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 .
This Office Action is in reply to Applicants’ correspondence of 12/04/2025
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Withdrawn Claim Rejections - 35 USC § 112 – Indefiniteness
The rejections of claim 1 under 35 USC 112(b) as set forth on page 3 of the Office Action of 06/04/2025, is withdrawn in light of the amendments to the claims.
New Claim Rejections - 35 USC § 112 – Indefiniteness
Necessitated by Claim Amendments
Claims 3 and 4 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.
Claims 3 and 4 are unclear over recitation of the limitation “wherein identifying spatial overlap in the specimen between probes”, as recited in claim 3 from which claim 4 depends, because there is not antecedent basis for any step of “identifying spatial overlap” in either claim 3 or in claim 1 from which claim 3 depends. It is unclear if the limitation is intended to require some particular methodological or technical step or process related to “identifying spatial overlap”, which is not required or inherent in claim 1 from which claim 3 depends.
Claim Rejections - 35 USC § 112 – Failure to Limit
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 7 set forth a limitation requiring that “at least some probes of the first and second sets of nucleic acid probes comprise nucleic acid detection sequences”, but the claim depends form claim 1 which requires sets of “nucleic acid probes, wherein each probe of the … set of nucleic acid probes selectively binds to a different member of a … group of nucleic acid sequences and is associated with a … nucleic acid segment in the specimen”. The claim 1 inherently requires that the probes comprise nucleic acid detection sequences, as broadly recited in claim 7.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 5-7 and 13-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Klemm et al (2014) in view of Rizzetto et al (2018).
Klemm et al teaches the identification of co-localization of nucleic acid segments in cells of a specimen. Relevant to claim 1, Klemm et al teaches (e.g.: p.552 – FISH buffers and probes; Supplementary Figure 3A ) providing a first set of probes that selectively bind to a first group of sequences associated with a first segment in the specimen (e.g.: Oct4 probe sequences in the Supplementary data) and a second set of probes that selectively bind to a second group of sequences associated with a second segment in the specimen (e.g.: GFP probe sequences in the Supplementary data) (relevant to claim 7), exposing the specimen to probes from the first and second set in a hybridization analysis to determine the co-localized presence of the presence of the target nucleic acid of the first and second sets of probes (e.g.: p.539: we tested the single-cell precision of the proposed RNA measurement by differentially labeling the 3' and 5' ends of a single transcriptional target, Oct4-IRES-GFP fusion mRNA (where Oct4 is the gene Pou5f1 and IRES is an internal ribosome entry site), and found that the labels were strongly correlated at the single-cell level (p = 0.90; Supplementary Fig. 3a).
Relevant to claims 5 and 6, Klemm et al teaches that probes are fluorescently labeled, and that probes to different targets are differentially labeled (e.g.: p.552 – FISH buffers and probes).
Relevant to claims 15 and 16, Klemm et al teaches probes directed to a Oct4-IRES-GFP fusion mRNA (claim 15) which is expressed from a transgenic allele (claim 16) (e.g.: p.539; p.552- Secondary somatic cell generation and reprogramming).
Klemm et al does not specifically teach probes that are derived from a single cell of the specimen (as recited in claim 1), probes that correspond to first and second analyses of nucleic acid segments from the specimen (claim 13), or correspond to CDR3 portion of a nucleic acid from the specimen (claim 14). However such elements related to the analysis of sequences in samples were known in the prior art and are taught by Rizzetto et al.
Rizzetto et al teaches sequence analyses of single B-cells (relevant to claim 1) to provide paired B-cell receptor (BCR) sequences including a paired heavy (IGH) and light (IGK or IGL) immunoglobulin chain from individual cells, including CDR3 regions (relevant to claim 13 and 14) (e.g.: p.2846; Table 1; Supplementary Text: 4- Generation of Single cell RNA-sequencing of human PBMC-derived B cells; 5- Sanger sequencing; Supplementary sequences).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used B-cell receptor sequences generated by the single cell sequencing methods of Rizzetto et al to generate probes for the analysis of a sample from which the single B-cells originated according to the profiling methods of Klemm et al. The skilled artisan would have been motivated to apply sequences generated by the methods of Rizzetto et al to a specimen based on the expressed teachings of Rizzetto et al that high-quality paired BCR sequences along are crucial for characterizing the dynamics of B-cell evolution and differentiation during an immune response, and the expressed teachings of Klemm et al that the quantitative technique for sorting cells on the basis of endogenous RNA abundance is broadly applicable to profiling transcriptionally distinct cellular states and the exemplification of Klemm et al that multiple probes to different targets can be used to colocalize different sequences in individual cells in a cellular population.
Claim(s) 2-4, 8 and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Klemm et al (2014) in view of Rizzetto et al (2018) as applied to claims 1, 5-7 and 13-16 above, and further in view of Wang et al (2012).
Klemm et al in view of Rizzetto et al renders obvious methods of determining co-localization of nucleic acids in a target specimen using sets of nucleic acid probes directed to first and second nucleic acid segments, as set forth above, relevant to claims 1 (from which claims 2, 3 and 4 depend) and claim 7 (form which claims 8 and 9 depend).
Klemm et al in view of Rizzetto et al does not teach the detection of spatial location or overlap (relevant to claim 2-4) of probes hybridized to a specimen, or detection probes (relevant to claim 8) labeled with fluorescent moieties (relevant to claim 9). However, such methodological steps in the detection of nucleic acid targets in the same location in a specimen were known in the art and are taught by Wang et al.
Wang et al teaches methods comprising the hybridization of probe sets specific to a plurality of nucleic acid targets (e.g.: Figure 1) to detect the spatial location (e.g.: p.24 - Microscopic imaging; Figure 2; Figure 3) of the target nucleic acids that are detected with fluorescent-labeled detection probes (e.g.: Figure 1).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used modified the methods rendered obvious by Klemm et al in view of Rizzetto et al to detect co-localization of probes directed to BCR sequences, as taught by Rizzetto et al using the probe design and detection method of Wang et al. The skilled artisan would have been motivated to use the methods of Wang et al based on the expressed teachings of Wang et al that such methods allow for the reliable and rapid detection of nucleic acid markers.
Withdrawn Double Patenting
The rejection of claims for issues related to double patenting over the conflicting claims of US Pat 11,466,310, as set forth on pages 4-6 of the Office Action of 06/04/2025, is withdrawn in light of the amendments to the claims.
New Double Patenting
Necessitated by Claim Amendments
Claims 1, 5, 6, 5-7, and 10-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 11,466,310 in view of Rizzetto et al (2018).
The conflicting claims are directed to identifying co-occurrence on nucleic acid segments in a sample using sets of probes generated from nucleic acid segments in nucleic acid fragments of the sample, and are directed to the same steps of the instantly rejected claims. The conflicting claims do not specifically require that the probes are “derived from a single cell of the specimen”, as set forth in the instantly rejected claims.
However, the conflicting claims are directed to probes associated with the heavy and light chains of the B-cell antigen receptor molecule (e.g.: conflicting claims 2-4).
Rizzetto et al teaches sequence analyses of single B-cells (relevant to claim 1) to provide paired B-cell receptor (BCR) sequences including a paired heavy (IGH) and light (IGK or IGL) immunoglobulin chain from individual cells, including CDR3 regions (relevant to claim 13 and 14) (e.g.: p.2846; Table 1; Supplementary Text: 4- Generation of Single cell RNA-sequencing of human PBMC-derived B cells; 5- Sanger sequencing; Supplementary sequences).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used B-cell receptor sequences generated by the single cell sequencing methods of Rizzetto et al in the methods of the conflicting claims. The skilled artisan would have been motivated to apply sequences generated by the methods of Rizzetto et al to a specimen based on the expressed teachings of Rizzetto et al that high-quality paired BCR sequences along are crucial for characterizing the dynamics of B-cell evolution and differentiation during an immune response.
Claims 2-4, 8 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 11,466,310 in view of Rizzetto et al (2018), as applied to claims 1, 5, 6, 5-7, and 10-17 above, and further in view of Wang et al (2012).
U.S. Patent No. 11,466,310 in view of Rizzetto et al renders obvious methods of determining co-localization of nucleic acids in a target specimen using sets of nucleic acid probes directed to first and second nucleic acid segments.
U.S. Patent No. 11,466,310 in view of Rizzetto et al does provide for the detection of spatial location or overlap (relevant to claim 2-4) of probes hybridized to a specimen, or detection probes (relevant to claim 8) labeled with fluorescent moieties (relevant to claim 9). However, such methodological steps in the detection of nucleic acid targets in the same location in a specimen were known in the art and are taught by Wang et al.
Wang et al teaches methods comprising the hybridization of probe sets specific to a plurality of nucleic acid targets (e.g.: Figure 1) to detect the spatial location (e.g.: p.24 - Microscopic imaging; Figure 2; Figure 3) of the target nucleic acids that are detected with fluorescent-labeled detection probes (e.g.: Figure 1).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used modified the methods rendered obvious by U.S. Patent No. 11,466,310 in view of Rizzetto et al to detect co-localization of probes directed to BCR sequences, as taught by Rizzetto et al using the probe design and detection method of Wang et al. The skilled artisan would have been motivated to use the methods of Wang et al based on the expressed teachings of Wang et al that such methods allow for the reliable and rapid detection of nucleic acid markers.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/ Primary Examiner, Art Unit 1683
Prosecution Insights