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 .
Election/Restrictions
Claims 48-66 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/30/2026.
Applicant’s election without traverse of Group III (claims 67-86) in the reply filed on 01/30/2026 is acknowledged.
Claim Objections
Claim 68 is objected to because of the following informalities: an “and” is missing between element (i) and element (ii). Appropriate correction is required.
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.
Claims 67 and 86 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wu (Wu C et al. Angewandte Chemie. 2014 Dec 1; 126(49): 13732-5).
Wu teaches a method for fabricating high-density RNA arrays. First, a high-density DNA array is fabricated using photolithographic methods resulting in a DNA molecule which is bound to a surface by its 3’ end. This molecule is enzymatically translated into its RNA complement from a surface-bound RNA primer and the DNA template destroyed, resulting in a single-stranded RNA molecule bound to the surface by its 5’ end (abstract). The DNA molecule and the RNA molecule of Wu are considered to be equivalent to the first and second oligonucleotides of the instant application under element (i) of claim 67. As is depicted in Figure 1 of Wu (a portion of which is replicated below), the RNA primer (aka the 3’ end sequence of the second oligonucleotide) hybridizes to the 3’ end of the DNA molecule (aka a 3’ end sequence of the first oligonucleotide).
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Regarding claim 86, Wu does not limit their invention to being constructed in the presence of a cell or tissue. Instead, Wu expressly describes in vitro synthesis of array bound oligonucleotides using standard (or based on standard) oligonucleotide manufacturing techniques.
Claims 67 and 86 are further rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sampas (US 10538796 B2.
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Sampas teaches a method for producing a ligation product on a support. As depicted in Fig. 1 (replicated to the left), two double stranded DNA molecules with sticky ends on both sides independently hybridize to surface-tethered oligonucleotides, which can be covalently or non-covalently attached to the support by either their 5’ or 3’ end (C7 L66-67). This results in the double stranded DNA molecules being indirectly attached to the surface in an orientation that is appropriate for the oligonucleotides to which they are hybridized.
The distal ends of each double stranded DNA molecule are configured to be complementary to each other, allowing them to hybridize and be ligated together. In some embodiments, a cleavable linker (#36 in Fig. 1) may be present, allowing for the release of one end of the ligation product from the support (C10 L7-67).
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A portion of Fig. 1 from Sampas is annotated to the left. If each double stranded DNA molecule is thought of as four single-stranded molecules, “B” could be considered equivalent to the first oligonucleotide of the instant application, attached indirectly to the substrate via hybridization to a surface-bound oligonucleotide and containing a cleavable linker (36). “C” could be considered equivalent to the second oligonucleotide of the instant application, which is indirectly attached to the substrate via hybridization with its complement which is itself indirectly attached to the substrate through hybridization with a surface-bound oligonucleotide. “A” could be considered equivalent to the splint of the instant application as it contains regions complementary to both “B” and “C” and facilitates ligation between the first and second oligonucleotides.
Therefore, the DNA molecules of Sampas are considered to be equivalent to the splint and the first and second oligonucleotides of the instant application under element (ii) of claim 67.
Regarding claim 86, Sampas does not limit their invention to being constructed in the presence of a cell or tissue. Instead, Sampas expressly describes in vitro synthesis of array bound oligonucleotides using standard (or based on standard) oligonucleotide manufacturing techniques.
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.
Claims 68-78 are rejected under 35 U.S.C. 103 as being unpatentable over Wu in view of Shalek (US 20200256862 A1, IDS reference).
Wu teaches the limitations of claim 67, from which claims 68-78 ultimately depend, as previously discussed. Wu further teaches that the plurality of second oligonucleotides is immobilized by its 5’ end and comprises a primer sequence which is complementary to the first oligonucleotide (abstract, fig. 1).
Wu does not specify the composition of the first oligonucleotide, simply stating that its sequence can be fabricated using photolithographic methods to be complementary to a desired RNA sequence, implying that any sequence is possible.
Shalek describes functionalized solid supports (beads, microarrays, microwells, microlids), and associated methods of making, for use in various nucleic acid analysis methods (abstract, ¶0090). Agents, such as spacers, ISPCR primers, barcodes, unique molecular identifiers (UMIs) and universal sequences, are attached to the solid support covalently or through a cleavable linker (¶0104-109). Figure 4C depicts an exemplary arrangement where a PEG spacer is most proximal to the solid support, followed by a ISPCR primer, a barcode, a UMI, and a universal sequence at the most distal. These agents can be in either a 3’ to 5’ arrangement or vice versa (¶0018). Furthermore, a capture sequence at the distal end may be included to in order to hybridize to a target nucleic acid. One embodiment of this capture sequence is a polyT tail (¶0132), but can be any entity capable of binding to a target of interest (¶0141). Shalek teaches that their solid support is capable for use in single-cell RNA-Seq methods in which the polyA tail of mRNA molecules is targeted (¶0197). Therefore, for this use case, the capture sequence across all features would be the same.
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Shalek further teaches that a barcode, or combination of barcodes, can be used to associate a target nucleic acid to a particular discrete volume (aka feature). A given population of UMIs, on the other hand, are typically associated with individual members of a set of identical, specific barcodes. In other words, each member of a set of origin (feature)-specific barcodes may be associated with a distinct or different UMI (¶015).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention, motivated to build an array suitable for use in nucleic acid assays, to fabricate the DNA molecule of Wu to be complementary to final desired probe structure of Shalek, thus resulting in Applicant’s invention. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.).
Furthermore, each of the domains recited in the instant claims are individually taught by Shalek, serve discrete, non-interfering functions, and are designed to be modular. Therefore, the number of workable arrangements of these domains is finite and predicable. Furthermore, per MPEP 2141.II.C: "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[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 at 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.
Regarding claims 75 and 77, the probe of Shalek can be capable of hybridizing to the polyA tail of mRNA molecules, as previously described. Therefore, the probe of Shalek should be terminated in a tail that is complementary to the polyA tail (i.e., polyT/U). As such, a skilled artisan would recognize that the fabricated DNA molecule of Wu (aka the first oligonucleotide) should comprise a polyA sequence at the 5’ end, so that when it is translated into RNA via the method of Wu, the final probe has the desired structure.
Claims 79-85 are rejected under 35 U.S.C. 103 as being unpatentable over Sampas in view of Stoeckius (WO 2021097255 A1, IDS reference).
Sampas teaches the limitations of claims 67, from which claims 68-78 ultimately depend, as previous discussed. Sampas does not teach various domains which may be present in the oligonucleotides.
Stoeckius teaches a method for splint-mediated ligation in which an oligonucleotide partially complementary to two polynucleotides hybridizes to both, acting as a “splint” to position them next to one another for ligation (page 14 (vii)). This is depicted in figure 2 below, wherein an acceptor oligonucleotide is immobilized to a substrate and is ligated to a donor oligonucleotide through the use of a universal splint oligonucleotide to generate a final capture probe. The acceptor and donor oligonucleotides can include various domains, such as (and without limitation) spatial barcodes, UMIs, functional domains (e.g., sequencing domain, universal primer), cleavage domains, ligation handle, a capture domain (e.g., a polyT sequence), to produce the final capture probe (¶0224, 0535). The ligation handles of Stoeckius are complementary to a universal ligation oligonucleotide meaning that ligation handles would need to be the same across all acceptor/donor oligonucleotides to ensure that the splint is capable of hybridizing and performing its function.
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It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the ligation products of Sampas to include the functional domains taught by Stoeckius. Both references relate to constructing immobilized oligonucleotide products and the inclusion of modular oligonucleotide domains is a well-known design technique for imparting desired downstream functionality. Therefore, the inclusion of these domains in the ligation product of Sampas represents a predictable enhancement. Applying a known technique to a known device (method or product) ready for improvement to yield predictable results is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, D.).
Additionally, each of the domains recited in the instant claims are individually taught by Stoeckius, serve discrete, non-interfering functions, and are designed to be modular. Therefore, the number of workable arrangements of these domains is finite and predicable. Per MPEP 2141.II.C: "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[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 at 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.
Conclusion
The following prior art made of record and not relied upon is considered pertinent to the applicant’s disclosure:
Kwiatkowski (US 6313284 B1) teaches a method for preparing a solid support by inverting a 3’-immobilized oligonucleotide so that the 5’-end is immobilized and there is a free 3’-end.
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/K.N.K./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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