DETAILED ACTION
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 .
Status of the Application
The Reply to Office Action filed September 8, 2025 is acknowledged.
Claims 2-3, 5, 8-13, 15-23, 32 and 35-36 were pending. Claims 2-3, 5, 8-10, 12-13, 15-23, 32, 35-36 and new claim 37 are being examined on the merits. Claim 11 is canceled.
Response to Arguments
Applicant’s arguments filed September 8, 2025 have been fully considered.
The following objections are WITHDRAWN in view of Applicant’s arguments and claim amendments:
Objection to claim 2
The following rejections are MODIFIED in view of Applicant’s amendments to the claims:
Prior art rejections
Response to arguments regarding prior art rejections
The prior art rejections have been modified in view of the instant amendments, however, to the extent that Applicant’s arguments relate to the instant rejections, the Examiner notes the following.
Applicant argues that the prior art rejections should be withdrawn because the cited art does not teach or suggest all of the limitations, of, in particular, independent claim 2 (Remarks, p. 10). Specifically, Applicant argues that Peter does not teach a flow cell (Remarks, p. 11).
The Examined agrees that the phrase “flow cell” does not literally appear in Peter, however, the Examiner disagrees that Peter does not teach or suggest flow cells. For example, in paras. 61 and 97, Peter explicitly states that the various primers in the method can contain sequences that are compatible with use in a number of next generation sequencing platforms. At least some of these recited platforms are generally understood in the art to be “flow cells”. In addition, Peter incorporates by reference several references, including Fox, which discusses these next generation sequencing platforms, and, in reference to the Illumina platform, notes that it incorporates a flow cell.
The rejections are modified in view of the instant amendments.
Information Disclosure Statement
The Information Disclosure Statement submitted September 8, 2025 has been considered.
Claim Interpretation
Independent claim 2, which is a product claim, recites “wherein the spatial barcode sequence of each nucleic acid probe … is decoded on the flow cell”. This statement of intended use is being construed as requiring a structural component in the product claim.
When determining the broadest reasonable interpretation (BRI) of a product claim,
statements in the claim reciting the purpose or intended use of the claimed product are determined to limit the claim if the purpose or intended use imposes a structural component on the product. See MPEP 2111.02 (II), 2111.04 (I). Here, the intended use is that the nucleic acid probes are decoded on the flow cell. Further, the instant specification recites that probes are “decoded” through sequencing (e.g., Example 1). Thus, the intended use limitation imposes the structural component on the nucleic acid probes that they must be capable of being sequenced on the flow cell. Such a structural requirement may be met, e.g., by the nucleic acid probe having sequences that correspond to next-generation sequencing platforms, such as the Illumina flow cell (see Peter, para. 61, cited below in conjunction with the prior art rejections).
Thus, the BRI of the intended use of the limitation “wherein the spatial barcode sequence of each nucleic acid probe … is decoded on the flow cell” is being construed, at least, as comprising the nucleic acid probe embodiments described in Peter as being capable of being sequenced on a flow cell.
The BRI of the limitation is not being construed to require a method step of actually performing a decoding/sequencing operation.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2-3, 5, 8-10, 12-13, 15-23, 32 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Peter1 et al. (U.S. Patent Pub. No. 2015/0148239) in view of Gunderson et al. (U.S. Patent Pub. No. 2006/0275782, cited on IDS of 06/01/2023) and Pawloski2 (Photolithographic synthesis of high-density DNA probe arrays: Challenges and opportunities, J. Vac. Sci. Technol. B, 25, 2537-2546, 2007), as evidenced by Fox3 (Applications of Ultra-high-Throughput Sequencing. In Belostotsky, D. (eds.) Plant Systems Biology. Methods in Molecular Biology. Vol. 553, Humana Press, 2009; pp. 79-108), Preston (The New Genome AnalyzerIIx Delivering more data, faster, and easier than ever before, Illumina, 2009) and Illumina (Illumina Adapter Sequences, 2025).
With regards to claims 2 and 37, Peter teaches a composition (a flow cell is provided that comprises an array of spatially addressed features that comprise oligonucleotides that identify the feature in which the oligonucleotide is present, see Abstract and para. 3, 61, 97, 133) comprising:
a plurality of nucleic acid probes on a solid support, wherein the nucleic acid probes are randomly located and directly or indirectly attached to a population of features on the flow cell (arrays are synthesized wherein each feature comprises an oligonucleotide that has at least one random sequence and therefore the oligonucleotides are randomly located on the array, paragraph 79),
such that a nucleic acid probe of the plurality of nucleic acid probes is directly or indirectly attached at a random feature of the population of features (the oligonucleotides may be covalently attached to the flow cell, paras. 37, 61, 71, 97) and comprises in a 5’ to 3’ direction:
i) a universal primer binding sequence (the oligonucleotide at each feature may comprise a universal sequence for amplification, paragraph 79, last sentence), and
ii) a spatial barcode sequence that differs from the spatial barcode sequence of other nucleic acid probes directly or indirectly attached at other features on the solid support (the oligonucleotide at each feature comprises a unique sequence barcode that is used to associate the oligonucleotide and its amplification products with a particular feature, and thus is considered a spatial barcode sequence, paragraph 73, last sentence and paragraph 79; para. 44: the barcode sequence may be at the 3’ end of the oligonucleotide, thus the primer binding sequence would be 5’ of the barcode sequence).
With regards to the limitation reciting that the spatial barcode sequence of the nucleic acid probes is decoded on the flow cell, as noted above in the Claim Interpretation section, this limitation is interpreted as requiring that the nucleic acid probes are capable of being sequenced on a flow cell. This capability is taught in Peter (barcode sequences of the oligonucleotide may be decoded during sequencing, paragraph 95; para. 61).
With regards to the limitations reciting that the flow cell comprises one or more fluidic channels in which the nucleic acid probes are attached, and that the probes comprise a capture sequence common to all the nucleic acid probes on the flow cell, as noted above, Peter teaches using the Illumina platform for sequencing (para. 61). The ordinary artisan understands that the Illumina platform referred to in Peter is a flow cell. Further, Peter incorporates by reference Fox (para. 61), which teaches that the Illumina platform incorporates a flow cell. In addition, Fox specifically teaches the “Illumina 1G Genome Analyzer” flow cell. Further, Preston teaches that the Genome Analyzer flow cell has 8 channels, with the surface “coated with a lawn of oligo pairs” (p. 5). With regards to claim 37, Preston also teaches that each channel has an inlet and an outlet, and thus the flow cell comprises one or more inlets and outlets. The recitations “for [delivering/removing] reagents” are statements of intended use and cannot be used to distinguish the art. In addition, Preston teaches that target DNA fragments have adapters ligated to them. The adapter-ligated target DNA fragments are then are hybridized to the flow cell and subjected to bridge amplification (p. 4). Preston does not teach the sequences of the nucleic acids that are immobilized on the flow cell, or the sequences of the adapters, but Illumina teaches the adapter sequences (p. 99), as follows:
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As can be seen, at least, the underlined sequence of “TCTTC” is common to both adapters. Since the adapters hybridize to the “lawn of oligo pairs” in the flow cell, the ordinary artisan would understand that the corresponding complementary sequence would appear in the oligo pairs immobilized on the flow cell surface, and thus the corresponding complementary sequence would be “a capture sequence [that is] common to all the [nucleic acid capture probes/oligo pairs]”.
Peter does not teach that the distribution of the population of features on the flow cell is random. However, Gunderson teaches this limitation (paras. 481-482).
Regarding the limitation requiring that population of features on the flow cell have an average pitch of less than 1 micron, Peter teaches a range of embodiments for the area of the arrays and the number of features that are placed in those arrays (from which the density of the array can be calculated) (para. 38). In addition, Pawloski explicitly teaches arrays with a ≤1 micron feature pitch (section III B: which corresponds to a density of 108 sequences/cm2 and greater). Pawloski also teaches pitches with submicron resolution (abstract, section III B – the ordinary artisan understands that if an entire array has a pitch that is less than one micron, then the average pitch across such an array would also be less than one micron). Finally, Pawloski teaches that arrays with higher resolution are more efficient (abstract).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to combine the methods of Peter and Gunderson since both references teach compositions and methods for detection and analysis of nucleic acid analytes using arrays/solid supports/flow cells of spatially addressed features, wherein samples are contacted with the array, and oligonucleotides fixed to the array hybridize to sample sequences or nucleic acid tags bound to the samples, and may be extended to incorporate sequences such as barcodes or labels into the analytes at one or more features of the array. Peter teaches that oligonucleotides comprising barcodes and primer sequences may be directly and randomly affixed to features of the array (see Figure 2). Peter further teaches compositions and methods that comprise contacting tissue sections to the oligonucleotides of the flow cell (Figure 3). Gunderson teaches that capture probes comprising identifier binding ligands (IBLs) may be attached to beads that are fixed to the array surface (see Figure 1). Thus, an ordinary practitioner would have been motivated to combine the compositions of Peter and Gunderson since the compositions taught by Peter for analyzing tissue sections on arrays may be directly applied to the compositions of Gunderson, as the bead arrays of Gunderson are designed for use with solutions of target analytes as well as samples comprising whole cells (Gunderson, paragraph 606). The compositions and methods of Peter may be used to determining whether a cell is normal or not, or to determine different types of cancer cells, and may be used on tissue samples that have been fixed in a variety of ways and using a plurality of different capture agents (see Peter, column 19, line 16 to column 2, line 19).
It would have been additionally obvious to further modify the Peter flow cell with the pitch taught in Pawloski. Peter teaches embodiments directed to a number of different feature densities, and Pawloski teaches optimizing feature density, including into the submicron scale, to increase the efficiency of the assay. The ordinary artisan would thus have been motivated to combine the teachings of Peter and Pawloski with intention of achieving the expected advantage of a flow cell with increased efficiency. The ordinary artisan would have had an expectation of success as the design and manufacture of nucleic acid arrays is well-known in the art.
With regards to claim 3, Peter teaches a composition wherein the population of random features on the flow cell is a pattern of discrete features, wherein a random feature in the pattern of discrete features is selected from the group consisting of: beads, wells, channels, raised regions and posts (the array may comprise microwells which may help to reduce lateral diffusion of amplification products, paragraph 90; beads, such as magnetic beads, may also be used on the surface of the array and may be attached to the oligonucleotides through a biotin/streptavidin binding pair, paragraph 73).
With regards to claim 5, Peter teaches a composition wherein the flow cell further comprises fiducial markers (fiducial features may be used in the array that is matched to a specific array feature, paragraph 85).
With regards to claims 8, 10 and 12, Peter teaches a composition wherein the nucleic acid probe further comprises a capture sequence that hybridizes to a nucleic acid sequence from a tissue section, wherein the tissue section is deposited on the flow cell, and further comprising a complementary copy of the nucleic acid sequence from the tissue section that is hybridized to the capture sequence (the oligonucleotide may comprise a specific primer sequence enabling the amplification or copying of a target sequence in the sample, wherein the array is contacted directly to the planar cellular sample such as a tissue section by sandwiching the sample between the array and coverslip or other surface, wherein the oligonucleotides of the array bind to nucleic acid tags of the sample and are extended to transfer a barcode sequence to the nucleic acid tags, paragraphs 66 and 79).
With regards to claim 13, Peter teaches a composition further comprising a polymerase, wherein the polymerase is a DNA polymerase, an RNA polymerase, or a reverse transcriptase (the oligonucleotides of the array that bind to the nucleic acid tags may be extended by a DNA polymerase or reverse transcriptase, paragraph 83).
With regards to claims 15-17, Peter teaches a composition wherein the biological sample is a tissue section, wherein the tissue section is a fresh-frozen tissue section or a fixed tissue section such as a deparaffinized formalin-fixed paraffin-embedded tissue (spatial information from the array features is combined with sequence information for nucleic acids derived from a native or pre-processed tissue section, paragraph 7; the tissue sections may be a cryosection, wherein a biopsy that has been obtained from a subject is snap frozen, embedded in optimal cutting temperature embedding material, frozen, cut into thin sections and fixed and mounted on a planar surface, paragraphs 29 and 115; the tissue sections may be formalin-fixed paraffin embedded (FFPE) tissue sections, wherein a piece of tissue from a biopsy is fixed in formaldehyde, embedded in wax, cut into thin sections, and mounted on a planar surface such as a slide (paragraphs 27 and 113), wherein a tissue section may applied to a slide following deparaffinization (paragraph 81).
With regards to claims 18 and 19, Peter teaches a composition wherein the tissue section is from a fish or a mammal, wherein the mammal is a human (the composition may be used in diagnostic procedures for human or non-human animals such as livestock or pets, paragraph 20).
With regards to claims 20-22, Peter teaches a composition wherein the nucleic acid sequence is RNA or mRNA, or wherein the nucleic acid sequence is DNA (the oligonucleotides may hybridize to DNA or RNA tags associated with a tissue section, or may be used to link barcodes with mRNA sequences, paragraphs 83 and 92; an oligonucleotide may act as a primer for reverse transcription of target RNA in the sample, paragraph 73).
With regards to claim 23, Peter teaches a composition wherein the universal primer binding sequence is a sequencing primer binding site (the oligonucleotides may comprise sequencing adapters, or other universal sequences for amplification, paragraph 79).
With regards to claim 32, Peter teaches a composition wherein the nucleic acid probe further comprises a unique molecular identifier sequence (the oligonucleotide may comprise a second barcode comprising random or semi-random sequence for counting molecules, paragraphs 79 and 95).
With regards to claim 36, Peter teaches a composition wherein the nucleic acid probe further comprises a cleavage site (the oligonucleotides of the arrays may comprise a cleavable linker allowing remove of the oligonucleotides from the array surface, paragraphs 6 and 79 and Figure 2).
With regards to claim 9, Gunderson teaches a composition wherein the capture sequence comprises a poly (T) capture sequence (beads on the array may comprise a poly-T sequence, wherein a mRNA target is pulled out of a sample with the probes attached, paragraph 457).
With regards to claim 35, Gunderson teaches a composition wherein the tissue section is permeabilized (samples may be treated in various ways to release target analytes, including the use of lysis buffers, sonication and electroporation, paragraph 87).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to incorporate additional features from the Gunderson arrays into the modified Peter method, discussed above, since both references teach compositions and methods for detection and analysis of nucleic acid analytes using arrays of spatially addressed features, wherein samples are contacted with the array, and oligonucleotides fixed to the array hybridize to sample sequences or nucleic acid tags bound to the samples, and may be extended to incorporate sequences such as barcodes or labels into the analytes at one or more features of the array. Peter teaches that oligonucleotides comprising barcodes and primer sequences may be directly and randomly affixed to features of the array (see Figure 2). Peter further teaches compositions and methods that comprise contacting tissue sections to the oligonucleotides of the array (Figure 3). Gunderson teaches that capture probes comprising identifier binding ligands (IBLs) may be attached to beads that are fixed to the array surface (see Figure 1). Thus, an ordinary practitioner would have been motivated to combine the compositions of Peter and Gunderson since the compositions taught by Peter for analyzing tissue sections on arrays may be directly applied to the compositions of Gunderson, as the bead arrays of Gunderson are designed for use with solutions of target analytes as well as samples comprising whole cells (Gunderson, paragraph 606). The compositions and methods of Peter may be used to determining whether a cell is normal or not, or to determine different types of cancer cells, and may be used on tissue samples that have been fixed in a variety of ways and using a plurality of different capture agents (see Peter, column 19, line 16 to column 2, line 19).
Conclusion
Claims 2-3, 5, 8-10, 12-13, 15-23, 32 and 35-37 are being examined, and are rejected. No claims are 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 CAROLYN GREENE whose telephone number is (571)272-3240. The examiner can normally be reached M-Th 7:30-5:30 EST.
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, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CAROLYN L GREENE/Examiner, Art Unit 1681
/GARY BENZION/Supervisory Patent Examiner, Art Unit 1681
1 Peter was cited on the PTO-892 Notice of References Cited mailed September 15, 2023.
2 Pawloski was cited on the PTO-892 Notice of References Cited mailed June 21, 2024.
3 Fox was cited in the PTO-892 Notice of References Cited mailed November 21, 2024.