DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Remarks
The amendments and remarks filed on 09/04/2025 have been entered and 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. The rejections and/or objections presented herein are the only rejections and/or objections currently outstanding. Any previously presented objections or rejections that are not presented in this Office Action are withdrawn. Claims 1-20 are pending; Claims 16-17 and 20 are amended; Claims 1-15 are withdrawn; and Claims 16-20 are under examination.
Withdrawal of Rejections
The rejection of claims 17 and 20 under 35 U.S.C. 112(b) is withdrawn due to the amendment to the claims filed on 09/04/2025.
The rejection of Claims 16, 17 and 20 under 35 U.S.C. 102(a)(1) as being anticipated by Simko et al. is withdrawn due to the amendment to the claims filed on 09/04/2025.
Claim Objections
Claim 16 is objected to due to the recitation of “wherein … the cell patch configured to release … in the tissue”. The recited phrase should be changed to “wherein … and the cell patch is configured to release … in the tissue”. Appropriate correction is required.
Claim Rejections - 35 USC § 112, First Paragraph
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 16-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The amended claim 16 is directed to a system comprising: (i) a cell patch comprising a cell monolayer, wherein the monolayer forms a cell density of greater than 1250 cells per square millimeter, and (ii) a micro-tissue structure folded around the cell patch; wherein the cell patch is configured to release and integrate into a tissue forming a cell density up to between 1250 cells per square millimeter and 4000 cells per square millimeter in the tissue.
Support for the claimed cell density range of “greater than 1250 cells per square millimeter” is not found in the specification of the originally filed application. Applicant, in the response filed on 09/04/2025 (page 7), points to the paragraph 0098-0101 and Fig. 11A for a written description of the claimed limitation. However, none of the disclosures specifically pointed by Applicant provides support for the claimed limitation “the monolayer forms a cell density of greater than 1250 cells per square millimeter” recited in claim 16. Such support is not found in the remaining of the speciation, either.
Furthermore, support for the claimed limitation “forming a cell density up to between 1250 cells per square millimeter and 4000 cells per square millimeter” (at last 3 lines of claim 16) is not found in the specification of the originally filed application. Applicant in the 09/04/2025 response (page 7) points to the paragraph 0098-0101 and Fig. 11A for a written description of the claimed limitation. However, none of the disclosures specifically pointed by Applicant provides support for the claimed limitation. It is noted that the para 0100 and Fig. 11A only disclose that the cell patch after integrating into tissue forms a cell density in a range from about 1000 to about 2000 cells/mm2, and there is no support for the claimed range “up to between 1250 cells per square millimeter and 4000 cells per square millimeter”. Such support is not found in the remaining of the speciation, either.
Therefore, the base claim 16 and dependent claims 17-20 are directed to new matter.
Claim Rejections - 35 USC § 103
Claims 16, 17, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Simko et al. (US 2017/0342374, 2017, cited in IDS).
Regarding Claims 16 and 17, Simko et al. teach a system and a method of generating the system through micro-tissue encapsulation by seeding cells to a tissue scaffold coated with extracellular matrix (abstract, claims 1 and 15), the system comprising: a cell patch and a micro-tissue structure comprising an extracellular matrix (ECM) folded (wrapping) around the cell patch (Claims 1 and 15, Fig. 1, paras 0004, 0006, 0013, 0022, 0024/last 5 lines, 0025, 0070), wherein the cell patch comprises a cell monolayer (paras 0012/last 2 lines, 0070/lines 8-13, and 0071; Claim 14); wherein the ECM comprises one or more proteins selected from collagen IV, laminin, a fibroblast growth factor protein, and a vascular endothelial growth factor protein (paras 0010, Claim 7); and wherein the micro-tissue structure and cell patch are injectable into tissue (0064-65, 0070, 0073, and Claim 2). Regarding the limitation “provide a physical barrier between the cell patch and an external environment” recited in Claim 16, Simko et al. teach that the micro-tissue structure comprising the ECM provides a physical protection to the cell patch so as to avoid damages caused by an external environment (Claim 3, para 0004/lines 7-10, 0024/last 5 lines, 0025/last 5 lines). Regarding the limitation “cell monolayer … maintains expression for cell-cell junctions and cytoskeletons for cells …” recited in Claim 16, this limitation is directed to an inherent feature the cell monolayer. Furthermore, Simko et al. expressively teach that the cell patch comprising the cell monolayer maintains expression of Z0-1 tight-junction protein and F-actin cytoskeleton protein for maintaining cell-cell junctions and cytoskeletons for cells (para 0071, Fig. 8).
The system of Simko et al. differs from the claimed system in that Simko et al. do not expressively teach the monolayer forms a cell density of more than 1250 cells/mm2. However, Simko et al. expressively teach seeding BCEC cells at a cell density of 250,000 cells per sample on squares of extracellular matrix (ECM: collagen and laminin) to form cell monolayers on the ECM squares and then a cell patch of cell monolayer folded by ECM raft, wherein the squares are coated on a glass coverslip/scaffold and each of the squares has a surface area of 200 mm x 200 mm (i.e. 0.2 x 0.2 mm = 0.04 mm2) (para 0070, Fig. 7). As Fig. 7 shows, there are 4 or 6 ECM squares on the glass scaffold for each sample. If assuming 6 ECM squares are coated on the scaffold for each sample, a total surface area of ECM squares used for seeding 250,000 cells would be 0.24 mm2, which results in a cell density of about 1 x106 cells/mm2 for forming a cell monolayer. It would be reasonable to expect the cells seeded at a density of 1 x106 cells/mm2 to form a monolayer having a cell density of more than1.25 x103 cells/mm2 (i.e. greater than 1250 cells per square millimeter), thus rendering the claimed cell density range to be obvious. Furthermore, Simko et al. teach that the system of cell patch comprising a cell monolayer is used for repairing damaged tissue after delivery to a desired site for repair (para 0004). It is noted that a specific cell density in the cell monolayer of Simko et al. is readily adjustable through optimizing by modifying preparation conditions, such as a number of seeded cells and an incubation time on ECM squares, for achieving a desirable outcome of repairing damaged tissue. It is further noted that generally, differences in a concentration (e.g. a cell density) will not support the patentability of subject matter unless there is evidence indicating such concentration/cell density is critical.
Regarding the limitation “the cell patch configured to release … and integrate into tissue forming a cell density up to between 1250 cells per square millimeter …” recited at the end of claim 16, this limitation is directed to what the cell patch does after being delivered to a target tissue. The cell patch suggested by Simko et al. has the same structure as the claimed cell patch. In the absence of evidence to the contrary, it is presumed that a substance having substantially the same structure is capable of performing substantially the same functions. Therefore, the teachings of Simko et al. meet the claimed limitation.
Regarding Claim 19, this claim requires the monolayer comprises 10-100 cells. It is noted that a specific number of cells in the monolayer of each cell patch is readily adjustable through optimizing or modifying a number of seeded cells, incubation time of cell culture, and sizes of tissue scaffold. Simko et al. further teach administering the system comprising micro-tissue structure and cell patch to a subject as a therapeutic agent (paras 0064-65, Claim 1), wherein a number of cells (cell patches) administered varies with specific application (para 0065); and Simko et al. expressively teach that 10,000 cells administered are present in around 200 – 250 cell patches (page 7, para 0064, right col, lines 3-5), which can be converted to about 40 – 50 cells per cell patch (monolayer). Thus, the teachings of Simko et al. render the claim 19 to be obvious.
Regarding Claim 20, Simko et al. teach the ECM is added with a vascular endothelial growth factor protein, as indicated above. Simko et al. further teach a muscle cell, i.e. murine skeletal myoblast cell, as a cell type used for forming the cell patch (para 0028, lines 2-4). The cell patch comprising a muscle cell monolayer taught by Simko et al. meets the limitation of “muscle tissue” recited in the claim.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Simko et al. (US 2017/0342374, 2017, cited in IDS), as applied to Claims 16, 17, 19 and 20, further in view of Chien et al. (US 2012/0027807, 2012, cited in IDS).
The teachings of Simko et al. are described above.
Regarding Claim 18, Simko et al. do not teach the micro-tissue structure forms a tube configuration. However, Simko et al. teach the geometries/shapes of the ECM/micro-tissue structure are readily adjustable (paras. 0022/lines 1-8, 0062/last 7 lines).
It would have been obvious to modify the system of Simko et al. through seeding cells onto a cylinder-shaped scaffold (precoated with ECM) in the method of Simko et al. for forming a micro-tissue structure having a tube configuration, so as to obtain the modified system comprising the micro-tissue structure having a tube configuration. This is because it is an obvious design choice to form the micro-tissue structure with a specific tube configuration. Furthermore, it is well known in the art to form an in vivo engineered tissue having a tube configuration by seeding cells onto a scaffold shaped as a cylinder, and such a tube-shaped engineered tissue is suitable for treating diseases such as cardiovascular disorders. In support, Chien et al. teach a tissue engineered myocardium having functional properties of cardiac muscle as well as a method of generating the tissue to be used for treating cardiovascular disorders (abstract, claims 21-22), wherein the tissue engineered myocardium is formed by seeding CVP cells onto a biopolymer scaffold that has any geometric shape, such as a spiral or V-shaped, or O-shaped scaffold, and the CVP cells form the tissue that conforms and remains the same shape of scaffold after removal of the scaffold; and wherein a hollow tube of the tissue engineered myocardium is formed by seeding the cells onto a scaffold shaped as a cylinder (para 0334).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Double Patenting
Claims 16, 17, 19, and 20 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over the claims 1-17 of US patent No. 12441981 (issued from the copending Application No. 17/535,094 cited in the previous double patenting rejections) in view of Simko et al. (US 2017/0342374, 2017, cited in IDS).
The claims of the ‘981 patent are directed in part to a system (micro-tissue raft) comprising: a cell patch and an extracellular matrix (micro-tissue structure) attached to the cell patch, wherein cells of the cell patch comprise a Zonula Occludens-1 (ZO-1) protein expression that maintains tight cell-cell junctions; wherein the ZO-1 protein expression assists folding of the extracellular matrix around the cell patch; wherein the cell patch forms a cell monolayer; wherein the extracellular matrix is configured to be responsive to tension forces expressed by the cell patch, wherein the tension forces cause the extracellular matrix/micro-tissue structure to fold into a specified geometry around the cell patch; wherein the tension forces are expressed by cell junctions of cells that form the cell patch; wherein the extracellular matrix/micro-tissue structure is configured to fold into the specified geometry in response to removal of a scaffold from the extracellular matrix; wherein the cell patch is configured to protect the cell patch from forces (as a barrier) during injecting; wherein the extracellular matrix comprises one or more of collagen IV, laminin, a fibroblast growth factor protein, and a vascular endothelial growth factor protein; wherein the extracellular matrix forms a tissue scaffold stamp; and wherein the extracellular matrix has a size of 200 mm x 200 mm.
The teachings of Simko et al. are described above.
The claims of the ‘981 patent differ from the instant claims in that the claims of the ‘981 patent do not expressively teach that the monolayer forms a cell density of more than 1250 cells/mm2. However, this limitation would have been obvious in view of Simko et al. for the reasons described above.
Regarding the limitation “the cell patch configured to release … and integrate into tissue forming a cell density up to between 1250 cells per square millimeter …” recited in instant claim 16, this limitation is directed to what the cell patch does after being delivered to a target tissue. The cell patch suggested by the claims of the ‘981 patent and Simko et al. has the same structure as the claimed cell patch. In the absence of evidence to the contrary, it is presumed that a substance having substantially the same structure is capable of performing substantially the same functions.
Regarding the limitations about maintaining expression for cell-cell junctions and cytoskeleton, and the monolayer of cell patch comprises a muscle tissue, and the monolayer of cell patch comprises 10 – 100 cells recited in the claims 16 and 19-20, it would have been obvious to one of ordinary skill in the art to adopt these features into the claimed system/micro-tissue raft of the ‘981 patent, because they are well known features in the art, as supported by Simko et al.
Therefore, in view of the teachings of Simko et al., the system of 16, 17, 19, and 20 of the instant application is deemed obvious over the system of Claims 1-17 of US patent No. 12441981.
Claims 16-20 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-17 of US patent No. 12441981 in view of Simko et al. (US 2017/0342374, 2017, cited in IDS), as applied to Claims 16, 17, 19, and 20, further in view of Chien et al. (US 2012/0027807, 2012, cited in IDS).
The claimed subject matter of the ‘981 patent are described above.
The teachings of Simko et al. and Chien et al. are described above.
Regarding Claim 18, the claims of the ‘981 patent and Simko et al. do not teach the micro-tissue structure/extracellular matrix forms a tube configuration.
It would have been obvious for the system of the ‘981 patent to comprises a micro-tissue structure/extracellular matrix having a tube configuration, because it is an obvious design choice to form the micro-tissue structure with a specific tube configuration. Furthermore, it is well known in the art to form an in vivo engineered tissue having a tube configuration is well suited for treating diseases such as cardiovascular disorders, as supported by Chien et al.
Therefore, in view of the teachings of the cited prior art, the system of 16-20 of the instant application is deemed obvious over the system of claims 1-17 of US patent No. 12441981.
Response to Arguments
As a first matter, the Examiner does not fully agree with Applicant's interview summary submitted on 09/04/2025 as well as the arguments based on the interview summary in the 09/04/2025 response (the para spanning pages 7 and 8). The subject mainly discussed in the 07/03/2025 interview is the new matter issue which was raised by the cell density range “greater than 1250 cells per square millimeter” added to the claim 16 of Applicant’s proposed amendment, as indicated in Examiner’s interview summary dated 07/08/2025. This discussed subject is not mentioned in the Applicant's interview summary. With regard to the outstanding 102 and 103 rejections, the Examiner indicated that it requires further consideration and search to determine whether the cited art references are still applicable to the proposed amendment under 35 U.S.C. 103. No agreement has been reached.
Applicant's arguments about the rejection of Claims 17 and 20 under 35 U.S.C. 112(b) in the 09/04/2025 response (page 7) have been fully considered but they are moot, because the rejection has been withdrawn, as indicated above.
Applicant's arguments about the rejection of Claims 16, 17 and 20 under 35 U.S.C. 102(a)(1) as being anticipated by Simko in the 09/04/2025 response (pages 7-8) have been fully considered but they are moot, because the rejection has been withdrawn, as indicated above.
Applicant's arguments about the rejections of Claims 16-20 under 35 U.S.C. 103 over Simko either alone or in combination with Chien in the 09/04/2025 response (pages 7-8) have been fully considered but they are not persuasive, because the ranges for cell densities recited in the claim 16 (i.e. greater than 1250 cells/mm2 and up to between 1250-4000 cells/mm2) are obvious over the teachings of Simko for the reasons indicated above in the 103 rejection (see pages 6 and 7 for details).
Overall, the conclusion of the obviousness of the newly amended claims 16-20 claim has been established for all the reasons indicated above.
Applicant’s comments about the double patenting rejections over claims of Application No. 17/535,094 (now issued as Patent No. 12441981) in the 09/04/2025 response (page 9) are acknowledged.
Conclusion
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 extension fee 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 date of this final action.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Qing Xu, Ph.D., whose telephone number is (571) 272-3076. The examiner can normally be reached on Monday-Friday from 9:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao, can be reached at (571) 272-0939. Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to the receptionist whose telephone number is (571) 272-1600.
/Qing Xu/
Patent Examiner
Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656