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 .
DETAILED ACTION
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
2. Applicant’s amendment filed May 8, 2026 is acknowledged. Claims 1-11 and 17-18 are canceled. Claims 12, 14 and 25 are amended. Claims 12-16 and 19-25 are pending in this application and under examination in this office action.
3. Applicant’s arguments filed on May 8, 2026 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Withdrawn
4. The rejection of claims 12-16 and 19-25 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in response to Applicant’s amendment to the claims.
The rejection of claims 12-16 and 19-25 under 35 U.S.C. 103 as being unpatentable over Ellis-Behnke et al. (US2005/0287186; issued as US7846891, cited previously) in view of Reiner et al. (Cell Stem Cell; 2018, 22; 128-137, cited previously), Yu et al. (Biomaterials, 2010; 31:5287-5296, cited previously), Vega et al. (J. Mater. Chem, 2016; 4:6803, cited previously) and Shapiro et al. (Cold Spring Harb. Perspect. Biol.2009;1:a003053, cited previously) and evidentiary references: Klinigener et al. (J. Neurosci. 2014; 34:9590-9606) and Ajoka et al. (Tissue Eng. 2015; 21:193-201) is withdrawn in response to Applicant’s arguments on p. 5 of the response and Applicant’s declaration under 37 CFR1.130 filed 0n 07/19/2024.
New Grounds of Rejection Necessitated by the Amendment
The following rejections are new grounds of rejections necessitated by the amendment filed on May 8, 2026.
Claim Objections
5. Claims 12, 14 and 25 are objected to because of the following informalities: The recitations “N-cadherin-Fc-carrier”, “Fc” and “EC1, EC2, EC3, EC4 and EC5” recited in claims 12, 14 and 25 are not unique or common abbreviations in the art. Applicants are required to spell out “N-cadherin-Fc-carrier”, “Fc” and “EC1, EC2, EC3, EC4 and EC5” at the first usage. Appropriate correction is required.
Claim Rejections - 35 USC § 103
6. 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 12-16,19-23 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Ellis-Behnke et al. (US2005/0287186; issued as US7846891) in view of Nabetani et al. (Pediatric Research; 2018; 83:356-363, published on Nov 8, 2017. Doi:10.1038/pr.2017.260), Yu et al. (Biomaterials, 2010; 31:5287-5296), Vega et al. (J. Mater. Chem, 2016; 4:6803) and Shapiro et al. (Cold Spring Harb. Perspect. Biol.2009;1:a003053) and evidentiary references: Klinigener et al. (J. Neurosci. 2014; 34:9590-9606), Ajoka et al. (Tissue Eng. 2015; 21:193-201), Kanemaru et al. (PNAS, 2013; 110:11612-11617) and Hirano et al. (Physiol. Rev., 2012; 92:597-634. Doi:10.1152/physrev.00014.2011).
Claims 12-16,19-23 and 25 as amended are drawn to methods for treatment of a neonatal brain injury selected from the group consisting of hypoxic encephalopathy, hypoxic ischemic encephalopathy, ischemic brain injury and brain injury due to physical damage, comprising promoting a migration of neuron cells to an affected area by transplanting into the brain a material comprising N-cadherin-Fc-carrier such that neuroblasts in the brain are recruited to the affected area; wherein N-cadherin-Fc-carrier contains a protein having all of EC1, EC2, EC3, EC4 and EC5 domains of N-cadherin. Claims 13 and 15 are drawn to the similar methods above and also include transplanting neuronal cells derived from pluripotent stem cells together with the material used in the method of independent claims 12 and 14.
Ellis-Behnke et al. (US2005/0287186) teaches a method of enhancing neural regeneration or repair to treat brain injury including ischemic brain injury, stroke or traumatic brain injury (see para.[0074]-[0078]) by introducing a biocompatible scaffold/material/composition at the site of injury in a patient with brain injury, wherein the biocompatible scaffold comprises a nanoscale structured material (i.e. a carrier) comprising self-assembling peptides including RADA16-I (see para. [0079]-[0089]) and incorporating additional regeneration promoting factors including N-cadherin encapsulated in polymeric nanoparticles or microparticles (see para. [0105]; [0111]) which are incorporated into the scaffold/material/composition (see para. [0101]-[0111] (see abstract; para. [0006]-[0012]; [0047]-[0049], [0062]-[0063]; [0067]-[0069]; [0074]-[0078]; [0101]-[0105]; [0111], in particular). Ellis-Behnke also teaches using the biocompatible scaffold/material/composition together with neuronal cells to produce molecules that promote regeneration or create environment permissive for regeneration, wherein the neuronal cells include neuronal cells derived from different progenitor cells including neural progenitor cells, glial progenitor cells, and/or stem cells, as in claims 13 and 15 (see para. [0116]-[0118]). Ellis-Behnke teaches that the carrier is a porous body as in claim 19 (see para. [0067]), a biomaterial or biocompatible polymer carrier as in clams 20-21, or a protein/polysaccharide biomaterial including collagen as in claims 22-23 (see para. [0130]-[0133], in particular).
The introduction of the biocompatible scaffold/material/composition comprising RADA16-I and incorporating N-cadherin encapsulated in polymeric nanoparticles or microparticles that are incorporated into the scaffold/material/composition at the site of injury in a patient with brain injury disclosed by Ellis-Behnke inherently promotes migration of neuroblasts or neuron cells to an affected area or neuroblasts are recruited to the affected area as evidenced by Klinigener et al. (see p.9590, abstract; J. Neurosci. 2014; 34:9590-9606), Ajoka et al. (see p. 193, abstract; Tissue Eng. 2015; 21:193-201), Kanemaru et al. (see p. 11614-11617; PNAS, 2013; 110:11612-11617) and Hirano et al. (see p. 607-608-610; Physiol. Rev., 2012; 92:597-634).
Ellis-Behnke teaches the same method of treating ischemic brain injury, stroke or traumatic brain injury (see para.[0074]-[0078]) by using the same material (i.e. N-Cadherin-carrier: a biocompatible material comprising a nanoscale structured material (i.e. a carrier) comprising self-assembling peptides including RADA16-I and incorporating additional regeneration promoting factors including N-Cadherin encapsulated in polymeric nanoparticles or microparticles which are incorporated into the scaffold/material/composition; see para.[0105]; [0111]; [0079]-[0089]; [0101]-[0111]) and the same active step (i.e. introducing the biocompatible material/composition at the site of injury; see para. [0098]-[0099]) in the same patient population (i.e. traumatic brain injury; see para. para.[0074]-[0078]) except a neonatal subject and that N-Cadherin is fused to a Fc as recited in independent claims.
While Ellis-Behnke does not teach neonatal, N-cadherin fused to a Fc (N-Cadherin-Fc-carrier), wherein the N-Cadherin-Fc-carrier contains a protein having all EC1-EC5 domains of N-Cadherin recited in independent clams 12, 14, and 25, Nabetani et al., Yu et al., Vega et al. and Shapiro et al. teach these limitations and provide motivation and an expectation of success in using a N-Cadherin-Fc-carrier in the Ellis-Behnke’s method for better treatment of brain injury including neonatal brain injury selected from the group consisting of hypoxic encephalopathy, hypoxic ischemic encephalopathy, ischemic brain injury and brain injury due to physical damage because neonatal brain injury can be treated based on enhancement of neurogenesis from neural stem cells as taught by Nabetani and N-Cadherin-Fc or N-Cadherin-Fc-carrier can enhance neuronal differentiation of neural stem cells into neurons and provide better environments for neuronal growth and neuronal differentiation as taught by Yu, Vega and Shapiro.
Nabetani et al. teach that neonatal brain injury including ischemic brain injury or hypoxic ischemic encephalopathy can be treated or improved by stem cell therapy, enhancement of the regenerative process by angiogenesis using mesenchymal stem cells and/or hematopoietic stem cells and enhancement of the regenerative process by neurogenesis using neural stem/progenitor cells neural stem/progenitor cells or mesenchymal/hematopoietic stem cells (p.357-361).
Yue et al. teach that a N-Cadherin-Fc fusion protein comprising the entire extracellular domain of N-cadherin fused to IgG-Fc (N-Cadherin-Fc) as in independent claims 12, 14 and 25 can stably adsorb to hydrophobic surface and enhance differentiation of P19 embryonal carcinoma cells or MEB5 neural stem cells into neural cells when cultured on N-Cadherin-Fc-coated surface (see p. 5287, abstract; p.5288, material and methods-2.1~2.4; p. 5289-5296).
Shapiro et al. teach that EC1 domain in the extracellular domain of N-cadherin is responsible for adhesive binding to partners of N-cadherin and EC1-EC5 domains are required for Ca2+ binding for cell adhesion as in independent claims 12, 14 and 25 (p. 2, col. 2, figure 1; p. 4-5).
Vega et al. teach that N-Cadherin-Fc immobilized on a 3D hydrogel matrix provides better environments for neuronal growth, wherein the 3D hydrogel matrix is conjugated with a controlled number of N-Cadherin-Fc as in independent claims 12, 14 and 25 (see p. 6803, abstract; p. 6804; p. 6805-6810, scheme 1, figures 1-2).
A person of ordinary skill in the art would have recognized that selecting and applying the known treatment of neonatal brain injury based on enhancement of regenerative processes by angiogenesis and neurogenesis using stem cells and neural stem cells disclosed by Nabetani, the known treatment of brain injury including ischemic brain injury and traumatic brain injury using a N-Cadherin-carrier disclosed by Ellis-Behnke, the known benefits of N-Cadherin-Fc for enhancing neural differentiation from stem cells or neural stem cells, and the known N-Cadherin-Fc-carrier for providing better environments for neuronal growth wherein the N-Cadherin-Fc-carrier contains a protein having all EC1-EC5 domains of N-Cadherin and wherein the carrier is a biomaterial or biocompatible polymeric carrier, a polymeric carrier or a protein or polysaccharide biomaterial and technique disclosed by Yue, Vega and Shapiro to the Ellis-Behnke’s method would have yielded the predictable result of promoting neuronal migration neonatal brain injury or treating neonatal brain injury, and resulted in an improved method of treating neonatal brain injury.
Using the known N-Cadherin-Fc-carrier containing a protein having all EC1-EC5 domains of N-Cadherin and a carrier including a biomaterial or biocompatible polymeric carrier, a polymeric carrier or a protein or polysaccharide biomaterial in the Ellis-Behnke’s method would promote neuronal or neuroblast migration in neonatal brain injury or treat neonatal brain injury, and expand application of the Ellis-Behnke’s method, and would increase patient’s satisfaction with treatment of neonatal brain injury using a N-Cadherin-Fc-carrier because i) Nabetani teaches that neonatal brain injury including traumatic brain injury and ischemic brain injury or hypoxic ischemic encephalopathy can be treated or improved by enhancement of regenerative processes by angiogenesis and neurogenesis using stem cells and neural stem cells; and ii) Yue, Vega and Shapiro teach a N-cadherin-Fc fusion protein immobilized on a carrier including a polymeric carrier or a protein or polysaccharide biomaterial and its benefits of providing better environments for neuronal growth and neuronal differentiation from neural stem cells; and iii) Ellis-Behnke teaches promoting neuroblasts migration to an affected area in a brain injury and treating brain injury including traumatic brain injury and ischemic brain injury/stroke using a N-cadherin-polymeric carrier.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known treatment of neonatal brain injury by enhancement of regenerative processes by angiogenesis and neurogenesis using stem cells and neural stem cells, the known treatment of N-Cadherin for treatment of brain injury disclosed by Ellis-Behnke, the known benefits of N-Cadherin-Fc for enhancing neural differentiation from stem cells or neural stem cells and the known N-Cadherin-Fc-carrier for providing better environments for neuronal growth wherein the N-Cadherin-Fc-carrier contains a protein having all EC1-EC5 domains of N-Cadherin and wherein the carrier is a biomaterial or biocompatible polymeric carrier, a polymeric carrier or a protein or polysaccharide biomaterial and technique disclosed by Nabetani, Yue, Vega and Shapiro to the Ellis-Behnke’s method to treat neonatal brain injury and promote neuronal or neuroblast migration, and yield the predictable result of treating neonatal brain injury and promoting neuronal or neuroblast migration neonatal brain injury. See KSR International Co. V. Teleflex Inc. 82 USPQ2d 1385 (2007); In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980); In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992); Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) and In re Kahn, 441 F.3d 977, 986, 78 USPQ2d 1329, 1335 (Fed. Cir. 2006) and also see MPEP § 2143. 01-I, MPEP § 2144.06 and MPEP §2144.07.
Claim Rejections - 35 USC § 103
7. Claims 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Ellis-Behnke et al. (US2005/0287186; was issued as US7846891) in view of Nabetani et al. (2018), Yu et al. (2010), Vega et al. (2016) and Shapiro et al. (2009) and evidentiary references: Klinigener et al. (2014), Ajoka et al. (2015), Kanemaru et al. (2013) and Hirano et al. (2012) as applied to claims 12-16,19-23 and 25 above, and further in view of Han (US2017/0182080, published Jun 29, 2017, priority Mar 14, 2014).
Ellis-Behnke, Nabetani, Yu, Vega and Shapiro are set forth above but do not teach gelatin or a gelatin sponge as in claims 23-24.
While Ellis-Behnke, Nabetani, Yu, Vega and Shapiro do not teach gelatin or a gelatin sponge as in claims 23-24, Han (US2017/0182080) teaches these limitations and provides motivation and an expectation of success in using gelatin or a gelatin sponge in the method of Ellis-Behnke, Nabetani, Yu, Vega and Shapiro.
Han teaches a functional scaffold for neural tissue repair and regeneration comprising gelatin, collagen or gel, sponge, albumin, fibrin, fibrinogen, laminin, fibronectin, vitronectin, or a synthetic peptide containing an exposed lysine or glutamine or porous sponge (see [0086]-[0090]; [0102]).
A person of ordinary skill in the art would have recognized that selecting and applying the known gelatin or gelatin sponge as a carrier and the known technique disclosed by Han to the method of Ellis-Behnke, Nabetani, Yu, Vega and Shapiro would have yielded the predictable result of promoting neuronal migration neonatal brain injury or treating neonatal brain injury, and resulted in an improved method of treating neonatal brain injury.
Using the known gelatin or a gelatin sponge as a carrier in the method of Ellis-Behnke, Nabetani, Yu, Vega and Shapiro would generate a N-Cadherin-Fc-gelatin or a N-Cadherin-Fc-gelatin sponge and treat neonatal brain injury and promote neuronal or neuroblast migration in neonatal brain injury or treat neonatal brain injury, and expand application of the method of Ellis-Behnke, Nabetani, Yu, Vega and Shapiro, and would increase patient’s satisfaction with treatment of neonatal brain injury using a N-Cadherin-Fc-carrier because i) Ellis-Behnke teaches treating brain injury including ischemic brain injury and traumatic brain injury, and promoting neuroblasts migration to affected area in a brain injury using a N-cadherin-polymeric carrier; ii) Nabetani teaches that neonatal brain injury including hypoxic ischemic encephalopathy, ischemic brain injury or traumatic brain injury can be treated or improved by enhancement of regenerative processes by angiogenesis and neurogenesis using stem cells and neural stem cells; iii) Yue, Vega and Shapiro teach N-cadherin-Fc fusion protein immobilized on a carrier including a polymeric carrier or a protein or polysaccharide biomaterial and their benefits of providing better environments for neuronal growth and neuronal differentiation from neural stem cells; and iv) and Han teaches gelatin or gelatin sponge has been successfully used as a carrier or scaffold for neural tissue repair and regeneration.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known gelatin or gelatin sponge as a carrier and the known technique disclosed by Han to the method of Ellis-Behnke, Nabetani, Yu, Vega and Shapiro to treat neonatal brain injury or promote neuronal or neuroblast migration, and yield the predictable result of treating neonatal brain injury and promoting neuronal or neuroblast migration neonatal brain injury. See KSR International Co. V. Teleflex Inc. 82 USPQ2d 1385 (2007); In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980); In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992); Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) and In re Kahn, 441 F.3d 977, 986, 78 USPQ2d 1329, 1335 (Fed. Cir. 2006) and also see MPEP § 2143. 01-I, MPEP § 2144.06 and MPEP §2144.07.
Conclusion
8. NO CLAIM IS ALLOWED.
9. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached Monday-Thursday, 7:00am-5:00pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Chang-Yu Wang
July 14, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
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