Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Specification
2. The use of trade names or marks used in commerce (including but not necessarily limited to Illumina, PacBio, etc.), has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Priority
3. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62952736, 62969458, 63087061, 63108088, and 17220529, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Each of these priority documents only make general mention of critical claim limitations such as: cell nucleus/nuclei, a cellular capture probe, a cellular barcode (especially in the context of an array), and an analyte capture probe. Therefore, the claims are afforded the priority date of the application as filed December 12, 2025.
Claim Rejections - 35 USC § 112
4. 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.
5. Claims 2-21 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 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. Claim 2, lines 1, 5, 10-12, 14, 18, 20 and 25 recite limitations related to a cell nucleus/nuclei, cellular capture probes, spatially-tagged cell nuclei and analyte capture probes are not described in the specification in such a way as to provide basis for this claim. Additionally, these limitations are not present in the claims as originally filed, therefore these limitations lack written description and constitute new matter.
6. 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.
7. Claims 2-21 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.
A. Claim 2 of the instant application recites the phrases “cellular capture probe,” “cellular barcode,” and “analyte capture probe” throughout the claim. There is no mention of these features in the specification or in the originally filed claims, and the claim language provides no insight into the nature of these features or where they originate in the method. Are these alternate names for features or sequences in the instant claim? Are they separate and distinct oligonucleotide sequences present in the assay or added after the fact? The nature of these features and their intended limitations to the claimed method are unclear and therefore this claim is indefinite.
B. Claims 3-21 are rejected for being dependent on a previously rejected claim.
Claim Rejections - 35 USC § 103
8. 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.
9. 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.
10. Claims 2, 3, 6-11 and 13-21 are rejected under 35 U.S.C. 103 as being unpatentable over Russell et al (Slide-tags enables single-nucleus barcoding for multimodal spatial genomics, Nature, 625, 101-109, published 13 December 2023) in view of Credle et al (Multiplexed analysis of fixed tissue RNA using ligation in situ hybridization, Nucleic Acids Research, 45, 14, e128, published 19 June 2017). This rejection is further evidenced by “Chromium Single Cell 3' Reagent Kits User Guide (v3.1 Chemistry)” Revision D, published 12 July 2022.
Regarding claim 2, Russell teaches a method for spatially tagging a nucleic acid analyte from a cell nucleus (abstract and FIG 1). Russell teaches a first substrate, comprising a tissue section (“the punched tissue regions were the placed onto the puck…” pg. 11, column 1 ¶ 1) wherein the tissue section comprises a plurality of cell nuclei (FIG 1), and a second substrate (“the puck was placed onto the glass slide…” pg. 11, column 1, ¶ 1). In this embodiment the bead array is on the puck, and the puck is on the glass slide, therefore the glass slide inherently ‘comprises a bead array.’ Russell teaches that the bead array comprises a plurality of spatial capture probes, each comprising a spatial barcode and a capture domain (i.e., a sequence complementary to a capture domain of a cellular capture probe, wherein the cellular capture probe comprises a cellular barcode, wherein the cell barcode identifies a cell nucleus among the plurality of cell nuclei; FIG 1, pg. 2 column 1 ¶ 2, pg. 11 column 1 ¶ 2). In this embodiment, the cellular capture probe comprising a cellular barcode is a capture sequence (e.g., capture sequence 1) from a single cell 3' GEM bead from the 10X single cell kit as evidenced by the Chromium Single Cell 3' Reagents Kit User guide pg. 14. Russell teaches that the spatial capture probes are cleaved from the bead array to interact with the cell nucleus to generate a spatially-tagged cell nucleus (FIG 1).
Russell does not teach steps (c) – (g) of instant claim 2.
However, Credle teaches a method wherein RNA is specifically detected from a tissue section (abstract) comprising: contacting the tissue section with a plurality of first probes and a plurality of second probes (e.g., first and second probes for each of RPS19 mRNA and GAPDH mRNA; FIG 2) wherein the first probes and the second probes each comprises a sequence that is substantially complementary to the nucleic acid analyte (i.e., the mRNA target; FIG 1). Credle teaches that each of the first and second probes comprise a universal adapter (FIG 1) and without further limitation to the claims either of these universal adapters are considered a capture probe domain that is complementary to a capture domain of an analyte capture probe comprising a cellular barcode (e.g., capture sequence 2, evidenced by Chromium Single Cell 3' Reagents Kit User guide pg. 14). Credle teaches hybridizing the first probe and the second probe to a nucleic acid analyte, ligating the first probe and the second probe to generate a ligation product, digesting the RNA (i.e., releasing the ligation product from the nucleic acid analyte), and hybridizing the ligation product to a PCR primer to prepare a sequencing library (FIG 1 and pg. 3 column 2 ¶ 3).
It would have been obvious to one having ordinary skill in the art to have modified the method taught by Russell to include the RNA detection steps taught by Credle, and to further modify the universal adapters of Credle to be complementary to one of the capture sequences of the 10X genomics GEM beads taught by Russell to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make these modifications because Credle specifically teaches that ligation-probe-based assays are capable of highly multiplexed RNA detection, with high sensitivity while being compatible with routine tissue stains for the analysis of tissue fragments (pg. 8 column 1 ¶ 4). In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the analysis of nucleic acid analytes in tissue sections.
Regarding claim 3, Credle teaches that the first probe and the second probe hybridize to adjacent sequences of the nucleic acid analyte (FIG 1).
Regarding claim 6, Credle teaches that the first and second probes are hybridized at 60 C (pg. 3 column 1 ¶ 1).
Regarding claims 7 and 8, Credle teaches that the first and second probes are ligated with Rnl2 (FIG 1 and pg. 3 column 1 ¶ 1).
Regarding claim 9, Credle teaches that the ligation product is released by contacting the tissue section with RNase H (FIG 1 and pg. 2 column 2 ¶ 3).
Regarding claim 10, Credle teaches that the first and second probe comprise universal adapter sites (i.e., a primer binding site; FIG 1).
Regarding claim 11, Russell teaches that the nucleic acids are captured by GEM beads comprising a polyT sequence (Russell pg. 11 column 1 ¶ 2 and evidenced by Chromium Next GEM Single Cell 3' Reagent Kits v3.1 pg. 14).
Regarding claim 13, Russell teaches that the tissue section is stained using hematoxylin and eosin (FIG 3 and associated caption).
Regarding claims 14 and 15, Credle teaches that the tissue section is treated with pepsin (i.e., a permeabilization agent; pg. 2 column 2 ¶ 4).
Regarding claim 16, Credle teaches that the nucleic acid analyte is mRNA (FIGs 1 and 2, pg. 2 column 1 ¶¶ 1 and 2).
Regarding claims 17 and 18, the combination of Russell in view of Credle teaches the capture of the ligation product and the nuclei tags on GEM beads (which comprise the cellular barcode) for sequencing (Russell pg. 11 column 1 ¶ 2 and evidenced by Chromium Next GEM Single Cell 3' Reagent Kits v3.1 pg. 14). It is noted hear that the spatial tag in the nucleic determines the location of the sample, but due to GEM bead capture the spatial barcode is associated directly with the cellular barcode and the cellular barcode is associated directly with the ligation product. Therefore knowing the spatial barcode and the associated cellular barcode inherently means that knowing the cellular barcode or the ligation product and its associated barcode also identify the location of the nucleic acid analyte in the tissue sample.
Regarding claim 19, Russell teaches that the puck (i.e., the first substrate) is placed on the glass slide (i.e., the second substrate; pg. 11 column 1 ¶ 1) prior to cleaving the spatial capture probes. Without further limitations to this claim any placement of one substrate on another comprises “aligning” these substrates.
Regarding claim 20, Russell teaches that the tissue section is a fresh-frozen tissue section (pg. 10 column 2 ¶ 7).
Regarding claim 21, Credle teaches that the tissue section is an FFPE tissue section (FIG 1).
11. Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Russell et al (Slide-tags enables single-nucleus barcoding for multimodal spatial genomics, Nature, 625, 101-109, published 13 December 2023) in view of Credle et al (Multiplexed analysis of fixed tissue RNA using ligation in situ hybridization, Nucleic Acids Research, 45, 14, e128, published 19 June 2017) as applied to claim 2 above, and further in view of So et al (United States Patent Application No US20180245142, published 30 August 2018).
Regarding claims 4 and 5, the combination of Russell in view of Credle teach the method of claim 2 as discussed fully above and incorporated here. Neither Russell nor Credle teaches that the first probe and the second probe hybridize to non-adjacent sequences of the nucleic acid analyte, nor do they teach extending the first or second probe with a DNA polymerase, thereby filling the gap between the first probe and the second probe and generating an extended first probe and/or an extended second probe.
However, So teaches an embodiment wherein a tissue section is placed on an array and a first and second probe are added to the tissue section wherein they hybridize to non-adjacent sequence of a nucleic acid analyte (FIG 9). So further teaches that the first probe is extended with a DNA polymerase to fill a gap between the first and second probe and generating an extended first probe (FIG 9 and [0181] and [0182]).
It would have been obvious to one having ordinary skill in the art to have substituted the RNA probes taught by the combination of Russell in view of Credle with the genomic DNA capture probes taught by So to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make this substitution in order to capture, and therefore determine the sequence of, region of a genome to more readily identify therapeutically relevant mutations. In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the capture and sequencing of nucleic acids in tissue samples.
12. Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Russell et al (Slide-tags enables single-nucleus barcoding for multimodal spatial genomics, Nature, 625, 101-109, published 13 December 2023) in view of Credle et al (Multiplexed analysis of fixed tissue RNA using ligation in situ hybridization, Nucleic Acids Research, 45, 14, e128, published 19 June 2017) as applied to claim 2 above, and further in view of Larman et al (United States Patent Application No. US20230039899, published 09 February 2023).
Regarding claim 12, the method of claim 2 is discussed fully above and incorporated here. Credle teaches that multiplexed nucleic acid detection can be performed on the order of >100-plex (abstract), but does not teach that the first and second probes are a probe pair of 5000 probe pairs.
However, Larman teaches a split probe detection method (i.e., a first a second probe of a probe pair; FIG 2) comprising a probe configured for the detection of 1-30,000 distinct target RNAs ([0011]). It is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01).
The courts have also found that “where the general conditions of a claim
are disclosed in the prior art, it is not inventive to discover the optimum or
workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105
USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 II.
Therefore, the claimed ranges merely represent an obvious variant and/or
routine optimization of the values of the cited prior art.
Double Patenting
13. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
14. Claims 2-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-21 of copending Application No. 19418014 in view of Russell et al (Slide-tags enables single-nucleus barcoding for multimodal spatial genomics, Nature, 625, published 13 December 2023).
The copending application teaches all of the limitations of instant claim 1, except for the limitations of steps (a) and (b), in copending claims 2, 6 and 8.
However, Russell teaches these limitations as discussed fully above and incorporated here.
It would have been obvious to one having ordinary skill in the art to have modified the copending claims with the limitations taught by Russell to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make these modifications in order prepare the composition disclosed in copending claim 2. In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the tagging of nucleic acid analytes in spatially tagged cell nuclei.
The limitations of instant claims 3-5 and 7-21 are taught by copending claims 3-9 and 12-21 in view of Russell.
This is a provisional nonstatutory double patenting rejection.
15. Claim 6 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-21 of copending Application No. 19418014 in view of Russell et al (Slide-tags enables single-nucleus barcoding for multimodal spatial genomics, Nature, 625, published 13 December 2023), and further in view of Credle et al (Multiplexed analysis of fixed tissue RNA using ligation in situ hybridization, Nucleic Acids Research, 45, 14, e128, published 19 June 2017).
Neither the copending claims nor Russell teach the limitations of instant claim 6.
However, these limitations are taught by Credle as discussed fully above and incorporated here.
It would have been obvious to one having ordinary skill in the art to have modified the copending claims in view of Russell to have incorporated the limitations of instant claim 6 as taught by Credle to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make these modifications because Credle teaches specific probe hybridization temperatures that would have been useful in experimental design. In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the ligation of probes targeting nucleic acid analytes in tissue sections.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
16. Applicant's arguments filed 08 July 2026 have been fully considered but they are not persuasive.
Applicant’s remarks provide passages that they argue adequately demonstrate possession of the invention and should afford the application priority to the 62/952,736 provisional filed 23 December 2019. While the outlined sections describe cell nuclei and methods of spatially tagging cell nuclei, the disclosed sections do not provide adequate basis for the terms “cellular capture probe” and “analyte capture probe” as discussed fully above. Without proper written description of these terms in the context of the instant claims, applicant’s arguments are not considered persuasive, priority for the instant application is maintained as 12 December 2025 and the rejections provided in the Office Action dated 16 April 2026 are maintained.
17. THIS ACTION IS MADE FINAL. 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.
Conclusion
18. No claims are allowed.
19. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN ELLIS YOUNG whose telephone number is (703)756-5397. The examiner can normally be reached M-T 0800 - 1630.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached at (571) 272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRIAN ELLIS YOUNG/Examiner, Art Unit 1684
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
Prosecution Insights