Office Action 1: Non-Final Rejection (2024-12-05)
Rejection types: Double Patenting

CLAIMS:
AMENDMENTS TO THE CLAIMS

1\. (Currently Amended) A method of generating a spatial transcriptomics gene expression image having subcellular resolution, comprising:a. providing a flat array surface comprising- high density clusters of probes , wherein each probe comprises a spatial barcode sequence and a capture domain; and wherein a location of each cluster on said flat array surface is known;
Eb.contacting said flat array surface with a tissue section under conditions such that RNA from cells in said tissue section hybridizes to said capture domain of said probes;
d-c.reverse transcribing target sequences from said RNA on 3' ends of said probes;
e-d generating second strand copies of said probes and eluting said second strand copies from said array;
f-e.generating a sequencing library from eluted second strand copies;
gf. sequencing said sequencing library to generate sequencing data; and
h-g.generating a spatial transcriptomics gene expression image having subcellular resolution from said sequencing data.

2\. (Original) The method of claim 1, wherein each probe in a given cluster comprises an identical spatial barcode sequence, and wherein said spatial barcode sequence for each cluster is unique.

3\. (Original) The method of claim 1, wherein said flat array surface comprises 0.5-2 million clusters per 1mm2 of surface.

4\. (Original) The method of claim 3, wherein said flat array surface comprises about 1.5 million clusters per 1mm2 of surface.

5\. (Original) The method of claim 1, wherein each cluster comprises at least 200 probes.

6\. (Currently Amended) The method of claim 1, wherein each cluster comprises at least 500 robes.

7\. (Currently Amended) The method of claim 1, wherein each cluster comprises at least 800 probes.

8\. (Currently Amended) The method of claim1, wherein each cluster has a diameter of 500-1200nm.

9\. (Original) The method of claim 8, wherein each cluster has an average diameter of 0.6pm.

10\. (Original) The method of claim 1, wherein said flat array surface comprises a material selected from glass, silicon, poly-L-lysine coated materials, nitrocellulose, polystyrene,cyclic olefin copolymers (COCs), cyclic olefin polymers (COPs), polyacrylamide,
polypropylene, polyethylene and polycarbonate.

11\. (Original) The method of claim 1, wherein said capture domain is identical for each probe.

12\. (Original) The method of claim 1, wherein said capture domain comprises a poly-T oligonucleotide comprising at least 10 deoxythymidine residues.

13\. (Original) The method of claim 1, wherein each probe further comprises a sequencing barcode.

14\. (Original) The method of claim 1, wherein each probe further comprises one or more filler sequences.

15\. (Original) The method of claim 1, wherein each probe further comprises a unique molecular identifier (UMI) barcode sequence.

16\. (Original) The method of claim 1, wherein each probe further comprises a cleavage domain comprising a binding site for a restriction endonuclease.

17\. (Original) The method of claim 1, further comprising imaging the tissue before or after reverse transcribing target sequences from said RNA on 3' ends of said probes.

18\. (Original) The method of claim 17, further comprising correlating the identified location of each cluster on said flat array surface with a corresponding location within said tissue section.

19\. (New) The method of claim 1, wherein the distance between centers of said clusters is 1 pm or less.

20\. (New) The method of claim 1, wherein said clusters are produced by bridge amplification.

OFFICE ACTION:
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 .
OBJECTION
2.	The specification is objected to because of the following informality: the continuation information must be updated to indicate the issue of the parent ‘981 application as US 11,713,480.
NON-PRIOR ART REJECTION
3.	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.
4.	Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,713,480.  Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims and the instant claims are related as species-genus.  That is, step a) of the pending claims of ‘providing’ is generic with respect to steps a) and b) of the patented claims, which include species relating to bridge amplification, distance between centers of clusters, and identification of location by sequencing.
ALLOWABLE SUBJECT MATTER
5.	Claims 1-20 are free of the prior art, but they are rejected for another reason.  The closest prior art and the reasons for allowance were determined during prosecution of the parent ‘981 application.
CONCLUSION
6.	No claims are allowable.
7.

APPLICANT REBUTTAL: REMARKS
1. Preliminary Remarks
Claims 1-20 are pending and under active consideration. No claims are amended or cancelled herein.
2. Patentability Remarks
The Examiner objects to the specification and indicates that the continuation information must be updated to indicate the issue of the parent application. The specification is updated herein to address this change.
The Examiner rejects claims 1-20 on the grounds of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,713,480. Submitted herewith is a terminal disclaimer over the '480 patent. Reconsideration of the rejection is respectfully requested.
Conclusion

NEXT OFFICE ACTION: EXAMINER’S COMMENTS
1.	The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2.	The terminal disclaimer filed on 01/21/25 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US ‘480 has been reviewed and is accepted.  The terminal disclaimer has been recorded.
3.

CITED REFERENCE SUMMARIES: Ref US11713480: Claims:
1. A method of generating a spatial transcriptomics gene expression image having subcellular resolution, comprising:
a. generating, on a flat array surface, high density, bridge-amplified clusters of probes having a distance between centers of said clusters of 1 μm or less, wherein each probe comprises a spatial barcode sequence and a capture domain;
b. identifying, by sequencing said spatial barcode sequence, a location on said flat array surface of each cluster;
c. contacting said flat array surface with a tissue section under conditions such that RNA from cells in said tissue section hybridizes to said capture domain of said probes;
d. reverse transcribing target sequences from said RNA on 3′ ends of said probes;
e. generating second strand copies of said probes and eluting said second strand copies from said array;
f. generating a sequencing library from eluted second strand copies;
g. sequencing said sequencing library to generate sequencing data; and
h. generating a spatial transcriptomics gene expression image having subcellular resolution from said sequencing data.
2. The method of claim 1, wherein each probe in a given cluster comprises an identical spatial barcode sequence, and wherein said spatial barcode sequence for each cluster is unique.
3. The method of claim 1, wherein said flat array surface comprises 0.5-2 million clusters per 1 mm2 of surface.
4. The method of claim 3, wherein said flat array surface comprises about 1.5 million clusters per 1 mm2 of surface.
5. The method of claim 1, wherein each cluster comprises at least 200 probes.
6. The method of claim 1, wherein each cluster comprises at least 500 probes.
7. The method of claim 1, wherein each cluster comprises at least 800 probes.
8. The method of claim 1, wherein each cluster has a diameter of 500-1200 nm.
9. The method of claim 8, wherein each cluster has an average diameter of 0.6 μm.
10. The method of claim 1, wherein said flat array surface comprises a material selected from glass, silicon, poly-L-lysine coated materials, nitrocellulose, polystyrene, cyclic olefin copolymers (COCs), cyclic olefin polymers (COPs), polyacrylamide, polypropylene, polyethylene and polycarbonate.
11. The method of claim 1, wherein said capture domain is identical for each probe.
12. The method of claim 1, wherein said capture domain comprises a poly-T oligonucleotide comprising at least 10 deoxythymidine residues.
13. The method of claim 1, wherein each probe further comprises a sequencing barcode.
14. The method of claim 1, wherein each probe further comprises one or more filler sequences.
15. The method of claim 1, wherein each probe further comprises a unique molecular identifier (UMI) barcode sequence.
16. The method of claim 1, wherein each probe further comprises a cleavage domain comprising a binding site for a restriction endonuclease.
17. The method of claim 1, further comprising imaging the tissue before or after reverse transcribing target sequences from said RNA on 3′ ends of said probes.
18. The method of claim 17, further comprising correlating the identified location of each cluster on said flat array surface with a corresponding location within said tissue section.