DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 25-40 are pending.
Election/Restrictions
Applicant’s election without traverse of Group IV, claim 25, drawn to a composition comprising a preparation of hydrogel capsules and a pharmaceutically acceptable excipient, as well as the species of the GIS located in SEQ ID NO: 1, in the reply filed on 27 October 2025 is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 27 January 2023 and 27 October 2025 were filed before the mailing of an Office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
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, 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 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 25-30 and 32-40 are rejected under 35 U.S.C. 103 as being unpatentable over Carmona et al. (WO 2019/067766 A1) in view of Zhijie et al. (PNAS, 2013) and Inaba et al. (Applied and Environmental Microbiology, 2018).
Carmona et al. throughout the reference teach an engineered active cell, or an implantable element comprising the engineered active cell, wherein the engineered active cell is an engineered retinal pigment epithelial (RPE) cell or an engineered cell derived from an RPE cell, and wherein the engineered active cell comprises an exogenous nucleic acid encoding a polypeptide (Abstract; Claim 1).
Regarding claims 25-29 and 32-35, Carmona et al. teach an implantable alginate hydrogel capsule encapsulating the engineered active cell (pg. 3, ln. 29; Fig. 5-8; Claims 27, 33). Carmona et al. teach that the implantable element is modified with a compound of formula (I), including the following afibrotic compounds (Table 1; Claims 29-31):
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256
1002
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264
764
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Carmona et al. teach that an exemplary encapsulated implantable element comprises an active cell, e.g., a plurality of active cells, e.g., a cluster of active cells, or a microcarrier, e.g., a bead, or a matrix comprising an active cell or active cells, and an enclosing element comprising a coating of derivatized alginate (pg. 19, ln. 8-11).
Carmona et al. that in some embodiments, the active cells, compositions, and implantable elements produce a therapeutic agent (such as a replacement agent) useful, e.g., for the treatment of a disease, disorder or condition in a subject, e.g., a blood clotting disorder or a lysosomal storage disease (pg. 1, ln. 27-30). In some embodiments, the replacement therapy or replacement protein is an enzyme, e.g., alpha-galactosidase, alpha-L-iduronidase (IDUA), or N-sulfoglucosamine sulfohydrolase (SGSH) (pg. 49, ln. 22-24).
Carmona et al. do not explicitly disclose compositions comprising a genetically modified cell comprising an exogenous transcription unit encoding a human IDUA protein inserted into the instantly claimed genomic insertion sites.
Carmona et al. teach RPE cells, e.g., ARPE-19 cells, may be engineered to express an exogenous polypeptide using the PiggyBac transposon system, which involves co-transfection of RPE cells with two plasmids: (1) a transposon vector containing a transcription unit capable of expressing a polypeptide of interest inserted between inverted terminal repeat (ITR) elements recognized by a PiggyBac transposase and (2) a plasmid that expresses a piggyBac transposase enzyme. The PiggyBac system mediates gene transfer through a "cut and paste" mechanism whereby the transposase integrates the transcription unit and ITRs into TTAA chromosomal sites of the RPE cells. Alternatively, RPE cells may be engineered to express a polypeptide of interest from an extrachromosomal vector by transfecting the cells with only the transposon vector (Example 11).
The system used by Carmona et al. to insert the exogenous transcription unit is the PiggyBac transposon system, which is known to insert the transcription unit into the TTAA chromosomal sites of the cells (pg. 149, ln. 29-31).
Zhijie et al. teach the host factor-independent piggyBac (PB) transposon was recently introduced as a highly efficient method for inserting multiple copies of exogenous DNA fragments into mammalian genomes. The PB transposase (PBase) recognizes a pair of terminal repeat sequences flanking the donor DNA fragment and inserts it into random TTAA sites on the chromosomal DNA in mammalian cells. It can insert fragments of as much as 9 kb with high efficiency and fragments of as much as 14 kb with reduced efficiency, and, most recently, it has been used for the insertion of a bacterial artificial chromosome into the genome of an embryonic stem cell. As many as 15 copies of the DNA fragment can be inserted per cell, and the individual copies are distributed over the genome, a property expected to average out position effects (Abstract; pg. 5004, col. 2).
Inaba et al. teach that the transposase-mediated insertion of the exogenous gene of interest into different chromosomal sites in the host cell may result in the production of the protein of interest in different amounts (Fig. 5; pg. 8).
Therefore, it would have been prima facie for a person of ordinary skill in the art prior to the effective filing date of the instant claims to try different TTAA chromosomal sites in the RPE cells for the insertion of said transcription units in order to obtain the highest amount of protein, which would necessarily would end up with the insertion sites of the instant claims, since they correspond to only TTAA chromosomal sites (specification, Figures 1A-1E).
Regarding claim 30, Carmona et al. teach that the engineered active cell comprises an exogenous transcription unit capable of producing the IDUA protein.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date of the instant claims to prepare the engineered active cell comprising a transcription unit comprising a sequence that is capable of producing a human IDUA protein, as reasonably suggested by Carmona et al.
Regarding claims 36-38, Carmona et al. teach that the compound of formula (I) includes (Table 1, compounds 112-114):
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164
466
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,
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114
480
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and
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142
394
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.
Carmona et al. teach that an implantable element may be coated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a material comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In an embodiment, the compound of Formula (I) is disposed on a surface, e.g., an inner or outer surface, of the implantable element. In some embodiments, the compound of Formula (I) is disposed on a surface, e.g., an inner or outer surface, of an enclosing component associated with an implantable element. In an embodiment, the compound of Formula (1) is distributed evenly across a surface. In an embodiment, the compound of Formula (I) is distributed unevenly across a surface (pg. 78, ln. 11 to pg. 79, ln. 20).
Regarding claims 39-40, Carmona et al. teach that in some embodiments, the implantable element has a mean diameter or size between 1 mm to 2 mm (pg. 60, ln. 8-24).
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date of the instant claims to prepare an implantable element according to Carmona et al. wherein the outer surface is coated with a compound of formula (I), such as compounds 112-114. Also, it would have been obvious to prepare an implantable element with a diameter of between 1 mm to 2 mm, as reasonably suggested by Carmona et al.
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. See MPEP 2144.05(I).
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Carmona et al. (WO 2019/067766 A1) in view of Zhijie et al. (PNAS, 2013) and Inaba et al. (Applied and Environmental Microbiology, 2018) as applied to claims 25-30 and 32-40 above, further in view of Rauh et al. (WO 2007/147014 A2).
Regarding claim 31, Carmona et al. teach that the alginate polymer may be covalently associated with an enclosing component of the implantable element (e.g., on the inner surface or outer surface of an implantable element) (pg. 55, ln. 5-8). An implantable element can include a protein or polypeptide, e.g. an antibody, protein, enzyme, or growth factor. An implantable element can include an active or inactive fragment of a protein or polypeptide, such as glucose oxidase (e.g., for glucose sensor), kinase, phosphatase, oxygenase, hydrogenase, reductase (pg. 56, ln. 3-6). See also pg. 58, ln. 12-15.
Carmona et al. do not explicitly disclose alginate covalently modified with a peptide comprising GRGDSP, as in claim 31.
Rauh et al. teach alginate hydrogels covalently modified with a cell adhesion peptide, and further comprising a cell (Abstract; [0006]). Biologically active molecules for cell adhesion or other cellular interaction are well known and widely recognized and available, including GRGDSP and GGGGRGDSP ([0020], [0065]; Claims 2, 15, 18-19, 24, 29, 32, 41, 53, 60). Rauh et al. teach that the uses of biopolymer hydrogels linked to cell attachment peptides in implantable compositions which may comprise cells are known. Biopolymer matrices are particularly useful due to the high degree of biocompatibility of the materials used, particularly alginates, chitosan, hyaluronan and compositions comprising mixtures thereof ([0004]).
Rauh et al. teach improved compositions of matter, involve enhanced retention of transplanted cells in a patient; enhanced retention and viability of implanted cells within tissue or organ structures; retention of living cells in a therapeutic mechanical scaffolding within a tissue or organ structure by use of an injectable combination of such living cells with a polymer agent; enhanced deposition of cells into a tissue or organ structure of a patient; and an induced deposition of autologous cells within a tissue or organ structure of the patient at least in part with an injected polymer agent ([0032]). Other of these systems and methods, which may include improved compositions of matter, involve additional cellular recruitment and deposition into tissue or organ structures receiving cell implant therapy; and use of factors adapted to recruit endogenous cells, including providing a cellular deposition recruiting factor ([0033]).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date of the instant claims to covalently bond cell attachment peptides comprising GRGDSP according to Rauh et al. to the alginate hydrogel according to Carmona et al. in order to attach to the cell and provide a biopolymer hydrogel comprising a cell, providing an improved composition of matter with improved properties.
Conclusion
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/N.W.S/Examiner, Art Unit 1616
/Mina Haghighatian/Primary Examiner, Art Unit 1616