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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after allowance or after an Office action under Ex Parte Quayle, 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on May 12, 2026 has been entered.
Applicant’s amendment filed on February 10, 2026 is acknowledged and has been entered. Claims 31-32 have been canceled. Claims 35-50 have been added. Claims 1-32 and 35-50 are pending.
Claims 1-32 and 35-50 are discussed in this Office action.
All of the amendments and arguments have been thoroughly reviewed and considered but are not found persuasive for the reasons discussed below. Any rejection not reiterated in this action has been withdrawn as being obviated by the amendment of the claims. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is made NON-FINAL to address New Grounds of Rejection
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 12, 2026 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Previous Grounds of Rejection
Priority
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. 18769778, 18645232, 18319244, 63209903, 63140703, 63062047 and US Patent 12006534, 11753678, 11680288, 11434525 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. The priority documents do not teach a method which includes the step of grouping cells into different populations based on the detected target sequence.
As none of the priority documents provide support for the method, as claimed, the earliest priority date for the claims is the filing date of the application, August 7, 2024.
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 –
(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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2 and 9-31 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Hernandez-Nueta US 20230031996 A1; February 2023, IDS reference).
With regard to claim 1, Hernandez-Nueta teaches a method for detecting different populations of cells in a tissue sample, the method comprising
within a plurality of cells of said tissue sample, forming a circular oligonucleotide by incorporating a reverse transcribed target sequence of an RNA molecule into the circular oligonucleotide (Abstract, where RNA templated ligation is part of the method; Fig 1-3, for example, where the method is depicted);
amplifying the circular oligonucleotide within each cell and detecting the target sequence (Abstract, where RNA templated ligation is part of the method; Fig 1-3, for example, where the method is depicted and includes amplification of a circular oligo formed on the template);
identifying one or more cell types based on the detected target sequence (paragraph 275-276 and 277, where target sequences are identified using the probes as claimed).
With regard to claim 2, Hernandez-Nueta teaches a method of claim 1, wherein forming the circular oligonucleotide comprises
contacting the tissue sample with a polynucleotide probe and hybridizing a first hybridization sequence of the polynucleotide probe to a first sequence of the RNA molecule, and hybridizing a second hybridization sequence of the polynucleotide probe to a second sequence of the RNA molecule, wherein said RNA molecule comprises the target sequence between the first sequence and the second sequence (Abstract, where RNA templated ligation is part of the method; Fig 1-3, for example, where the method is depicted and includes amplification of a circular oligo formed on the template; see also paragraphs 13, 30, 62 and 202, where gap filling ligation is described);
extending with a reverse transcriptase the polynucleotide probe along the target sequence to generate a complement of the target sequence, and ligating the complement of the target sequence to the polynucleotide probe thereby forming the circular oligonucleotide (Abstract, where RNA templated ligation is part of the method; Fig 1-3, for example, where the method is depicted and includes amplification of a circular oligo formed on the template; see also paragraphs 13, 30, 62 and 202, where gap filling ligation is described).
With regard to claim 9, Hernandez-Nueta teaches a method of claim 2, wherein the polynucleotide probe comprises DNA, RNA, LNA, or a combination thereof (paragraph 123, where the probe sequence can include LNA and PNA and can include DNA).
With regard to claim 10, Hernandez-Nueta teaches a method of claim 2, wherein the polynucleotide probe consists of DNA (paragraph 123, where the probe sequence can include LNA and PNA and can include DNA).
With regard to claim 11, Hernandez-Nueta teaches a method of claim 1, wherein the tissue sample is immobilized to a solid support (paragraph 163, where the tissue sample can be present on a slide).
With regard to claim 12, Hernandez-Nueta teaches a method of claim 9, wherein the polynucleotide probe is about 50 to about 100 nucleotides (paragraph 315 where the length of a probe or primer can be 18 to 50 basepairs).
With regard to claim 13, Hernandez-Nueta teaches a method of claim 2, wherein the polynucleotide probe is a single-stranded polynucleotide comprising an amplification primer binding sequence, a sequencing primer binding sequence, or both an amplification primer binding sequence and a sequencing primer binding sequence (paragraph 123, where the probe sequence can include LNA and PNA and can include DNA).
With regard to claim 14, Hernandez-Nueta teaches a method of claim 13, wherein detecting comprises sequencing (paragraph 37, where sequencing is described).
With regard to claim 15, Hernandez-Nueta teaches a method of claim 1, wherein detecting comprises repeated cycles of labeled oligonucleotide hybridization and detection (paragraph 37, where sequencing is described).
With regard to claim 16, Hernandez-Nueta teaches a method of claim 14, wherein sequencing comprises incorporating one or more labeled nucleotides into a sequencing primer bound to an amplification product comprising a copy of the target sequence in the tissue sample and detecting the label for each incorporated nucleotide (paragraph 37, where sequencing is described).
With regard to claim 17, Hernandez-Nueta teaches a method of claim 1, wherein the target sequence is about 50 to about 200 nucleotides (paragraph 135, where the RNA target can be short, as in shorter than 200 or long, as in longer than 200 nt).
With regard to claim 18-25, Hernandez-Nueta teaches a method of claim 1, wherein the tissue sample comprises breast tissue, lung tissue, colon tissue, lymph tissue, kidney tissue, bone tissue, tonsil tissue, or brain tissue (paragraph 85).
With regard to claim 26, Hernandez-Nueta teaches a method of claim 1, further comprising detecting a plurality of proteins in the tissue sample (paragraph 74, where proteins are included as analytes).
With regard to claim 27, Hernandez-Nueta teaches a method of claim 26, comprising detecting a protein in or on a cell within the plurality of different cells (paragraph 74, where proteins are included as analytes).
With regard to claim 28, Hernandez-Nueta teaches a method of claim 1, further comprising contacting the tissue sample with a stain and detecting the stain, wherein the stain comprises an ER stain, Golgi stain, F-actin stain, lysosomal stain, mitochondrial stain, nucleolar stain, or plasma membrane stain (paragraph 117).
With regard to claim 29, Hernandez-Nueta teaches a method of claim 1, further comprising determining a location of a cell within the tissue sample, wherein the location of the cell is based on the detected target sequence (paragraph 149 and 219, for example, where locations of analytes are determined).
With regard to claim 30, Hernandez-Nueta teaches a method of claim 2, further comprising determining a phenotype of a cell and grouping the cells into different populations based on the phenotype (paragraph 149 and 219, for example, where locations of analytes are determined).
With regard to claim 33, Hernandez-Nueta teaches a method of claim 26, further comprising identifying one or more cell types based on the detected target sequence and a detected protein (paragraph 275-276 and 277, where target sequences are identified using the probes as claimed).
With regard to claim 34, Hernandez-Nueta teaches a method of claim 28, further comprising identifying one or more cell types based on the detected target sequence and a detected stain (paragraph 275-276 and 277, where target sequences are identified using the probes as claimed).
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) 3-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hernandez-Nueta US 20230031996 A1; February 2023, IDS reference) as applied over claims 1-2 and 9-31 above and further in view of Vigneault et al. (US Patent 10,393,743: August 2019).
With regard to claim 3, Vigneault teaches a method of claim 1, wherein the plurality of cells comprise T cells (Fig 3A, where mRNA targets include TCR-alpha, TCR-beta, CD4 and CD8; col. 20, where a variety of TCR sequences were included and encompassed by the term).
With regard to claim 4, Vigneault teaches a method of claim 3, wherein the RNA molecule encodes for a chimeric antigen receptor (Example 2, col. 102, where a chimeric antigen receptor is described).
With regard to claim 5, Vigneault teaches a method of claim 1, wherein the RNA molecule comprises a T cell receptor alpha variable (TRAV) gene sequence, T cell receptor alpha joining (TRAJ) gene sequence, T cell receptor alpha constant (TRAC) gene sequence, T cell receptor beta variable (TRBV) gene sequence, T cell receptor beta diversity (TRBD) gene sequence, T cell receptor beta joining (TRBJ) gene sequence, T cell receptor beta constant (TRBC) gene sequence, T cell receptor gamma variable (TRGV) gene sequence, T cell receptor gamma joining (TRGJ) gene sequence, T cell receptor gamma constant (TRGC) gene sequence, T cell receptor delta variable (TRDV) gene sequence, T cell receptor delta diversity (TRDD) gene sequence, T cell receptor delta joining (TRDJ) gene sequence, or T cell receptor delta constant (TRDC) gene sequence (Fig 3A, where mRNA targets include TCR-alpha, TCR-beta, CD4 and CD8; col. 20, where a variety of TCR sequences were included and encompassed by the term).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have adjusted the teachings of Hernandez-Nueta to include detection of a variety of target sequences including T Cell receptors as taught by Vigneault to arrive at the claimed invention with a reasonable expectation for success. Hernandez-Nueta teaches “improved methods for analyzing nucleic acids present in a biological sample are needed. Provided herein are methods and compositions that address” (paragraph 3). While Hernandez-Nueta teaches the application of in situ sequencing, Hernandez-Nueta does not teach or suggest the inclusion of T cell receptor targets as claimed. Vigneault teaches “the methods described herein use a sequence readout to analyze proteins of individual cells and are not limited by the number of fluorophores that can be used concurrently in the same experiment or their spectral overlap. Further, the methods described herein are amenable to many biologically-relevant assays and subsequent DNA sequencing. The methods described herein utilize affinity-oligonucleotide conjugates (e.g., antibody-oligonucleotide conjugates or tetramer-oligonucleotide conjugates)” (col. 1). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of Hernandez-Nueta to include detection of a variety of target sequences including a breadth of specific T Cell receptors as taught by Vigneault to arrive at the claimed invention with a reasonable expectation for success.
Claim(s) 6-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hernandez-Nueta US 20230031996 A1; February 2023, IDS reference) in view of Vigneault et al. (US Patent 10,393,743: August 2019) as applied over claims 3-5 and 32 above and further in view of Salinas dissertation (“GENERATION OF NATURAL KILLER CELLS FROM UMBILICAL CORD BLOOD STEM CELLS, CHARACTERISATION AND APPLICATION FOR IMMUNOTHERAPY”, 2013, University College of London, p 1-291).
With regard to claim 6, Salinas teaches a method of claim 1, wherein the plurality of cells comprises NK cells (p 132, where NK cells are characterized).
With regard to claim 7, Salinas teaches a method of claim 1, wherein the plurality of cells comprises allogenic cells (p 133, where allogenic cells are characterized).
With regard to claim 8, Salinas teaches a method of claim 1, wherein the plurality of cells comprises non-allogenic cells (p 133, where allogenic cells are characterized).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have adjusted the teachings of Hernandez-Nueta and Vigneault to include natural killer (NK) and allogenic and non-allogenic cells as described by Salinas to arrive at the claimed invention with a reasonable expectation for success. While Hernandez-Nueta and Vigneault in combination teach methods that include in situ based detection of various targets, neither Hernandez-Nueta or Vigneault teach specific focus on NK or allogenic or non-allogenic cells. Salinas teaches “In vitro generation of high numbers of activated NK cells using HSC would facilitate multiple infusions and treatment of patients with large tumour burden, allowing to by-pass the limitations of NK cell numbers and activation state of blood-derived NK cells. However, comprehensive studies about the use of fresh or cryopreserved HSC and of different HSC sources for protocols of NK cell production in vitro have yet to be performed. The aim of this thesis was to investigate these variables and establish an optimal protocol for the generation of NK cells in vitro” (Abstract). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of Hernandez-Nueta and Vigneault to include natural killer (NK) and allogenic and non-allogenic cells as described by Salinas to arrive at the claimed invention with a reasonable expectation for success.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Landegren et al. (US 20160289750 A1; October 2016).
Conclusion
No claims are allowed. All claims stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE KANE MUMMERT whose telephone number is (571)272-8503. The examiner can normally be reached M-F 9:00-5:30.
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/STEPHANIE K MUMMERT/Primary Examiner, Art Unit 1681
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