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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 23, 2026 has been entered.
Status of Claims
Claims 1-2 and 5-20 are currently pending. Claims 3-4 are canceled. Claims 1, 5-12 and 14 are amended.
Claims 10-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim.
Claims 1-2, 5-9 and 20 are examined on their merits.
Previous Rejections
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Rejections Withdrawn
Claim Rejections - 35 USC § 103
Upon further consideration the rejection of claims 1-9 under 35 U.S.C. 103 as being unpatentable over Wu et al. WO 2019/028166 (2/7/2019) (6/25/2025 IDS) in view of de Rutte et al. Massively parallel Encapsulation of Single Cells with Structured Microparticles and Secretion-based Flow Sorting, bioRxiv, 11 March 2020, pp 1-23, XP055921908 (3/11/2020)(6/25/2025 IDS) and Niemeyer et al. EP 3590885 (1/8/2020) is withdrawn.
New Objection
Claim Objection
Claim 6 is objected to because of the following informalities: The claim recites “atarget” and a space should be placed between “a” and “target”. Appropriate correction is required.
New Rejections
Claim Rejections - 35 USC §112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 5-9 and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation “the interior volume” in line 13. There is insufficient antecedent basis for this limitation in the claim. Specifically, claim 1, on line 7, recites “at least one open interior volume.” The phrase “at least one open interior volume” encompasses multiple open interior volumes, so it is unclear whether just one, more than one, or all of the at least one open interior volumes are being addressed in claim 1 with the limitation “the interior volume” in line 13.
It is suggested that amending claim 1 to recite “the at least one interior volume” in line 13 would overcome this lack of clarity.
Claims 2, 5-9 and 20 are rejected as depending from claim 1.
Claim 9 is rejected under 35 USC 112, second paragraph (pre-AIA ) for reciting the limitation “the particle” in line 2. Claim 9 depends from claim 1, and claim 1 recites “a plurality of hydrogel particles”. There is insufficient antecedent basis for this limitation in the claim.
For purposes of this office action claim 9 will be interpreted as if the particle is referring to the plurality of hydrogel particles.
It is suggested that amending claim 9 to recite “the plurality of hydrogel particles” would overcome this lack of clarity.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
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 1-2, 5-9 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. WO 2019/028166 (2/7/2019) (6/25/2025 IDS) in view of de Rutte et al. Massively parallel Encapsulation of Single Cells with Structured Microparticles and Secretion-based Flow Sorting, bioRxiv, 11 March 2020, pp 1-23, XP055921908 (3/11/2020)(6/25/2025 IDS), Niemeyer et al. EP 3590885 (1/8/2020) and McKee et al. CN 105473996 (4/6/2016) as evidenced by the specification.
Wu et al. teach hydrogel beads which are made of a hydrogel polymer and a genetic material which can be a cell, wherein the bead has multiple pores that allow diffusion of a reagent through the bead while retaining the genetic material. (See [0004]). The diameter of the bead can be from about 2 to about 100 micrometers in diameter. (See [0084]). The bead is a particle that has a plurality of micropores as called for in instant claim 2.
Wu teaches that the pore size of the hydrogel can be engineered to allow the diffusion of enzymes and smaller size primers (less than 50 base pairs) while retaining larger nucleic acids (greater than 300 base pairs). (See [0035]). Wu teaches that the pore size can be finely tuned by varying the ratio of the concentration of the polymer to the concentration of crosslinker. (See [0030]). Wu teaches that cells that are 2 micrometers in diameter can be captured. (See [0037]). Since cells that are 2 micrometers in diameter can be captured within the particle, the pore size and open interior volume must be at least about a micron as called for in instant claim 1.
Wu teaches an embodiment in which the encapsulated nucleic acids can be sequenced within the hydrogel beads. The sequencing can be sequencing by synthesis. (See [0055-56]). Wu teaches that in the methods of sequencing by synthesis, a primer may be used. (See [0077]).
Wu does not teach antibodies that are covalently linked to the particle, and Wu does not expressly teach that the particles have a nanoporous structure in the mesh of cross-linked polymers. Wu also does not teach polymers of acrylamide and bisacrylamide, Wu does not teach wherein 70% or more of the hydrogel particles vary in the largest dimension by a factor of 10 or less. These deficiencies are made up for with the teachings of Rutte et al, Niemeyer et al, and McKee et al.
Rutte et al. (Rutte) teaches the fabrication of structured hydrogel microparticles containing cavities. (See Figure 1 and page 4). The structured hydrogel microparticles containing cavities are further functionalized with an antibody or biotinylated antibody for cell adhesion. Antibodies are called for in instant claim 5. Biotin is covalently linked to the particle as called for in instant claim 9. (See page 4, first paragraph and Figure S1G).
Cells are then introduced to particles. (See Figure 3). Rutte teaches that its approach, which it terms “dropicles” are able to capture circulating cells within the cavities of the microparticles, so that the secretions of the cell can be further analyzed. (See page 3, second paragraph). Circulating cells are called for in instant claim 7 and they are a target capture moiety as called for in claim 6. The secretions of the cell are further analyzed through cell lysis. Cell lysis is called for in instant claim 8.
Rutte teaches that its approach, which uses cavity-containing hydrogel microparticles to perform functional single-cell secretion analysis and sorting using only commonly accessible lab infrastructure. (See Abstract). The microparticles act as a solid support which facilitates cell attachment, templates formation of uniform aqueous compartments which prevent cross-talk between cells, and captures secreted proteins. This reads on the aqueous liquid permeating the interior of the micropores which allows analytes in the fluid to access the reagent as called for in instant claim 1. Rutte notes that microparticles are easily distributed and used, democratizing access to high-throughput functional cell screening. (See Abstract).
Niemeyer et al. (Niemeyer) teaches a composite material comprising DNA hydrogel and silica nanoparticles. (See Abstract). It is a DNA polymer material with designed properties including adhesiveness, stiffness and plasticity. By incorporating silica nanoparticles into the DNA hydrogel, the mechanical stiffness and elastic properties can be improved. The composite material is mechanically stable and has a porous structure such that the three-dimensional structures allow the diffusion of chemical and biological substances through the wall of the structures.
Niemeyer teaches that in a preferred embodiment, the mesh size is estimated to be bigger than 100 nm and smaller than 500 nm, as determined by the 200 nm tracer particles freely moving inside the hydrogel mesh structure, while the 500 nm tracer particles are restrained inside the hydrogel mesh structure. This range of mesh size bigger than 100 nm and less than 500 nm overlaps with the mesh size of at least about 200 nm is called for in instant claim 1. Since the 200 nm tracer particles are moving freely inside the hydrogel mesh structure, there is open interior volume in the hydrogel mesh as called for in instant claim 1. There is also a nanoporous structure in the mesh as called for in instant claim 1.
Niemeyer also teaches microgels, which are monodisperse microporous hydrogel microparticles, as evidenced by the specification at [0062]. Monodisperse microporous hydrogel microparticles vary from each other in their largest dimension by less than 10% as called for in instant claim 20, as evidenced by the specification at [0066].
McKee et al. (McKee) teaches an automated method and apparatus for processing biomolecule assays. (See Abstract). McKee describes Western blotting and teaches that polyacrylamide-bisacrylamide matrices are the starting point of the process. Specifically the gel matrix is the separation medium and separates molecules by size and charge using a gel matrix created by the crosslinking of acrylamide monomers and bisacrylamide. (See page 18). McKee teaches that the pore size of the polyacrylamide gel can be changed by changing the relative concentration of acrylamide and bisacrylamide cross-linking agent. Additionally, polyacrylamide gels can be prepared to have a pore size gradient. (See page 18). There is thus great control of polyacrylamide pore size and crosslink density and polyacrylamide-bisacrylamide is particularly flexible and adaptable for specified uses. (See page 18). Crosslinked polymers comprising acrylamide and bisacrylamide are called for in instant claim 1.
One of ordinary skill in the art before the earliest effective filing date of the invention making the Wu hydrogel beads with multiple micropores that can capture cells that are 2 micrometers in diameter would also have made them microgels having a nanoporous structure with a mesh size that is bigger than 100 nm and smaller than 500 nm and functionalize the cavities with a biotinylated antibody in order to adhere 200 nm cells that can access the inside of the hydrogel mesh structure as taught by Rutte and Niemeyer. This would allow for the democratization of access to high-throughput functional cell screening.
One of ordinary skill in the art before the earliest effective filing date of the invention making the Wu hydrogel beads with multiple micropores that can capture cells that are 2 micrometers in diameter would use acrylamide and bisacrylamide crosslinker taught by McKee in order to have a polymer and crosslinker that is flexible and can adjustable pore size and density as well as being adaptable to a variety of biologic specified uses as taught by McKee.
Response to Remarks
Applicants’ arguments of June 23, 2026 have been fully considered and are found to be mostly persuasive as described further below. Applicants note new claim 20 and where support can be found for it.
Obviousness Rejections
Applicants argue that the obviousness rejection does not identify the reason why a person of ordinary skill in the art would have combined the teachings of the prior art because Buehler does not motivate the use of a polymer made of acrylamide and bisacrylamide in a hydrogel because Buehler teaches hydrogels that are improved compared to such hydrogels (the use of acrylate crosslinkers, zero length crosslinkers and noncovalent crosslinkers.) Buehler does not disclose the use of polyacrylamide and bisacrylamide for the improved hydrogels. Rather Buehler criticizes higher concentration methylene bisacrylamide-based systems as opaque, hydrophobic and difficult to prepare, a skilled artisan would not have been motivated to use acrylamide and biscarylamide.
Applicants assert that because Beuhler does not explicitly teach the use of acrylamide and biscarylamide to control the pore size and crosslinking density and because Beuhler disparages the use of high concentrations of bisacrylamide, a person of ordinary skill in the art would not have been motivated to selected those materials for a hydrogel particle or for the claimed hydrogel.
Response
Applicants’ arguments are found to be persuasive regarding Beuhler and the rejections have been withdrawn above.
Please note the new rejections applied above. As stated in the rejection one of ordinary skill in the art before the earliest effective filing date of the invention making the Wu hydrogel beads with multiple micropores that can capture cells that are 2 micrometers in diameter would have made them microgels having a nanoporous structure with a mesh size that is bigger than 100 nm and smaller than 500 nm and functionalize the cavities with a biotinylated antibody in order to adhere 200 nm cells that can access the inside of the hydrogel mesh structure as taught by Rutte and Niemeyer. This would allow for the democratization of access to high-throughput functional cell screening. The motivation would be to have easier, cheaper access to high-throughput cell screening. The references teach that this is a stated goal of their inventions: easier access to high-throughput screening. Lower cost and being able to achieve high throughput screening more easily is a highly motivating reason to combine teachings.
Similarly, McKee teaches that acrylamide and bisacrylamide crosslinker allow for good control of the pore size and crosslink density. This is a powerful motivation because persons of ordinary skill in the art are able to control these features so that they can adapt them to meet their objectives in their research. Varying crosslink density can affect the properties of the hydrogel and make it adaptable to suit varying research needs. Flexibility is sought after and makes a system or hydrogel more desirable for use in research.
The references themselves speak to a desire for this flexibility. Wu states at [0023] that it is to be readily understood that the aspects of the present disclosure, as generally described herein, and illustrated in the Figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein.
Conclusion
No claims are allowed.
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/SARAH CHICKOS/
Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619
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