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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07-14-2025 has been entered.
Applicants' Response and Amendment to the claims filed 07-14-2025 have been entered. Claim 21 has been added. Claims 7-20 have been canceled. Claims 1-6, 21 are pending and under consideration.
Priority
This application is a 371 of PCT/EP2019/075413 filed on 09/20/2019 which claim priority from US provisional application 62/734,064 filed on 09/20/2018.
New-Claim Rejections - 35 USC § 112 (New matter)
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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.
Claim 21 is 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In the instant case, the recitation of limitation “the ASCs do not attach to the gelatin” is considered new matter. Upon further review of the instant specification, examiner could only find support for “the ASCs do not attach to the gelatin”. There is no explicit or implicit support for “the ASCs do not attach to the gelatin”. Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of the concept of “the ASCs do not attach to the gelatin” as claimed. In case if applicants have evidence to support otherwise, applicants are invited to indicate page and line number for the written support specifically for “the ASCs do not attach to the gelatin” recited in claims of the instant application. This is a new matter rejection.
New-Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 21 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 21 does not satisfy the requirements of 112(d) because they contain a reference to a previous claim but do not specify a further limitation of the subject matter claimed. Specifically, claim 21 depends from claim 1 and recites “further including at least one of (a) and (b) wherein: (a) the ASCs do not attach to the gelatin; (b) the ASCs are embedded in the extracellular matrix”. However, Claim 21 encompasses embodiment with the biomaterial is further including only “(b) the ASCs are embedded in the extracellular matrix” which is already recited in claim 1. Thus, claim 21 does not further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Maintained - Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3-6 are rejected under 35 U.S.C. 102 (a)(2) as being anticipated by Alsberg et al (Pub. No.:US2018/0371416 Al, Pub. Date: Dec. 27, 2018, Provisional application No. 61/623,654, filed on Apr. 13, 2012.).
Claims interpretation:
According to the specification of the claimed invention, the gelatin of the invention is in form of particles, beads, spheres, microspheres and the like (Page 15, lines 24-25) and the gelatin of the invention is a macroporous microcarrier (Page 16, lines 4). Therefore, gelatin is interpreted in view of the instant disclosure as encompassing gelatin microcarriers and gelatin microspheres.
According to the specification of the claimed invention, the extracellular matrix of the biomaterial of the invention is derived from the ASCs (Page 18, lines 25-26). Therefore, the extracellular matrix is interpreted as encompassing self-secreted extracellular matrix of ASCs.
According to the specification of the claimed invention, the ASCs within the biomaterial of the invention form a tissue (referred to as ASCs tissue) (Page 19, lines 9-10). Therefore, the biomaterial can be interpreted as a tissue and since extracellular matrix is self-secreted extracellular matrix of ASCs, the ASCs are embedded in the extracellular matrix within the tissue.
Regarding to claim 1, Alsberg et al teach “a tissue construct comprising includes a self-assembled, scaffold-free, high density cell aggregate. The cell aggregate includes a plurality of cells and a plurality of biocompatible and biodegradable nanoparticles and/or microparticles that are incorporated within the cell aggregate” (Abstract).
Alsberg et al teach “the cell aggregate is a self-assembled cell sheet that comprises undifferentiated and/or substantially differentiated progenitor cells, a plurality of nanoparticles and/or microparticles, and a self-secreted extracellular matrix of the undifferentiated and/or substantially differentiated progenitor cells that can bind to or permit the adhesion of cells in the aggregate” ([0012], page 2) and “….. the population of cells can comprise a population of human adipose derived stem cells” ([0075], page 7, right column).
Alsberg et al teach “the nanoparticles and/or microparticles can be formed from a biocompatible and biodegradable polymer. Examples of biocompatible, biodegradable polymers include natural polymers, such as gelatin, …” ([0062], page 5). The population of cells can comprise a population of human adipose derived stem cells ([0075], page 7). Thus, Alsberg et al teaches the scaffold-free tissue construct comprising differentiated human adipose derived stem cells, a gelatin, and self-secreted extracellular matrix is a scaffold-free biomaterial due to the synthesis of the extracellular matrix by the ASCs that are embedded in the extracellular matrix.
Regarding to claim 3, Alsberg et al teach “the nanoparticles and/or microparticles can be formed from a biocompatible and biodegradable polymer. Examples of biocompatible, biodegradable polymers include natural polymers, such as gelatin, …” ([0062], page 5).
Regarding to claim 4, Alsberg et al teach “hydrated microspheres were roughly spherical with similar average diameters (60.9±50.1 µm, "low Gp"; 54.3±47.9 µm, "high Gp")…... ” ([0143], page 17).
Regarding to claim 5, Alsberg et al teach “…… These culture systems take advantage of the abundant cell-cell interactions that occur in 3D high density culture, without the potential interference of a biomaterial scaffold……” ([0004], page 1) and “….the bioactive agent can induce the formation of a cell sheet, graft, or structure….” ([0011], page 1).
Regarding to claim 6, Alsberg et al teach that mesenchymal stem cells (MSCs) can differentiate into many cell types of the connective tissue lineage including chondrocytes under appropriate conditions ([0003], Page 1), and “the system of self-assembling, microsphere-incorporated MSC sheets reported here is versatile, and may accommodate the formation of sheets containing other cells with chondrogenic potential including adipose derived stem cells or mature chondrocytes” ([0126], Page 14).
Thus, claims 1, 3-6 are being anticipated by Alsberg et al.
Maintained- Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 2 is rejected under 35 U.S.C. 103 as being unpatentable over Alsberg et al (Pub. No.:US2018/0371416 Al, Provisional application No. 61/623,654, filed on Apr. 13, 2012.) in view of Yu et al (Biomaterials 120 (2017) 66-80, Doi: 10.1016/j.biomaterials.2016.12.017, Available online 23 December 2016).
The teachings of Alsberg et al have been described above and are incorporated herein in their entirety. The teachings of Alsberg et al differ from claimed invention by not disclosing use of gelatin derived from porcine. Yu et al cure the deficiency.
Regarding to claim 2, Yu et al teach decellularized adipose tissue microcarriers as a dynamic culture platform for human adipose-derived stem/stromal cell expansion (Title), and Cultispher-S microcarriers compose of crosslinked porcine gelatin (Page 67, left column). Yu et al also teach the use of adipose-derived ECM (Page 78, left col., 3rd para.) and the use of complex tissue-specific ECM-derived microcarriers provides a promising approach for ASC expansion under dynamic conditions (Page 79, left col., 3rd para.).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Alsberg et al by using gelatin derived from porcine as taught by Yu et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Yu et al stated that “the ability to produce large ASC populations from small patient biopsies would represent a clinical advantage for the translation of innovative autologous or allogeneic therapies from the 'benchtop to the bedside” (Page 66, right column) and “this study demonstrates the promising application of our novel DAT microcarriers as a 3-D dynamic cell expansion platform to obtain large populations of multipotent ASCs from small tissue samples. From a clinical perspective, the natural composition and cell-supportive qualities of the DAT microcarriers may be favorable for their application as an injectable cell delivery vehicle for autologous or allogeneic cell-based therapies. The studies in the current paper confirmed that the ASCs expanded on the DAT microcarriers retained their multilineage differentiation capacity upon extraction and induction using conventional culturing methods.” One of ordinary skill in the art would have had a reasonable expectation of success in doing so because both Yu et al were successful in generation of decellularized adipose tissue microcarriers as a dynamic culture platform for human adipose-derived stem/stromal cell expansion (title) and provide detail for producing such scaffold-free biomaterial and for transplantation of such scaffold-free biomaterial to damaged tissues.
Response to Arguments
Applicant's arguments filed 07-14-2025 have been fully considered but they are not persuasive.
1. Applicant argues that external growth factor loaded cell aggregates are structurally different from the neo-synthesized matrix of the present invention as explained in Professor DuFrane's previously filed declaration:
In Alsberg et al, the cells attach to each other and are not embedded in the matrix. In the claimed invention, the cells are embedded in a neo-synthesized extracellular matrix.
In Alsberg et al, the reference to "embedded" appears in paragraph [0054] and is explained as distinguished from, and thus different from, being embedded in a matrix.
Therefore, Alsberg et al teaches that the cells are adhered in the aggregate - they adhere to each other. The progenitor cells can bind to or permit adhesion in the aggregate. There is no disclosure of [the progenitor or any other] cells being embedded in the matrix (Remarks, page 5-6).
This is further confirmed in Alsberg et al [0012]: In other embodiments, the cell aggregate is a self-assembled cell sheet that comprises undifferentiated and/or substantially differentiated progenitor cells, a plurality of nanoparticles and/or microparticles, and a self-secreted extracellular matrix of the undifferentiated and/or substantially differentiated progenitor cells that can bind to or permit the adhesion of cells in the aggregate. The self-secreted extracellular matrix of the cells that can include compounds selected from the group consisting of proteins like collagen; proteoglycan; glycoprotein; gycosaminoglycan, or any combination thereof." (emphasis added) (see remarks, page 5-7)
Response to Arguments:
As applicant cited Alsberg et al [0012] that teaches “a self-secreted extracellular matrix of the undifferentiated and/or substantially differentiated progenitor cells” which satisfies the claim limitation of “the multi-dimension of the biomaterial is due to the synthesis of the extracellular matrix by the ASCs”.
The arguments are not commensurate with the scope of the claims:
The base claim 1 recites “A scaffold-free biomaterial having a multi-dimensional structure comprising differentiated adipose-derived stem cells (ASCs) , an extracellular matrix and gelatin” which encompass any biomaterial comprising ASCs (including ASCs cell aggregates), an extracellular matrix and gelatin.
The claims do not specify structure of a scaffold-free biomaterial or exclude “the cells in the aggregate” structure.
The specification of the claimed invention does not define the term “embedded”. Alsberg et al teach “a self-secreted extracellular matrix of the undifferentiated and/or substantially differentiated progenitor cells”. Thus, “a self-secreted extracellular matrix” should be secreted outside and surrounding the cells that are general definition of being “embedded”.
The term “embedded” can also be interpreted as product by process as directed to “ASCs” and “extracellular matrix”. See MPEP 2113: [E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted).
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632