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 .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/28/2024, 04/18/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims
This office action is in response to Applicant's Response to Election / Restriction filed on March 31, 2026. No claims amendment are made in the response filed on 03/31/2026.
Claims 1-26 are currently pending, with claims 3 and 9-26 withdrawn.
Claims 1, 2, and 4-8 are under examination. This is the first action on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-21) in the reply filed on March 31, 2026 is acknowledged 1.
Applicant’s election without traverse of the following species in the reply filed on March 31, 2026 is acknowledged:
1) azide as the first functional group;
2) amine as the second functional group; and
3) reversibly cross-link the polymer chains via cleavable molecules that are cleavable by acid (claim 8) as the reversibly cross-linking chemistry.
Claims 1, 2, and 4-8 read on the elected species. Claims 3 and 9-21 are withdrawn as being drawn to non-elected species.
Claims 3 and 9-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Examination on the merits commences on claims 1, 2, and 4-8.
Priority
The priority date of the instant claims 1, 2, and 4-8 is November 21, 2022, filling date of the US provisional application NO. 63/427,018.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
Claim 1 recites the term "hydrogel," which is defined by the specification as follows:
"As used herein, a “hydrogel” refers to a three-dimensional polymer network structure that includes polymer chains and is at least partially hydrophilic and contains water within spaces between the polymer chains. A hydrogel may include any suitable combination of hydrophilic, hydrophobic, and/or amphiphilic polymer(s), so long as the overall polymer network is hydrophilic and contains water within spaces between the polymer chains. Hydrogels include chemical hydrogels in which both the bonding to form the polymer chains, and any cross-linking between the polymer chains, is covalent; such cross-linking during hydrogel formation may be irreversible, as distinguished from the present reversible cross-linking which is performed after the hydrogel is formed. In some cases, the chemical hydrogel may include, or may consist essentially of, brush-like structures of polymer chains attached to a surface, substantially without physical or covalent crosslinks between polymer chains, or alternatively polymer chains with multiple attachment points to a surface, resulting in loops, but also lacking interchain crosslinks. Hydrogels also include physical hydrogels in which the bonding to form the polymer chains, and any cross-linking within the polymer chains, is not covalent. Nonlimiting examples of physical hydrogels include agarose and alginate." ([0052])
Claim 1 recites the term "polymer chains," which is defined by the specification as follows:
"As used herein, the “polymer chain” of a hydrogel is intended to mean those portions of the hydrogel that are polymerized with one another during the polymerization process. Polymer chains may be cross-linked to form the hydrogel. For example, cross-linkers may be added during or after the polymerization process that forms the polymer chains. Additionally, or alternatively, in some examples the polymer chains may be deposited on a substrate surface that includes functional groups to which functional groups of the polymer chains become coupled. The polymer chains may be coupled to the surface, e.g., via reactions between the functional groups of the polymer chains and the functional groups at the surface, and such coupling may cross-link the polymer chains to form the hydrogel. Such cross-linking may cause the polymer chains to covalently or non-covalently attach to one another, or may occur as a result of chain entanglement during polymerization and/or attachment to a surface. As provided herein, polymer chains also or alternatively may be reversibly cross-linked after the hydrogel is formed, e.g., using functional groups in a manner such as described in greater detail below."([0053])
For the purpose of applying prior art, claim 1 recites "second functional groups coupled to the polymer chains" and "reversibly cross-linking" polymer chains in a hydrogel. However, the term "reversibly cross-linking" or "reversibly cross-link" is not expressly defined with any structural features in the application's disclosure.
The specification discloses that any suitable functional groups may be included to reversibly cross-link polymer chains of the hydrogel:
"Any suitable functional groups may be included in a hydrogel and used to couple amplification primers 121, 122 to the hydrogel and/or to reversibly cross-link polymer chains 110 of the hydrogel to one another. In some examples, the functional groups (e.g., 120, 130, and/or 230) independently may be selected from the group consisting of: azide, amine, thiol, diol, aldehyde, alkyne, strained cyclooctyne, and an inverse electron-demand (IED) Diels-Alder group. The functional groups may be included in polymer chains 110 of the hydrogel 100, 200, or 300 during synthesis of the hydrogel. The cross-linking density may be controlled by tuning the content of the functional moieties 120, 130, and/or 230 in the polymer chains. Additionally, as noted above with reference to FIGS. 2A-2C, one type of functional group may be converted to another type of functional group within the hydrogel. " ([0072])
The ordinary meaning of "reversible cross-linking" in the context of hydrogels encompass a wide range of mechanisms with different types of functional groups, including covalent hydrogel networks that are degradable; Covalent adaptable networks (e.g., hydrazone gels, or imine gels); Non-covalent associating networks (e.g., alginate, or hydrogen bonding). (see Rosales2 at page 8: “Reversible crosslinks for 3D hydrogels”)
Accordingly, in light of the specification and under BRI, functional groups that "reversible cross-links" polymer chains in a hydrogel is interpreted to encompass any functional groups capable of forming a network of polymer chains in a degradable hydrogel.
For the purpose of applying prior art, claim 1 recites:
"first functional groups coupled to the polymer chains";
"amplification primers coupled to the polymer chains via the first functional groups" ; and
"second functional groups coupled to the polymer chains."
The application's disclosure does not expressly define the terms "couple" or "coupled."
Under BRI and in light of the specification, "A coupled to B" is interpreted to mean that A is physically associated with B, either directly or indirectly, through covalent or non-covalent interactions.
This interpretation is consistent with the specification. For example, Fig. 1 illustrates amplification primers covalently coupled to hydrogel polymers, while also being indirectly coupled to a substrate that is in physical contact with the hydrogel (see also [0056-0057]). See also the definition of amplification primers as being couple to the substrate:
"[a]n “amplification primer” is intended to mean a primer that is coupled to the substrate." ([0036])
Claim Rejections - 35 USC § 102
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 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 1-2 and 4-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Khurana (WO2021108499A1 - On-flow cell three-dimensional polymer structures; Published 2021-06-03; cited as Foreign Patent Document #C05 in IDS filed on 04/18/2024).
Khurana relates to the field of NGS sequencing (e.g. [0008]-[0009]) and teaches methods for making on-flow cell, three- dimensional sequencing matrix comprising amplification primers for cluster amplification within a hydrogel (e.g. [00071]; [00082]; [000321] Figs 19-20).
Regarding claim 1, Khurana teaches a hydrogel on a substrate (Fig. 19, hydrogel within a flow cell by polymerization of PAZAM + di-DBCO-PEG with primer grafting; [000191]; Fig. 20, oligo-bearing hydrogel beads packed in flow cell or on glass slide; [000331]), comprising:
a three-dimensional network of polymer chains (Fig. 19, 20);
first functional groups coupled to the polymer chains (Fig. 20, acrydite ; [000331] “copolymerization of acrylamide and acrydite-modified oligos into large polyacrylamide beads”);
amplification primers coupled to the polymer chains via the first functional groups (Fig. 20, acrydite-modified oligos); and
second functional groups coupled to the polymer chains (Fig. 20, acrylamide comprising amine functional group) and reversibly cross-linking the polymer chains to one another ([000266] hydrogel precursor solution comprising at least one type of monomer, a reversible or cleavable crosslinker, and a photoinitiator.).
Regarding claim 2, Khurana teaches the first and second functional groups are of different types than one another (Fig. 20).
Regarding claim 4, Khurana teaches wherein the first and second functional groups are azide ( [000321] azide-alkyne click reaction) and amine ([000321] acrylamide comprising amine functional group) comprising groups.
Regarding claim 5, Khurana teaches wherein the second functional groups reversibly cross-link the polymer chains via cleavable molecules ([000266] cleavable crosslinker).
Regarding claim 6, Khurana teaches the cleavable molecules are cleavable using a chemical agent ([000270] e.g. reducing agent).
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.
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Khurana (WO2021108499A1 - On-flow cell three-dimensional polymer structures; Published 2021-06-03; cited as Foreign Patent Document #C05 in IDS filed on 04/18/2024), in view of Quay (US20140037714A1 - Amino acid lipids and uses thereof; published 2014-02-06) .
The teachings of Khurana are recited above and applied as for base claim 6/5/1.
Regarding claim 7, Khurana teaches various cleavable molecules, including linkers that are cleavable by chemical agents, heat, electric fields, or light ([000270]). While Khurana does not explicitly disclose linkers cleavable by acid, this feature would have been obvious in view of the knowledge in the art, as supported by Quay.
Quay teaches animo acid lipid polymers that can act as crosslinkers in substrates such as hydrogels ([0030]; [0191]) . Quay teaches acid-cleavable linkers include linkers comprising hydrazone, an acetal, a ketal, an imine, an ether ([0077).
Quay also indicates that acid-cleavable linkers are well-known in the art, evidenced by cited patent documents, dating back to the early 1990s :
“[0078] Examples of acid-labile groups and linkers are given in U.S. Patent Nos. 7,098,032 ; 6,897,196 ; 6,426,086 ; 7,138,382 ; 5,563,250 ; and 5,505,931 .”
Accordingly, a person of ordinary skill in the art would have found it prima facie obvious to use acid-cleavable linkers, as taught by Quay, in place of the cleavable linkers of Khurana, leading to the predictable result of hydrogel comprising cleavable linkers.
Khurana already teaches linkers that are cleavable by chemical agents (e.g., reducing agents). Given the knowledge in the art, a skilled artisan would have recognized that an acid-responsive linkers would perform the same function ꟷ cleavage with presence of a stimuli ꟷ as the reducing agent-responsive linkers disclosed in Khurana. Such a modification represents a simple substitution of one known cleavable linker for another to obtain predictable results, see MPEP 2141.
Regarding claim 8, Quay teaches acid-cleavable linkers include linkers comprising hydrazone, an acetal, a ketal, an imine ([0077).
Double Patenting- Obvious Type
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 5-6 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 17 and 19 of U.S. Patent No. 12502665B2 in view of Shin (Shin et al. "Hydrogels for efficient multiplex PCR." Biotechnology and Bioprocess Engineering 25.4 (2020): 503-512).
Instant claim 1 recites:
A hydrogel on a substrate (‘665 Patent, claim 17), comprising:
a three-dimensional network of polymer chains (‘665 Patent, claim 17);
first functional groups coupled to the polymer chains;
amplification primers ('665 Patent, claim 17) coupled to the polymer chains via the first functional groups; and
second functional groups coupled to the polymer chains and reversibly cross-linking the polymer chains to one another (‘665 Patent, claim 19).
The '665 Patent includes claims that substantially overlap with the subject matter of instant claim 1, including forming a three-dimensional polymer matrix on a substrate (e.g., a flow cell) via polymerization of a precursor solution comprising monomers and oligonucleotide primers ('665 Patent, claim 17).
Although the '665 Patent does not explicitly recite that the primers and polymers are coupled within the matrix via functional groups, this feature would have been obvious in the context of polymerizing a precursor solution comprising monomers and oligonucleotides to form a polymer matrix. A person of ordinary skill in the art would have understood that the monomers and oligonucleotides are polymerized and held within the matrix through functional groups, as approaches for forming polymer matrixes using functionalized monomers are well-known in the art, this is supported by Shin (see Fig. 5; page 507 "Primer Conjugation on Hydrogels").
Therefore, the instant claim1 lacks patentable distinction over the '665 patent in view of Shin. Therefore, instant claims 1 and 5-6 are obvious over claims 17 and 19 of the '665 patent, in view of Shin.
Prior Art
Below are relevant prior art not used in rejection but pertinent to the claims or disclosure.
Hydrogel materials have been extensively studied in the field of life science and biomaterial engineering. Specifically, hydrogels comprising immobilized primers are disclosed in the following applications.
single-cell sequencing :
De Rop et al. Hydrop enables droplet-based single-cell ATAC-seq and single-cell RNA-seq using dissolvable hydrogel beads. Elife. 2022 Feb 23;11:e73971.];
Wang, Yongcheng, et al. "Dissolvable polyacrylamide beads for high‐throughput droplet DNA barcoding." Advanced Science 7.8 (2020): 1903463.
Biomaterial fabrication and tissue engineering :
Qi, H., Ghodousi, M., Du, Y. et al. DNA-directed self-assembly of shape-controlled hydrogels. Nat Commun 4, 2275 (2013). doi.org/10.1038/ncomms3275.
Expansion microscopy (ExM):
Gao (US20190256633A1 - Swellable and Structurally Homogenous Hydrogels and Methods of Use Thereof; published 2019-08-22) (see [0085])
Spatially addressable molecular arrays:
Schnall-Levin (US20210332424A1 - Methods of generating an array; Published on 2021-10-28) (see [0431]; [0437] ; [0444] for examples);
Mir (US9376677B2 - Arrays and methods of use; Published 2016-06-28) )Col 32, lines 24-27; col 33, lines 56-62).
In-gel multiplex PCR:
Kim, Junsun, et al. "Multiplex real-time PCR using temperature sensitive primer-supplying hydrogel particles and its application for malaria species identification." PLoS One 13.1 (2018): e0190451.;
Shin, Juny, and Cheulhee Jung. "Hydrogels for efficient multiplex PCR." Biotechnology and Bioprocess Engineering 25.4 (2020): 503-512.
Functional groups for chemical labeling, such as oligo conjugation using click chemistry (i.e., alkyne-azide cycloaddition catalyzed by Cu) is well known in the art.
See Sahoo. "Fluorescent labeling techniques in biomolecules: a flashback." RSC advances 2.18 (2012): 7017-7029.
Degradable hydrogels comprising crosslinkers cleavable by acid are known in the art:
See Kleine-Brüggeney (US20200399428A1 - Systems, methods and hydrogels for cell culture and analysis ; 2020-12-24) ([0351-0356]);
See also. Vetrík, Miroslav, et al. "Hydrazone-based hydrogel hydrolytically degradable in acidic environment." Polymer degradation and stability 96.5 (2011): 756-759.
Conclusion
No claims are allowed.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 Claims 22-26 are withdrawn as being drawn to non-elected group II.
2 Rosales et al. The design of reversible hydrogels to capture extracellular matrix dynamics. Nat Rev Mater. 2016;1:15012. doi: 10.1038/natrevmats.2015.12. Epub 2016 Feb 2. PMID: 29214058; PMCID: PMC5714327.
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