DETAILED CORRESPONDENCE
Status of the Application
The final rejection mailed on August 30, 2024 is VACATED in favor of the instant non-final rejection.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/07/2024 has been entered.
Claims 1-6, 8-9, 11, and 13-21 are pending in this application.
Applicant’s amendment to the claims filed 08/07/2024 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks filed on 08/07/2024 in response to the Advisory Action mailed on 06/28/2024 are acknowledged and have been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections – 35 USC § 103
The rejection of Claims 1-2, 6, 8, 11 and 13-21 under 35 U.S.C. 103 as unpatentable over Alsberg et al. (US 2019/0054207; cited on the form PTO-892 mailed 10/12/2023; herein referred to as Alsberg ‘207) in view of Genizer et al. (Instruction Manual: Manual Operation of Liposome Hand-Extruder, Genizer, 2020; cited on Form PTO-892 mailed on 10/12/2023; herein referred to Genizer A) and further in view of evidentiary reference Genizer et al. (Brochure: High Pressure Hand Driven Liposome Extruder Brochure, Genizer 2020; cited on Form PTO-892 mailed on 10/12/2023; herein referred to as Genizer B) is withdrawn in view of Applicants remarks that the references do not teach or suggest a method of forming a gel particle slurry as recited in the amended claim 1 of “providing a first solution in a first depot, the first solution includes an aqueous solution of cross-linkable alginate macromers and an optional first crosslinker; providing a second solution in a second depot that is separated from the first depot by a mixing unit that includes a mixing element, the second solution comprising a second crosslinker and/or polymer macromer that is capable of crosslinking the cross-linkable alginate macromers; and reversibly transferring the first solution and the second solution through the mixing unit between the first depot and the second depot such that the first solution and the second solution are mixed and agitated to crosslink the cross-linkable alginate macromers to form the gel particle slurry comprising crosslinked hydrogel particles”, as Genizer A and B teach a liposome hand-extruder designed to produce unilamellar populations of liposomes via forcing a multilamellar sample through a filter to produce a homogeneous sized material.
The rejection of Claims 3-4 under 35 U.S.C. 103 as unpatentable over Alsberg ‘207 and Genizer A as applied to claims 1-2, 6, 8, 11 and 13-21, and further in view of Koflo et al. (Clear PVC Static Mixer, website archived https://web.archive.org/web/20190417085611/https://www.koflo.com/static-mixers/stock-static-mixers/stock-clear-pvc-static-mixers.html, published on 04/17/2019, visited on 09/27/2023; cited on the Form PTO-892 mailed on 10/12/2023; herein referred to as Koflo) is withdrawn in view of Applicants remarks that the references do not teach or suggest a method of forming a gel particle slurry as recited in the amended claim 1, as Genizer A and B teach a liposome hand-extruder designed to produce unilamellar populations of liposomes via forcing a multilamellar sample through a filter to produce a homogeneous sized material.
The rejection of claim 5 under 35 U.S.C. 103 as unpatentable over Alsberg ‘207, Genizer A, and Koflo as applied to claims 1-4, 6, 8, 11 and 13-21 above, and further in view of Ashby et al. (Ashby Cross Company Inc., Luer Lock Adaptors, website archived https://web.archive.org/web/20180707120942/http://www.ashbycross.com/luer-locks.htm, published on 07/07/2018, visited on 9/27/2023; cited on the attached Form PTO-892; herein referred to as Ashby) is withdrawn in view of Applicants remarks that the references do not teach or suggest a method of forming a gel particle slurry as recited in the amended claim 1, as Genizer A and B teach a liposome hand-extruder designed to produce unilamellar populations of liposomes via forcing a multilamellar sample through a filter to produce a homogeneous sized material.
The rejection of claim 9 under 35 U.S.C. 103 as unpatentable over Alsberg ‘207 and Genizer A as applied to claims 1-2, 6, 8, 11 and 13-21 above, and further in view of Alsberg et al. (WO 2019/199899; cited on the Form PTO-892 mailed 10/12/2023; herein referred to as Alsberg ‘899) is withdrawn in view of Applicants remarks that the references do not teach or suggest a method of forming a gel particle slurry as recited in the amended claim 1, as Genizer A and B teach a liposome hand-extruder designed to produce unilamellar populations of liposomes via forcing a multilamellar sample through a filter to produce a homogeneous sized material.
Claims 1-2, 6, 8, 11 and 13-21 are rejected under 35 U.S.C. 103 as unpatentable over Alsberg ‘207 in view of Larsen et al. (BMC Biotechnol, 2015, 15:29; cited on the attached Form PTO-892; herein referred to as Larsen).
Claim 1 as amended is drawn to a method of forming a gel particle slurry, the method comprising:
providing a first solution in a first depot, the first solution includes an aqueous solution of cross-linkable alginate macromers and an optional first crosslinker;
providing a second solution in a second depot that is separated from the first depot by a mixing unit that includes a mixing element, the second solution comprising a second crosslinker and/or polymer macromer that is capable of crosslinking the cross-linkable alginate macromers; and
reversibly transferring the first solution and the second solution through the mixing unit between the first depot and the second depot such that the first solution and the second solution are mixed and agitated to crosslink the cross-linkable alginate macromers to form the gel particle slurry comprising crosslinked hydrogel particles.
Alsberg ‘207 generally describes hydrogels with dynamically adjustable mechanical properties [title].
Regarding claim 1 and the limitation of providing a first solution that includes a cross linkable hydrogel polymer macromer, Alsberg ‘207 teaches “a composition that includes a dual crosslinkable hydrogel that includes a plurality of polymer macromers which are crosslinked with a first agent and a second agent different than the first agent, wherein the crosslinks formed using the second agent are reversible and repeatable to allow the mechanical properties of the hydrogel to be dynamically adjusted” [abstract]. Alsberg ‘207 further teaches a scheme of preparing an alginate macromer by reacting with NaIO4 and EDC/NHS to produce an oxidized methacrylated alginate (OMA) that can then be crosslinked using UV irradiation to produce a single-crosslinked hydrogel (SO) [Figure 1], which is outlined in paras 0038 and 0044, with more detail given in para 0068 regarding the combination of reagents sodium alginate, sodium periodate (NaIO4), N-hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) being added to the alginate in water corresponding to an aqueous solution, and occurring in solution that is inherently within a container or depot common in the art such as a beaker.
Regarding claim 1 and the limitation of providing a second solution comprising a second crosslinker and/or polymer macromer that is capable of crosslinking the cross-linkable hydrogel polymer macromers, Alsberg ‘207 teaches the subsequent crosslinking of the SO by addition of Ca2+ to form a dual-crosslinked hydrogel (ST) [Figure 1], outlined in para 0070 by the adding a solution of 50 mM CaCl2 to photocrosslinked hydrogels, in which the solution is inherently housed in a container or depot common in the art such as a beaker.
Regarding claim 1 and the limitation of combining the two solutions to form a gel particle slurry, Alsberg ‘207 teaches in Figure 1 and paras 0068-0070 that the combination of the above-described solutions containing OMA and Ca2+, respectively, results in a crosslinked hydrogel in a solution, therein satisfying the limitation of forming a gel particle slurry as a suspension of a solid in a liquid.
Alsberg does not teach that the two depots are separated by a mixing unit that includes a mixing element, or the reversible transfer of first and second solutions through the mixing unit to crosslink the crosslinkable hydrogel polymer macromers to form the gel particle slurry.
Larsen describes the rheological characterization of an injectable alginate gel system [title] and discloses a method involving the formulation of two-component kits and subsequent mixing of the two components to obtain alginate gel matrices [abstract] as an alternative alginate gelling system that provides improved control over the rate of gel formation [p 2, col 1, paras 2-3].
Regarding claim 1 and the limitation of two depots separated by a mixing unit that includes a mixing element and the reversible transfer of first and second solutions through the mixing unit, Larsen teaches the use of two syringes as depots that house two solutions that are separated by a chamber in which contents are mixed to form a gel [Figure 1], and teaches the corresponding method of providing an aqueous sodium alginate solution in one syringe, providing an insoluble strontium or calcium alginate particles dispersed in an aqueous medium in another syringe, mixing the contents of the two syringes in a three-way connector that connects the two syringes, and forming a gel upon mixing [Figure 1 legend].
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine Alsberg ‘207 and Larsen to modify the method of Alsberg ‘207 by using the apparatus and method of mixing as taught by Larsen to arrive at the claimed invention, since the combination of known prior art elements according to known methods results in a predictable result. One of ordinary skill in the art would have been motivated to modify the method of Alsberg ‘207, because Larsen teaches an alginate gelling system that provides improved control over the rate of gel formation. One of ordinary skill in the art would have had a reasonable expectation of success because both Alsberg ‘207 and Larsen discuss methods for producing alginate hydrogels.
Regarding claim 2, Larsen teaches the use of two syringes as depots to house two solutions that are separated by a chamber in which contents are mixed [Figure 1].
Regarding claim 6, Larsen teaches the use of two syringes as depots to house two solutions that are separated by a chamber in which contents are mixed [Figure 1].
Regarding claim 8, Alsberg ‘207 teaches a method of making a dual-crosslinked hydrogel by using UV to activate a photoinitiator to initially form an SO [Figure 1, para 0069], followed by the introduction of a second, different crosslinker as CaCl2 to form the dual-crosslinked hydrogel [Figure 1, para 0070].
Regarding claims 11 and 15, Alsberg ‘207 teaches “the polymer macromers can include biodegradable acrylated and/or methacrylated natural polymer macromers. The acrylated and/or methacrylated, natural polymer macromers can be polysaccharides, which are optionally oxidized, such as oxidized, acrylated and/or methacrylated alginates” [para 0010].
Regarding claims 13-14, Alsberg ‘207 teaches “the polymer macromers can be photocrosslinkable with the first agent and be ionically crosslinkable with the second agent, such as calcium ions” [para 0011].
Regarding claims 16 and 21, Alsberg ‘207 teaches the preparation of OMA in water with a photoinitiator [paras 0068-0069, Figure 1] which corresponds to a first aqueous solution of OMA and first crosslinker that is a photocrosslinker, and the addition of a second solution of 50 mM CaCl2 [para 0070, Figure 1]. The addition of CaCl2 satisfies the limitation of a calcium sulfate slurry, as the Ca2+ ion is active component driving the ionic crosslinking [Figure 1]. As Larsen teaches the apparatus and method for reversibly mixing solutions from two depots, it would have been obvious for one of skill in the art to add the two sets of reagents for the two reactions of preparing (1) OMA and (2) a Ca2+ ion slurry, as taught by Alsberg ‘207, into the two respective depots for their controlled mixing for the formation of the gel particle slurry, as Genizer A teaches using this method and apparatus for the controlled mixing of particles and molecules to produce slurries suitable for downstream biocompatible applications.
Regarding claim 17, Alsberg ‘207 teaches a method of hydrogel preparation in [paras 0068-0070] without the use of preservative as defined as 70% ethanol by the instant specification.
Regarding claim 18, Alsberg ‘207 teaches a method of hydrogel preparation in [paras 0068-0070] that excludes any washing step.
Regarding claim 19, Larsen teaches “for sterile gel preparations 0.22 µm filtered alginate solutions and insoluble alginate dispersions sterilized by autoclaving were used” [p 10, col 1, para 1]. While Larsen explicitly states the use of sterile components for the production of sterile gels using the method taught in [Figure 1], one of ordinary skill in the art would have recognized that the syringes used to carry the method of sterile gel preparation are sterile.
Regarding claim 20, Alsberg ‘207 teaches “embodiments described herein relate to hydrogels having repeatable and reversible dynamically adjustable mechanical properties, methods of forming the hydrogels, and to their use in regenerative medicine, cell-based technologies, drug delivery, and tissue engineering applications” [para 0005], and that “the dynamically adjustable hydrogel can be substantially cytocompatible (i.e. substantially non-cytotoxic)” [para 0006], therefore satisfying the limitation of a biocompatible gel particle slurry.
Therefore, the method of claims 1-2, 6, 8, 11 and 13-21 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 3-5 are rejected under 35 U.S.C. 103 as unpatentable over Alsberg ‘207 and Larsen as applied to claims 1-2, 6, 8, 11 and 13-21 above, and further in view of Koflo et al. (Clear PVC Static Mixer, website archived https://web.archive.org/web/20190417085611/https://www.koflo.com/static-mixers/stock-static-mixers/stock-clear-pvc-static-mixers.html, published on 04/17/2019, visited on 09/27/2023; cited on the Form PTO-892 mailed on 10/12/2023; herein referred to as Koflo).
Claim 3 is drawn to the method of claim 2, wherein the mixing element is a static screw or helical mixing element.
The combined teachings of Alsberg ‘207 and Larsen as applied to claims 1-2, 6, 8 and 10-20 are discussed above. These references do not teach the mixing element is a static screw or helical mixing element.
Koflo describes the features of custom PVC static mixers [title] with listed applications of admixing of water treatment chemicals, pH control, and other uses in a wide range of industries beyond those listed. Koflo furthermore teaches the static mixers are sealed within the housing to allow for the benefit of improved mixing efficiency.
Regarding the limitation of ‘the mixing element is a static screw or helical mixing element’ of instant claim 3, Koflo teaches a cylindrical mixing unit within which a static mixer is fixed from end to end [as shown in each image in the reference].
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine Alsberg ‘207, Larsen, and Koflo to modify the combined method of Alsberg ‘207 and Larsen by using a static mixer as the mixing element, as taught by Koflo, to arrive at the claimed invention, since the combination of known prior art elements according to known methods results in a predictable result. One of ordinary skill in the art would have been motivated to further modify the combined method of Alsberg ‘207 and Larsen by using the static mixing element of Koflo, because Koflo teaches the use static mixing elements allows for improved mixing efficiency. One of ordinary skill in the art would have had a reasonable expectation of success because Alsberg ‘207 and Larsen teach methods for the production of alginate hydrogels, and Larsen and Koflo teach apparatuses for the controlled production of mixtures.
Regarding claim 4, the combined teachings of Alsberg ‘207, Larsen and Koflo as related to claim 3 are discussed above, including the limitation of 'the mixing element is fixed within the chamber and extends substantially the length of the chamber'.
Regarding claim 5, Larsen teaches the two syringes are connected as shown in [Figure 1] with a Luer lock connection [p 9, col 2, para 4].
Therefore, the method of claims 3-5 would have been obvious to one of ordinary skill in the art.
Claim 9 is rejected under 35 U.S.C. 103 as unpatentable over Alsberg ‘207 and Larsen as applied to claims 1-2, 6, 8, 11 and 13-21 above, and further in view of Alsberg et al. (WO 2019/199899; cited on the Form PTO-892 mailed 10/12/2023; herein referred to as Alsberg ‘899).
Claim 9 is drawn to the method of claim 1, wherein the average size of the hydrogel particles in the slurry are 5 nm to 10 mm.
The combined teachings of Alsberg ‘207 and Larsen as applied to claims 1-2, 6, 8, 11 and 13-21 are discussed above. These references do not teach the size of hydrogel particles in a slurry.
Alsberg ‘899 describes bioink and crosslinkable support medium for printing [title], wherein a system for forming scaffold-free 3D tissue construct is disclosed with the advantages of using "a self-healing, shear thinning, crosslinkable, biocompatible hydrogel support medium" [abstract] to “overcome … limitations of scaffold-based approaches … [by] using multicellular building blocks that self-assemble into geometries such as aggregates, sheets, strands and rings. These building blocks have been organized and fused into larger and more complicated structures, sometimes comprised of multiple cell types, and then they produce extracellular matrix (ECM) to form mechanically functional three-dimensional (3D) tissue constructs" [para 0002].
Regarding the limitation of a gel particle slurry wherein hydrogel particles have an average diameter of about 5 nm to 10 mm, Alsberg ‘899 teaches a method for producing a hydrogel slurry [para 00101] wherein afterwards "A petri dish was filled with OMA microgel slurry at room temperature to serve as a supporting bath and placed on the building platform" [para 00107], and “the hydrogel support medium can include a plurality of hydrogel particles that include a plurality of crosslinkable biodegradable natural polymer macromers. The hydrogel particles can have an average diameter of about 10 nm to about 10 mm. The natural polymer macromers can be at least partially crosslinked" [para 0010].
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method for producing the gel particle slurry of Alsberg ‘207 and Larsen to include hydrogel particles of 10 nm – 10 mm diameter, as taught by Alsberg ‘899, to arrive at the claimed invention, as the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill in the art would have been motivated to apply the method of Alsberg ‘899 to the gel slurry of Alsberg ‘207 and Larsen, as Alsberg ‘899 teaches that using hydrogel supports for scaffold-free tissue engineering provides a powerful strategy using multicellular building blocks that self-assemble into geometries such as aggregates, sheets, strands and rings to form mechanically functional three-dimensional (3D) tissue constructs. One of ordinary skill in the art would have had a reasonable expectation of success to practice such methods because Alsberg ‘207, Alsberg ‘899 and Larsen teach methods for the preparation of alginate hydrogels.
Therefore, the method of claim 9 would have been obvious to one of ordinary skill in the art.
Response to Remarks: Beginning page 6 of Applicant’s response to the 35 U.S.C. 103 rejection of claims 1-2, 6, 8 and 11-20; Applicant in summary contends that Alsberg ‘207 does not teach all of the features of claim 1 as amended, for Alsberg ‘207 does not teach to combine an first aqueous solution of alginate macromers with a second solution of crosslinker, stating that Figure 1 of Alsberg ‘207 does not show an aqueous solution of alginate macromers as it has an elastic modulus according to [para 0078], and therefore the CaCl-2 when added would not produce a gel particle slurry. Applicant further contends an aqueous solution of alginate macromer could not be formed into a disk with a biopsy punch as detailed in [para 0069 and 0074] of Alsberg ‘207 describing the treatment of hydrogels before the addition of CaCl2. Applicant additionally contends that Genizer A and B do not address the deficiencies of Alsberg ‘207. Applicant contends specifically regarding claim 16 that Alsberg ‘207 does not teach a first solution including aqueous oxidized, acrylated and/or methacrylate alginate, and a second solution of a calcium sulfate slurry, since Alsberg ‘207 teaches the OMA is photocrosslinked to form the hydrogel before the addition of calcium, and thus the reference cannot teach an aqueous OMA solution and a calcium solution are combined to form a particle slurry. Applicant contends regarding claim 9 that Alsberg ‘899 does not teach reversibly transferring of a first and second solution through a mixing unit to obtain a gel particle slurry.
Applicant’s remarks are considered and found not convincing, as Alsberg ‘207 teaches the combining of two solutions to form a gel particle slurry. As described in the rejection above, Alsberg ‘207 teaches "a composition that includes a dual crosslinkable hydrogel that includes a plurality of polymer macromers which are crosslinked with a first agent and a second agent different than the first, wherein the crosslinks formed using the second agent are reversible and repeatable to allow the mechanical properties of the hydrogel to be dynamically adjusted" [abstract]. Alsberg ‘207 provides a scheme of preparing an alginate macromer by producing OMA that can be photocrosslinked via UV radiation [Figure 1], wherein the alginate macromer is prepared in an aqueous solution [para 0068]. As the UV radiation is not provided in the solution with the macromer components, the aqueous solution as described by Alsberg ‘207 before UV irradiation satisfies the limitations of the first solution as recited by the claim. Alsberg ‘207 additionally teaches the addition of 50 mM CaCl2 solution [para 0070], a cross linking agent, in which the solution is inherently housed in a container or depot common in the art such as a beaker, therefore satisfying the limitations of the second solution recited in the claim. Alsberg ‘207 further teaches the combination of two solutions to form a hydrogel [Figure 1]. Therefore the scheme of Alsberg ‘207 encompasses the limitation of forming a gel particle slurry recited in the claim. As Larsen teaches the use of two syringes as depots that house two solutions that are separated by a chamber in which contents are mixed [Figure 1], it would have been obvious for one of skill in the art to use the method of Larsen to combine the solutions of Alsberg ‘207 to arrive at the claimed invention.
In view of the teachings of Alsberg ‘207 and Larsen as described here and in the section above, the remaining dependent claims 2-6, 8-9, 11 and 13-21 are rejected for the reasons stated in the section above.
Double Patenting
The double patenting rejection of claims 1-2, 6, 8, 11 and 13-21 as unpatentable over claims 1 and 6-10 of U.S. Patent No. 11,116,875 in view of Alsberg ‘207, Genizer A, and evidentiary reference Genizer B is withdrawn in view of Applicants remarks that the references do not teach or suggest a method of forming a gel particle slurry as recited in the amended claim 1 of “providing a first solution in a first depot, the first solution includes an aqueous solution of cross-linkable alginate macromers and an optional first crosslinker; providing a second solution in a second depot that is separated from the first depot by a mixing unit that includes a mixing element, the second solution comprising a second crosslinker and/or polymer macromer that is capable of crosslinking the cross-linkable alginate macromers; and reversibly transferring the first solution and the second solution through the mixing unit between the first depot and the second depot such that the first solution and the second solution are mixed and agitated to crosslink the cross-linkable alginate macromers to form the gel particle slurry comprising crosslinked hydrogel particles”, as Genizer A and B teach a liposome hand-extruder designed to produce unilamellar populations of liposomes via forcing a multilamellar sample through a filter to produce a homogeneous sized material.
The double patenting rejection of Claims 3-4 as unpatentable over claims 1 and 6-10 of U.S. Patent No. 11,116,875, Alsberg ‘207 and Genizer A as applied to claims 1-2, 6, 8, 11 and 13-21, and further in view of Koflo is withdrawn in view of Applicants remarks that the references do not teach or suggest a method of forming a gel particle slurry as recited in the amended claim 1, as Genizer A and B teach a liposome hand-extruder designed to produce unilamellar populations of liposomes via forcing a multilamellar sample through a filter to produce a homogeneous sized material.
The double patenting rejection of claim 5 as unpatentable over claims 1 and 6-10 of U.S. Patent No. 11,116,875, Alsberg ‘207, Genizer A, and Koflo as applied to claims 1-4, 6, 8, 11 and 13-21 above, and further in view of Ashby is withdrawn in view of Applicants remarks that the references do not teach or suggest a method of forming a gel particle slurry as recited in the amended claim 1, as Genizer A and B teach a liposome hand-extruder designed to produce unilamellar populations of liposomes via forcing a multilamellar sample through a filter to produce a homogeneous sized material.
The double patenting rejection of claim 9 as unpatentable over claims 1 and 6-10 of U.S. Patent No. 11,116,875, Alsberg ‘207 and Genizer A as applied to claims 1-2, 6, 8, 11 and 13-21 above, and further in view of Alsberg ‘899 is withdrawn in view of Applicants remarks that the references do not teach or suggest a method of forming a gel particle slurry as recited in the amended claim 1, as Genizer A and B teach a liposome hand-extruder designed to produce unilamellar populations of liposomes via forcing a multilamellar sample through a filter to produce a homogeneous sized material.
Claims 1-2, 6, 8, 11 and 13-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,116,875 (cited in the Form PTO-892 mailed 10/12/2023; hereafter “patent”) in view of Alsberg ‘207 and Larsen.
Claim 1 of the current application is drawn to a method of forming a gel particle slurry, the method comprising:
providing a first solution in a first depot, the first solution includes an aqueous solution of cross-linkable alginate macromers and an optional first crosslinker;
providing a second solution in a second depot that is separated from the first depot by a mixing unit that includes a mixing element, the second solution comprising a second crosslinker and/or polymer macromer that is capable of crosslinking the cross-linkable alginate macromers; and
reversibly transferring the first solution and the second solution through the mixing unit between the first depot and the second depot such that the first solution and the second solution are mixed and agitated to crosslink the cross-linkable alginate macromers to form the gel particle slurry comprising crosslinked hydrogel particles.
Regarding instant claim 1 and the limitation of ‘providing a first solution that includes a cross-linkable hydrogel polymer macromer and a first crosslinker in a first depot’, claim 1 of the patent recites a method of regulating cell behavior comprising “providing a dual crosslinkable hydrogel that includes a plurality of polymer macromers that are crosslinked with a first agent and a second agent different than the first agent”.
The claims of the patent do not recite alginate macromers or the reversible transfer of solutions through a mixing element in order to crosslink the hydrogel.
Alsberg ‘207 generally describes hydrogels with dynamically adjustable mechanical properties [title].
Regarding instant claim 1 and the limitation of an aqueous solution of alginate macromers, Alsberg ‘207 discloses “a composition that includes a dual crosslinkable hydrogel that includes a plurality of polymer macromers which are crosslinked with a first agent and a second agent different than the first agent, wherein the crosslinks formed using the second agent are reversible and repeatable to allow the mechanical properties of the hydrogel to be dynamically adjusted” [abstract]. Alsberg ‘207 further discloses a scheme of preparing an alginate macromer by reacting with NaIO4 and EDC/NHS to produce an oxidized methacrylated alginate (OMA) that can then be crosslinked using UV irradiation to produce a single-crosslinked hydrogel (SO) [Figure 1], which is outlined in paras 0038 and 0044, with more detail given in para 0068 regarding the combination of reagents sodium alginate, sodium periodate (NaIO4), N-hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) being added to the alginate in water corresponding to an aqueous solution, and occurring in solution that is inherently within a container or depot common in the art such as a beaker.
Regarding instant claim 1 and the limitation of providing a second solution comprising a second crosslinker and/or polymer macromer that is capable of crosslinking the cross-linkable hydrogel polymer macromers, Alsberg ‘207 discloses the subsequent crosslinking of an SO by addition of Ca2+ to form a dual-crosslinked hydrogel (ST) [Figure 1], outlined in para 0070 by the adding a solution of 50 mM CaCl2 to photocrosslinked hydrogels, in which the solution is inherently housed in a container common in the art such as a beaker which meets the limitation of the term depot.
Regarding instant claim 1 and the limitation of combining the two solutions to form a gel particle slurry, Alsberg ‘207 discloses in Figure 1 and paras 0068-0070 that the combination of the two solutions containing OMA and Ca2+, respectively, results in dual-crosslinked hydrogel in a solution, therein satisfying the limitation of forming a gel particle slurry as a suspension of a solid in a liquid.
Larsen describes the rheological characterization of an injectable alginate gel system [title] and discloses a method involving the formulation of two-component kits and subsequent mixing of the two components to obtain alginate gel matrices [abstract] as an alternative alginate gelling system that provides improved control over the rate of gel formation [p 2, col 1, paras 2-3].
Regarding claim 1 and the limitation of two depots separated by a mixing unit that includes a mixing element and the reversible transfer of first and second solutions through the mixing unit, Larsen discloses the use of two syringes as depots that house two solutions that are separated by a chamber in which contents are mixed to form a gel [Figure 1], and discloses the corresponding method of providing an aqueous sodium alginate solution in one syringe, providing an insoluble strontium or calcium alginate particles dispersed in an aqueous medium in another syringe, mixing the contents of the two syringes in a three-way connector that connects the two syringes, and forming a gel upon mixing [Figure 1 legend].
In view of Alsberg ‘207 and Larsen, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of the patent according to Alsberg ‘207 and Larsen to arrive at the claimed invention, since the combination of known prior art elements according to known methods results in a predictable result. One of ordinary skill in the art would have been motivated to modify the method of the patent by using the method of Alsberg ‘207 and the apparatus and method of Larsen, because Alsberg ‘207 discloses a method for the generation of biocompatible crosslinked hydrogel polymers and Larsen discloses an alginate gelling system that provides improved control over the rate of gel formation. One of ordinary skill in the art would have had a reasonable expectation of success because the claims of the patent are related to a dual crosslinked hydrogel, and Alsberg ‘207 and Larsen discuss crosslinked hydrogel polymers for biocompatible applications.
Regarding instant claim 2, Larsen discloses the use of two syringes as depots to house two solutions that are separated by a chamber in which contents are mixed [Figure 1].
Regarding instant claim 6, Larsen discloses the use of two syringes as depots to house two solutions that are separated by a chamber in which contents are mixed [Figure 1].
Regarding instant claim 8, Alsberg ‘207 discloses a method of making a dual-crosslinked hydrogel by using UV to activate a photoinitiator to initially form an SO [Figure 1, para 0069], followed by the introduction of a second, different crosslinker as CaCl2 to form the dual-crosslinked hydrogel [Figure 1, para 0070].
Regarding instant claim 10, Alsberg ‘207 discloses the crosslinking of hydrogel polymer macromers that are at least partially crosslinked [Figure 1].
Regarding instant claims 11 and 15, Alsberg ‘207 discloses “the polymer macromers can include biodegradable acrylated and/or methacrylated natural polymer macromers. The acrylated and/or methacrylated, natural polymer macromers can be polysaccharides, which are optionally oxidized, such as oxidized, acrylated and/or methacrylated alginates” [para 0010].
Regarding instant claims 13-14, Alsberg ‘207 discloses “the polymer macromers can be photocrosslinkable with the first agent and be ionically crosslinkable with the second agent, such as calcium ions” [para 0011].
Regarding instant claims 16 and 21, Alsberg ‘207 discloses the preparation of OMA in water with a photoinitiator [paras 0068-0069, Figure 1] which corresponds to a first aqueous solution of OMA and first crosslinker that is a photocrosslinker, and the addition of a second solution of 50 mM CaCl2 [para 0070, Figure 1]. The addition of CaCl2 satisfies the limitation of a calcium sulfate slurry, as the Ca2+ ion is active component driving the ionic crosslinking [Figure 1].
Regarding instant claim 17, Alsberg ‘207 discloses a method of hydrogel preparation in [paras 0068-0070] without the use of preservative as defined as 70% ethanol by the instant specification. This rejection was previously applied to claim 17 and has been modified in view of applicant’s amendments.
Regarding instant claim 18, Alsberg ‘207 discloses a method of hydrogel preparation in [paras 0068-0070] that excludes any washing step. This rejection was previously applied to claim 18 and has been modified in view of applicant’s amendments.
Regarding instant claim 19, Larsen discloses “for sterile gel preparations 0.22 µm filtered alginate solutions and insoluble alginate dispersions sterilized by autoclaving were used” [p 10, col 1, para 1]. While Larsen explicitly states the use of sterile components for the production of sterile gels using the method taught in [Figure 1], the syringes used to carry the method of sterile gel preparation are implicitly understood to be sterile.
Regarding instant claim 20, Alsberg ‘207 discloses “embodiments described herein relate to hydrogels having repeatable and reversible dynamically adjustable mechanical properties, methods of forming the hydrogels, and to their use in regenerative medicine, cell-based technologies, drug delivery, and tissue engineering applications” [para 0005], and that “the dynamically adjustable hydrogel can be substantially cytocompatible (i.e. substantially non-cytotoxic)” [para 0006], therefore satisfying the limitation of a biocompatible gel particle slurry.
Claims 3-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,116,875 (hereafter “patent”) in view of Alsberg ‘207 and Larsen and as applied to claims 1-2, 6, 8, 11 and 13-21 above, and further in view of Koflo.
Instant claim 3 is drawn to the method of instant claim 2, wherein the mixing element is a static screw or helical mixing element.
The claim(s) of the patent and the disclosures of Alsberg ‘207 and Larsen are discussed above as applied to claims 1-2, 6, 8, 11 and 13-21. These references do not disclose the limitation of ‘the mixing element is a static screw or helical mixing element’.
Koflo describes the features of custom PVC static mixers [title] with listed applications of admixing of water treatment chemicals, pH control, and other uses in a wide range of industries beyond those listed. Koflo furthermore discloses the static mixers are sealed within the housing to allow for the benefit of improved mixing efficiency.
Regarding the limitation of ‘the mixing element is a static screw or helical mixing element’ of instant claim 3, Koflo discloses a cylindrical mixing unit within which a static mixer is fixed from end to end [as shown in each image in the reference].
In view of Alsberg ‘207, Larsen, and Koflo, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the patent, Alsberg ‘207 and Larsen by using a static mixer as the mixing element, as disclosed by Koflo, to arrive at the claimed invention, since the combination of known prior art elements according to known methods results in a predictable result. One of ordinary skill in the art would have been motivated to modify the combined method of the patent, Alsberg ‘207 and Larsen by using the static mixing element of Koflo, because Koflo discloses the use static mixing elements allows for improved mixing efficiency. One of ordinary skill in the art would have had a reasonable expectation of success because the claims of the patent, Alsberg ‘207 and Larsen recite methods for the production biocompatible mixtures and Koflo discloses apparatuses for the controlled and efficient production of such mixtures.
Regarding instant claim 4, the combined teachings of the patent, Alsberg ‘207, Larsen and Koflo as related to claim 3 are discussed above, including the limitation of 'the mixing element is fixed within the chamber and extends substantially the length of the chamber'.
Regarding instant claim 5, Larsen discloses the two syringes are connected as shown in [Figure 1] with a Luer lock connection [p 9, col 2, para 4].
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,116,875 (hereafter “patent”) in view of Alsberg ‘207 and Larsen as applied to claims 1-2, 6, 8, 11 and 13-21 above, and further in view of Alsberg ‘899.
Instant claim 9 is drawn to the method of claim 1, wherein the average size of the hydrogel particles in the slurry are 5 nm to 10 mm.
The claim(s) of the patent and the disclosures of Alsberg ‘207 and Larsen are discussed above as applied to claims 1-2, 6, 8, 11 and 13-21. These references do not disclose the limitations of ‘the gel particle slurry includes particles having an average diameter of 5 nm to 10 mm’.
Alsberg ‘899 describes bioink and crosslinkable support medium for printing [title], wherein a system for forming scaffold-free 3D tissue construct is disclosed with the advantages of using "a self-healing, shear thinning, crosslinkable, biocompatible hydrogel support medium" [abstract] to “overcome … limitations of scaffold-based approaches … [by] using multicellular building blocks that self-assemble into geometries such as aggregates, sheets, strands and rings. These building blocks have been organized and fused into larger and more complicated structures, sometimes comprised of multiple cell types, and then they produce extracellular matrix (ECM) to form mechanically functional three-dimensional (3D) tissue constructs" [para 0002].
Regarding the limitation of a gel particle slurry with an average diameter of 5 nm to 10 mm, Alsberg ‘899 discloses a method for producing a hydrogel slurry [para 00101] wherein afterwards "A petri dish was filled with OMA microgel slurry at room temperature to serve as a supporting bath and placed on the building platform" [para 00107], and “the hydrogel support medium can include a plurality of hydrogel particles that include a plurality of crosslinkable biodegradable natural polymer macromers. The hydrogel particles can have an average diameter of about 10 nm to about 10 mm. The natural polymer macromers can be at least partially crosslinked" [para 0010].
In view of Alsberg ‘207, Larsen, and Alsberg ‘899, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method for producing the gel particle slurry of the patent, Alsberg ‘207 and Larsen to include hydrogel particles of 10 nm – 10 mm diameter, as disclosed by Alsberg ‘899, to arrive at the claimed invention, as the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill in the art would have been motivated to apply the method of Alsberg ‘899 to the combined method for producing the gel slurry of the patent, Alsberg ‘207 and Larsen, as Alsberg ‘899 teaches that using hydrogel supports for scaffold-free tissue engineering provides a powerful strategy using multicellular building blocks that self-assemble into geometries such as aggregates, sheets, strands and rings to form mechanically functional three-dimensional (3D) tissue constructs. One of ordinary skill in the art would have had a reasonable expectation of success to practice such methods because the claims of the patent, Alsberg ‘207, Alsberg ‘899 and Larsen recite methods for the preparation of biocompatible gel particle slurries.
Response to Remarks: Beginning page 14 of Applicant’s response to the double patenting rejection of claims 1-2, 6, 8 and 11-20; Applicant in summary contends that the combination of the ‘875 patent, Alsberg ‘207, Genizer A and Genizer B do not teach the amended method of claim 1, as the ‘875 patent does not recite an aqueous solution of alginate macromer or the combination of a first and second solution via reversible transfer in a mixing unit, and instead the ‘875 patent recites the adjustment of hydrogel properties and not the generation of a hydrogel. Applicant contends that Alsberg ‘207 teaches the addition of CaCl2 to an already formed hydrogel reiterated from above in the remarks to rejections under 35 USC 103.
Applicant’s remarks are considered and found not convincing. As the ‘875 patent does not recite a method of combining solutions to generate the gel particle slurry of claim 1, the ‘875 patent recites a method of regulating cell behavior comprising “providing a dual crosslinkable hydrogel that includes a plurality of polymer macromers that are crosslinked with a first agent and a second agent different than the first agent”, which corresponds to the crosslinked macromer of instant claim 1. As discussed above in the double patenting rejections as well as the rejections under 35 USC 103, Alsberg ‘207 similarly discloses "a composition that includes a dual crosslinkable hydrogel that includes a plurality of polymer macromers which are crosslinked with a first agent and a second agent different than the first, wherein the crosslinks formed using the second agent are reversible and repeatable to allow the mechanical properties of the hydrogel to be dynamically adjusted" [abstract], and provides a scheme of preparing an alginate macromer by producing OMA that can be photocrosslinked via UV radiation [Figure 1], wherein the alginate macromer is prepared in an aqueous solution [para 0068]. As the UV radiation is not provided in the solution with the macromer components, the aqueous solution as described by Alsberg ‘207 before UV irradiation satisfies the limitations of the first solution as recited by the claim. Alsberg ‘207 additionally discloses the addition of 50 mM CaCl2 solution [para 0070], a cross linking agent, in which the solution is inherently housed in a container or depot common in the art such as a beaker, therefore satisfying the limitations of the second solution recited in the claim. Alsberg ‘207 further discloses the combination of two solutions to form a hydrogel [Figure 1]. Therefore the scheme of Alsberg ‘207 encompasses the limitation of forming a gel particle slurry recited in the claim. As Larsen teaches the use of two syringes as depots that house two solutions that are separated by a chamber in which contents are mixed [Figure 1], it would have been obvious for one of skill in the art to use the method of Larsen to combine the solutions of Alsberg ‘207 in forming the crosslinked macromer of the ‘875 patent to arrive at the claimed invention.
In view of the claims of the ‘875 patent, and the disclosures of Alsberg ‘207 and Larsen as described here and in the section above, the remaining dependent claims 2-6, 8-9, 11 and 13-21 are rejected for the reasons stated in the section above.
Conclusion
Status of the Claims:
Claims 1-6, 8-9, 11 and 13-21 are pending.
Claims 1-6, 8-9, 11 and 13-21 are rejected.
No claim is in condition for allowance.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656
Prosecution Insights