DETAILED 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 .
2. Applicant's election with traverse of Group I (claims 1-3 and 5-14) in the reply filed on 10/30/2025 is acknowledged. The traversal is on the ground(s) that the office has not shown that a serious burden would result if all the claims are examined together. This is not found persuasive.
MPEP 808.02 states:
In order to demonstrate a serious search burden, the examiner must show by appropriate explanation one of the following:
(A) Separate classification thereof: This shows that each invention has attained recognition in the art as a separate subject for inventive effort, and also a separate field of search. Patents need not be cited to show separate classification.
(B) A separate status in the art when they are classifiable together: Even though they are classified together, each invention can be shown to have formed a separate subject for inventive effort when the examiner can show a recognition of separate inventive effort by inventors. Separate status in the art may be shown by citing patents which are evidence of such separate status, and also of a separate field of search.
(C) A different field of search: Where it is necessary to search for one of the inventions in a manner that is not likely to result in finding art pertinent to the other invention(s) (e.g., searching different classes/subclasses or electronic resources, or employing different search queries), a different field of search is shown, even though the two are classified together. The indicated different field of search must in fact be pertinent to the type of subject matter covered by the claims. Patents need not be cited to show different fields of search.
In the instant case, the examiner has shown that Groups I-III have separate classification. Separate classification shows that each invention has attained recognition in the art as a separate subject for inventive effort, and also a separate field of search (MPEP 808.02). Therefore, searching all the claims together would impose serious search burden.
The requirement is still deemed proper and is therefore made FINAL.
3. Claims 1-3, 5-14, 17-21 and 24-25 are pending. Claims 4, 15-16, 22-23 and 26-53 are canceled. Claims 17-21 and 24-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/30/2025.
4. Claims 1-3 and 5-14 are under examination.
Information Disclosure Statement
5. The information disclosure statements (IDS) submitted on 12/4/2023 have been considered by the examiner.
Specification
6. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, see pages 62-63 and 66, for example. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
7. Claims 1-3 and 5-14 are objected to because of the following informalities:
Claim 1 recites “specific proteins of interest” in step a), and “detecting proteins” in step c). It is unclear if the “proteins” mentioned in step c) is the same proteins mentioned in step a). If so, the term “the” should be added before “proteins” in step c).
Claims 2-3 and 5-14 depend from clam 1 and are objected to for the same reasons.
Claim Rejections - 35 USC § 102
8. 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.
9. Claims 1-3, 5-6 and 9-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Giesen et al. (Nature Methods, 2014, 11(4): 417-422).
Giesen et al. teaches a method of highly multiplexed imaging of tumor tissues with subcellular resolution by mass spectrometry (title). Giesen et al. teaches that to gain spatial information, immunohistochemical and immunocytochemical methods have been coupled with high-resolution laser ablation to CyTOF mass cytometry (abstract). The method allows simultaneous imaging of 32 proteins and protein modifications at subcellular resolution (abstract).
Regarding claim 1, Giesen et al. teaches that the method comprises:
a) introducing into breast cancer tissue or cell metal-labeled antibodies (metal reads on a tagging moiety) that bind to markers including HER2, PR, H3, and cytokeratin,
b) detecting proteins (analytes) and metal label (tagging moieties) by imaging mass cytometry which couples laser ablation techniques and CyTOF mass spectrometry,
c) spatially detecting proteins in the cell or tissue samples using single-cell segmentation.
d) constructing a map of the analytes in the cell or tissue based on the data from steps b) and c) (see page 422 under Methods (online methods) and Figs. 1 and 3).
Regarding claims 2 and 3, Giesen et al. teaches simultaneous imaging of 32 proteins and protein modifications at subcellular resolution (abstract), the 32 proteins include receptor e.g. HER2 and PR.
Regarding claim 5, Giesen et al. teaches metal isotopes tagged to antibodies (page 417, last sentence).
Regarding claim 6, Giesen et al. teaches contacting tissue sample with an metal-labeled antibody master mix (page 422 under Methods (online methods under “Preparation of breast cancer tissue section for IHC, IFM and imaging mass cytometry analyses”), and supplemental Table 2).
Regarding claim 9, Giesen et al. teaches detecting proteins by imaging mass cytometry (abstract).
Regarding claim 10, Giesen et al. teaches determining nuclear and cytosolic distributions of proteins (analytes),e.g. Staining for the protein H3 was used to identify cell nuclei. The cell membrane proteins β-catenin, HER2 and cytokertin8/18 were used to detect the cell boundaries (page 424, column 2). Giesen teaches detecting p53 and actin (supplemental Table 2) which are located in the nucleus and cytoplasm.
Regarding claim 11, Giesen et al. teaches that multiple regions, such as the invasive front, center and periphery must be imaged (page 421, column 2, para 4). Giesen et al. teaches serial tissue sections can be analyzed by imaging mass cytometry (page 421, column 2, para 2).
Regarding claim 12, Giesen et al. teaches that as imaging approaches provide only a single snapshot of tumor development, multiple images over time may be necessary to reveal relevant phenotypes (page 421, column 2, para 4).
Regarding claim 13, Giesen et al. teaches steps b) and c) are performed sequentially (online Methods).
Regarding claim 14, Giesen et al. teaches detecting proteins in breast cancer tissue which comprises breast cancer cells.
10. Claims 1-3 and 5-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ganesh et al. (Sci Adv, 27 January 2021, 7: eabd0957, pages 1-16).
Ganesh et al teaches a method of three-dimensional spatially
resolved metabolomic profiling framework (3D-SMF) to map out the spatial organization of metabolic fragments and protein signatures in immune cells of human tonsils (abstract).
Regarding claim 1, Ganesh et al. teaches that the method comprising:
a) staining human tonsil tissues with metal-conjugated antibody (isotope-tagged antibody) cocktail mix for immune markers overnight at 4°C (page 1, last para), wherein immune markers are protein markers, e.g. PD-L1, CD20 and histone 3 (page 5, column 2),
b) detecting analytes (metabolites) and tagging moieties (isotope-tagged antibody) in the cell or tissue (Fig. 3),
c) spatially detecting proteins in the cell or tissue sample (Fig. 3F, page 6, column 2, para 1 and abstract),
c) constructing a map of the metabolites and antibody labels in the cell or tissue sample (Fig. 3G).
Regarding claim 2, Ganesh et al. teaches detecting metabolites and proteins (Fig. 3G).
Regarding claim 3, Ganesh et al. teaches detecting CD20, CD3, PD-L1 (page 5, column 2), which are receptors.
Regarding claim 5, Ganesh et al. teaches staining human tonsil tissues with isotope-tagged antibody cocktail mix (page 1, last para).
Regarding claim 6, Ganesh et al. teaches staining human tonsil tissues with isotope-tagged antibody cocktail mix (page 1, last para), the cocktail mix comprising two or more isotope-tagged antibodies each reacting with a different specific protein (page 5, column 2).
Regarding claim 7, Ganesh et al. teaches using three-dimensional spatially
resolved metabolomic profiling framework (3D-SMF) to map out the spatial organization of metabolic fragments and protein signatures in immune cells of human tonsils (abstract).
Regarding claim 8, Ganesh et al. teaches using TOF-SIMS imaging to acquire 3D dataset (Fig. 3C and page 12, column 2, para 2).
Regarding claim 9, Ganesh et al. teaches that the efficiency of antibody detection was validated by IMC (imaging mass cytometry) measurements in tonsil tissue (page 1, last para).
Regarding claim 10, Ganesh et al. teaches detecting nuclear and cytosolic distribution of analytes (page 3, column 2, para 2 and page 5, column 2). Ganesh teaches detecting histone 3, intercalator (DNA), and Granzyme B (page 5, right column and Table 1).
Regarding claim 11, Ganesh et al. teaches performing multiple 3D-SMF measurements in spatially distinct regions (page 7, column 1, para 2).
Regarding claim 12, Ganesh et al. teaches that to validate the presented 3D-SMF results, another set of TOF-SIMS data in the same GC from serial tissue
sections of the tonsil samples was obtained (page 7, last para), indicating the method was repeated at multiple points in time.
Regarding claim 13, Ganesh et al. teaches that the efficiency of antibody detection was validated by IMC (imaging mass cytometry) measurements in tonsil tissue (page 1, last para, page 5, column 1, last two lines), indicating metabolites and proteins are detected sequentially.
Regarding claim 14, Ganesh et al. teaches that the tonsil tissue comprises immune cells (abstract).
Double Patenting
11. 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.
12. Claims 1-3, 5, 6 and 11-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 11-16, 18, 20 and 22 of copending Application No. 18/452,178. Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5, 11-16, 18, 20 and 22 of copending Application No. 18/452,178 disclose a method of detecting multiple protein interactions within a cell or tissue sample, the method comprising:
a) applying to the cell or tissue sample at least a first targeting moiety and a second targeting moiety, wherein the first targeting moiety interacts with a first specific protein of interest and the second targeting moiety interacts with a second protein of interest in the cell or tissue sample, wherein an interaction between the first specific protein of interest and the second specific protein of interest causes the first targeting moiety and second targeting moiety to be in close proximity to each other, wherein when the first targeting moiety and the second targeting moiety are in close proximity to each other, at least one detectable signal is produced;
b) imaging the detectable signal or signals in the cell or tissue sample;
c) deactivating the detectable signal or signals;
d) repeating steps a), b), and c), wherein the first targeting moiety and the second targeting moiety are different in each repetition,
wherein step b) further comprises taking images of the cell or tissue sample at multiple spatial and/or temporal locations,
wherein the method further comprising a step of detecting subcellular spatial protein networks in the cell or tissue sample.,
wherein the at least one imaging moiety comprises an antibody and the antibody is pre-conjugated with a fluorescent dye, and wherein the detectable signal comprises the fluorescent dye,
wherein steps are repeated at least three times,
wherein subcellular spatial protein networks in the cell or tissue sample are detected.
13. Claims 1-3, 5, 6 and 9-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 11-16, 18, 20 and 22 of copending Application No. 18/452,178, in view of Giesen et al. (Nature Methods, 2014, 11(4): 417-422).
The teaching of the claims of copending application have been set forth above as they apply to claims 1-3, 5, 6 and 11-13.
The claims of copending application do not teach detecting proteins by imaging mass cytometry (IMC), and the detecting comprises determining nuclear and cytosolic distributions of the proteins.
The teachings of Giesen et al. have been discussed above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of the copending application to detect proteins in cytoplasm and nucleus by IMC in view of Giesen et al. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Giesen et al. teaches that their method of highly multiplexed imaging of tumor tissues with subcellular resolution by imaging mass cytometry can provide spatial information of the proteins and allow simultaneous imaging of 32 proteins and protein modifications at subcellular resolution (abstract).
Conclusion
14. No claims are allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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/HONG SANG/Primary Examiner, Art Unit 1646