DETAILED ACTION
Response to Amendments and Arguments
The amendment filed 21 September 2026 is acknowledged. The amendment introduced new limitations regarding the substrate into independent claims 1 and 18. Additionally, two new claims, claims 21 and 22, were added.
In regard to the office action mailed 22 June 2026, after thorough review and consideration of Applicant’s amendments and arguments, the following actions are taken:
(1) Applicant’s arguments, see pages 6-11, filed 21 September 2026, with respect to the rejection(s) of claim(s) 1-20 under 35 U.S.C 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the previously cited art.
Applicant first argues the previously presented rejections do not address the limitations which have been incorporated into the independent claims. This argument is persuasive, and the amendment necessitates the new ground(s) of rejection which follows.
Applicant further argues the art does not address the technical challenges associated with bead-based sequencing on large diameter substrates or the problem of non-uniform distribution of reagents on the substrate surface leading to deleterious effects such as reduced sequencing efficiency and increased risk of contamination and bias. Applicant specifically highlights the differences between Macosko’s array and the instant array, underscoring differences in bead count, substrate size, and ability to be mounted to a chuck for rotational application of reagents, and states that Stickels’s improvements to Macosko’s arrays do not address these differences. As a result, the Applicant concludes that no teaching, suggestion, or motivation to combine these references with Barbee with a reasonable expectation of success exists. The Examiner does not find these arguments to be persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). According to MPEP § 2141.I [emphasis added],
The Supreme Court in KSR reaffirmed the familiar framework for determining obviousness as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), but stated that the Federal Circuit had erred by applying the teaching-suggestion-motivation (TSM) test in an overly rigid and formalistic way. KSR, 550 U.S. at 404, 82 USPQ2d at 1391. Specifically, the Supreme Court stated that the Federal Circuit had erred in four ways: (1) "by holding that courts and patent examiners should look only to the problem the patentee was trying to solve " (Id. at 420, 82 USPQ2d at 1397); (2) by assuming "that a person of ordinary skill attempting to solve a problem will be led only to those elements of prior art designed to solve the same problem" (Id.); (3) by concluding "that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘obvious to try’" (Id. at 421, USPQ2d at 1397); and (4) by overemphasizing "the risk of courts and patent examiners falling prey to hindsight bias" and as a result applying "[r]igid preventative rules that deny factfinders recourse to common sense" (Id.). See also Novartis Pharms. Corp. v. West-Ward Pharms. Int'l Ltd., 923 F.3d 1051, 1059, 2019 USPQ2d 171676 (Fed. Cir. 2019); Apple Inc. v. Samsung Elecs. Co., 839 F.3d 1034, 1047-48, 120 USPQ2d 1400, 1410 (Fed. Cir. 2016); and Aventis Pharma S.A. v. Hospira, Inc., 675 F.3d 1324, 1332, 102 USPQ2d 1445, 1449 (Fed. Cir. 2012).
…
When considering obviousness of a combination of known elements, the operative question is thus "whether the improvement is more than the predictable use of prior art elements according to their established functions."
In the case of the instant claims, Barbee discloses a sequencing array capable of immobilizing beads to at least 1 billion individually addressable locations upon said array in which these locations can be electronically/digitally mapped. Macosko and Stickel teach the concept of, and methods for, developing a bead-barcoding and indexing scheme which ultimately enables high-resolution spatial sequencing analysis of tissue samples. Once the barcoded beads are generated, they are immobilized onto an array surface for sequencing. The skilled artisan prior to the effective filing date of the claimed invention would recognize that the indexable beads of Macosko and Stickel could be immobilized by Barbee’s array as both were known in the art and doing so represents nothing more than the predictable use of prior art elements according to their established functions.
(2) Claims 21 and 22 are rejected under 35 U.S.C 103 in view of the previously cited art.
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 1-9, 11, 13-17, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Macosko [WO 2019213254 A1; previously cited] in view of Barbee [US 20190153520 A1; IDS Reference; previously cited] and Stickels [Stickels RR, et al. Nature biotechnology. 2021 Mar;39(3):313-9; previously cited].
Macosko provides a composition (e.g. an array) described as a glass slide (substrate) upon which a plurality of beads has been immobilized. Each bead includes at least 10-109 attached oligonucleotides/probes comprised of a macromolecule-specific capture sequence and a bead identification sequence (barcode) where the barcode is common and unique to all the oligonucleotides attached to a single bead [Macosko p6¶2, p32¶2].
To manufacture this array, Macosko first generated barcoded beads by performing polynucleotide synthesis on the surface of the beads in a pool-and-split fashion. In an exemplary embodiment in which 12 split-pool cycles were performed, approximately one billion unique, bead-specific barcodes were generated and randomly applied to a glass slide prepared with a capture material, ultimately resulting in an array with approximately one million immobilized beads. The location of each immobilized bead was then determined via in situ sequencing which associated the bead barcodes to specific locations on the array. Macosko further discloses a kit containing their slide-capture bead array composition, as well as instructions for its use [Macosko, p59¶1-p60¶4, p75-76, Example 2-3].
Macosko does not teach (1) the substrate has a diameter of at least 100mm, (2) a surface of the substrate being configured to affix to a chuck, or (3) that at least 1 billion beads are immobilized to the individually addressable locations of the substrate.
Barbee discloses devices, systems, and methods for processing analytes using open substrates having higher efficiency than flow cells as a result of requiring less reagent volume and ability to deliver reagents faster to the substrate surface. Additional benefits include avoiding contamination carryover, shorter completion time, reduced system costs, and flexibility in both target analyte and application or process (e.g., sequencing, barcoding, etc.). These systems and methods make use of substrate which is rotatable about an axis and comprises an array of individually addressable locations to which an analyte may be immobilized at each location via an intermediary support, such as a bead. The substrate includes those with a radius of at least 50mm (i.e. a diameter of at least 100mm). To facilitate rotation of the substrate, it is affixed to a chuck, such as a vacuum chuck. The array may be a planar array in the general shape of a circle with at least 1 to at least 100,000,000,000 individually addressable locations. These locations are located and/or identified electronically or digitally for mapping purposes [Barbee, ¶0176-0177, 0181-0182, 0188, 0191].
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filling date of the claimed invention to immobilize the barcoded beads of Macosko to the substrate of Barbee, essentially substituting the substrate of Macosko for the substrate of Barbee, as this represents nothing more than the predictable use of prior art elements according to their established functions. Additionally, as Barbee teaches that use of their substrate includes advantages such as reduced operating cost and reduced risk of contamination, this substitution would integrate these benefits into the spatial profiling composition of Macosko. A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02). The use of a known technique to improve similar devices (methods or products) in the same way 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, C.
Macosko also does not explicitly disclose the inclusion of indexed data comprising identities and locations of the plurality of barcode sequences on the barcoded substrate in a kit, a deficiency which is not remedied by Barbee.
However, Stickels describes various ways in which they improved Macosko’s composition in order to increase resolution, as well as attempts to facilitate the adoption of the technology. This included providing barcode locations in a publicly accessible online repository thereby streamlining use of the composition [Stickels p318C2]. Therefore, a skilled artisan prior to the effective filling date of the claimed invention, attempting to produce a kit for spatially barcoding samples and looking for ways to maximize adoption of the kit within the art, would have been motivated to provide indexed data of the barcodes within Macosko’s kit, which includes Barbee’s substrate, in order to simplify use of the composition, effectively removing an entire step from the workflow by performing it for the consumer.
Regarding claims 2 and 4-7, Barbee’s substrate is described as being a circular, planar array which is arbitrarily or evenly spaced/distributed and is comprised of silicon and coated at the surface with an aminosilane [Barbee, ¶0180,0182].
Regarding claim 3, a substrate with a radius of 50mm, as taught by Barbee, would have a surface area of approximately 7,850mm2 (A=πr2) [Barbee, ¶0181]. Macosko teaches that the spacing between features on an array can vary based upon the desired density and states than an array of their invention has features which are separated by less 0.5µm to 100µm [Macosko, p14¶2].
Regarding claim 8, Macosko teaches that performing additional split-pool cycles during barcoded bead production can result in an even greater number of possible spatial barcode sequences than described by the present disclosure [Macosko, p41¶3-p42¶1]. Therefore, as the substrate of Barbee includes embodiments in which the number of individually addressable locations is greater than 10 billion and Macosko describes how to scale the manufacture of barcoded beads, the skilled artisan could conceive of an array in which at least 10 billion beads are immobilized to a substrate.
Regarding claims 9, 11, and 14-16, Macosko describes an embodiment in which the macromolecule-specific capture sequence portion of the bead-attached oligonucleotides is described as a poly-dT tail of sufficient length to allow for capture of a poly-A tailed RNA and is common to all of the probes on a solid support [Macosko, p3¶2, p43¶2]. However, additional embodiments are possible to allow for a wide range of macromolecule targets such as the use of DNA-barcoded antibodies in which the barcode effectively tags a capture antibody for detection by the capture sequence. In this way, antibody-bound proteins can be spatially identified [Macosko, p52¶1].
Regarding claims 13 and 17, Macosko states that the plurality of oligonucleotides further comprises a cleavable site of bead attachment, a handle sequence, a bead-specific spatial barcode, a unique molecular identifier, and a capture region, such as a polydT tail [Macosko, p76¶1].
Claims 18-20 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Macosko in view of Barbee.
Macosko describes the way in which spatial profiling technologies have offered only very low resolution on spatial capture arrays which limits the amount of information able to be obtained from a sample, particularly large tissue samples [Macosko p1¶4]. To address this problem, Macosko provides a composition (e.g. an array) described as a glass slide (substrate) upon which a plurality of beads has been immobilized. Each bead includes at least 10-109 attached oligonucleotides/probes comprised of a macromolecule-specific capture sequence and a bead identification sequence (barcode) where the barcode is common and unique to all the oligonucleotides attached to a single bead [Macosko p6¶2, p32¶2].
To manufacture this array, Macosko first generated barcoded beads by performing polynucleotide synthesis on the surface of the beads in a pool-and-split fashion. In an exemplary embodiment in which 12 split-pool cycles were performed, approximately one billion unique, bead-specific barcodes were generated and randomly applied to a glass slide prepared with a capture material, ultimately resulting in an array with approximately one million immobilized beads. The location of each immobilized bead was then determined via in situ sequencing which associated the bead barcodes to specific locations on the array [Macosko p75-76, Example 2-3].
Macosko does not teach (1) the substrate has a diameter of at least 100mm, (2) a surface of the substrate being configured to affix to a chuck, or (3) that at least 1 billion beads are immobilized to the individually addressable locations of the substrate.
Barbee discloses devices, systems, and methods for processing analytes using open substrates having higher efficiency than flow cells as a result of requiring less reagent volume and ability to deliver reagents faster to the substrate surface. Additional benefits include avoiding contamination carryover, shorter completion time, reduced system costs, and flexibility in both target analyte and application or process (e.g., sequencing, barcoding, etc.). These systems and methods make use of substrate which is rotatable about an axis and comprises an array of individually addressable locations to which an analyte may be immobilized at each location via an intermediary support, such as a bead. The substrate includes those with a radius of at least 50mm (i.e. a diameter of at least 100mm). To facilitate rotation of the substrate, it is affixed to a chuck, such as a vacuum chuck. The array may be a planar array in the general shape of a circle with at least 1 to at least 100,000,000,000 individually addressable locations. These locations are located and/or identified electronically or digitally for mapping purposes [Barbee, ¶0176-0177, 0181-0182, 0188, 0191].
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filling date of the claimed invention to immobilize the barcoded beads of Macosko to the substrate of Barbee, essentially substituting the substrate of Macosko for the substrate of Barbee, as this represents nothing more than the predictable use of prior art elements according to their established functions. Additionally, as Barbee teaches that use of their substrate includes advantages such as reduced operating cost and reduced risk of contamination, this substitution would integrate these benefits into the spatial profiling composition of Macosko. A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02). The use of a known technique to improve similar devices (methods or products) in the same way 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, C.
Regarding claim 19, a substrate with a radius of 50mm, as taught by Barbee, would have a surface area of 7,850mm2 (A=πr2) [Barbee, ¶0181]. Macosko teaches that the spacing between features on an array can vary based upon the desired density and states than an array of their invention has features which are separated by less 0.5µm to 100µm [Macosko, p14¶2].
Regarding claim 20, Barbee describes how their substrate is configured to rotate such that solutions are directed across the array due to the applied centrifugal force. A fluid film of nearly constant thickness across the array can be achieved by continuously rotating the substrate over a period of time. By modifying the rotational velocity or viscosity of the applied solution, films of various thicknesses can be obtained [Barbee, ¶0191-0196]
Conclusion
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 Kara N Kovach whose telephone number is (571)272-8134. The examiner can normally be reached Monday - Friday, 9am - 3pm.
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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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/K.N.K./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
