location in the tissue section is increased/decreased compared to the presence of the nucleic acid at the different location in the tissue section, wherein the different locations in the tissue section are locations of non-cancerous tissue and/or non-tumor tissue, as set forth in claims 4-5, as well as wherein the tissue section was previously fixed and/or stained, wherein the tissue section was previously stained by hematoxylin, eosin, immunohistochemistry, and/or immunofluorescence, as set forth in claim 21.
Imler similarly discloses methods of pairs of probes being ligated, including in situ tissue related studies of released and captured probes (e.g., as per para [0023]-[0026], [0074]-[0076], and/or [0107]-[0108]). Further, Imler discloses H&E stained tissue and diagnostic gene differential expression analysis as per Fig. 5 and/or Example 5.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to correlate the methods of Fodor in view of So and further in view of Barany with the differential gene expression analysis as per Imler. One of ordinary skill in the art would have been motivated to do so since such differences in gene expression can reasonably aid in defining the boundary between healthy tissue and tumor.
One of ordinary skill in the art would have had a reasonable expectation of success as of the application’s effective filing date in combining the teachings of the prior art references to arrive at the invention as presently claimed since it merely requires the addition of an analysis step of gene expression, wherein specific genes were shown useful in distinguishing cancer vs. healthy tissue.
Fodor et al., So et al., Barany et al., and Larman et al
Claims 2, 6-13, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Fodor et al. (WO 2016/138496 A1, cited in IDS of 08/30/2023) in view of So et al. (WO 2017/019456 A2, cited in IDS of 08/30/2023) and further in view of Barany et al. (U.S. PGPub 2016/0319334 A1) and further in view of Larman et al. (U.S. PGPub 2018/0208967 A1, cited in IDS of 08/30/2023).
Fodor in view of So and further in view of Barany is relied on as above, however, the references are silent as to the limitations of further determining (i) all or a part of a ligation product sequence corresponding to the nucleic acid hybridized to the capture domain or a complement thereof, and (ii) the spatial barcode or a complement thereof, and using the determined sequences of (i) and (ii) to identify the presence of the nucleic acid at the location in the tissue section, as set forth in claim 3, as well as wherein the nucleic acid is mRNA and the releasing the ligation product from the nucleic acid comprises contacting the tissue section with RNase H enzyme, as set forth in claims 14-19.
Larman discloses methods of annealing and ligating multi-part probes to mRNA in a sample using RNase H to release (e.g., as per the Abstract, para [0084]-[0087], [0131]-[0135], and/or [0138]-[0140]). Larman combined with So (specifically at para [0258]-[0265]) also discloses extending a 3' end of the capture probe using the hybridized ligation product as a template to generate an extended capture probe, as set forth in claim 18 and generating a single-stranded nucleic acid comprising a nucleic acid sequence that is complementary to all or a part of the extended capture probe, as set forth in claim 19.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to extend the methods of Fodor in view of So and further in view of Barany to mRNA as per Larman. One of ordinary skill in the art would have been motivated to do so since such a combination would not require RNA extraction or reverse transcription, advantageously saving time and increasing sensitivity (e.g., as per Larman in para [0098]).
Given the teachings of the prior art and the level of the ordinary skilled artisan at the time of the application’s effective filing date, it must be considered, absent evidence to the contrary, that said skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
Conclusion
No claims are allowed.
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/JEREMY C FLINDERS/
Primary Examiner, Art Unit 1684
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