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 .
The Final Rejection mailed on 2/26/2026 is VACATED in view of the IDS filing of 2/25/2026, which necessitates the following new grounds of rejection.
Applicant’s submission of an information disclosure statement under 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p) on 2/25/2026 prompted the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
Applicant’s arguments and amendments have been thoroughly reviewed and considered. The arguments are directed to the prior art rejections presented in the Final Rejection of 2/26/2026, which is now vacated as described above, and thus, these arguments are rendered moot. Claims 2-3, 5-16, 18-20, and 23-31 are pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 2/25/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 2-3, 5, 7-10, 14-16, 18-20, 23-29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (WO 2018/217862 A1; cited in Applicant’s IDS).
Zhou teaches methods to enable determination of spatial information of biological molecules with a zipcode array (Abstract). The biomolecules used can be mRNA (para. 10). Para. 15 describes detecting the spatial distribution of a biological sample using RNA molecules in said sample, where the RNA is first contacted with first oligonucleotides on a first surface. Reverse transcription then occurs to extend the first oligonucleotides using the RNA to create cDNA, creating second oligonucleotides. Then, the RNA is removed from the second oligonucleotides (para. 16), and the second oligonucleotides can be contacted with a zipcode array. The second oligonucleotides may undergo a template switching extension reaction (see para. 16) before being extended using the zipcodes on the zipcode array, creating third oligonucleotides. The zipcodes contain coordinate information that allows for spatial coordinate detection (para. 16). The third oligonucleotides can then be sequenced.
An similar illustrative example of this method is shown in Figures 18 and 19. A first oligonucleotide is attached to a substrate via its 5’ end, and contains a poly(T) sequence that attaches to a poly(A) sequence on a sample RNA. This first oligonucleotide is analogous to the claimed first probe. Extension then occurs via reverse transcription to generate cDNA, and terminal transferase activity of the reverse transcriptase adds a poly(C) sequence of untemplated oligonucleotides (instant claims 8 and 27; see para. 167). This poly(C) sequence can then hybridize to a template switching oligonucleotide with a poly(G) sequence and an adapter, and then further extension of the first oligonucleotide occurs to generate a sequence complementary to the template switching adapter. The RNA and template switching sequence are then removed, and the extended first oligonucleotide is contacted with a zipcode array, where the zipcodes are attached to the array at their 5’ end, and contain a portion that is the same as the template switching adapter (“Adapter A”) along with the zipcode. Further extension of the first oligonucleotides can then occur to incorporate the zipcode sequence (instant claim 3; para. 168).
After this incorporation, the zipcode containing cDNA can be amplified via PCR and may then undergo sequencing analysis (instant claims 7, 15, and 24-25; para. 169), where a library of cDNA sequences is specifically taught. Zhou teaches that the zipcodes are specifically designed to detect the distribution of nucleic acids in space and to allow for the identification of a specific location of a sequence (para. 59). Thus, as the extended oligonucleotides contain both the target sequence and the zipcode sequences, they can determine the presence and location of a target sequence (instant claims 16 and 26).
However, in these above teachings of Zhou, the first oligonucleotide is on a first array/gel matrix substrate, and the zipcodes are on a zipcode array (i.e. a second substrate). Nonetheless, Zhou provides several teachings where two oligonucleotides interact with each other on a single array. Figure 17 shows such a configuration in the context of tagmentation, and Figures 23 and 24 show this in the context of creating sequencing libraries (paras. 190-196). MPEP 2141.03 I states, “A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.”
The zipcode arrays of Zhou are particularly designed so that the spatial coordinates of each zipcode oligonucleotide would be known (see Figure 1 for example). The ordinary artisan would thus want to keep this zipcode array structure. However, the ordinary artisan would also recognize that by incorporating the oligonucleotides that are intended to bind to target mRNA in a sample into the zipcode array, only a single array would need to be used, thus cutting down on overall resources and method steps, and particularly eliminating the need to develop an initial/gel matrix. As these oligonucleotides are not target specific (i.e. they bind to the target RNA via a poly(T) sequence, and not a particular gene in the RNA sequence), they can be placed all along the zipcode array with a reasonable expectation of success of binding to a target. As at least some of the oligonucleotides would be close enough to the zipcode sequences to hybridize to them (similar to the sequences binding to one another in Figures 17 and 23-24), they could then be fully extended to achieve the final spatially labeled product as shown in Figure 19 of Zhou. There would additionally be a reasonable expectation of success as Figure 12 of Zhou shows that biological samples can be used directly with non-gel substrates, and still result in zipcoded products. This combination of the teachings of Zhou would be possible through the creativity, skill, and knowledge of the ordinary artisan.
Thus, claims 2-3, 7-8, 15-16, and 24-27 are prima facie obvious over Zhou.
Regarding claim 5, Zhou teaches the use of UMIs specifically (para. 149), but this appears to be in relation to initial oligonucleotides that attach to target molecules, and not zipcode oligonucleotides. However, in para. 86, Zhou teaches that zipcode oligonucleotides can be synthesized by using random embedding with various constraints. Figure 7, along with paras. 6, 8, 10, 12, and 91 describe zipcodes with multiple segments (e.g. upper and lower portions, separated by a separator). Each portion provides positional information. Thus, a single zipcode portion could alone be considered analogous to the spatial barcode of the instant claims. As this would leave another zipcode portion, which would be both a known sequence and a partially random sequence, this would act as analogous to a UMI. Zhou teaches that this zipcode design allows for easy distinguishing of x and y location coordinates on an array (para. 91), and para. 92 describes how separating the zipcode in this manner can provide a large number of overall unique zipcodes, meaning more target molecules could be analyzed at once. Both of these benefits would improve method efficiency, and would thus be motivating to the ordinary artisan.
Thus, claim 5 is prima facie obvious over Zhou.
Regarding claims 9 and 28, Zhou teaches throughout that tissue samples may be used (paras. 4, 6, 8, and 53), and para. 53 in particular notes that the tissues can contain nucleic acids.
Regarding claims 10 and 29, Zhou teaches the use of mRNA from a tissue section, where said tissue is fixed/permeabilized to obtain mRNA on a hydrogel substrate (paras. 109-110 and 146-151). As noted above, Zhou generally teaches the analysis of tissues that contain nucleic acids, and so it would be prima facie obvious to the ordinary artisan that if a tissue sample was being used, in order to obtain target nucleic acids from said tissue, the tissue would need to be treated to expose said nucleic acids, allowing them to hybridize to the oligonucleotides on the substrate. As Zhou teaches clear methods for obtaining and targeting mRNAs from tissue specifically, the ordinary artisan would be motivated to use the fixing/permeabilization methods taught by the reference to be successful in the methods of Zhou described above in the rejection of claims 2, 9, 20, and 28.
Thus, claims 10 and 29 are prima facie obvious over Zhou.
Regarding claim 14, as noted above, paras. 38 and 168 of Zhou teach that the RNA and attached template switching oligonucleotide may be removed from the extended oligonucleotide shown in Figure 19 via denaturation.
Regarding claims 18 and 23, the “Adapter C” sequence on the zipcodes of paras. 167-169 and Figure 19 can be used as a primer binding site during PCR (see para. 169 in particular), thus acting as a functional domain.
Regarding claims 19 and 31, Zhou teaches that the substrates of their invention may be slides (para. 52), and teaches the use of gels and array chips that are attached to slides (paras. 112, 150, 156). As the substrates of Zhou may be used to attach nucleic acids (e.g. paras. 4, 6-7, 81, 129, 142-143, 167, and 191), it would thus be prima facie obvious that a slide could be used as at least a part of the substrate in the teachings of Zhou described above in the rejection of claims 2 and 20.
Claims 6, 11-13, and 30 and are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (WO 2018/217862 A1; cited in Applicant’s IDS) in view of Frisén et al. (WO 2018/091676 A1; cited in a previous Office Action).
Zhou renders obvious the methods of claims 2-3, 5, 7-10, 14-16, 18-20, 23-29, and 31, as described above.
Regarding claim 6, it is first noted that the claim does not state when the 3’ end of the second probe must be blocked in the method of claim 2, or that said second probe must be blocked for the entire method. Zhou does not teach that the zipcodes of their invention may be blocked.
Frisén teaches methods for spatially tagging nucleic acid molecules in a biological specimen, where said methods include probes on solid substrates (Abstract). These methods can also involve first and second strand cDNA synthesis (page 16, para. 1). Frisén teaches that capture probes may be blocked on their 3’ ends prior to contacting the biological specimen (page 51, para. 3) in order to avoid inappropriate or unwanted modification of the capture probes (page 52, para. 1). Frisén also teaches many means by which to reversibly block capture probes (page 52, paras. 2-3). This is particularly useful when biological tissue samples must be modified after contact with the substrate, so that after such modification is complete, the reversible block may be removed from the probe (page 51, para. 3 through page 52, para. 3). Frisén also teaches means of removing a blocking moiety/domain in conjunction with modifying tissue samples (page 53, paras. 1 and 3)
As noted above in the rejections of claims 9-10 and 28-29, in Zhou, a tissue sample may be used, where it is attached to the substrate and then fixed/permeabilized to release the RNA that then attaches to the oligonucleotides on said substrate. As the extended oligonucleotides and the zipcodes are both attached to the same substrate in the teachings of Zhou used above in the rejection of claims 2 and 20, the tissue sample would thus be affixed to the substrate containing both of these sequences. Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Frisén to block the free 3’ ends of the oligonucleotides and zipcodes on the substrate of Zhou while the tissue sample is being modified to release its nucleic acids. This would ensure that these sequences are not modified in an unwanted manner before they are to be used, so that they may work in the method of Zhou described above as intended. As Frisén teaches that these blocking modifications can be reversible, there would be a reasonable expectation of success that after the nucleic acids are released from the tissue sample, these blocks can be removed, and the method of Zhou can proceed as described above.
Thus, claim 6 is prima facie obvious over Zhou in view of Frisén.
Regarding claims 11-13 and 30, while Zhou does teach that zipcodes can be attached to arrays via linkers (para. 129), the reference does not teach the use of cleavable linkers. Zhou does teach that sequencing in their invention generally occurs in designated sequencing equipment (paras. 114 and 159), and notes a general in-solution phase for their described sequencing libraries (Figure 11)
Frisén teaches the aspects described above in the rejection of claim 6. Additionally, the reference teaches that their capture probes may be attached to the solid support via a cleavable chemical cross-linker (pages 11-12, joining para.). Frisén also teaches that releasing the capture probes from the surface of the solid support may be done using a cleavage domain such as the cleavable chemical cross-linker (page 11).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Frisén to add cleavable linkers to the oligonucleotides of Zhou that are extended by the RNA and zipcodes. This is because the ordinary artisan would recognize that the oligonucleotides of Zhou, in order to be used in a sequencing library in the manner suggested by Zhou (e.g. being placed into a sequencing device/system), would need to be removed from the substrate of Zhou described above in the rejection of claims 2 and 20. Zhou does teach that nucleic acids may be attached to substrates via linkers, but does not provide many details about said linkers. Frisén, which teaches a similar method, notes that their cleavable linkers are specifically for removing probes from their array. By including such a cleavable linker sequence, the oligonucleotides can be removed from the substrate by means that do not interfere with the sequences important to extension or identification of the target/zipcode sequence. Frisén also teaches that cleavable chemical cross-linkers can successfully perform such a function, and are known in the art (page 12, para. 1), providing a reasonable expectation of success in obtaining and using these cleavable linkers specifically.
Thus, claims 11-13 and 30 are prima facie obvious over Zhou in view of Frisén.
Conclusion
No claims are currently allowable.
Applicant's submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on 2/25/2026 prompted the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(b). 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 FRANCESCA F GIAMMONA whose telephone number is (571)270-0595. The examiner can normally be reached M-Th, 7-5pm.
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/F.F.G./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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