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 .
Priority
The instant application was filed 06/26/2023 and is a national stage entry of PCT/US2021/065746 with an international filing date: 12/30/2021 which claims priority from provisional application 63132103 , filed 12/30/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/27/2023, 12/11/2023, 3/15/2024, 6/10/2024, 9/13/2024, 12/12/2024, 3/10/2025 , 6/5/ is being considered by the examiner.
Claim Objections
Claim 146 is objected to because of the following informalities:
Claim 146 is objected to as it recites “DAPI” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 144-163 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.
Independent claim 144 is drawn to a method of decreasing hybridization of analytes from a biological sample to capture probes in an area of an array that is not covered by the biological sample, the method comprising: (a) contacting the biological sample with the array, wherein the array comprises a plurality of capture probes, wherein a capture probe comprises: (i) a cleavage domain; (ii) a spatial barcode, and (iii) a capture domain; and (b) cleaving the cleavage domain of the plurality of capture probes not covered by the biological sample, thereby releasing the plurality of capture probes from the area of the array not covered by the biological sample and decreasing hybridization of analytes from the biological sample in the area of the array not covered by the biological sample.
The claims thus encompass any biological sample, any array, any capture probes comprising any cleavage domain, any spatial barcode, and any capture domain.
The specification provides no limiting definition of a biological sample. Thus the claims encompass any sample from any species. This includes any bodily fluid, isolated nucleic acid, isolated proteins, cells, tissues, fixed samples, frozen samples, etc.
The specification provides no standard or definition or standard of what is required of an array. Thus this is an enormous genus.
The specification teaches, “ The "capture domain" can be an oligonucleotide, a polypeptide, a small molecule, or any combination thereof, that hybridizes or hybridizes specifically to a desired analyte, ligation product, or analyte capture agent. In some embodiments, a capture domain can be used to capture or detect a desired analyte. (page 27)” Thus this encompasses an enormous genus.
The specification teaches, “A "spatial barcode" is a contiguous nucleic acid segment or two or more non-contiguous nucleic acid segments that function as a label or identifier that conveys or is capable of conveying spatial information. In some embodiments, a capture probe includes a spatial barcode that possesses a spatial aspect, where the barcode is associated with a particular location within an array or a particular location on a substrate. “(page 31) The specification provides no specific guidance on how to attach such a spatial barcode to a polypeptide or small molecule. Further the claims provide no specific order for the cleavage domain, spatial barcode and capture domain.
Dependent claims provide limitations with respect to photocleavable linkers, restriction enzymes, CRISPR, RNAse, DNase, etc. to provide for cleavage.
The claims provide no specific guidance on how to selectively cleave probes not covered by the biological sample while leaving the probes covered by the biological sample intact. One of skill in the art recognizes reagents diffuse and light penetrates cells and thin tissue slices.
While some dependent claim recite, “the method further comprises hybridizing a cleavage probe to the cleavage domain of the capture probe in the area of the array not covered by the biological sample.” It is unclear how the cleavage probe is limited to this area/ Further as it is further comprising, it includes doing so after step (b) of claim 144.
Thus the claims fail to provide adequate written description on how to decrease hybridization of analytes from the biological sample in the area of the array not covered by the biological sample.
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.
Claim144-163 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 144 recites, “b) cleaving the cleavage domain of the plurality of capture probes not covered by the biological sample.” The recitation is vague unclear and incomplete as it merely provides an intended outcome but provides no indication on how this is done
Claim 150 recites, “the method further comprises hybridizing a cleavage probe to the cleavage domain of the capture probe in the area of the array not covered by the biological sample.” The claim is vague and unclear how and when this is done. The further comprising suggests it happens after step (b). However, step (b) provides for the cleavage of the cleavage domain. Further the context of the claim implies the cleavage probe is limited to the capture probes not covered by the sample, but probes would have to be in some liquid and thus would diffuse into areas covered by the sample. Thus the claim is vague and unclear.
Claim 163 recites, “wherein the array comprises one or more features. The specification states, “A "feature" is an entity that acts as a support or repository for various molecular entities used in spatial analysis.” (page 21) Thus it appears an array can encompass a single feature, which could be interpreted as a single capture probe. Thus the claim is confusing and unclear.
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 144-163 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Williams (WO2020243579) .
The applied reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
With regards to claim 144, Williams discloses a method of determining a location of an analyte in a biological sample (e.g. tissue sample), using arrays of capture probes comprising a linker / cleavage domain, a spatial barcode and a capture domain. Williams teaches the cleavage domain/ linker is a photo-sensitive chemical bond ((p. 53, Il. 7-33; p. 55, Il. 5-29; p. 60, 1. 9 - p. 61, I. 20; p. 139, Il. 8-33; Fig. 10) Williams teaches A biological sample may be contacted with only a portion of an array. Capture probes on an array may be deactivated or eliminated outside of areas corresponding to regions of interest of a biological sample. A mirror, mirror array, a lens, a moving stage, and/or a photomask can be used to direct the light to regions of the array that correspond to areas outside one or more regions of interest in the biological sample. Some embodiments include deactivating or eliminating capture probes, e.g., capture probes comprising a photocleavable bond using light, cf. p. 139, Il. 8-33
With regards to claims 145-146, Williams teaches, “ In some instances, imaging is done using a brightfield microscope. In some instances, the biological sample is stained using H&E and then imaged using a brightfield microscope. In some instances, the biological sample is examined for detection of one or more immune infiltrates. In some instances, detection of one or more immune infiltrates is performed on a biological sample that has been stained using H&E.”
With regards to claims 147-149, Williams teaches, “ cases, photo-masks can be used such that only specific regions of the array are exposed to cleavable stimuli (e.g., exposure to UV light, exposure to light, exposure to heat induced by laser). When a photo-cleavable linker is used, the cleavable reaction is triggered by light, and can be highly selective to the linker and consequently biorthogonal. Typically, wavelength absorption for the photocleavable linker is located in the near-UV range of the spectrum. In some embodiments, /.max of the photocleavable linker is from about 300 nm to about 400 nm, or from about 310 nm to about 365 nm. In some embodiments, max of the photocleavable linker is about 300 nm, about 312 nm, about 325 nm, about 330 nm, about 340 nm, about 345 nm, about 355 nm, about 365 nm, or about 400 nm.”
With regards to claim 150-155, Williams teaches, “ For example, the substrate can be contacted with a nucleic acid molecule that hybridizes to the cleavage domain of the capture probe to provide or reconstitute a nickase recognition site, e.g., a cleavage helper probe. Thus, contact with a nickase enzyme will result in cleavage of the cleavage domain thereby releasing the capture probe from the feature. Such cleavage helper probes can also be used to provide or reconstitute cleavage recognition sites for other cleavage enzymes, e.g., restriction enzymes.” Williams also teaches cleavage of probes by CRISPR/cas9
With regards to claims 157-158, “In some embodiments, a laser, e.g., a scanning laser, can be used to deactivate or eliminate capture probes. In some embodiments, the eliminated member of the plurality of capture probes can be washed away. “
With regards to claims 159-160, Williams teaches, “n some embodiments, biological analytes (e.g., DNA, RNA, proteins, metabolites, small molecules, and lipids) are released and captured onto the spatially barcoded microcapillary array, preserving their spatial information.
With regards to claims 161-162, Williams teaches, “Methods disclosed herein can be performed on any type of sample. In some embodiments, the sample is a fresh tissue. In some embodiments, the sample is a frozen sample. In some embodiments, the sample was previously frozen. In some embodiments, the sample is a fixed sample, for example a formalin-fixed, paraffin embedded (FFPE) sample.”
With regards to claim 163, Williams teaches, “: a feature can include capture probes that can participate in an assay of at least three different types of analytes via three different capture domains.”
Summary
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/ Primary Examiner, Art Unit 1683