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 .
Claim Status
1. The Amendment filed 03/09/2026 has been entered. Claims 1 – 3, 5, 8, 9, 12 – 14, 16 – 19, 21, and 23 – 24 remain pending. Claims 4, 6, and 7 have been cancelled. Claims 1 – 3, 5, 8, 9, and 12 – 14, and 16 are under consideration.
Election/Restrictions
2. Applicant’s election without traverse of Group I (claims 1 – 9, 11 – 14, and 16) in the reply filed on 12/18/2024 is acknowledged.
3. Claims 19 – 19, 21, and 23 – 24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/18/2024.
Priority
4. The present application represents the United States National Stage of International Application No. PCT/US2020/040914, filed July 6, 2020, which claims priority to U.S. Provisional Application Serial. No. 62/871,825, filed July 9, 2019.
Withdrawn Claim Rejections
5. The rejection of claims 1, 2, 12 – 14, and 16 under 35 U.S.C. 102(a)(1) and (a)(2) is withdrawn in view of Applicant’s amendment to claim 1.
6. The rejection of claim 4 under 35 U.S.C. 102(a)(1) and (a)(2) is rendered moot in view of Applicant’s cancellation of the claim.
7. The rejection of claims 1 – 3, 12 – 14, and 16 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1.
8. The rejection of claims 1, 2, 8, 9, 12 – 14, and 16 are rejected under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1.
9. The rejection of claims 6 and 7 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of these claims.
Claim Interpretation
10. For the purpose of applying prior art, step (a) of claim 1 is interpreted as the one or more hollow biomaterial tubes is/are a three-dimensional scaffold.
11. For the purpose of applying prior art, “degradable” in step (a) of claim 1 is interpreted as “a biomaterials capacity to be broken down into portions or pieces of the biomaterial polymers” based on Applicant’s specification at para. 0017.
12. For the purpose of applying prior art, “an engineered tissue” of step (d) of claim 1 is interpreted as aggregates of cells prepared in accordance with the recited method steps of claim 1 based on Applicant’s specification at para. 0031.
13. For the purpose of applying prior art, claim 2 is interpreted as the method of claim 1 where in step (a) more than one hollow biomaterial tubes are arranged into a three-dimensional scaffold. Claim 2 does not recite any active method steps.
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.
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.
14. Claim(s) 1, 2, 5, 8, 9, 12 – 14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over by Li (Li, Qiang, et al. Scientific reports 8.1 (2018): 3531.), hereinafter Li as evidenced by Li-2018 (Li Q, et. al. Biofabrication. 2018 Feb 1;10(2):025006), hereinafter Li-2018 in view of Yamamoto (Yamamoto, Masaya, et al. Tissue Engineering Part A 16.1 (2010): 299-308), hereinafter Yamamoto.
Regarding step (a) of claim 1 and claim 8, Li teaches providing alginate tubes (AlgTubes) (“hollow biomaterial tubes comprising a degradable hydrogel” of claim 1 and “alginate” of claim 8) formed into a cylinder including an inner surface opposite an outer surface that can be dissolved with EDTA (Figure 1; page 2, para. 3 – 4; page 10, para. 8 – 9). AlgTubes are hollow as evidenced by Li-2018 (page 13, left col. para. 3).
Regarding step (b) of claim 1, Li teaches cells are inside the AlgTubes and the cells comprise stem cells (page 1, para. 1; page 2, para. 5; page 3, last para.) but does not teach seeding cells onto the outer surface of the AlgTubes.
Regarding step (c) of claim 1, Li teaches circulating culture medium through the AlgTubes using a prototype bioreactor comprising a bellow bottle (“reservoir”) that is controlled by a mechanic stage (“directional fluid pumping device”) to flow the medium into or withdrawn the medium from the container of AlgTubes (“circulating a culture medium through the hollow biomaterial tubes”) (Figure 6; page 4, last para.; page 6, para. 1). Li does not teach “a second inlet”.
Regarding step (d) of claim 1, Li teaches culturing the AlgTubes with cells inside the tubes including cell clusters and cell spheroids to promote proliferation and initiate differentiation (Figure 1D; page 3, last para.; Figure 6D). Li teaches in Figure 1D that cells cultured in the AlgTubes form cell clusters at day 1, cell spheroids at day 4, and a fibrous cell mass at day 7 (Figure 1 legend). Li teaches in Figure 6D a thickness greater than 1 mm in at least one direction.
Regarding claim 2, Li teaches a plurality of AlgTubes in Figure 2B and 6. Li teaches the AlgTubes allow quick nutrient diffusion through the hydrogel shell (page 2, para. 2). Li teaches culturing cells in the AlgTubes where the cells expanded and formed fibrous cell masses with very few dead cells and the cells could be cultured long-term (page 2, para. 5 – 7).
Regarding claim 9, Li teaches the AlgTubes are made from sodium alginate that is crosslinked and the AlgTubes could be dissolved (“dissolvable alginate” and “sodium alginate polymers”) (page 2, para. 4; page 10, para. 3, 8, and 9).
Regarding claim 13, Li teaches seeding the AlgTubes with cells that are glioblastoma cells isolated from patients (page 2, para. 5 – 7; Figure 1; page 10, last para.).
Li does not teach “seeding cells onto the outer surface of the one or more hollow biomaterial tubes” or “a second inlet” of claim 1 or “the outer surface of the one or more hollow biomaterial tubes comprises cell adhesion molecules” of claim 5 or the cells are “endothelial cells” of claims 12 and 14 or “the engineered tissue comprises blood vessels” of claim 16. However, Li teaches culturing the AlgTubes with cells inside of the tubes where the cells expanded and formed fibrous cell masses with very few dead cells (page 2, para. 6). Li teaches the AlgTubes allowed long-term culturing of cells with high growth rate, high cell viability and high volumetric yield without losing stem cell properties, all offering large advancements over current culturing methods (Abstract). Li teaches alginate hydrogels can be quickly processed in large scales, can be easily dissolved to release the product, allow quick nutrient diffusion through the hydrogel shell, are mechanically and chemically stable for cell cultures, and are transparent allowing optical monitoring (page 2, para. 2). Li teaches alginates are affordable and available in large quantities and have no toxicity (page 2, para. 2). Li teaches the Algtubes will significantly advance the precision of personalized medicine (page 10, para. 1).
Regarding “seeding cells onto the outer surface of the one or more hollow biomaterial tubes” of step (b) of claim 1, Yamamoto teaches a method of preparing a scaffold comprising a plurality of hollow alginate cylindrical tubes and seeding the scaffold with cells (page 300, left col. para. 2 – 4; and right col. para. 1 – 2; page 302, left col. para. 1 – 3 and right col. para. 3; Figure 1 – 2 and 4; page 303, right col. para. 2; page 304, right col. para. 2).
Regarding “second inlet” of step (c) of claim 1, Yamamoto teaches circulating culture media through a 3 mm alginate scaffold in a flow chamber where the chamber comprises a first and second inlet (page 302, left col. last para.; Figure 5; page 303, right col. para. 3). Yamamoto teaches the chamber was connected to a closed-tube circuit with a reservoir of culture media and a peristaltic pump (page 302, left col. last para.).
Regarding claim 5, Yamamoto teaches the alginate scaffold comprises fibronectin and Matrigel to facilitate cell attachment (page 300, right col. para. 3).
Regarding claim 12 and 14, Yamamoto teaches human umbilical vein endothelial cells and human smooth muscle cells (“endothelial cells”, “umbilical vein endothelial cells”, “vascular smooth muscle cells”, “mammalian cells” of claim 12; “endothelial cells” and “vascular smooth muscle cells” of claim 14) are seeded on the alginate scaffold (page 302, left col. para. 1).
Regarding claim 16, Yamamoto teaches the alginate scaffold mimics the typical structure of blood vessel capillaries and the honeycomb alginate scaffold with aligned pores recapitulate the process of neovasculature formation by generating stable co-cultures of vascular vessels in vitro (page 302, right col. para. 1; page 307, left col. para. 1). Yamamoto teaches the HUVECs could be confluent in the alginate scaffolds which is an endothelial cell density closer to that of native vessels (page 304, right col. last para.).
Yamamoto teaches pluripotent stem cells offer considerable clinical potential for the regenerative therapy of injured and diseased tissues (page 299, left col. para. 1). Yamamoto teaches cellular grafts fabricated from bone marrow-derived stem cells for repair of myocardial infarction have met with little success likely because functional engraftment of in vitro generated vascular cells within injured or diseased tissues failed because of cell death and/or the ability of the graft to connect with the existing circulatory system (page 299, left col. para. 1). Yamamoto teaches a synthetic, microfabricated matrix with tubular channels that allow colonization with vascular cells could provide an ideal substrate upon which biologically compatible, vascularized tissue grafts can be built (page 299, left col. para. 1). Yamamoto teaches the alginate scaffold allows endothelial cells that are seeded onto the alginate to sprout into tube-like structures (page 307, left col. para. 1). Yamamoto teaches the alginate scaffold with aligned pores can provide a substrate suitable for establishing durable vascular modules that may ultimately enhance organ revascularization (page 300, left col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Li regarding a method of culturing cells in AlgTubes in a bioreactor with the teachings of Yamamoto regarding a method of preparing an engineered tissue comprising an alginate scaffold seeded with endothelial cells and smooth muscle cells and circulating culture media through the scaffold to arrive at the claimed method for preparing a large engineered tissue, the method comprising (a) providing one or more hollow biomaterial tubes arranged into a three-dimensional scaffold, each of the one or more hollow biomaterial tubes comprising a degradable hydrogel formed into a cylinder including an inner surface opposite an outer surface; (b) seeding cells onto the outer surface of the one or more hollow biomaterial tubes of the three-dimensional scaffold, each tube comprising a first tube end and a second tube end, wherein the cells comprise stem cells; (c) circulating a culture medium through the hollow biomaterial tubes, wherein circulating comprises forming a fluid circuit between the one or more hollow biomaterial tubes and a directional fluid pumping device comprising a first inlet, a second inlet, and a reservoir, wherein the first tube end is in fluid contact with the first inlet and the second tube end is in fluid contact with the second inlet, and wherein the first and second inlets introduce the culture medium from the reservoir into one or more hollow biomaterial tubes; and (d) culturing the seeded scaffold to promote one or more of proliferation, differentiation, and maturation of the seeded cells to form an engineered tissue having a thickness greater than 1 mm in at least one dimension. One would have been motivated to combine the teachings of Li and Yamamoto in a method of preparing an affordable vascularized tissue for drug discovery and regenerative medicine as Li teaches alginates are affordable and available in large quantities and have no toxicity and the AlgTubes will significantly advance the precision of personalized medicine and Yamamoto teaches a synthetic, microfabricated matrix with tubular channels that allow colonization with vascular cells could provide an ideal substrate upon which biologically compatible, vascularized tissue grafts can be built. One would have a reasonable expectation of success in combining the teachings as Li teaches culturing the AlgTubes resulted in the formation of fibrous cell masses with very few dead cells and Li teaches the AlgTubes allowed long-term culturing of cells with high growth rate, high cell viability and high volumetric yield without losing stem cell properties and Yamamoto teaches the alginate scaffold allows endothelial cells that are seeded onto the alginate to sprout into tube-like structures and Yamamoto teaches the alginate scaffold with aligned pores can provide a substrate suitable for establishing durable vascular modules that may ultimately enhance organ revascularization.
15. Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li (Li, Qiang, et al. Scientific reports 8.1 (2018): 3531.), hereinafter Li as evidenced by Li-2018 (Li Q, et. al. Biofabrication. 2018 Feb 1;10(2):025006), hereinafter Li-2018 in view of Yamamoto (Yamamoto, Masaya, et al. Tissue Engineering Part A 16.1 (2010): 299-308), hereinafter Yamamoto as applied to claims 1, 2, 5, 8, 9, 12 – 14, and 16 above, and further in view of Moldovan (Moldovan, Leni, et al. Biotechnology Journal 12.12 (2017): 1700444; previously cited), hereinafter Moldovan.
Li in view of Yamamoto make obvious the limitations of claim 1 as set forth above. Li and Yamamoto do not teach placing cell spheroids between hollow biomaterial tubes of the scaffold of claim 3. However, Yamamoto teaches after seeding the endothelial cells, some cell aggregates were observed (page 304, right col. para. 2).
Moldovan teaches spheroids are increasingly used for 3D normal or pathological tissue models to biofabrication, and injection of pre-formed cell spheroids has been shown to increase cell survival and efficiency of pro-angiogenic cell therapy compared to single-cell suspensions (page 1, right col. para. 1). Moldovan teaches producing spheroids of endothelial colony forming cells (ECFC) and smooth-muscle forming cells (SMFC) from pluripotent stem cells and assembling the spheroids into 3D biofabricated constructs (page 2, left col. para. 3 – 5 and right col. para. 1, 3, and 5 – 6; Figure 1). Moldovan teaches spheroids of ECFC and SMFC cells can fuse and form prevascular cell cords when placed in contact to each other and this interaction would promote their fusion into a tissue-like structure (page 5, right col. para. 1 – 2; Figure 4; page 8, left col. para. 3). Moldovan teaches the combination of SMFC and ECFC in spheroids made the spheroids more robust (page 8, left col. para. 3). Moldovan teaches SMFC spheroids formed a tubular construct of densely populated cellular structure that expressed smooth-muscle actin (page 6, left col. and right col. para. 1; Figure 5). Moldovan teaches the tubular construct has insufficient structural cohesion which could be addressed by incorporation of stronger biomaterials such as polymeric fibrillar scaffolds (page 9, left col. last para. and right col. para. 1). Moldovan teaches ECFC of iPSC origin are a very promising cell population for cardiovascular medicine and it has been proposed to lead cells into alginate/fibrin microspheres but this procedure requires complex preparations followed by specialized bioreactor cultivation (page 1, right col. para. 2). Moldovan teaches spheroids have been used for tissue engineering including for vascular constructs (page 7, left col. para. 1). Moldovan teaches vascularization of engineered tissues is essential for their survival but it has remained a stumbling block (page 7, right col. last para.). Moldovan teaches large vessels are essentially composed of a thick layer of smooth muscle cells and these spheroids could be used in the construction of vascular grafts (page 9, left col. para. 2 – 3).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Li regarding a method of culturing cells in AlgTubes in a bioreactor with the teachings of Yamamoto regarding a method of preparing an engineered tissue comprising an alginate scaffold seeded with endothelial cells and smooth muscle cells and circulating culture media through the scaffold with the teachings of Moldovan regarding cell spheroids containing ECFC and SMFC that fuse when placed in contact with each other to form a tissue construct to arrive at the claimed method where the cells are spheroids and seeding comprises placing the cell spheroids between hollow biomaterial tubes of the scaffold. One would have been motivated to combine the teachings of Li, Yamamoto, and Moldovan in a method of producing a vascularized engineered tissue for regenerative medicine as Li teaches alginates are affordable and available in large quantities and have no toxicity and the AlgTubes will significantly advance the precision of personalized medicine and Yamamoto teaches a synthetic, microfabricated matrix with tubular channels that allow colonization with vascular cells could provide an ideal substrate upon which biologically compatible, vascularized tissue grafts can be built and Moldovan teaches injection of pre-formed cell spheroids has been shown to increase cell survival and efficiency of pro-angiogenic cell therapy compared to single-cell suspensions and Moldovan teaches the tubular construct has insufficient structural cohesion which could be addressed by incorporation of stronger biomaterials and Moldovan teaches ECFC of iPSC origin are a very promising cell population for cardiovascular medicine and it has been proposed to lead cells into alginate/fibrin. One would have a reasonable expectation of success in combining the teachings as Li teaches the AlgTubes allowed long-term culturing of cells with high growth rate, high cell viability and high volumetric yield without losing stem cell properties and Yamamoto teaches the alginate scaffold allows endothelial cells that are seeded onto the alginate to sprout into tube-like structures and Yamamoto teaches endothelial cell aggregates were observed on the scaffold after seeding and Moldovan teaches spheroids of ECFC and SMFC cells can fuse and form prevascular cell cords when placed in contact to each other and this interaction would promote their fusion into a tissue-like structure.
Applicant’s Arguments/ Response to Arguments
16. Applicant Argues: On page 6, last para. and page 7, Applicant asserts that the structures of Ling do not allow for seeding cells onto the three-dimensional scaffold since the cut passages are simply holes that are bored in the scaffold. Applicant asserts that the cut passages of Ling have only inner surfaces and the claimed hollow biomaterial tubes have outer surfaces onto which cells can be seeded to help form vessel-like structures.
Response to Argument: The previous rejections of the claims citing the teachings of Ling have been withdrawn in view of Applicant’s amendment to claim 1 to require the hollow biomaterial tubes comprise a degradable hydrogel and seeding cells onto the outer surface of the one or more hollow biomaterial tubes. In the new rejection set forth above, Li teaches hollow biomaterial tubes comprising alginate (AlgTubes) having an inner surface opposite an outer surface (Figure 1). Li does not teach seeding the outer surface of the AlgTubes with cells. Yamamoto teaches a method of preparing a scaffold comprising a plurality of hollow alginate cylindrical tubes and seeding the scaffold with cells (page 300, left col. para. 2 – 4; and right col. para. 1 – 2; page 302, left col. para. 1 – 3 and right col. para. 3; Figure 1 – 2 and 4; page 303, right col. para. 2; page 304, right col. para. 2). One would have been motivated to combine the teachings of Li and Yamamoto in a method of preparing an affordable vascularized tissue for drug discovery and regenerative medicine as Li teaches alginates are affordable and available in large quantities and have no toxicity and the AlgTubes will significantly advance the precision of personalized medicine and Yamamoto teaches a synthetic, microfabricated matrix with tubular channels that allow colonization with vascular cells could provide an ideal substrate upon which biologically compatible, vascularized tissue grafts can be built. One would have a reasonable expectation of success in combining the teachings as Li teaches culturing the AlgTubes resulted in the formation of fibrous cell masses with very few dead cells and Li teaches the AlgTubes allowed long-term culturing of cells with high growth rate, high cell viability and high volumetric yield without losing stem cell properties and Yamamoto teaches the alginate scaffold allows endothelial cells that are seeded onto the alginate to sprout into tube-like structures and Yamamoto teaches the alginate scaffold with aligned pores can provide a substrate suitable for establishing durable vascular modules that may ultimately enhance organ revascularization.
Conclusion
No claims allowed.
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.
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/Z.M.B./Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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