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 .
DETAILED ACTION
Status of the Claims
Claims 1-24 are pending. Claims 1-4, 7-19 and 23-24 are the subject of this NON-FINAL Office Action. Claims 5-6 and 20-22 are withdrawn. This is the first action on the merits.
Election/Restrictions
Applicant’s election of the species of a level of determining cell morphology, using a single cell, sequencing molecular profiling, nanowell with sensor, and gene expression analysis without traverse in the Reply filed 07/21/2025 is acknowledged. Thus, claims 5-6 and 20-22 are withdrawn pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Thus, the requirement for election of species is hereby made FINAL.
Claim Notes
Applicants’ claims read on conventional use of time-lapse imaging (e.g. to track GFP-tagged proteins, LUC-tagged proteins, etc.) followed by molecular analysis (e.g. genotyping, gene expression analysis, protein expression analysis, etc.). It should be abundantly clear to any skilled artisan, especially in light of the prosecution history of the parent applications, that this is not allowable subject matter at the time of effective filing in 2015. See e.g. US20110092762 (single cell morphology determination followed by gene expression analysis using single-cell arrays); US20140336065 (concurrent live-imaging and expression analysis of iPSC); WO1999028499A1; US 20020168765; WO 02079504 A2; US 20100003666 A1; US20090029370.
Claim Rejection - 35 USC § 112 – Written Description
The following is a quotation 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.
Claims 7 is rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain 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, at the time the application was filed, had possession of the full scope of the claimed invention.
The specification fails to demonstrate possession of the genus of “image analysis algorithms.” Instead, the specifications discloses a single, very specific TIMING algorithm. A single specific species never satisfies the genus when the context is a non-conventional applications as here.
Claim Rejections - 35 USC § 102
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 –
(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.
Claims 1-4, 7-19 and 23-24 are rejected under 35 U.S.C. § 102(a)(2) as being anticipated by ELF (US20170159048).
As to claims 1 and 18-19, ELF teaches method of integrating evaluation of cellular activity of a cell and molecular profiles of said cell, said method comprising: (a) performing time-lapse imaging microscopy on the cell to generate a plurality of temporal images, wherein the temporal images are analyzed by a method comprising cell tracking on the single cell, cell segmentation on the single cell, cellular classification, or combinations thereof (Abstract and para. 0047); (b) characterizing a molecular profile by sequencing nucleic acids of the single cell (Abstract and para. 0107); and (c) integrating data from the analyzed temporal images and the molecular profile data of the single cell (Abstract and paras. 0026 & 0106).
As to claims 2-3, any cell type can be used such as stem cells (para. 0027).
As to claim 4, the single cell behavior is morphology (Abstract and para. 0047).
As to claim 7, any calculation or procedure used to connect the phenotype (e.g. cell morphology) to the genetic information (e.g. gene expression) must use an algorithm as broadly understood (a step-by-step procedure for solving a problem or accomplishing some end).
As to claims 8-11, the cell is imaged multiple times during confinement in a nanowell (Figures 1-12, showing nanowells where cells are cultured and analyzed).
As to claims 12-17, the array used can include biosensors for nanowells (paras. 0113 & 0185).
As to claims 23-24, drugs are screened, which “facilitates” a treatment (paras. 0033, 0127 & 0181).
Claim Rejection - 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.
Claims 1-4, 7-17 and 23-24 are rejected under 35 U.S.C. § 103 as being unpatentable over Mehling et al, Real-time tracking, retrieval and gene expression analysis of migrating human T cells, Lab Chip, 2015,15, 1276-1283, 12/10/2014, Liadi et al., Quantitative high-throughput single-cell cytotoxicity assay for T cells, J Vis Exp. 2013 Feb 2;(72):e50058. doi: 10.3791/50058 and ROBINS (US 2016/0002731), in view of ELF (US20170159048).
To the extent the claims are generally directed to measuring aspects of tumor cells (e.g. T-cell cell motility or movement) and correlating to how those aspects indicate tumor cell responsiveness to an immunotherapy, all on a nanowell platform, this is addressed below. This is common in the art.
As to claims, numerous prior art documents provide motivation to detect T-cell or killer cell motility and gene expression as a correlative to immunotherapeutic effectiveness. For example, Mehling teaches to track CD4+ T-cells (e.g. motility, or migration) and gene expression using microfluidic migration chambers (Fig. 3). Mehling uses Kolmogorov–Smirnov test, Mann–Whitney test, and paired Student 2-sided t test (pg. 1278, col. 2). Mehling suggests to apply such assays to screen for immunotherapy effectiveness:
Migration of human T cells plays a central role in protective immunity but also in the pathogenesis of autoimmune diseases such as MS. The latter is supported by the fact that two highly efficacious drugs for the treatment of MS impact on T cell migration: Fingolimod acts as a functional antagonist on the S1P receptor (S1PR), hereby preventing recirculation of T cells from SLT to peripheral blood;19 natalizumab blocks adhesion of blood T cells to endothelial cells and as a consequence migration across the blood–brain barrier
(pg. 1279, col. 2). ROBINS teaches
In solid tumor samples obtained from patients before and after immunotherapy with an inhibitor of a negative regulator of immune response
(e.g., anti-PD-1 antibody), a high level of infiltrating T cell presence and high clonality (i.e., evidence of T cell migration to the tumor and clonal proliferation within the tumor) were associated with a positive response to immunotherapy. In contrast, a minimal infiltrating T cell repertoire and low clonality in solid tumors (i.e., evidence of a restricted and non-specific T cell response within the tumor) were associated with failure to respond to treatment.
(para. 0078; see also para. 0115). Finally, Liadi teaches the same nanowell device used here, to time-lapse detect single CAR-T cell characteristics (e.g. apoptosis) and molecular characteristics (e.g. proteins secreted) (Figs. 1-2). In other words, a skilled artisan would have been aware of the connection between motility, gene expression and immunotherapy effectiveness, and had the ability to screen accordingly.
Mehling does not explicitly teach gene expression analysis and time-lapse imaging of single cells on a single nanoarray, or sequencing.
However, this was a known technique in the art to allow integrated information as to cell characteristics and molecular characteristics of single cells. For example, as explained above, ELF explains that such an integration fulfills “a need for a technology that can handle large cell libraries and that can monitor phenotypic characteristics with high spatial and temporal resolution” (para. 0005). As explained above, ELF also teaches both cellular characterization of cells using time-lapse imaging, followed by sequencing in the same well.
Thus, it would have been prima facie obvious to a person of ordinary skill in the art before effective filing to combine familiar single-cell techniques for determining immunotherapy effectiveness with familiar single-cell arrays for highly parallel integrated cellular and molecular analyses to achieve greater throughput and resolution with a reasonable expectation of success.
Double Patenting- Obvious Type
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Instant claims 1-4, 7-19 and 23-24 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over conflicting claims 1-86 of U.S. Patent No. 10746736.
The instant claims are obvious over the conflicting claims because the conflicting claims teach a species of method of performing the same method as here, specifically using TIMING.
Instant claims 1-4, 7-19 and 23-24 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over conflicting claims 1-17 of U.S. Patent No. 11774449.
The instant claims are obvious over the conflicting claims because the conflicting claims teach a species of method of performing the same method as here, specifically using TIMING.
Prior Art
The following prior art also teaches cell imaging followed by molecular analysis of the cell: US 20150141261; US 20150247191; US20130296196; US20110092762; US 20140087376; US 20130225431; US 20140024032; US20140336065; US 20140220560; US20160252495; US 20160046999; WO 2015041219; US 20150119282; US20110021369; Le et al, Real-time RNA profiling within a single bacterium, Proc Natl Acad Sci USA. 2005 Jun 28;102(26):9160-4. doi: 10.1073/pnas.0503311102. Epub 2005 Jun 20.
The following prior art also suggests to detect T-cell migration/motility to determine immunotherapy effectiveness: US 20060073469; US 20080300165, para. 0196; US 20200246452.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aaron Priest whose telephone number is (571)270-1095. The examiner can normally be reached 8am-6pm.
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/AARON A PRIEST/Primary Examiner, Art Unit 1681