DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 14 2024 has been entered.
Receipt of Arguments/Remarks filed on November 14 2024 is acknowledged. Claims 1-10, 12, 16 and 19-20 were/stand cancelled. Claims 11, 24 and 29 were amended. Claims 31-34 were added. Claims 11, 13-15, 17-18 and 21-34 are pending and are examined on the merits herein.
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 .
Withdrawn Rejections
The amendments filed November 14 2024 are sufficient to overcome the rejection of claims 11, 13-15, 17-18 and 21-30 under 35 U.S.C. 103 as being unpatentable over Jiang et al. (Journal of Materials Chemistry, 2017, cited in the Office action mailed on 12/8/23) in view of Raza et al. (Journal of Visualized Experiments, 2012) as evidenced by Schultz et al. (Soft Matter, 2013). The claims now require inducing assembly of beta-cell spheroids from the plurality of beta cells after exposing the hydrogel forming solution to UV light.
The amendments filed November 14 2024 are sufficient to overcome the rejection of claims 11, 13-15, 17-18 and 21-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17463362 (USPGPUB No. 20220064624) in view of Raza et al. Copending ‘362 does not claim a process of making and the claims now require inducing assembly of beta-cell spheroids from the plurality of beta cells after exposing the hydrogen forming solution to UV light.
The amendments filed November 14 2024 are sufficient to overcome the rejection of claims 11, 13-15, 17-18 and 21-30 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 8, 18, 22-26, 29-32, 35 and 46-48 of copending Application No. 18184562 in view of Jiang et al. and Raza et al. as evidenced by Schultz et al. The amendments have sufficiently distinguished the instant claims from copending ‘562.
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 11, 13-15, 17-18 and 21-34 are rejected under 35 U.S.C. 103 as being unpatentable over Jiang et al. (Journal of Materials Chemistry, 2017, cited in the Office action mailed on 12/8/23) in view of Lin et al. (Biomaterials, 2011) and Anseth et al. (Biomacromolecules, 2009) as evidenced by Schultz et al. (Soft Matter, 2013, cited in the Office action mailed on May 14 2024).
Applicant Claims
The instant application claims a process for forming a composition, comprising: introducing a plurality of beta cells with a hydrogel forming solution comprising a photoreactive monomer, a photoinitiator, and a dithiol linker; introducing an oil to the plurality of beta cells and the hydrogel forming solution; and inducing assembly of beta-cell spheroids form the plurality of beta cells after exposing the hydrogel forming solution to ultraviolet light to form a composition comprising the plurality of beta cells dispersed in or encapsulated within a hydrogel, the beta-cell spheroids secreting insulin within the hydrogel.
The instant application claim a process for inducing assembly of beta-cell spheroids, comprising: introducing a hydrogel forming solution comprising a photoreactive monomer, a dithiol linker, and a photoinitiator to a microfluidic device; introducing a plurality of beta cells to the microfluidic device; contacting the hydrogel forming solution and the plurality of beta cells with an oil in the microfluidic device to form droplets comprising the plurality of beta cells and the hydrogel forming solution in the oil; and inducing beta-cell spheroid assembly from the plurality of beta cells after exposing the hydrogel forming solution to ultraviolet light to form a composition comprising beta-cell spheroids encapsulated within a hydrogel formed from the photoreactive monomer and the dithiol linker, the beta-cell spheroids secreting insulin within the hydrogel.
The instant application claims a process for forming an implantable therapeutic composition for the treatment of Type 1 diabetes, the process comprising: introducing a plurality of beta cells with a hydrogel forming solution comprising a photoreactive monomer, a photoinitiator, and a dithiol linker; introducing an oil to the plurality of beta cells and the hydrogel forming solution; and inducing assembly of beta-cell spheroids from the plurality of beta cells after exposing the hydrogel forming solution to ultraviolet light to form an implantable therapeutic composition comprising the beta-cell spheroids encapsulated within a hydrogel, the beta-cell spheroids secreting insulin within the hydrogel.
As elected the photoreactive monomer is polyethylene glycol norbornene and the dithiol linker is polyethylene glycol-dithiol.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Jiang et al. is directed to a microfluidic-based cell encapsulation platform to achieve high long-term cell viability in photopolymerized polyethylene glycol norbornene (PEGNB) hydrogel microspheres. Cell encapsulation within photopolymerized polyethylene glycol based hydrogel scaffolds has been demonstrated as a robust strategy for cell delivery. A promising PEG-based scaffold material, PEGNB, is formed by step-growth photopolymerization and is not inhibited by oxygen. PEGNB has been shown to be more cytocompatibility than PEGDA (polyethylene glycol diacrylate) and allows for orthogonal addition reactions. Microfluidically generated PEGNB droplets are collected and polymerized under UV exposure. PEGNB microencapsulation platform is capable of generating cell-laden hydrogel microspheres at high rates with well-controlled size distributions and high long-term cell viability (abstract). Microfluidic emulsification, a two-phase microfluidic technique capable of generating monodisperse aqueous droplets in continuous oil phase has improved microgel fabrication providing a potential tool for high throughput single cell encapsulation (page 173, left column, first paragraph). The hydrogel forming solution comprised PEGNB (4-arm), a dithiol linker (Sigma Aldrich Mn 1500) and a photoinitiator. The PEGNB has a Mn of 20,000 Da while the dithiol linker has a Mn of 1500 Da (page 175, left column, hydrogel forming solution). Cells were cultured in DMEM and supplemented with fetal bovine serum (page 175, left column, cell culture). Taught is suspension of cells in a hydrogel-forming solution followed by injection into a microfluidic device. Fluorocarbon oil is used as the oil. Cell-laden droplets were collected and polymerized into hydrogel microspheres by exposing to UV light for 20 seconds (100 mW/cm2) (page 175, left column, microfluidic cell encapsulation). Hydrogel microsphere size range in diameter from 90 to 130 microns (page 176).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Jiang et al. teaches a dithiol linker from Sigma-Aldrich with a Mn of 1500, Jiang et al. does not expressly teach PEG dithiol. However, as evidenced by Schultz et al. the dithiol linker from Sigma Aldrich with a Mn of 1500 is a linear PEG dithiol (page 1571, Experimental methods).
While Jiang et al. teaches cell encapsulation, Jiang et al. does not expressly teach beta-cells. However, this deficiency is cured by Lin et al. and Anseth et al.
Lin et al. is directed to PEG hydrogels formed by thiol-ene photo-click chemistry and their effect on the formation and recovery of insulin-secreting cell spheroids. One emerging application of photopolymerized PEG hydrogels is the fabrication of bioactive and immune-isolating barriers for encapsulation of cells, including insulin secreting pancreatic β-cells (page 9686, left column). Cells at desired densities were suspended in polymer solutions and exposed to UV conditions (section 2.8, page 9687). Fig. 4 shows the viability of β-cells. This shows that PEG4NB hydrogels was significantly higher than PEGDA hydrogels. This result was not surprising since the gelation time for step-growth polymerization was much faster than chain-growl polymerization thus limiting the cellular damage caused by the radical species. When cells in these two systems were cultured for extended period of time, cells in the PEG4NB hydrogels eventually survived and proliferated while cells in PEGDA hydrogels died off rapidly. This study demonstrates that PEG4NB hydrogels offer a superior microenvironment for cell survival in 3D (section 3.4, page 9691). It is taught that the encapsulated β-cells formed viable and functional cell spheroids within thiol-ene hydrogels (section 4, page 9694).
Anseth et al. is directed to glucagon-like peptide-1 functionalized PEG hydrogels promote survival and function of encapsulated pancreatic β-cells. Type 1 diabetes mellitus (DM) is an autoimmune disease in which the including producing β-cells in the pancreatic islets of Langerhans are destroyed by the patient’s autoimmunity. The damaged β-cells fails to produce insulin to maintain a normal glycemic condition. Recently, islets encapsulated in semipermeable material such as PEG hydrogels have been suggested as an attractive means to prevent transplanted islets from host immune destruction and potentially decrease the needs of administering immunosuppressants. The PEG hydrogel barrier permits facile exchange of nutrients and waste to maintain islet survival, while preventing infiltration of large immune cells and antibodies from recognizing the allogenic or xenogeneic islet grafts. PEG hydrogel does not significantly hinder the diffusion of insulin secreted by encapsulated islets (page 2460). It is taught that pancreatic β-cells encapsulated in PEG hydrogels had higher viability and secreted more insulin upon glucose stimulation (page 2467, conclusion). The encapsulated mouse islets were exposed to glucose solutions and insulin secretion was subsequently monitored (page 2462; Fig. 2).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Jiang et al., Lin et al. and Anseth et al. and utilize the microfluidic device of Jiang et al. to form a PEG hydrogel to encapsulate beta-cells. One skilled in the art would have been motivated to utilize a microfluidic device as this device has improved microgel fabrication providing a potential tool for high throughput single cell encapsulation as taught by Jiang et al. One skilled in the art would have a reasonable expectation of success as Jiang et al. teaches the hydrogel can be utilized encapsulate cells and Lin et al. teaches thiol-ene hydrogel formation with a PEG-norbornene (same photoreactive monomer of Jiang et al.) to encapsulate beta-cells. One skilled in the art would have been motivated to utilize a fluorocarbon oil as this oil is utilized in the microfluidic device as taught by Jiang et al. Therefore, based on the teachings of Jiang et al. Lin et al. and Anseth et al., it would have been obvious to one skilled in the art to combine PEGNB, PEG dithiol, a photoinitiator, beta cells, culture medium and fluorocarbon oil then polymerizing the mixture with UV light in order to form a hydrogel which encapsulates the beta cells.
Regarding the claimed beta-cell spheroids, as taught by Lin et al. cells at desired densities were suspended in polymer solutions and exposed to UV conditions (section 2.8, page 9687). Lin et al. teaches that the encapsulated β-cells formed viable and functional cell spheroids within thiol-ene hydrogels (section 4, page 9694). This suggests assembly of beta-cell spheroids after exposing the hydrogen forming solution to UV light.
Regarding the beta-cell spheroids secreting insulin, Lin et al. teaches that the spheroids secret insulin, however, these are after chymotrypsin treatment. However, Anseth et al. teaches the formation of encapsulated beta-cells which secrete insulin within the hydrogel. Anseth et al. teaches the semipermeable nature of the PEG allows for the cells to secrete the insulin while in the hydrogel. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Jiang et al., Lin et al. and Anseth et al. and utilize the encapsulated beta-cell spheroids as a 3D cellular structure for tissue engineering with a reasonable expectation of success. Since Type I diabetics do not produce their own insulin, as taught by Anseth et al. the use of hydrogels encapsulating beta-cells can be used for tissue engineering to replace the lack of insulin in these subjects.
Regarding claims 14-15 and 22, Jiang et al. teach exposing to UV light for 20 seconds (100 mW/cm2) which falls within the scope claimed.
Regarding claim 23 and 30, Lin et al. teaches beta cells prior to exposing the hydrogen forming solution to UV which then assembly to beta-cell spheroids.
Regarding claims 17-18 and 25-26, Jiang et al. teaches PEGNB has a Mn of 20,000 Da while the dithiol linker has a Mn of 1500 Da. These amounts fall within the scope claimed.
Regarding claim 28, Jiang et al. teach 4 arm PEG.
Regarding claim 29, Jiang et al. teach microspheres with 90 to 130 microns
Regarding claims 31-32, Anseth et al. shows glucose-stimulated insulin secretion from encapsulated islets 7 days after photoencapsulation (Figure 4). Since the desire would be to provide insulin to a type 1 diabetic, one skilled in the art would desire a release over a period of 1 day or more.
Regarding claim 33, the hydrogel with the encapsulated beta-cells are clearly capable of being implanted. As the cited prior art discusses the cytotoxicity of the hydrogels.
Double Patenting
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 11, 13-15, 17-18 and 21-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 12077638 (copending Application No. 15335184) in view of Jiang et al., Lin et al. and Anseth et al. as evidenced by Schulz et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims a process for forming a composition, comprising: introducing a plurality of beta cells with a hydrogel forming solution comprising a photoreactive monomer, a photoinitiator, and a dithiol linker; introducing an oil to the plurality of beta cells and the hydrogel forming solution; and inducing assembly of beta-cell spheroids form the plurality of beta cells after exposing the hydrogel forming solution to ultraviolet light to form a composition comprising the plurality of beta cells dispersed in or encapsulated within a hydrogel, the beta-cell spheroids secreting insulin within the hydrogel.
The instant application claim a process for inducing assembly of beta-cell spheroids, comprising: introducing a hydrogel forming solution comprising a photoreactive monomer, a dithiol linker, and a photoinitiator to a microfluidic device; introducing a plurality of beta cells to the microfluidic device; contacting the hydrogel forming solution and the plurality of beta cells with an oil in the microfluidic device to form droplets comprising the plurality of beta cells and the hydrogel forming solution in the oil; and inducing beta-cell spheroid assembly from the plurality of beta cells after exposing the hydrogel forming solution to ultraviolet light to form a composition comprising beta-cell spheroids encapsulated within a hydrogel formed from the photoreactive monomer and the dithiol linker, the beta-cell spheroids secreting insulin within the hydrogel.
The instant application claims a process for forming an implantable therapeutic composition for the treatment of Type 1 diabetes, the process comprising: introducing a plurality of beta cells with a hydrogel forming solution comprising a photoreactive monomer, a photoinitiator, and a dithiol linker; introducing an oil to the plurality of beta cells and the hydrogel forming solution; and inducing assembly of beta-cell spheroids from the plurality of beta cells after exposing the hydrogel forming solution to ultraviolet light to form an implantable therapeutic composition comprising the beta-cell spheroids encapsulated within a hydrogel, the beta-cell spheroids secreting insulin within the hydrogel.
As elected the photoreactive monomer is polyethylene glycol norbornene and the dithiol linker is polyethylene glycol-dithiol.
Patent ‘638 claims a method of preparing a plurality of microparticles in a microfluidics device in an oxygen-controlled environment comprising the steps of: (a) providing a continuous phase comprising a non-aqueous liquid and an aqueous phase comprising a polyethylene glycol (PEG)-based photodegradable macromer having a molecular weight selected from the range of 200 to 20,000 Daltons, a biological material, and an initiator; (b) forming a composition comprising microdroplets of said aqueous phase dispersed in said non-aqueous liquid; (c) controlling oxygen concentration in the microdroplets to enhance viability of the biological material, wherein the controlling comprises: (i) providing said composition comprising said microdroplets and said non-aqueous liquid in a first channel of said microfluidics device; (ii) flowing said oxygen-free gas through a second channel, adjacent to said first channel; (iii) diffusing at least some of said oxygen-free gas into a region of the microfluidics device between the first and second channels; and (iv) varying a supply pressure of the oxygen-free gas in order to vary the oxygen concentration within the microdroplets; and (d) partially polymerizing said monomer or said macromer in said microdroplets, wherein, as polymerization is impeded by dissolved oxygen, only a fraction of a radial volume of each microdroplet is polymerized and the rest remains as a liquid film of un-polymerized aqueous phase on a polymerized core thereby generating microparticles within said aqueous phase having a smaller radius than said microdroplets; wherein the partially polymerizing step is at least partially controlled via the controlling oxygen concentration step (c); and wherein the microparticles have a mean diameter of less than or equal to 1000 μm. Fluorocarbon oil is claimed. Ultraviolet light is claimed. The macromer is a PEG based macromer. Beta cells are claimed.
While Patent ‘638 claims beta cells, spheroid formation is not expressly taught or secreting insulin from spheroids within the hydrogel is not claimed. While Patent ‘638 claims a PEG based macromer, UV light and photopolymerization, Patent ‘638 does not expressly claim PEG norbornene, PEG dithiol. However, these deficiencies are cured by Jiang et al., Lin et al. and Anseth et al.
Jiang et al. is directed to a microfluidic-based cell encapsulation platform to achieve high long-term cell viability in photopolymerized polyethylene glycol norbornene (PEGNB) hydrogel microspheres. Cell encapsulation within photopolymerized polyethylene glycol based hydrogel scaffolds has been demonstrated as a robust strategy for cell delivery. A promising PEG-based scaffold material, PEGNB, is formed by step-growth photopolymerization and is not inhibited by oxygen. PEGNB has been shown to be more cytocompatible than PEGDA (polyethylene glycol diacrylate) and allows for orthogonal addition reactions. Microfluidically generated PEGNB droplets are collected and polymerized under UV exposure. PEGNB microencapsulation platform is capable of generating cell-laden hydrogel microspheres at high rates with well-controlled size distributions and high long-term cell viability (abstract). Microfluidic emulsification, a two-phase microfluidic technique capable of generating monodisperse aqueous droplets in continuous oil phase has improved microgel fabrication providing a potential tool for high throughput single cell encapsulation (page 173, left column, first paragraph). The hydrogel forming solution comprised PEGNB (4-arm), a dithiol linker (Sigma Aldrich Mn 1500) and a photoinitiator. The PEGNB has a Mn of 20,000 Da while the dithiol linker has a Mn of 1500 Da (page 175, left column, hydrogel forming solution). Cells were cultured in DMEM and supplemented with fetal bovine serum (page 175, left column, cell culture). Taught is suspension of cells in a hydrogel-forming solution followed by injection into a microfluidic device. Fluorocarbon oil is used as the oil. Cell-laden droplets were collected and polymerized into hydrogel microspheres by exposing to UV light for 20 seconds (100 mW/cm2) (page 175, left column, microfluidic cell encapsulation). Hydrogel microsphere size range in diameter from 90 to 130 microns (page 176).
Lin et al. is directed to PEG hydrogels formed by thiol-ene photo-click chemistry and their effect on the formation and recovery of insulin-secreting cell spheroids. One emerging application of photopolymerized PEG hydrogels is the fabrication of bioactive and immune-isolating barriers for encapsulation of cells, including insulin secreting pancreatic β-cells (page 9686, left column). Cells at desired densities were suspended in polymer solutions and exposed to UV conditions (section 2.8, page 9687). Fig. 4 shows the viability of β-cells. This shows that PEG4NB hydrogels was significantly higher than PEGDA hydrogels. This result was not surprising since the gelation time for step-growth polymerization was much faster than chain-growl polymerization thus limiting the cellular damage caused by the radical species. When cells in these two systems were cultured for extended period of time, cells in the PEG4NB hydrogels eventually survived and proliferated while cells in PEGDA hydrogels died off rapidly. This study demonstrates that PEG4NB hydrogels offer a superior microenvironment for cell survival in 3D (section 3.4, page 9691). It is taught that the encapsulated β-cells formed viable and functional cell spheroids within thiol-ene hydrogels (section 4, page 9694).
Anseth et al. is directed to glucagon-like peptide-1 functionalized PEG hydrogels promote survival and function of encapsulated pancreatic β-cells. Type 1 diabetes mellitus (DM) is an autoimmune disease in which the including producing β-cells in the pancreatic islets of Langerhans are destroyed by the patient’s autoimmunity. The damaged β-cells fails to produce insulin to maintain a normal glycemic condition. Recently, islets encapsulated in semipermeable material such as PEG hydrogels have been suggested as an attractive means to prevent transplanted islets from host immune destruction and potentially decrease the needs of administering immunosuppressants. The PEG hydrogel barrier permits facile exchange of nutrients and waste to maintain islet survival, while preventing infiltration of large immune cells and antibodies from recognizing the allogenic or xenogeneic islet grafts. PEG hydrogel does not significantly hinder the diffusion of insulin secreted by encapsulated islets (page 2460). It is taught that pancreatic β-cells encapsulated in PEG hydrogels had higher viability and secreted more insulin upon glucose stimulation (page 2467, conclusion). The encapsulated mouse islets were exposed to glucose solutions and insulin secretion was subsequently monitored (page 2462; Fig. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘638, Jiang et al., Lin et al. and Anseth et al. and utilize beta cells. One skilled in the art would have been motivated to utilize beta cells as patent ‘638 specifically claims beta cells.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘638, Jiang et al., Lin et al. and Anseth et al. and utilize PEG norbornene and PEG dithiol in the polymerization of Patent ‘638. One skilled in the art would have been motivated to utilize these monomers as patent ‘638 teaches use of a photoinitiator for polymerization (i.e. photopolymerization) and teaches a PEG based macromer. Jiang et al. teaches photopolymerization with a photoinitiator using PEG norbornene and dithiol which as evidenced by Schultz et al., the dithiol linker from Sigma Aldrich with a Mn of 1500 is a linear PEG dithiol (page 1571, Experimental methods). Therefore, there is a reasonable expectation of success as both are directed to polymerization with similar monomers to accomplish the same thing (i.e. encapsulation of cells).
Regarding the claimed beta-cell spheroids, as taught by Lin et al. cells at desired densities were suspended in polymer solutions and exposed to UV conditions (section 2.8, page 9687). Lin et al. teaches that the encapsulated β-cells formed viable and functional cell spheroids within thiol-ene hydrogels (section 4, page 9694). This suggests assembly of beta-cell spheroids after exposing the hydrogen forming solution to UV light.
Regarding the beta-cell spheroids secreting insulin, Lin et al. teaches that the spheroids secret insulin, however, these are after chymotrypsin treatment. However, Anseth et al. teaches the formation of encapsulated beta-cells which secrete insulin within the hydrogel. Anseth et al. teaches the semipermeable nature of the PEG allows for the cells to secrete the insulin while in the hydrogel. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘638, Jiang et al., Lin et al. and Anseth et al. and utilize the encapsulated beta-cell spheroids as a 3D cellular structure for tissue engineering with a reasonable expectation of success. Since Type I diabetics do not produce their own insulin, as taught by Anseth et al. the use of hydrogels encapsulating beta-cells can be used for tissue engineering to replace the lack of insulin in these subjects.
Regarding claims 14-15 and 22, Jiang et al. teach exposing to UV light for 20 seconds (100 mW/cm2) which falls within the scope claimed.
Regarding claims 17-18 and 25-26, Jiang et al. teaches PEGNB has a Mn of 20,000 Da while the dithiol linker has a Mn of 1500 Da. These amounts fall within the scope claimed.
Regarding claim 28, Jiang et al.. teach 4 arm PEG.
Regarding claim 29, Jiang et al. teach microspheres with 90 to 130 microns.
Regarding claims 31-32, Anseth et al. shows glucose-stimulated insulin secretion from encapsulated islets 7 days after photoencapsulation (Figure 4). Since the desire would be to provide insulin to a type 1 diabetic, one skilled in the art would desire a release over a period of 1 day or more.
Regarding claim 33, the hydrogel with the encapsulated beta-cells are clearly capable of being implanted. As the cited prior art discusses the cytotoxicity of the hydrogels.
Claims 11, 13-15, 17-18 and 21-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 53-72 of copending Application No. 18783794 (USPGPUB No. 20250092203) in view of Jiang et al., Lin et al. and Anseth et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘794 claims a method of preparing a plurality of microparticles in an oxygen-controlled environment via a microfluidic device, the method comprising: forming a composition of aqueous microdroplets dispersed in a non- aqueous liquid, wherein the aqueous microdroplets comprise a polymer precursor and an initiator; controlling an oxygen concentration of the composition to a predetermined level; and based on the oxygen content of the composition, fully polymerizing the polymer precursor of the microdroplets, or partially polymerizing the polymer precursor of the microdroplets, thereby forming the plurality of microparticles. Beta-cells are claimed. Fluorocarbon oil is claimed.
While Copending ‘794 claims beta cells, spheroid formation is not expressly taught or secreting insulin from spheroids within the hydrogel is not claimed. While Copending ‘794 claims a polymer precursor, UV light and photopolymerization, Copending ‘794 does not expressly claim PEG norbornene, PEG dithiol. However, these deficiencies are cured by Jiang et al., Lin et al. and Anseth et al.
The teachings of Jiang et al., Lin et al. and Anseth et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Copending ‘794, Jiang et al., Lin et al. and Anseth et al. and utilize beta cells. One skilled in the art would have been motivated to utilize beta cells as patent ‘638 specifically claims beta cells.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Copending ‘794, Jiang et al., Lin et al. and Anseth et al. and utilize PEG norbornene and PEG dithiol in the polymerization of Copending ‘794. One skilled in the art would have been motivated to utilize these monomers as Copending ‘794 teaches use of a photoinitiator for polymerization (i.e. photopolymerization). Jiang et al. teaches photopolymerization with a photoinitiator using PEG norbornene and dithiol which as evidenced by Schultz et al., the dithiol linker from Sigma Aldrich with a Mn of 1500 is a linear PEG dithiol (page 1571, Experimental methods). Therefore, there is a reasonable expectation of success as both are directed to polymerization with similar monomers to accomplish the same thing (i.e. encapsulation of cells).
Regarding the claimed beta-cell spheroids, as taught by Lin et al. cells at desired densities were suspended in polymer solutions and exposed to UV conditions (section 2.8, page 9687). Lin et al. teaches that the encapsulated β-cells formed viable and functional cell spheroids within thiol-ene hydrogels (section 4, page 9694). This suggests assembly of beta-cell spheroids after exposing the hydrogen forming solution to UV light.
Regarding the beta-cell spheroids secreting insulin, Lin et al. teaches that the spheroids secret insulin, however, these are after chymotrypsin treatment. However, Anseth et al. teaches the formation of encapsulated beta-cells which secrete insulin within the hydrogel. Anseth et al. teaches the semipermeable nature of the PEG allows for the cells to secrete the insulin while in the hydrogel. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Copending ‘794, Jiang et al., Lin et al. and Anseth et al. and utilize the encapsulated beta-cell spheroids as a 3D cellular structure for tissue engineering with a reasonable expectation of success. Since Type I diabetics do not produce their own insulin, as taught by Anseth et al. the use of hydrogels encapsulating beta-cells can be used for tissue engineering to replace the lack of insulin in these subjects.
Regarding claims 14-15 and 22, Jiang et al. teach exposing to UV light for 20 seconds (100 mW/cm2) which falls within the scope claimed.
Regarding claims 17-18 and 25-26, Jiang et al. teaches PEGNB has a Mn of 20,000 Da while the dithiol linker has a Mn of 1500 Da. These amounts fall within the scope claimed.
Regarding claim 28, Jiang et al.. teach 4 arm PEG.
Regarding claim 29, Jiang et al. teach microspheres with 90 to 130 microns.
Regarding claims 31-32, Anseth et al. shows glucose-stimulated insulin secretion from encapsulated islets 7 days after photoencapsulation (Figure 4). Since the desire would be to provide insulin to a type 1 diabetic, one skilled in the art would desire a release over a period of 1 day or more.
Regarding claim 33, the hydrogel with the encapsulated beta-cells are clearly capable of being implanted. As the cited prior art discusses the cytotoxicity of the hydrogels.
Response to Arguments
Regarding the non-statutory double patenting, the arguments are acknowledged. However, the rejections are maintained since applicant has not made any substantive arguments traversing the rejection.
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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